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Lysyl Oxidase (LOX) gene missense mutation causes Thoracic Aortic Aneurysm and Dissection (TAAD) in Humans because of inadequate cross-linking of collagen and elastin in the aortic wall

Mutation carriers may be predisposed to vascular diseases because of weakened vessel walls under stress conditions.

 

Reporter: Aviva Lev-Ari, PhD, RN

 

Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans

  1. Vivian S. Leea,
  2. Carmen M. Halabia,b,
  3. Erin P. Hoffmanc,1,
  4. Nikkola Carmichaelc,d,
  5. Ignaty Leshchinerc,d,
  6. Christine G. Liand,e,
  7. Andrew J. Bierhalsf,
  8. Dana Vuzmanc,d,
  9. Brigham Genomic Medicine2,
  10. Robert P. Mechama,
  11. Natasha Y. Frankc,d,g,3, and
  12. Nathan O. Stitzielh,i,j,3

Edited by J. G. Seidman, Harvard Medical School, Boston, MA, and approved June 7, 2016 (received for review January 27, 2016)

  • Author contributions: V.S.L., R.P.M., N.Y.F., and N.O.S. designed research; V.S.L., C.M.H., and N.O.S. performed research; E.P.H., N.C., C.G.L., D.V., B.G.M.P., R.P.M., and N.Y.F. contributed new reagents/analytic tools; V.S.L., C.M.

Significance

The mechanical integrity of the arterial wall is dependent on a properly structured ECM. Elastin and collagen are key structural components of the ECM, contributing to the stability and elasticity of normal arteries. Lysyl oxidase (LOX) normally cross-links collagen and elastin molecules in the process of forming proper collagen fibers and elastic lamellae. Here, using whole-genome sequencing in humans and genome engineering in mice, we show that a missense mutation in LOX causes aortic aneurysm and dissection because of insufficient elastin and collagen cross-linking in the aortic wall. These findings confirm mutations in LOX as a cause of aortic disease in humans and identify LOX as a diagnostic and potentially therapeutic target.

Abstract

Thoracic aortic aneurysms and dissections (TAAD) represent a substantial cause of morbidity and mortality worldwide. Many individuals presenting with an inherited form of TAAD do not have causal mutations in the set of genes known to underlie disease. Using whole-genome sequencing in two first cousins with TAAD, we identified a missense mutation in the lysyl oxidase (LOX) gene (c.893T > G encoding p.Met298Arg) that cosegregated with disease in the family. Using clustered regularly interspaced short palindromic repeats (CRISPR)/clustered regularly interspaced short palindromic repeats-associated protein-9 nuclease (Cas9) genome engineering tools, we introduced the human mutation into the homologous position in the mouse genome, creating mice that were heterozygous and homozygous for the human allele. Mutant mice that were heterozygous for the human allele displayed disorganized ultrastructural properties of the aortic wall characterized by fragmented elastic lamellae, whereas mice homozygous for the human allele died shortly after parturition from ascending aortic aneurysm and spontaneous hemorrhage. These data suggest that a missense mutation in LOX is associated with aortic disease in humans, likely through insufficient cross-linking of elastin and collagen in the aortic wall. Mutation carriers may be predisposed to vascular diseases because of weakened vessel walls under stress conditions. LOX sequencing for clinical TAAD may identify additional mutation carriers in the future. Additional studies using our mouse model of LOX-associated TAAD have the potential to clarify the mechanism of disease and identify novel therapeutics specific to this genetic cause.

SOURCE

http://www.pnas.org/content/early/2016/07/15/1601442113.abstract

Missense LOX Mutation Linked to Aortic Rupture, Aneurysm

NEW YORK (GenomeWeb) – Researchers from Washington University School of Medicine have linked a LOX gene variant with aortic rupture and aneurysm.

As they reported in the online early edition of the Proceedings of the National Academy of Sciences yesterday, the researchers sequenced two first cousins from a family with a history of aortic ruptures and aneurysms to uncover a missense mutation in the lysyl oxidase (LOX) gene, which encodes a protein that cross-links elastin and collagen. When they used CRISPR/Cas9 genome engineering to introduce the mutation into a mouse model, mice heterogeneous for the mutation had disorganized aortic walls, while mice homozygous for the mutation died shortly after birth of ascending aneurysm and spontaneous hemorrhage, suggesting that the LOX variant might be causal.

Read more @ the Source

SOURCE

https://www.genomeweb.com/sequencing/missense-lox-mutation-linked-aortic-rupture-aneurysm

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Christopher J. Lynch, MD, PhD, the New Office of Nutrition Research, Director

Curator: Larry H. Bernstein, MD, FCAP

 

Christopher J. Lynch to direct Office of Nutrition Research

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

http://www.nih.gov/news-events/news-releases/christopher-j-lynch-direct-office-nutrition-research

 

Christopher J. Lynch, Ph.D., has been named the new director of the Office of Nutrition Research (ONR) and chief of the Nutrition Research Branch within the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Lynch officially assumed his new roles on Feb. 21, 2016. NIDDK is part of the National Institutes of Health.

Lynch will facilitate nutrition research within NIDDK and — through ONR — across NIH, in part by forming and leading a trans-NIH strategic working group. He will also continue and extend ongoing efforts at NIDDK to collaborate widely to advance nutrition research.

“Dr. Lynch is a leader in the nutrition community and his expertise will be vital to guiding the NIH strategic plan for nutrition research,” said NIH Director Francis S. Collins, M.D., Ph.D.  “As NIH works to expand nutrition knowledge, Dr. Lynch’s understanding of the field will help identify information gaps and create a framework to support future discoveries to ultimately improve human health.”

NIH supports a broad range of nutrition research, including studies on the effects of nutrient and dietary intake on human growth and disease, genetic influences on human nutrition and metabolism and other scientific areas. ONR was established in August 2015 to help NIH develop a strategic plan to expand mission-specific nutrition research.

NARRATIVE:
Our laboratory is dedicated to developing cures for metabolic diseases like Obesity, Diabetes and MSUD. We have several projects:
Project 1: How Antipsychotic Drugs Exert Obesity and Metabolic Disease Side effects
Project 2: Impact of Branched Chain Amino Acid (BCAA) signaling and metabolism in obesity and diabetes.
Project 3: Adipose tissue transplant as a treatment for Maple Syrup Urine Disease.
Project 4: How Gastric Bypass Surgery Provides A Rapid Cure For Diabetes And Other Obesity Co-Morbidities Like Hypertension
Project 5: Novel Mechanism Of Action Of Cannabinoid Receptor 1 Blockers For Improvement Of Diabetes

Timeline

  1. Klingerman CM, Stipanovic ME, Hajnal A, Lynch CJ. Acute Metabolic Effects of Olanzapine Depend on Dose and Injection Site. Dose Response. 2015 Oct-Dec; 13(4):1559325815618915.

View in: PubMed

  1. Lynch CJ, Kimball SR, Xu Y, Salzberg AC, Kawasawa YI. Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover. Physiol Genomics. 2015 Nov; 47(11):569-80.

View in: PubMed

  1. Lynch CJ, Xu Y, Hajnal A, Salzberg AC, Kawasawa YI. RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats. PLoS One. 2015; 10(4):e0123966.

View in: PubMed

  1. Shin AC, Fasshauer M, Filatova N, Grundell LA, Zielinski E, Zhou JY, Scherer T, Lindtner C, White PJ, Lapworth AL, Ilkayeva O, Knippschild U, Wolf AM, Scheja L, Grove KL, Smith RD, Qian WJ, Lynch CJ, Newgard CB, Buettner C. Brain Insulin Lowers Circulating BCAA Levels by Inducing Hepatic BCAA Catabolism. Cell Metab. 2014 Nov 4; 20(5):898-909.

View in: PubMed

  1. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014 Dec; 10(12):723-36.

View in: PubMed

  1. Olson KC, Chen G, Xu Y, Hajnal A, Lynch CJ. Alloisoleucine differentiates the branched-chain aminoacidemia of Zucker and dietary obese rats. Obesity (Silver Spring). 2014 May; 22(5):1212-5.

View in: PubMed

  1. Zimmerman HA, Olson KC, Chen G, Lynch CJ. Adipose transplant for inborn errors of branched chain amino acid metabolism in mice. Mol Genet Metab. 2013 Aug; 109(4):345-53.

View in: PubMed

  1. Olson KC, Chen G, Lynch CJ. Quantification of branched-chain keto acids in tissue by ultra fast liquid chromatography-mass spectrometry. Anal Biochem. 2013 Aug 15; 439(2):116-22.

View in: PubMed

  1. She P, Olson KC, Kadota Y, Inukai A, Shimomura Y, Hoppel CL, Adams SH, Kawamata Y, Matsumoto H, Sakai R, Lang CH, Lynch CJ. Leucine and protein metabolism in obese Zucker rats. PLoS One. 2013; 8(3):e59443.

View in: PubMed

  1. Lackey DE, Lynch CJ, Olson KC, Mostaedi R, Ali M, Smith WH, Karpe F, Humphreys S, Bedinger DH, Dunn TN, Thomas AP, Oort PJ, Kieffer DA, Amin R, Bettaieb A, Haj FG, Permana P, Anthony TG, Adams SH. Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity. Am J Physiol Endocrinol Metab. 2013 Jun 1; 304(11):E1175-87.

View in: PubMed

  1. Klingerman CM, Stipanovic ME, Bader M, Lynch CJ. Second-generation antipsychotics cause a rapid switch to fat oxidation that is required for survival in C57BL/6J mice. Schizophr Bull. 2014 Mar; 40(2):327-40.

View in: PubMed

  1. Carr TD, DiGiovanni J, Lynch CJ, Shantz LM. Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival. Cancer Prev Res (Phila). 2012 Dec; 5(12):1394-404.

View in: PubMed

  1. Lynch CJ, Zhou Q, Shyng SL, Heal DJ, Cheetham SC, Dickinson K, Gregory P, Firnges M, Nordheim U, Goshorn S, Reiche D, Turski L, Antel J. Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels. Am J Physiol Endocrinol Metab. 2012 Mar 1; 302(5):E540-51.

View in: PubMed

  1. Albaugh VL, Singareddy R, Mauger D, Lynch CJ. A double blind, placebo-controlled, randomized crossover study of the acute metabolic effects of olanzapine in healthy volunteers. PLoS One. 2011; 6(8):e22662.

View in: PubMed

  1. She P, Zhang Z, Marchionini D, Diaz WC, Jetton TJ, Kimball SR, Vary TC, Lang CH, Lynch CJ. Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington’s disease. Am J Physiol Endocrinol Metab. 2011 Jul; 301(1):E49-61.

View in: PubMed

  1. Fogle RL, Hollenbeak CS, Stanley BA, Vary TC, Kimball SR, Lynch CJ. Functional proteomic analysis reveals sex-dependent differences in structural and energy-producing myocardial proteins in rat model of alcoholic cardiomyopathy. Physiol Genomics. 2011 Apr 12; 43(7):346-56.

View in: PubMed

  1. Zhou Y, Jetton TL, Goshorn S, Lynch CJ, She P. Transamination is required for {alpha}-ketoisocaproate but not leucine to stimulate insulin secretion. J Biol Chem. 2010 Oct 29; 285(44):33718-26.

View in: PubMed

  1. Agostino NM, Chinchilli VM, Lynch CJ, Koszyk-Szewczyk A, Gingrich R, Sivik J, Drabick JJ. Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice. J Oncol Pharm Pract. 2011 Sep; 17(3):197-202.

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  1. Li J, Romestaing C, Han X, Li Y, Hao X, Wu Y, Sun C, Liu X, Jefferson LS, Xiong J, Lanoue KF, Chang Z, Lynch CJ, Wang H, Shi Y. Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity. Cell Metab. 2010 Aug 4; 12(2):154-65.

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  1. Culnan DM, Albaugh V, Sun M, Lynch CJ, Lang CH, Cooney RN. Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat. Am J Physiol Gastrointest Liver Physiol. 2010 Sep; 299(3):G751-60.

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  1. Hajnal A, Kovacs P, Ahmed T, Meirelles K, Lynch CJ, Cooney RN. Gastric bypass surgery alters behavioral and neural taste functions for sweet taste in obese rats. Am J Physiol Gastrointest Liver Physiol. 2010 Oct; 299(4):G967-79.

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  1. Lang CH, Lynch CJ, Vary TC. BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice. Am J Physiol Regul Integr Comp Physiol. 2010 Sep; 299(3):R935-44.

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  1. Albaugh VL, Vary TC, Ilkayeva O, Wenner BR, Maresca KP, Joyal JL, Breazeale S, Elich TD, Lang CH, Lynch CJ. Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents. Schizophr Bull. 2012 Jan; 38(1):153-66.

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  1. Fogle RL, Lynch CJ, Palopoli M, Deiter G, Stanley BA, Vary TC. Impact of chronic alcohol ingestion on cardiac muscle protein expression. Alcohol Clin Exp Res. 2010 Jul; 34(7):1226-34.

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  1. Lang CH, Frost RA, Bronson SK, Lynch CJ, Vary TC. Skeletal muscle protein balance in mTOR heterozygous mice in response to inflammation and leucine. Am J Physiol Endocrinol Metab. 2010 Jun; 298(6):E1283-94.

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  1. Albaugh VL, Judson JG, She P, Lang CH, Maresca KP, Joyal JL, Lynch CJ. Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis. Mol Psychiatry. 2011 May; 16(5):569-81.

View in: PubMed

  1. Lang CH, Lynch CJ, Vary TC. Alcohol-induced IGF-I resistance is ameliorated in mice deficient for mitochondrial branched-chain aminotransferase. J Nutr. 2010 May; 140(5):932-8.

View in: PubMed

  1. She P, Zhou Y, Zhang Z, Griffin K, Gowda K, Lynch CJ. Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance. J Appl Physiol (1985). 2010 Apr; 108(4):941-9.

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  1. Herman MA, She P, Peroni OD, Lynch CJ, Kahn BB. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels. J Biol Chem. 2010 Apr 9; 285(15):11348-56.

View in: PubMed

  1. Li P, Knabe DA, Kim SW, Lynch CJ, Hutson SM, Wu G. Lactating porcine mammary tissue catabolizes branched-chain amino acids for glutamine and aspartate synthesis. J Nutr. 2009 Aug; 139(8):1502-9.

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  1. Lu G, Sun H, She P, Youn JY, Warburton S, Ping P, Vondriska TM, Cai H, Lynch CJ, Wang Y. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest. 2009 Jun; 119(6):1678-87.

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  1. Nairizi A, She P, Vary TC, Lynch CJ. Leucine supplementation of drinking water does not alter susceptibility to diet-induced obesity in mice. J Nutr. 2009 Apr; 139(4):715-9.

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  1. Meirelles K, Ahmed T, Culnan DM, Lynch CJ, Lang CH, Cooney RN. Mechanisms of glucose homeostasis after Roux-en-Y gastric bypass surgery in the obese, insulin-resistant Zucker rat. Ann Surg. 2009 Feb; 249(2):277-85.

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  1. Culnan DM, Cooney RN, Stanley B, Lynch CJ. Apolipoprotein A-IV, a putative satiety/antiatherogenic factor, rises after gastric bypass. Obesity (Silver Spring). 2009 Jan; 17(1):46-52.

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  1. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab. 2007 Dec; 293(6):E1552-63.

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  1. She P, Reid TM, Bronson SK, Vary TC, Hajnal A, Lynch CJ, Hutson SM. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle. Cell Metab. 2007 Sep; 6(3):181-94.

View in: PubMed

  1. Vary TC, Lynch CJ. Nutrient signaling components controlling protein synthesis in striated muscle. J Nutr. 2007 Aug; 137(8):1835-43.

View in: PubMed

  1. Vary TC, Deiter G, Lynch CJ. Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts. J Nutr. 2007 Aug; 137(8):1857-62.

View in: PubMed

  1. Vary TC, Anthony JC, Jefferson LS, Kimball SR, Lynch CJ. Rapamycin blunts nutrient stimulation of eIF4G, but not PKCepsilon phosphorylation, in skeletal muscle. Am J Physiol Endocrinol Metab. 2007 Jul; 293(1):E188-96.

View in: PubMed

  1. Vary TC, Lynch CJ. Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts. J Nutr. 2006 Sep; 136(9):2284-90.

View in: PubMed

  1. Lynch CJ, Gern B, Lloyd C, Hutson SM, Eicher R, Vary TC. Leucine in food mediates some of the postprandial rise in plasma leptin concentrations. Am J Physiol Endocrinol Metab. 2006 Sep; 291(3):E621-30.

View in: PubMed

  1. Albaugh VL, Henry CR, Bello NT, Hajnal A, Lynch SL, Halle B, Lynch CJ. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity (Silver Spring). 2006 Jan; 14(1):36-51.

View in: PubMed

  1. Vary TC, Lynch CJ. Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation. Am J Physiol Endocrinol Metab. 2006 Apr; 290(4):E631-42.

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  1. Vary TC, Goodman S, Kilpatrick LE, Lynch CJ. Nutrient regulation of PKCepsilon is mediated by leucine, not insulin, in skeletal muscle. Am J Physiol Endocrinol Metab. 2005 Oct; 289(4):E684-94.

View in: PubMed

  1. Vary TC, Lynch CJ. Biochemical approaches for nutritional support of skeletal muscle protein metabolism during sepsis. Nutr Res Rev. 2004 Jun; 17(1):77-88.

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  1. Lynch CJ, Halle B, Fujii H, Vary TC, Wallin R, Damuni Z, Hutson SM. Potential role of leucine metabolism in the leucine-signaling pathway involving mTOR. Am J Physiol Endocrinol Metab. 2003 Oct; 285(4):E854-63.

View in: PubMed

  1. Lynch CJ, Hutson SM, Patson BJ, Vaval A, Vary TC. Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. Am J Physiol Endocrinol Metab. 2002 Oct; 283(4):E824-35.

View in: PubMed

  1. Lynch CJ, Patson BJ, Anthony J, Vaval A, Jefferson LS, Vary TC. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Am J Physiol Endocrinol Metab. 2002 Sep; 283(3):E503-13.

View in: PubMed

  1. Vary TC, Lynch CJ, Lang CH. Effects of chronic alcohol consumption on regulation of myocardial protein synthesis. Am J Physiol Heart Circ Physiol. 2001 Sep; 281(3):H1242-51.

View in: PubMed

  1. Lynch CJ, Patson BJ, Goodman SA, Trapolsi D, Kimball SR. Zinc stimulates the activity of the insulin- and nutrient-regulated protein kinase mTOR. Am J Physiol Endocrinol Metab. 2001 Jul; 281(1):E25-34.

View in: PubMed

 

Global deletion of BCATm increases expression of skeletal muscle genes associated with protein turnover.

Lynch CJ1Kimball SR2Xu Y2Salzberg AC3Kawasawa YI4.   Author information
Physiol Genomics. 2015 Nov;47(11):569-80.  http://dx.doi.org:/10.1152/physiolgenomics.00055.2015

Consumption of a protein-containing meal by a fasted animal promotes protein accretion in skeletal muscle, in part through leucine stimulation of protein synthesis and indirectly through repression of protein degradation mediated by its metabolite, α-ketoisocaproate. Mice lacking the mitochondrial branched-chain aminotransferase (BCATm/Bcat2), which interconverts leucine and α-ketoisocaproate, exhibit elevated protein turnover. Here, the transcriptomes of gastrocnemius muscle from BCATm knockout (KO) and wild-type mice were compared by next-generation RNA sequencing (RNA-Seq) to identify potential adaptations associated with their persistently altered nutrient signaling. Statistically significant changes in the abundance of 1,486/∼39,010 genes were identified. Bioinformatics analysis of the RNA-Seq data indicated that pathways involved in protein synthesis [eukaryotic initiation factor (eIF)-2, mammalian target of rapamycin, eIF4, and p70S6K pathways including 40S and 60S ribosomal proteins], protein breakdown (e.g., ubiquitin mediated), and muscle degeneration (apoptosis, atrophy, myopathy, and cell death) were upregulated. Also in agreement with our previous observations, the abundance of mRNAs associated with reduced body size, glycemia, plasma insulin, and lipid signaling pathways was altered in BCATm KO mice. Consistently, genes encoding anaerobic and/or oxidative metabolism of carbohydrate, fatty acids, and branched chain amino acids were modestly but systematically reduced. Although there was no indication that muscle fiber type was different between KO and wild-type mice, a difference in the abundance of mRNAs associated with a muscular dystrophy phenotype was observed, consistent with the published exercise intolerance of these mice. The results suggest transcriptional adaptations occur in BCATm KO mice that along with altered nutrient signaling may contribute to their previously reported protein turnover, metabolic and exercise phenotypes.

 

RNA sequencing reveals a slow to fast muscle fiber type transition after olanzapine infusion in rats.

Lynch CJ1Xu Y1Hajnal A2Salzberg AC3Kawasawa YI4. Author information
PLoS One. 2015 Apr 20;10(4):e0123966. http://dx.doi.org:/10.1371/journal.pone.0123966. eCollection 2015.

Second generation antipsychotics (SGAs), like olanzapine, exhibit acute metabolic side effects leading to metabolic inflexibility, hyperglycemia, adiposity and diabetes. Understanding how SGAs affect the skeletal muscle transcriptome could elucidate approaches for mitigating these side effects. Male Sprague-Dawley rats were infused intravenously with vehicle or olanzapine for 24h using a dose leading to a mild hyperglycemia. RNA-Seq was performed on gastrocnemius muscle, followed by alignment of the data with the Rat Genome Assembly 5.0. Olanzapine altered expression of 1347 out of 26407 genes. Genes encoding skeletal muscle fiber-type specific sarcomeric, ion channel, glycolytic, O2- and Ca2+-handling, TCA cycle, vascularization and lipid oxidation proteins and pathways, along with NADH shuttles and LDH isoforms were affected. Bioinformatics analyses indicate that olanzapine decreased the expression of slower and more oxidative fiber type genes (e.g., type 1), while up regulating those for the most glycolytic and least metabolically flexible, fast twitch fiber type, IIb. Protein turnover genes, necessary to bring about transition, were also up regulated. Potential upstream regulators were also identified. Olanzapine appears to be rapidly affecting the muscle transcriptome to bring about a change to a fast-glycolytic fiber type. Such fiber types are more susceptible than slow muscle to atrophy, and such transitions are observed in chronic metabolic diseases. Thus these effects could contribute to the altered body composition and metabolic disease olanzapine causes. A potential interventional strategy is implicated because aerobic exercise, in contrast to resistance exercise, can oppose such slow to fast fiber transitions.

 

Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

Shin AC1Fasshauer M1Filatova N1Grundell LA1Zielinski E1Zhou JY2Scherer T1Lindtner C1White PJ3Lapworth AL3,Ilkayeva O3Knippschild U4Wolf AM4Scheja L5Grove KL6Smith RD2Qian WJ2Lynch CJ7Newgard CB3Buettner C8. Author information
Cell Metab. 2014 Nov 4;20(5):898-909. http://dx.doi.org:/10.1016/j.cmet.2014.09.003   Epub 2014 Oct 9

Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes.

 

Branched-chain amino acids in metabolic signalling and insulin resistance.

Lynch CJ1Adams SH2Author information
Nat Rev Endocrinol. 2014 Dec; 10(12):723-36. http://dx.doi.org:/10.1038/nrendo.2014.171

Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM.

 

Leucine and protein metabolism in obese Zucker rats.

She P1Olson KCKadota YInukai AShimomura YHoppel CLAdams SHKawamata YMatsumoto HSakai RLang CHLynch CJAuthor information
PLoS One. 2013;8(3):e59443. http://dx.doi.org:/10.1371/journal.pone.0059443   Epub 2013 Mar 20.

Branched-chain amino acids (BCAAs) are circulating nutrient signals for protein accretion, however, they increase in obesity and elevations appear to be prognostic of diabetes. To understand the mechanisms whereby obesity affects BCAAs and protein metabolism, we employed metabolomics and measured rates of [1-(14)C]-leucine metabolism, tissue-specific protein synthesis and branched-chain keto-acid (BCKA) dehydrogenase complex (BCKDC) activities. Male obese Zucker rats (11-weeks old) had increased body weight (BW, 53%), liver (107%) and fat (∼300%), but lower plantaris and gastrocnemius masses (-21-24%). Plasma BCAAs and BCKAs were elevated 45-69% and ∼100%, respectively, in obese rats. Processes facilitating these rises appeared to include increased dietary intake (23%), leucine (Leu) turnover and proteolysis [35% per g fat free mass (FFM), urinary markers of proteolysis: 3-methylhistidine (183%) and 4-hydroxyproline (766%)] and decreased BCKDC per g kidney, heart, gastrocnemius and liver (-47-66%). A process disposing of circulating BCAAs, protein synthesis, was increased 23-29% by obesity in whole-body (FFM corrected), gastrocnemius and liver. Despite the observed decreases in BCKDC activities per gm tissue, rates of whole-body Leu oxidation in obese rats were 22% and 59% higher normalized to BW and FFM, respectively. Consistently, urinary concentrations of eight BCAA catabolism-derived acylcarnitines were also elevated. The unexpected increase in BCAA oxidation may be due to a substrate effect in liver. Supporting this idea, BCKAs were elevated more in liver (193-418%) than plasma or muscle, and per g losses of hepatic BCKDC activities were completely offset by increased liver mass, in contrast to other tissues. In summary, our results indicate that plasma BCKAs may represent a more sensitive metabolic signature for obesity than BCAAs. Processes supporting elevated BCAA]BCKAs in the obese Zucker rat include increased dietary intake, Leu and protein turnover along with impaired BCKDC activity. Elevated BCAAs/BCKAs may contribute to observed elevations in protein synthesis and BCAA oxidation.

 

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity.

Lackey DE1Lynch CJOlson KCMostaedi RAli MSmith WHKarpe FHumphreys SBedinger DHDunn TNThomas APOort PJKieffer DAAmin RBettaieb AHaj FGPermana PAnthony TGAdams SH.
Am J Physiol Endocrinol Metab. 2013 Jun 1; 304(11):E1175-87. http://dx.doi.org:/10.1152/ajpendo.00630.2012

Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain α-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1α subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferator-activated receptor-γ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.

 

Some cannabinoid receptor ligands and their distomers are direct-acting openers of SUR1 K(ATP) channels.

Lynch CJ1Zhou QShyng SLHeal DJCheetham SCDickinson KGregory PFirnges MNordheim UGoshorn SReiche D,Turski LAntel J.   Author information
Am J Physiol Endocrinol Metab. 2012 Mar 1;302(5):E540-51.
http://dx.doi.org:/10.1152/ajpendo.00258.2011

Here, we examined the chronic effects of two cannabinoid receptor-1 (CB1) inverse agonists, rimonabant and ibipinabant, in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia. Rimonabant and ibipinabant (10 mg·kg⁻¹·day⁻¹) elicited body weight-independent improvements in insulinemia and glycemia during 10 wk of chronic treatment. To elucidate the mechanism of insulin lowering, acute in vivo and in vitro studies were then performed. Surprisingly, chronic treatment was not required for insulin lowering. In acute in vivo and in vitro studies, the CB1 inverse agonists exhibited acute K channel opener (KCO; e.g., diazoxide and NN414)-like effects on glucose tolerance and glucose-stimulated insulin secretion (GSIS) with approximately fivefold better potency than diazoxide. Followup studies implied that these effects were inconsistent with a CB1-mediated mechanism. Thus effects of several CB1 agonists, inverse agonists, and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known CB1 activities. In vivo rimonabant and ibipinabant caused glucose intolerance in CB1 but not SUR1-KO mice. Electrophysiological studies indicated that, compared with diazoxide, 3 μM rimonabant and ibipinabant are partial agonists for K channel opening. Partial agonism was consistent with data from radioligand binding assays designed to detect SUR1 K(ATP) KCOs where rimonabant and ibipinabant allosterically regulated ³H-glibenclamide-specific binding in the presence of MgATP, as did diazoxide and NN414. Our findings indicate that some CB1 ligands may directly bind and allosterically regulate Kir6.2/SUR1 K(ATP) channels like other KCOs. This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia.

 

Transamination is required for {alpha}-ketoisocaproate but not leucine to stimulate insulin secretion.

Zhou Y1Jetton TLGoshorn SLynch CJShe PAuthor information
J Biol Chem. 2010 Oct 29;285(44):33718-26. http://dx.doi.org:/10.1074/jbc.M110.136846

It remains unclear how α-ketoisocaproate (KIC) and leucine are metabolized to stimulate insulin secretion. Mitochondrial BCATm (branched-chain aminotransferase) catalyzes reversible transamination of leucine and α-ketoglutarate to KIC and glutamate, the first step of leucine catabolism. We investigated the biochemical mechanisms of KIC and leucine-stimulated insulin secretion (KICSIS and LSIS, respectively) using BCATm(-/-) mice. In static incubation, BCATm disruption abolished insulin secretion by KIC, D,L-α-keto-β-methylvalerate, and α-ketocaproate without altering stimulation by glucose, leucine, or α-ketoglutarate. Similarly, during pancreas perfusions in BCATm(-/-) mice, glucose and arginine stimulated insulin release, whereas KICSIS was largely abolished. During islet perifusions, KIC and 2 mM glutamine caused robust dose-dependent insulin secretion in BCATm(+/+) not BCATm(-/-) islets, whereas LSIS was unaffected. Consistently, in contrast to BCATm(+/+) islets, the increases of the ATP concentration and NADPH/NADP(+) ratio in response to KIC were largely blunted in BCATm(-/-) islets. Compared with nontreated islets, the combination of KIC/glutamine (10/2 mM) did not influence α-ketoglutarate concentrations but caused 120 and 33% increases in malate in BCATm(+/+) and BCATm(-/-) islets, respectively. Although leucine oxidation and KIC transamination were blocked in BCATm(-/-) islets, KIC oxidation was unaltered. These data indicate that KICSIS requires transamination of KIC and glutamate to leucine and α-ketoglutarate, respectively. LSIS does not require leucine catabolism and may be through leucine activation of glutamate dehydrogenase. Thus, KICSIS and LSIS occur by enhancing the metabolism of glutamine/glutamate to α-ketoglutarate, which, in turn, is metabolized to produce the intracellular signals such as ATP and NADPH for insulin secretion.

 

Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice.

Agostino NM1Chinchilli VMLynch CJKoszyk-Szewczyk AGingrich RSivik JDrabick JJ.
J Oncol Pharm Pract. 2011 Sep; 17(3):197-202. http://dx.doi.org:/10.1177/1078155210378913

Tyrosine kinase is a key enzyme activity utilized in many intracellular messaging pathways. Understanding the role of particular tyrosine kinases in malignancies has allowed for the design of tyrosine kinase inhibitors (TKIs), which can target these enzymes and interfere with downstream signaling. TKIs have proven to be successful in the treatment of chronic myeloid leukemia, renal cell carcinoma and gastrointestinal stromal tumor, and other malignancies. Scattered reports have suggested that these agents appear to affect blood glucose (BG). We retrospectively studied the BG concentrations in diabetic (17) and nondiabetic (61) patients treated with dasatinib (8), imatinib (39), sorafenib (23), and sunitinib (30) in our clinical practice. Mean declines of BG were dasatinib (53 mg/dL), imatinib (9 mg/dL), sorafenib (12 mg/dL), and sunitinib (14 mg/dL). All these declines in BG were statistically significant. Of note, 47% (8/17) of the patients with diabetes were able to discontinue their medications, including insulin in some patients. Only one diabetic patient developed symptomatic hypoglycemia while on sunitinib. The mechanism for the hypoglycemic effect of these drugs is unclear, but of the four agents tested, c-kit and PDGFRβ are the common target kinases. Clinicians should keep the potential hypoglycemic effects of these agents in mind; modification of hypoglycemic agents may be required in diabetic patients. These results also suggest that inhibition of a tyrosine kinase, be it c-kit, PDGFRβ or some other undefined target, may improve diabetes mellitus BG control and it deserves further study as a potential novel therapeutic option.

 

Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity.

Li J1Romestaing CHan XLi YHao XWu YSun CLiu XJefferson LSXiong JLanoue KFChang ZLynch CJWang HShi Y.    Author information
Cell Metab. 2010 Aug 4;12(2):154-65. http://dx.doi.org:/10.1016/j.cmet.2010.07.003

Oxidative stress causes mitochondrial dysfunction and metabolic complications through unknown mechanisms. Cardiolipin (CL) is a key mitochondrial phospholipid required for oxidative phosphorylation. Oxidative damage to CL from pathological remodeling is implicated in the etiology of mitochondrial dysfunction commonly associated with diabetes, obesity, and other metabolic diseases. Here, we show that ALCAT1, a lyso-CL acyltransferase upregulated by oxidative stress and diet-induced obesity (DIO), catalyzes the synthesis of CL species that are highly sensitive to oxidative damage, leading to mitochondrial dysfunction, ROS production, and insulin resistance. These metabolic disorders were reminiscent of those observed in type 2 diabetes and were reversed by rosiglitazone treatment. Consequently, ALCAT1 deficiency prevented the onset of DIO and significantly improved mitochondrial complex I activity, lipid oxidation, and insulin signaling in ALCAT1(-/-) mice. Collectively, these findings identify a key role of ALCAT1 in regulating CL remodeling, mitochondrial dysfunction, and susceptibility to DIO.

 

BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice.

Lang CH1Lynch CJVary TC.   Author information
Am J Physiol Regul Integr Comp Physiol. 2010 Sep; 299(3):R935-44.
http://dx.doi.org:/10.1152/ajpregu.00297.2010

Endotoxin (LPS) and sepsis decrease mammalian target of rapamycin (mTOR) activity in skeletal muscle, thereby reducing protein synthesis. Our study tests the hypothesis that inhibition of branched-chain amino acid (BCAA) catabolism, which elevates circulating BCAA and stimulates mTOR, will blunt the LPS-induced decrease in muscle protein synthesis. Wild-type (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout mice were studied 4 h after Escherichia coli LPS or saline. Basal skeletal muscle protein synthesis was increased in knockout mice compared with WT, and this change was associated with increased eukaryotic initiation factor (eIF)-4E binding protein-1 (4E-BP1) phosphorylation, eIF4E.eIF4G binding, 4E-BP1.raptor binding, and eIF3.raptor binding without a change in the mTOR.raptor complex in muscle. LPS decreased muscle protein synthesis in WT mice, a change associated with decreased 4E-BP1 phosphorylation as well as decreased formation of eIF4E.eIF4G, 4E-BP1.raptor, and eIF3.raptor complexes. In BCATm knockout mice given LPS, muscle protein synthesis only decreased to values found in vehicle-treated WT control mice, and this ameliorated LPS effect was associated with a coordinate increase in 4E-BP1.raptor, eIF3.raptor, and 4E-BP1 phosphorylation. Additionally, the LPS-induced increase in muscle cytokines was blunted in BCATm knockout mice, compared with WT animals. In a separate study, 7-day survival and muscle mass were increased in BCATm knockout vs. WT mice after polymicrobial peritonitis. These data suggest that elevating blood BCAA is sufficient to ameliorate the catabolic effect of LPS on skeletal muscle protein synthesis via alterations in protein-protein interactions within mTOR complex-1, and this may provide a survival advantage in response to bacterial infection.

 

Alcohol-induced IGF-I resistance is ameliorated in mice deficient for mitochondrial branched-chain aminotransferase.

Lang CH1Lynch CJVary TCAuthor information
J Nutr. 2010 May;140(5):932-8. http://dx.doi.org:/10.3945/jn.109.120501

Acute alcohol intoxication decreases skeletal muscle protein synthesis by impairing mammalian target of rapamycin (mTOR). In 2 studies, we determined whether inhibition of branched-chain amino acid (BCAA) catabolism ameliorates the inhibitory effect of alcohol on muscle protein synthesis by raising the plasma BCAA concentrations and/or by improving the anabolic response to insulin-like growth factor (IGF)-I. In the first study, 4 groups of mice were used: wild-type (WT) and mitochondrial branched-chain aminotransferase (BCATm) knockout (KO) mice orally administered saline or alcohol (5 g/kg, 1 h). Protein synthesis was greater in KO mice compared with WT controls and was associated with greater phosphorylation of eukaryotic initiation factor (eIF)-4E binding protein-1 (4EBP1), eIF4E-eIF4G binding, and 4EBP1-regulatory associated protein of mTOR (raptor) binding, but not mTOR-raptor binding. Alcohol decreased protein synthesis in WT mice, a change associated with less 4EBP1 phosphorylation, eIF4E-eIF4G binding, and raptor-4EBP1 binding, but greater mTOR-raptor complex formation. Comparable alcohol effects on protein synthesis and signal transduction were detected in BCATm KO mice. The second study used the same 4 groups, but all mice were injected with IGF-I (25 microg/mouse, 30 min). Alcohol impaired the ability of IGF-I to increase muscle protein synthesis, 4EBP1 and 70-kilodalton ribosomal protein S6 kinase-1 phosphorylation, eIF4E-eIF4G binding, and 4EBP1-raptor binding in WT mice. However, in alcohol-treated BCATm KO mice, this IGF-I resistance was not manifested. These data suggest that whereas the sustained elevation in plasma BCAA is not sufficient to ameliorate the catabolic effect of acute alcohol intoxication on muscle protein synthesis, it does improve the anabolic effect of IGF-I.

 

Impact of chronic alcohol ingestion on cardiac muscle protein expression.

Fogle RL1Lynch CJPalopoli MDeiter GStanley BAVary TCAuthor information
Alcohol Clin Exp Res. 2010 Jul;34(7):1226-34. http://dx.doi.org:/10.1111/j.1530-0277.2010.01200.x

BACKGROUND:

Chronic alcohol abuse contributes not only to an increased risk of health-related complications, but also to a premature mortality in adults. Myocardial dysfunction, including the development of a syndrome referred to as alcoholic cardiomyopathy, appears to be a major contributing factor. One mechanism to account for the pathogenesis of alcoholic cardiomyopathy involves alterations in protein expression secondary to an inhibition of protein synthesis. However, the full extent to which myocardial proteins are affected by chronic alcohol consumption remains unresolved.

METHODS:

The purpose of this study was to examine the effect of chronic alcohol consumption on the expression of cardiac proteins. Male rats were maintained for 16 weeks on a 40% ethanol-containing diet in which alcohol was provided both in drinking water and agar blocks. Control animals were pair-fed to consume the same caloric intake. Heart homogenates from control- and ethanol-fed rats were labeled with the cleavable isotope coded affinity tags (ICAT). Following the reaction with the ICAT reagent, we applied one-dimensional gel electrophoresis with in-gel trypsin digestion of proteins and subsequent MALDI-TOF-TOF mass spectrometric techniques for identification of peptides. Differences in the expression of cardiac proteins from control- and ethanol-fed rats were determined by mass spectrometry approaches.

RESULTS:

Initial proteomic analysis identified and quantified hundreds of cardiac proteins. Major decreases in the expression of specific myocardial proteins were observed. Proteins were grouped depending on their contribution to multiple activities of cardiac function and metabolism, including mitochondrial-, glycolytic-, myofibrillar-, membrane-associated, and plasma proteins. Another group contained identified proteins that could not be properly categorized under the aforementioned classification system.

CONCLUSIONS:

Based on the changes in proteins, we speculate modulation of cardiac muscle protein expression represents a fundamental alteration induced by chronic alcohol consumption, consistent with changes in myocardial wall thickness measured under the same conditions.

 

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Vaccine for Heart Disease

Writer and Curator: Larry, MD, FCAP 

 

 

Introduction

Research investigators at Wayne State University in collaboration with La Jolla Institute for Allergy and Immunology (LJAI) are developing a T-cell peptide-based vaccine for cardiovascular disease, specifically, to reduce immune-based inflammatory plaques in arteries.  The scientists published their findings in the December 2013 issue of Frontiers in Immunology, titled “Atheroprotective vaccination with MCH-II restricted peptides from Apo B-100.”  These experiments show proof of concept for the development of an autoantigen-specific vaccine for reducing the amount of atherosclerotic plaques in mice.
The published work was done in the laboratory of Klaus Ley, M.D., a prominent vascular biolist of LIAI based on the discovery by Harley Tse, Ph.D., Professor of immunology and microbiology at Wayne Stae University School of Medicine, and Wayne State’s Cardiovascular Research Institute with Michael Shae, Ph.D., adjunct assistant professor of immunology and microbiology.Shaw and Tse are the first to demonstrate that two T-cell epitopes of the autoantigen apoB100 are deeply involved in the development of the disease. The discovery is reported in J Immunol Clin Res Apr-Jun, 2014; 2: “Identification of two immunogenic T cell epitopes of ApoB100 and their Autoimmune Implications.”

 

Atheroprotective Vaccination with MHC-II Restricted Peptides from ApoB-100.

Tse K, Gonen A, Sidney J, Ouyang H, Witztum JL, Sette A, Tse H, Ley K
Front Immunol. 2013 Dec 27; 4:493.
http://dx.doi.org:/10.3389/fimmu.2013.00493 eCollection 2013.

BACKGROUND:  Subsets of CD4(+) T-cells have been proposed to serve differential roles in the development of atherosclerosis. Some T-cell types are atherogenic (T-helper type 1), while others are thought to be protective (regulatory T-cells). Lineage commitment toward one type of helper T-cell versus another is strongly influenced by the inflammatory context in which antigens are recognized. Immunization of atherosclerosis-prone mice with low-density lipoprotein (LDL) or its oxidized derivative (ox-LDL) is known to be atheroprotective. However, the antigen specificity of the T-cells induced by vaccination and the mechanism of protection are not known.

METHODS: Identification of two peptide fragments (ApoB3501-3516 and ApoB978-993) from murine ApoB-100 was facilitated using I-Ab prediction models, and their binding to I-Ab determined. Utilizing a vaccination scheme based on complete and incomplete Freund’s adjuvant (CFA and IFA) [1 × CFA + 4 × IFA], we immunized Apoe(-/-)mice with ApoB3501-3516 or ApoB978-993 emulsified in CFA once and subsequently boosted in IFA four times over 15 weeks. Spleens, lymph nodes, and aortas were harvested and evaluated by flow cytometry and real time RT-PCR. Total atherosclerotic plaque burden was determined by aortic pinning and by aortic root histology.

RESULTS:  Mice immunized with ApoB3501-3516 or ApoB978-993 demonstrated 40% reduction in overall plaque burden when compared to adjuvant-only control mice. Aortic root frozen sections from ApoB3501-3516 immunized mice showed a >60% reduction in aortic sinus plaque development. Aortas from both ApoB3501-3516 and ApoB978-993 immunized mice contained significantly more mRNA for IL-10. Both antigen-specific IgG1 and IgG2c titers were elevated in ApoB3501-3516 or ApoB978-993 immunized mice, suggesting helper T-cell immune activity after immunization.

CONCLUSION: Our data show that MHC Class II restricted ApoB-100 peptides can be atheroprotective, potentially through a mechanism involving elevated IL-10.

Atherosclerosis is decreased in ApoB3501–3516 and ApoB978–993

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873602/bin/fimmu-04-00493-g001.jpg

Atherosclerosis is decreased in ApoB3501–3516 and ApoB978–993-treated mice compared to controls. (A) Vaccination schedule: 8-week-old female Apoe−/− mice were immunized once with either PBS or peptide in CFA, then boosted four more times with PBS or peptide in IFA. WD was maintained for 13 weeks. Mice were sacrificed and organs harvested at 23 weeks of age. (B,C) Results of aortic pinning analysis after Sudan IV staining are shown with representative photographs. N = 12–15 in each group, *p < 0.05 when compared to 1× CFA + 4× IFA group. (D) Representative aortic root staining sections after ORO staining, counter-stained with hematoxylin. (E) Plaque area from aortic roots stained from each group. Lesion sizes from 30 to 40 μm distal to start of the aortic valve were averaged per group. N = 5 in each group, *p < 0.05 when compared to 1× CFA + 1× IFA control group.

 

Inhibition of T cell response to native low density lipoprotein reduces atherosclerosis

Andreas Hermansson, DFJ Ketelhuth, D Strodthoff, M Wurm, E. Hansson, et al.
J. Exp. Med. Mar 2015; 207(5): 1081-1093
http://www.jem.org/cgi/doi/10.1084/jem.20092243

Atherosclerosis is a chronic inflammatory disease in which lipoproteins accumulate, eliciting an inflammatory response in the arterial wall. Adaptive immune responses that engage clonally expanded T cell populations contribute to this process, as do innate immune responses that are mounted by macrophages and other cells. Several studies have suggested that components of low-density lipoprotein (LDL) particles trigger vascular inflammation (Tabas et al., 2007; Hartvigsen et al., 2009).

As a consequence of oxidation, the double bonds of fatty acid residues in phospholipids, cholesteryl esters, and triglycerides are cleaved, thus generating reactive aldehydes and truncated lipids (Esterbauer et al., 1990). Among the latter, modified phospholipids, such as lysophosphatidylcholine and oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine (ox-PAPC), induce endothelial cells, macrophages, and B1-type B cells to initiate innate immune responses, effecting adhesion molecule expression, chemokine production, and secretion of natural antibodies containing germline IgM sequences (Leitinger et al., 1997; Binder et al., 2004; Gharavi et al., 2007).

Immune responses to oxidized low-density lipoprotein (oxLDL) are proposed to be important in atherosclerosis. To identify the mechanisms of recognition that govern T cell responses to LDL particles, we generated T cell hybridomas from human ApoB100 transgenic (huB100tg) mice that were immunized with human oxLDL. Surprisingly, none of the hybridomas responded to oxidized LDL, only to native LDL and the purified LDL apolipoprotein ApoB100.

However, sera from immunized mice contained IgG antibodies to oxLDL, suggesting that T cell responses to native ApoB100 help B cells making antibodies to oxLDL. ApoB100 responding CD4+ T cell hybridomas were MHC class II–restricted and expressed a single T cell receptor (TCR) variable (V)  chain, TRBV31, with different V chains. Immunization of huB100tgxLdlr/ mice with a TRBV31-derived peptide induced anti-TRBV31 antibodies that blocked T cell recognition of ApoB100. This treatment significantly reduced atherosclerosis by 65%, with a concomitant reduction of macrophage infiltration and MHC class II expression in lesions. In conclusion, CD4+ T cells recognize epitopes on native ApoB100 protein, this response is associated with a limited set of clonotypic TCRs, and blocking TCR-dependent antigen recognition by these T cells protects against atherosclerosis.

 

Impact of multiple antigenic epitopes from ApoB100, hHSP60 and Chlamydophila pneumoniae on atherosclerotic lesion development in Apobtm2SgyLdlrtm1HerJ mice

Xinjie Lu, Min Xia, V Endresz, I Faludi, A Szabo, et al.
Atherosclerosis Nov 2012; 225(1): 56–68
http://www.sciencedirect.com.scopeesprx.elsevier.com/science/article/pii/S0021915012004935
http://dx.doi.org:/10.1016/j.atherosclerosis.2012.07.021

Highlights

► We produced 5 constructs using dendroaspin as a scaffold for immunization study. ► All constructs have the effect on lesion reduction. ► Modulation in atherosclerosis-related autoimmunity appears by Tregs.

Atherosclerosis is increasingly recognized as a complex chronic inflammatory disease of the arterial walls [1], [2] and [3], as evidenced by the presence of inflammatory cells, activated immune cells and cytokines in lesions, all of which indicate involvement of the immune system. Atherosclerotic plaques are known to contain macrophage-derived foam cells in which macrophages interact with T-cells to produce a wide array of cytokines that can exert both pro- and anti-inflammatory effects.

 

Antibodies against aldehyde-modified ApoB100, a major constituent of low-density lipoprotein, reduce atherosclerosis in mice expressing human ApoB100, suggesting an immunogenic role of ApoB100. Antibodies against epitopes of the human heat shock protein 60 (hHSP60) molecule (hHSP60153–163: AELKKQSKPVT and hHSP60303-312: PGFGDNRKNQ) are present in atherosclerotic patients and share considerable homology with human cytomegalovirus (HCMV)-derived protein (immediate early protein UL122) and Porphyromonas gingivalis microbial HSP60. Sequence homology between microbial HSP60 and hHSP60 has been suggested to result in immunological cross-reactivity, which may play a role in atherogenesis. Titers of Cpn antibodies are not always positively associated with the Cpn organism in atheroma; however, these antibodies might exert cross-reactivity to non-Cpn antigens.

Immunization of mice with a single construct containing multiple epitopes derived from ApoB100, hHSP60 and Cpn was more effective in reducing early atherosclerotic lesions through the induction of a specific Treg-cell response than was the construct containing either mono- or bi-epitopes. This approach offers attractive opportunities for the design of protein-based, multivalent vaccines against atherosclerosis.

 

Immunization with a combination of ApoB and HSP60 epitopes significantly reduces early atherosclerotic lesion in Apobtm2SgyLdlrtm1Her/J mice

Xinjie Lu, Daxin Chen, Valeria Endreszb, Min Xia, Ildiko Faludi, et. al.
Atherosclerosis 212 (2010) 472–480
http://dx.doi.org:/10.1016/j.atherosclerosis.2010.06.007

Objective: HSP60 is emerging as an immune-dominant target of autoantibodies in atherosclerosis and recent studies have revealed oxLDL as a key antigen in the development of atherosclerosis. In this study, we assay whether immunizing Apobtm2SgyLdlrtm1Her/J mice with a combination of ApoB and human HSP60 peptides has an additive effect on athero-protection compared to ApoB or HSP60 peptides applied alone by following atherosclerotic lesion development. Methods and results: In this study, 2 weeks after the first immunization, Apobtm2SgyLdlrtm1Her/J mice were placed on a high-fat diet for 8 weeks followed by 2 weeks on a normal diet allowing the mice to adapt to the environment before sacrifice. High levels of ApoB and HSP60 antibodies were detectable in week 2 and week 12 following the first immunization with KLH-conjugated ApoB and HSP60 peptides either individually or in combination. Histological analyses demonstrated that mice immunized with both, ApoB and HSP60 peptides, showed the most significant reduction in atherosclerotic lesions (41.3%; p < 0.001) compared to a reduction of 14.7% (p < 0.05) and 21.1% (p < 0.01) in mice immunized with ApoB or HSP60 peptides, respectively; control mice were immunized with either PBS or adjuvant alone. These results

were further supported by significant differences in the cellular and humoral immune responses between test animals. Conclusions: Immunization with a combination of ApoB and HSP60 peptide antigens significantly reduced early atherosclerotic lesions in the Apobtm2SgyLdlrtm1Her/J mouse model of atherosclerosis. This approach offers promise as a novel strategy for developing anti-atherosclerotic agents.

 

Chlamydophila (Chlamydia) pneumoniae infection promotes vascular smooth muscle cell adhesion and migration through IQ domain GTPase-activating protein 1

Lijun Zhang, Xiankui Li, Lijun Zhang, Beibei Wang, Tengteng Zhang, Jing Ye
Microb Pathogen 2012; 53(5–6): 207–213
http://dx.doi.org:/10.1016/j.micpath.2012.07.005

Highlights

► C. pneumoniae infection increases the adhesion of vascular smooth muscle cells. ► C. pneumoniae infection promotes the migration of vascular smooth muscle cells. ► IQGAP1 expression was increased in the infected vascular smooth muscle cells. ► Depletion of IQGAP1 inhibits the infection-induced cell adhesion and migration.

The mechanisms for Chlamydophila (Chlamydia) pneumoniae (C. pneumoniae) infection-induced atherosclerosis are still unclear. Cell adhesion has important roles in vascular smooth muscle cell (VSMC) migration required in the development of atherosclerosis. However, it is still unknown whether IQ domain GTPase-activating protein 1 (IQGAP1) plays pivotal roles in C. pneumoniae infection-induced the adhesion and migration of rat primary VSMCs. Accordingly, in this study, we demonstrated that rat primary VSMC adhesion (P < 0.001) and migration (P < 0.01) measured by cell adhesion assay and Transwell assay, respectively, were significantly enhanced after C. pneumoniae infection. Reverse transcription-polymerase chain reaction analysis revealed that the mRNA expression levels of IQGAP1 in the infected rat primary VSMCs were found to increase gradually to reach a peak and then decrease gradually to a level similar to the control. We further showed that the increases in rat primary VSMC adhesion to Matrigel (P < 0.001) and migration (P < 0.01) caused by C. pneumoniae infection were markedly inhibited after IQGAP1 knockdown by a pool of four short hairpin RNAs. Taken together, our results suggest that C. pneumoniae infection may promote the adhesion and migration of VSMCs possibly by upregulating the IQGAP1 expression.

 

Rosiglitazone negatively regulates c-Jun N-terminal kinase and toll-like receptor 4 proinflammatory signalling during initiation of experimental aortic aneurysms

Grisha Pirianov, Evelyn Torsney, Franklyn Howe, Gillian W. Cockerill
Atherosclerosis 2012; 225(1): 69–75
http://dx.doi.org:/10.1016/j.atherosclerosis.2012.07.034

Highlights

► Rosiglitazone has a marked effect on both aneurysm rupture and development. ► Rosiglitazone modulates inflammation by blocking TLR4/JNK signalling. ► Specific antagonists of JNK and TLR4 may be therapeutic for aneurysms.

Development and rupture of aortic aneurysms (AA) is a complex process involving inflammation, cell death, tissue and matrix remodelling. The thiazolidinediones (TZDs) including Rosiglitazone (RGZ) are a family of drugs which act as agonists of the nuclear peroxisome proliferator-activated receptors and have a broad spectrum of effects on a number of biological processes in the cardiovascular system. In our previous study we have demonstrated that RGZ has a marked effect on both aneurysm rupture and development, however, the precise mechanism of this is unknown.

Methods and results  In the present study, we examined possible targets of RGZ action in the early stages of Angiotensin II-induced AA in apolipoprotein E-deficient mice. For this purpose we employed immunoblotting, ELISA and antibody array approaches. We found that RGZ significantly inhibited c-Jun N-terminal kinase (JNK) phosphorylation and down-regulated toll-like receptor 4 (TLR4) expression at the site of lesion formation in response to Angiotensin II infusion in the initiation stage (6–72 h) of experimental AA development. Importantly, this effect was also associated with a decrease of CD4 antigen and reduction in production of TLR4/JNK-dependant proinflammatory chemokines MCP-1 and MIP-1α.  Conclusion These data suggest that RGZ can modulate inflammatory processes by blocking TLR4/JNK signalling in initiation stages of AA development.

 

Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine.

Gonen A, Hansen LF, Turner WW, Montano EN, Que X,…, Hartvigsen K.
J Lipid Res. 2014 Oct;55(10):2137-55.
http://dx.doi.org:/10.1194/jlr.M053256.  Epub 2014 Aug 20.

Immunization with homologous malondialdehyde (MDA)-modified LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specific epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modification of human LDL with OSE to use as an immunogen would be impractical for generalized use. Furthermore, when MDA is used to modify LDL, a wide variety of related MDA adducts are formed, both simple and more complex. To define the relevant epitopes that would reproduce the atheroprotective effects of immunization with MDA-LDL, we sought to determine the responsible immunodominant and atheroprotective adducts. We now demonstrate that fluorescent adducts of MDA involving the condensation of two or more MDA molecules with lysine to form malondialdehyde-acetaldehyde (MAA)-type adducts generate immunodominant epitopes that lead to atheroprotective responses. We further demonstrate that a T helper (Th) 2-biased hapten-specific humoral and cellular response is sufficient, and thus, MAA-modified homologous albumin is an equally effective immunogen. We further show that such Th2-biased humoral responses per se are not atheroprotective if they do not target relevant antigens. These data demonstrate the feasibility of development of a small-molecule immunogen that could stimulate MAA-specific immune responses, which could be used to develop a vaccine approach to retard or prevent atherogenesis.

 

Low density lipoprotein oxidation and atherogenesis: from experimental models to clinical studies.

Napoli C
G Ital Cardiol. 1997 Dec; 27(12):1302-14.

Oxidative modifications of low-density lipoproteins (LDL) (“oxidation hypothesis”) appears to be the pathophysiologic mechanism implicated in early atherogenesis. Oxidized LDL (ox-LDL) may also induce several pro-atherogenic mechanisms, such as the regulation of vascular tone, by interfering with nitric oxide, the stimulation of cytokines and chemotactic factors (MCP-1, M-CSF, VCAM-1, etc.) and transcription factors (AP1 and NFk beta). These phenomena complicate the spectrum of direct and indirect actions of ox-LDL. The immunogenicity of ox-LDL was used to generate monoclonal antibodies against many epitopes of ox-LDL, such as malondialdehyde-lysine (MDA-2) or 4-hydroxynonenal-lysine (NA59). These antibodies showed the occurrence of ox-LDL in vivo. Another issue is the role of the humoral and cellular immune system in atherogenesis, in particular whether the immune response to ox-LDL enhances or reduces early atherogenesis. Moreover, the induction of autoantibodies against ox-LDL and the recognition by “natural” antibodies, and the use of the antigens to screen human sera may serve as a marker of atherosclerosis. In this review, we have stressed the importance of methodologic approach in the assessment of LDL-oxidation and the fact that lipoprotein (a) may also undergo oxidative modifications. Several clinical conditions are associated with increased rate of LDL-oxidation. Recently, we have observed the presence of LDL oxidation-specific epitopes in human fetal aortas. Antioxidants studies in primary prevention of atherosclerosis have produced contradictory results. This may be explained in part by the selection of patients who had advanced lesions and were often smokers. New trails suggest that antioxidants be administered early in children. Lastly, antioxidant studies in the secondary prevention of coronary heart disease (CHAOS, WACS, and HOPE) show clear evidence of the benefits of antioxidants in reducing new cardiovascular events.

 

Summary:

Atheroprotective Vaccine

Tech ID: 19640 / UC Case 2006-250-0
http://www.ucop.edu//ncd/12343.html

Atherosclerosis is a chronic inflammatory disease and immunological mechanisms are of central importance. It is known that oxidized LDL and its oxidized moieties were a major class of immunodominant epitopes within the atherosclerotic plaque. Oxidation of LDL leads to the generation of a variety of oxidized lipids and oxidized lipid-apo-B adducts.

Technology Description

UC San Deigo researchers proposed that an immunization strategy could be used to inhibit the progression of atherosclerosis by showing that immunization of rabbits and/or mice (and ultimately humans) with MDA-LDL could inhibit atherosclerosis. To develop a safe vaccine for human use would require the identification of the specific immunogenic oxidation-specific epitope(s) that provides the atheroprotective immunity. Until now, the mechanism of the protection, that is, the immunodominant epitope(s) has not yet been determined.

UC San Diego researchers have been able to identify a small group of MDA-derived adducts which are immunodominant and atheroprotective in mice following immunization. The invention described here has the potential to provide an antigen to formulate a wholly synthetic vaccine to inhibit  the development of atherosclerosis in man. Furthermore, in vivo levels of the adducts, and the autoantibodies recognizing them, may be used as diagnostic tools in patients with cardiovascular and other inflammatory diseases.

State Of Development

Mice have been immunized with the adducts resulting in atheroprotection. Techniques are currently being developed for a totally synthetic immunogen suitable for human clinical studies. Assays are also being developed.

Intellectual Property Info

A patent application has been filed on this technology.

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Diet and Cholesterol

Writer and Curator: Larry H. Bernstein, MD, FCAP 

 

Introduction

We are all familiar with the conundrum of diet and cholesterol.  As previously described, cholesterol is made by the liver. It is the backbone for the synthesis of sex hormones, corticosteroids, bile, and vitamin D. It is also under regulatory control, and that is not fully worked out, but it has health consequences. The liver is a synthetic organ that is involved with glycolysis, gluconeogenesis, cholesterol synthesis, and unlike the heart and skeletal muscles – which are energy transducers – the liver is anabolic, largely dependent on NADPH.  The mitochondria, which are associated with aerobic metabolism, respiration, are also rich in the liver.  The other part of this story is the utilization of lipids synthesized by the liver in the vascular endothelium.  The vascular endothelium takes up and utilizes/transforms cholesterol, which is involved in the degenerative development of pathogenic plaque.  Plaque is associated with vascular rigidity, rupture and hemorrhage, essential in myocardial inmfarction. What about steroid hormones?  There is some evidence that sex hormone differences may be a factor in coronary vascular disease and cardiac dysfunction.  The evidence that exercise is beneficial is well established, but acute coronary events can occur during exercise.  WE need food, and food is at the center of the discussion – diet and cholesterol.  The utilization of food varies regionally, and is dependent on habitat.  But it is also strongly influence by culture.  We explore this further in what follows.

A high fat, high cholesterol diet leads to changes in metabolite patterns in pigs – A metabolomic study

Jianghao Sun, Maria Monagas, Saebyeol Jang, Aleksey Molokin, et al.
Food Chemistry 173 (2015) 171–178
http://dx.doi.org/10.1016/j.foodchem.2014.09.161

Non-targeted metabolite profiling can identify biological markers of dietary exposure that lead to a better understanding of interactions between diet and health. In this study, pigs were used as an animal model to discover changes in metabolic profiles between regular basal and high fat/high cholesterol diets. Extracts of plasma, fecal and urine samples from pigs fed high fat or basal regular diets for 11 weeks were analysed using ultra-high performance liquid chromatography with high-resolution mass spectrometry (UHPLC–HRMS) and chemometric analysis. Cloud plots from XCMS online were used for class separation of the most discriminatory metabolites. The major metabolites contributing to the discrimination were identified as bile acids (BAs), lipid metabolites, fatty acids, amino acids and phosphatidic acid (PAs), phosphatidylglycerol (PGs), glycerophospholipids (PI), phosphatidylcholines (PCs) and tripeptides. These results suggest the developed approach can be used to identify biomarkers associated with specific feeding diets and possible metabolic disorders related to diet.

Nutritional metabolomics is a rapidly developing sub-branch of metabolomics, used to profile small-molecules to support integration of diet and nutrition in complex bio-systems research. Recently, the concept of ‘‘food metabolome’’ was introduced and defined as all metabolites derived from food products. Chemical components in foods are absorbed either directly or after digestion, undergo extensive metabolic modification in the gastrointestinal tract and liver and then appear in the urine and feces as final metabolic products. It is well known that diet has a close relationship with the long-term health and well-being of individuals. Hence, investigation of the ‘‘food metabolome’’ in biological samples, after feeding specific diets, has the potential to give objective information about the short- and long-term dietary intake of individuals, and to identify potential biomarkers of certain dietary patterns. Previous studies have identified potential biomarkers after consumption of specific fruits, vegetables, cocoa, and juices. More metabolites were revealed by using metabolomic approaches compared with the detection of pre-defined chemicals found in those foods.

Eating a high-fat and high cholesterol diet is strongly associated with conditions of obesity, diabetes and metabolic syndrome, that are increasingly recognized as worldwide health concerns. For example, a high fat diet is a major risk factor for childhood obesity, cardiovascular diseases and hyperlipidemia. Little is known on the extent to which changes in nutrient content of the human diet elicit changes in metabolic profiles. There are several reports of metabolomic profiling studies on plasma, serum, urine and liver from high fat-diet induced obese mice, rats and humans. Several potential biomarkers of obesity and related diseases, including lysophosphatidylcholines (lysoPCs), fatty acids and branched-amino acids (BCAAs) have been reported.

To model the metabolite response to diet in humans, pigs were fed a high fat diet for 11 weeks and the metabolite profiles in plasma, urine and feces were analyzed. Non-targeted ultra high performance liquid chromatography tandem with high resolution mass spectrometry (UHPLC–MS) was utilized for metabolomics profiling. Bile acids (BAs), lipid metabolites, fatty acids, amino acids and phosphatidic acid (PAs), phosphatidylglycerol (PGs), glycerophospholipids (PI), phosphatidylcholines (PCs), tripeptides and isoflavone conjugates were found to be the final dietary metabolites that differentiated pigs fed a high-fat and high cholesterol diet versus a basal diet. The results of this study illustrate the capacity of this metabolomic profiling approach to identify new metabolites and to recognize different metabolic patterns associated with diet.

Body weight, cholesterol and triglycerides were measured for all the pigs studied. There was no significant body weight gain between pigs fed diet A and diet B after 11 weeks of treatment. The serum cholesterol and triglyceride levels were significantly higher in pigs fed with diet B compared with the control group at the end of experiment.

Plasma, urine and fecal samples were analyzed in both positive and negative ionization mode. To obtain reliable and high-quality metabolomic data, a pooled sample was used as a quality control (QC) sample to monitor the run. The QC sample (a composite of equal volume from 10 real samples) was processed as real samples and placed in the sample queue to monitor the stability of the system. All the samples were submitted in random for analysis. The quantitative variation of the ion features across the QC samples was less than 15%. The ion features from each possible metabolite were annotated by XCMS online to confirm the possible fragment ions, isotopic ions and possible adduct ions. The reproducibility of the chromatography was determined by the retention time variation profiles that were generated by XCMS. The retention time deviation was less than 0.3 min for plasma samples, less than 0.3 min for fecal samples, and less than 0.2 min for urine samples, respectively. On the basis of these results of data quality assessment, the differences between the test samples from different pigs proved more likely to reflect varied metabolite profiles rather than analytical variation. The multivariate analysis results from the QC sample showed the deviation of the analytical system was acceptable.
Good separation can be observed between pigs on the two diets, which is also reflected in the goodness of prediction (Q2), of 0.64 using data from the positive ionization mode. For negative ionization mode data, better separation appears with a Q2of 0.73.

Cloud plot is a new multidimensional data visualization method for global metabolomic data (Patti et al., 2013). Data characteristics, such as the p-value, fold change, retention time, mass-to-charge ratio and signal intensity of features, can be presented simultaneously using the cloud plot. In this study, the cloud plot was used to illustrate the ion features causing the group separation. In Fig. 2 and 82 features with p < 0.05 and fold change >2, including visualisation of the p-value, the directional fold change, the retention time and the mass to charge ratio of features, are shown. Also, the total ion chromato-grams for each sample were shown. The upper panel in (2A) shows the chromatograms of plasma samples from pigs fed the high fat diet, while the lower panel shows the chromatograms of samples from pigs fed the regular diet. Features whose intensity is increased are shown in green, whereas features whose intensity is decreased are shown in pink (2A). The size of each bubble corresponds to the log fold change of the feature: the larger the bubble, the larger the fold changes. The statistical significance of the fold change, as calculated by a Welch t-test with unequal variances, is represented by the intensity of the feature’s color where features with low p-values are brighter compared to features with high p-values. The Y coordinate for each feature corresponds to the mass-to-charge ratio of the compound, as determined by mass spectrometry. Each feature is also color coded, such as features that are shown with a black outline have database hits in METLIN, whereas features shown without a black outline do not have any database hits.

From the cloud plot (Fig. 2A), 82 discriminating ion features from positive data and 48 discriminating ions features from negative data were considered as of great importance for class separation. After filtering out the fragment ions, isotope annotations, and adduct ions, thirty-one metabolites were tentatively assigned using a Metlin library search (Table S4).

Among the assigned metabolites detected, five of the highest abundant metabolites were identified as bile acid and bile acid conjugates (Fig. 2B). This series of compounds shared the following characteristics; the unconjugated bile acids showed [M-H] ion as base peak in the negative mode.

The characteristic consistent with bile acid hyodeoxycholic acid (HDCA) was confirmed with a reference standard. For the conjugated bile acids (usually with glycine and taurine), the [M-H] and [M+H]+ are always observed as the base peaks. For example, the ion feature m/z 448.3065 at 21.18 min was identified as chenodeoxycholic acid glycine conjugate. The neutral loss of 62 amu (H2O + CO2) was considered as a characteristic fragmentation pathway for bile acid glycine conjugates. This above mentioned characteristic can easily identify a series of bile acids compounds. The five metabolite ions detected in plasma were significantly different between pigs fed the high fat diet (Fig. 2B, red bars) and regular diet (Fig. 2B, blue bars) for 11 weeks, and were identified as chenodeoxycholic acid glycine conjugate, tauroursodeoxycholic acid, hyodeoxycholic acid, deoxycholic acid glycine conjugate and glycocholic acid; chenodeoxycholic acid glycine and hyodeoxycholic acid.

Figures 1-4 , not shown.
Fig 1. The PCA score plot of plasma (A) (+)ESI data with all the ion features; (B) (+)ESI data with selected ion features; (C) (-)ESI data with all ion features; (D) (-)ESI data with selected ion features. Samples were taken from pigs fed diet A (BS, blue) and diet B (HF, red). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig 2. Cloud plot showing 82 discriminatory ion features (negative ion data) in plasma, and (B) box-plot of data set of the five most abundant bile acids identified in plasma (negative ion data) samples.

Fig. 3. PCA score plot of fecal samples from pigs fed diet A (BS, blue) and diet B (HF, red) (A) week 0, (B) week 2, (C) week 4 (D) week 6, (E) week 11 for distal samples (F) week 11 for proximal colon samples. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 4. PCA and PLS-DA score plot of urine samples from (+)ESI-data (A and C) and (-)ESI-data (B and D) taken at the end of the study (week 11) from pigs fed diet A (BS, blue) and diet B (HF, red). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Plasma, fecal and urine metabolites from pigs fed either a high fat or regular diet were investigated using a UHPLC–HRMS based metabolomic approach. Their metabolic profiles were compared by multivariate statistical analysis.
Diet is logically believed to have a close relationship with metabolic profiles. Feeding a high fat and high cholesterol diet to pigs for 11 weeks resulted in
an increase in bile acids and their derivatives in plasma, fecal and urine samples, though at this stage, there was no significant weight gain observed.

In a previous study, a significantly higher level of muricholic acid, but not cholic acid, was found in pigs fed a high fat diet. The gut microbiota of these pigs were altered by diet and considered to regulate bile acid metabolism by reducing the levels of tauro-beta-muricholic acid. In our study, the unconjugated bile acids, hyodeoxycholic acid and deoxycholic acid were found to be significantly higher in the fecal samples of pigs fed a high-fat diet.

Chenodeoxycholic acid glycine was 8.6 times higher in pigs fed a high fat and high cholesterol diet compared to those fed a regular diet. These results confirm that feeding a high fat and high cholesterol diet leads to a changing metabolomic pattern over time, represented by excretion of certain bile acids in the feces. We also found that several metabolites associated with lipid metabolism were increased in the feces of pigs fed the high-fat diet. Feeding the high fat diet to pigs for 11 weeks did not induce any overt expression of disease, except for significantly higher levels of circulating cholesterol and triglycerides in the blood. It is likely, however, that longer periods of feeding would increase expression of metabolic syndrome disorders and features of cardiovascular disease in pigs, as have been previously demonstrated. Products of lipid metabolism that changed early in the dietary treatment could be useful as biomarkers. This may be important because the composition of the fats in the diet, used in this study, was complex and from multiple sources including lard, soybean oil and coconut oil.

In summary, a number of metabolite differences were detected in the plasma, urine and feces of pigs fed a high fat and high cholesterol diet versus a regular diet that significantly increased over time. PCA showed a clear separation of metabolites in all biological samples tested from pigs fed the different diets. This methodology could be used to associate metabolic profiles with early markers of disease expression or the responsiveness of metabolic profiles to alterations in the diet. The ability to identify metabolites from bio-fluids, feces, and tissues that change with alterations in the diet has the potential to identify new biomarkers and to better understand mechanisms related to diet and health.

Amino acid, mineral, and polyphenolic profiles of black vinegar, and its lipid lowering and antioxidant effects in vivo

Chung-Hsi Chou, Cheng-Wei Liu, Deng-Jye Yang, Yi-Hsieng S Wuf, Yi-Chen Chen
Food Chemistry 168 (2015) 63–69
http://dx.doi.org/10.1016/j.foodchem.2014.07.035

Black vinegar (BV) contains abundant essential and hydrophobic amino acids, and polyphenolic contents, especially catechin and chlorogenic acid via chemical analyses. K and Mg are the major minerals in BV, and Ca, Fe, Mn, and Se are also measured. After a 9-week experiment, high-fat/cholesterol-diet (HFCD) fed hamsters had higher (p < 0.05) weight gains, relative visceral-fat sizes, serum/liver lipids, and serum cardiac indices than low-fat/cholesterol diet (LFCD) fed ones, but BV supplementation decreased (p < 0.05) them which may resulted from the higher (p < 0.05) fecal TAG and TC contents. Serum ALT value, and hepatic thiobarbituric acid reactive substances (TBARS), and hepatic TNF-α and IL-1β contents in HFCD-fed hamsters were reduced (p < 0.05) by supplementing BV due to increased (p < 0.05) hepatic glutathione (GSH) and trolox equivalent antioxidant capacity (TEAC) levels, and catalase (CAT) and glutathione peroxidase (GPx) activities. Taken together, the component profiles of BV contributed the lipid lowering and antioxidant effects on HFCD fed hamsters.

World Health Organization (WHO) reported that more than 1.4 billion adults were overweight (WHO, 2013). As we know, imbalanced fat or excess energy intake is one of the most important environmental factors resulted in not only increased serum/liver lipids but also oxidative stress, further leading cardiovascular disorders and inflammatory responses. Food scientists strive to improve serum lipid profile and increase serum antioxidant capacity via  medical foods or functional supplementation.

Vinegar is not only used as an acidic seasoning but also is shown to have some beneficial effects, such as digestive, appetite stimulation, antioxidant, exhaustion recovering effects, lipid lowering effects, and regulations of blood pressure. Polyphenols exist in several food categories, such as vegetable, fruits, tea, wine, juice, and vinegar that have effects against lipid peroxidation, hypertension, hyperlipidemia, inflammation, DNA damage, and. Black vinegar (BV) (Kurosu) is produced from unpolished rice with rice germ and bran through a stationary surface fermentation and contains higher amounts of amino acids and organic acids than other vinegars. Black vinegar is also characterised as a health food rather than only an acidic seasoning because it was reported to own a DPPH radical scavenging ability and decrease the adipocyte size in rat models. Moreover, the extract of BV shows the highest radical scavenging activity in a DPPH radical system than rice, grain, apple, and wine vinegars. The extract suppresses increased lipid peroxidation in mouse skin treated with 12-o-tetradecanoylphorbol-13-acetate.

This study focused on the nutritional compositions in BV, and the in-vivo lipid lowering and antioxidant effects. First, the amino acid, mineral, and polyphenolic profile of BV were identified. Hypolipidemic hamsters induced by a high-fat/cholesterol diet (HFCD) were orally administered with different doses of BV. Serum lipid profile and liver damage indices liver and fecal lipid contents, as well as hepatic antioxidant capacities [thiobarbituric acid reactive substances (TBARS), glutathione (GSH), trolox equivalent antioxidant capacity (TEAC), and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)] and hepatic cytokine levels were assayed to demonstrated physiological functions of BV.

Higher serum AST, ALT, and free fatty acids, as well as hepatic cholesterol, triacylglycerol, MDA, hydroperoxide, and cytokine (IL-1β and TNF-α) levels were easily observed in a high-fat-consumption rodent. Several reports indicated some amino acids antioxidant activities in vitro and in vivo. Acidic amino acids, such as Asp and Glu and hydrophobic amino acids, such as Ile, Leu, and Val display high antioxidant properties. Recently, an in vivo study indicated that a pepsin hydrolyzation significantly enhanced Asp, Glu, Leu, and Val contents in chicken livers; meanwhile, chicken-liver hydrolysates showed an antioxidant capacity in brain and liver of D-galactose treated mice. In addition, it was also reported that Mg and Se play important roles in SOD and GPx activities, respectively. Uzun and Kalender (2013) used chlorpyrifos, an organophosphorus insecticide, to induce hepatotoxic and hematologic changes in rats, but they observed that catechin can attenuate the chlorpyrifos-induced hepatotoxicity by increasing GPx and glutathione-S-transferase activities and decreasing MDA contents. Meanwhile, chlorogenic acid elevated SOD, CAT, and GPx activities with concomitantly decreased lipid peroxidation of liver and kidney in streptozotocin-nicotinamide induced type-2 diabetic rats. Hence, it is reasonable to assume that increased antioxidant capacities and decreased damage in livers of HFCD fed hamsters supplemented with BV should be highly related to the components, i.e. amino acid profile, mineral profile, and polyphenol contents, as well as the lowered liver lipid accumulations.

In analyses of amino acids, minerals and polyphenols, BV contained abundant essential amino acids and hydrophobic amino acids. Mg, K, Ca, Fe, Mn, and Se were measured in BV where K and Mg were major. Gallic acid, catechin, chlorogenic acid, p-hydroxybezoic acid, p-cumeric acid, ferulic acid, and sinapic acid were also identified in BV where catechin and chlorogenic acid were the majorities. Meanwhile, the lipid-lowering and antioxidant effects of BV were also investigated via a hamster model. BV supplementation apparently decreased weight gain (g and %), relative size of visceral fat, serum/liver TC levels, serum cardiac index, and hepatic TBARS values and damage indices (serum ALT and hepatic TNF-α and IL-1β) but increased fecal lipid contents and hepatic antioxidant capacities (GSH level, TEAC level, CAT activity, and GPx activity) in HFCD fed hamsters. To sum up, those benefits could be attributed to a synergetic effect of compounds in BV.

Analysis of pecan nut (Carya illinoinensis) unsaponifiable fraction – Effect of ripening stage on phytosterols and phytostanols composition

Intidhar Bouali, Hajer Trabelsi, Wahid Herchi, Lucy Martine, et al.
Food Chemistry 164 (2014) 309–316
http://dx.doi.org/10.1016/j.foodchem.2014.05.029

Changes in 4-desmethylsterol, 4-monomethylsterol, 4,4-dimethylsterol and phytostanol composition were quantitatively and qualitatively investigated during the ripening of three varieties of Tunisian grown pecan nuts. These components have many health benefits, especially in lowering LDL-cholesterol and preventing heart disease. The phytosterol composition of whole pecan kernel was quantified by Gas Chromatography–Flame Ionization Detection (GC–FID) and identified by Gas Chromatography–Mass Spectrometry (GC–MS). Fifteen phytosterols and one phytostanol were quantified. The greatest amount of phytosterols (2852.5 mg/100 g of oil) was detected in Mahan variety at 20 weeks after the flowering date (WAFD). Moore had the highest level of phytostanols (7.3 mg/100 g of oil) at 20 WAFD. Phytosterol and phytostanol contents showed a steep decrease during pecan nut development. Results from the quantitative characterization of pecan nut oils revealed that β-sitosterol, D5-avenasterol, and campesterol were the most abundant phytosterol compounds at all ripening stages.

Association between HMW adiponectin, HMW-total adiponectin ratio and early-onset coronary artery disease in Chinese population

Ying Wang, Aihua Zheng, Yunsheng Yan, Fei Song, et al.
Atherosclerosis 235 (2014) 392-397
http://dx.doi.org/10.1016/j.atherosclerosis.2014.05.910

Objective: Adiponectin is an adipose-secreting protein that shows atheroprotective property and has inverse relation with coronary artery disease (CAD). High-molecular weight (HMW) adiponectin is reported as the active form of adiponectin. In the present study, we aimed to investigate the association between total adiponectin, HMW adiponectin, HMW-total adiponectin ratio and the severity of coronary atherosclerosis, and to compare their evaluative power for the risk of CAD. Methods: Serum levels of total and HMW adiponectin were measured in 382 early-onset CAD (EOCAD) patients and 305 matched controls undergoing coronary angiography by enzyme-linked immunosorbent assay (ELISA). Gensini score was used to evaluate the severity of coronary atherosclerosis. Results: CAD onset age was positively correlated with HMW adiponectin (r = 0.383, P < 0.001) and HMW-total adiponectin ratio (r = 0.429, P < 0.001) in EOCAD patients. Total and HMW adiponectin and HMW-total adiponectin ratio were all inversely correlated with Gensini score (r=0.417, r=0.637, r=0.578, respectively; all P < 0.001). Multivariate binary logistic regression analysis demonstrated that HMW adiponectin and HMW-total adiponectin ratio were both inversely correlated with the risk of CAD (P < 0.05). ROC analysis indicated that areas under the ROC curves of HMW adiponectin and HMW-total adiponectin ratio were larger than that of total adiponectin (P < 0.05). Conclusions: Adiponectin is cardioprotective against coronary atherosclerosis onset in EOCAD patients. HMW adiponectin and HMW-total adiponectin ratio show stronger negative associations with the severity of coronary atherosclerosis than total adiponectin does. HMW adiponectin and HMW-total adiponectin ratio are effective biomarkers for the risk of CAD in Chinese population.

Gender and age were well matched between patients and controls. EOCAD patients were tended to have a history of diabetes or hypertension, more current smoking, and more use of lipid lowering drugs. Levels of total cholesterol, LDL-c, FPG, HbA1c and triglycerides were significantly higher in the patients than in controls, while HDL-cholesterol, total adiponectin, HMW adiponectin, and HMW-total adiponectin ratio were significantly lower in the patients. EOCAD patients developed different degrees of coronary atherosclerosis, and had significantly higher levels of high-sensitivity CRP and larger circumferences of waist and hip than controls.

Spearman correlation coefficients between selected cardiovascular risk factors, Gensini score and adiponectin were significant. Total and HMW adiponectin and HMW-total adiponectin ratio were all inversely correlated with Gensini score, BMI and pack years of cigarette smoking. Total and HMW adiponectin were negatively associated with triglycerides and circumference of waist and hip. LDL-cholesterol and high-sensitivity CRP were inversely correlated with HMW adiponectin and HMW-total adiponectin ratio, while HDL-cholesterol and age were positively correlated with them. FPG was only inversely associated with HMW-total adiponectin ratio.

All participants were divided into four groups according to their Gensini score, group A (control, n = 305), group B (<20, n = 154), group C (20-40, n = 121) and group D (>40, n = 105). With the increasing of Gensini score, a stepwise downward trend was observed in levels of total and HMW adiponectin and HMW-total adiponectin ratio (P < 0.001). Specifically, total adiponectin of four groups were 1.58 (0.61-4.36) mg/ml, 1.21 (0.70-2.83) mg/ml, 1.00 (0.73-1.88) mg/ml, and 0.76 (0.37-1.19) mg/ml, respectively. Except group A with B and group B with C, the differences of pairwise comparisons among all the other groups were statistically significant (all P < 0.05). HMW adiponectin of four groups were 0.91 (0.39-3.26) mg/ml, 0.55 (0.32-1.49) mg/ml, 0.46 (0.21-0.876) mg/ml, and 0.23 (0.14-0.39) mg/ml, respectively. The differences of pairwise comparisons among all the other groups were statistically significant (all P < 0.05) except group B with C. HMW-total adiponectin ratio of four groups were 0.58 (0.31-0.81), 0.47 (0.26-0.69), 0.41 (0.24-0.57), and 0.36 (0.21-0.42), respectively. The differences of pairwise comparisons among all the other groups were statistically significant (all P < 0.05) except group B with C. In the model of multivariate binary logistic regression analysis, after adjustment for conventional cardiovascular risk factors, HMW adiponectin (OR = 0.234, P < 0.011) and HMW-total adiponectin ratio (OR = 0.138, P < 0.005) remained inversely correlated with the risk of CAD, while no significant association was observed between total adiponectin and CAD

Areas under the ROC curves were compared pairwise to identify the diagnostic power for CAD among total adiponectin, HMW adiponectin, and HMW-total adiponectin ratio. HMW adiponectin and HMW-total adiponectin ratio showed greater capability for identifying CAD than total adiponectin did (0.797 vs. 0.674, 0.806 vs. 0.674; respectively, all P < 0.05); however, no significant difference was observed between HMW and HMW-total ratio (P > 0.05).

Associations between total adiponectin, HMW adiponectin, HMW-total adiponectin ratio and the severity of coronary atherosclerosis

Associations between total adiponectin, HMW adiponectin, HMW-total adiponectin ratio and the severity of coronary atherosclerosis in EOCAD patients (evaluated by Gensini score). *P < 0.05; **P < 0.001; ***P < 0.005 by Mann-Whitney U test.

Compares diagnostic power

Compares diagnostic power

Fig. Compares diagnostic power among total adiponectin, HMW adiponectin and HMW-total adiponectin ratio for CAD by ROC curves. Diagnostic power for CAD was based on discriminating patients with or without coronary atherosclerosis. The area under the curve for HMW-total adiponectin ratio (dotted black line) was larger than that for total adiponectin (fine black line) (0.806 [95%CI 0.708-0.903] vs. 0.674 [95%CI 0.552-0.797], P < 0.05) and HMW adiponectin (bold black line) (0.806 [95%CI 0.708-0.903] vs. 0.797 [95%CI 0.706-0.888], no statistically difference). Sensitivity, specificity and optimal cut off value for them were total adiponectin (57.38%, 75.86%, 1.11 mg/ml), HMW (55.74%, 93.1%, 0.49 mg/ml) and H/T (78.69%, 75.86%, 0.52), respectively.

There are two strengths in our study. One is the precise Gensini scoring system to carefully evaluate stenosis of coronary artery or branches > 0% diameter as coronary lesion, another is the specific study subjects of EOCAD in a Chinese Han population that is particularly genetically determined and not influenced by racial/ethnic disparities. The limitations of our study lie in the interference of medications such as the effect of lipid lowering drugs on the levels of adiponectin, and cardiovascular risk factors. Smoking is a conventional cardiovascular risk factor, whose interaction with HMW adiponectin level is rarely investigated, but it has been revealed to be associated with HMW adiponectin level in men according to the study from Kawamoto R et al. We did not adjust the result for the pack/year variable in the multivariate logistic regression analysis for the limitation of small sample size of male subjects in our study. The relatively small study sample also restrained our conclusion generalizable to all populations. Future researches in larger study samples and different populations are in need to validate our findings, and to explore the association of smoking with adiponectin in male subgroup analysis, and to investigate the potential mechanisms by which adiponectin affects the progression of coronary atherosclerosis.

In summary, the present study has demonstrated that adiponectin is protective against coronary atherosclerosis onset in EOCAD patients. HMW adiponectin and HMW-total adiponectin ratio show stronger negative associations with the severity of coronary atherosclerosis than total adiponectin does. HMW adiponectin and HMW-total adiponectin ratio are more effective biomarkers for the risk of CAD than total adiponectin.

Berberis aristata combined with Silybum marianum on lipid profile in patients not tolerating statins at high doses

Giuseppe Derosa, Davide Romano, Angela D’Angelo, Pamela Maffioli
Atherosclerosis 239 (2015) 87-92
http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.043

Aim: To evaluate the effects of Berberis aristata combined with Silybum marianum in dyslipidemic patients intolerant to statins at high doses.
Methods: 137 euglycemic, dyslipidemic subjects, with previous adverse events to statins at high doses, were enrolled. Statins were stopped for 1 month (run-in), then they were re-introduced at the half of the previously taken dose. At randomization, patients tolerating the half dose of statin, were assigned to
add placebo or B. aristata/S. marianum 588/105 mg, 1 tablet during the lunch and 1 tablet during the dinner, for six months. We evaluated lipid profile and safety parameters variation at randomization, and after 3, and 6 months.
Results: B. aristata/S. marianum reduced fasting plasma glucose (-9 mg/dl), insulin (-0.7 mU/ml), and HOMA-index (-0.35) levels compared to baseline and also to placebo. Lipid profile did not significantly change after 6 months since the reduction of statin dosage and the introduction of B. aristata/S. marianum, while it worsened in the placebo group both compared to placebo and with active treatment (+23.4 mg/dl for total cholesterol, +19.6 mg/dl for LDL-cholesterol, +23.1 mg/dl for triglycerides with placebo compared to B. aristata/S. marianum). We did not record any variations of safety parameters
in either group. Conclusions: B. aristata/S. marianum can be considered as addition to statins in patients not tolerating high dose of these drugs.

Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are effective medications for reducing the risk of death and future cardiovascular disease. In the latest years, however, statin intolerance (including adverse effects related to quality of life, leading to decisions to decrease or stop the use of an otherwise-beneficial drug) has come to the forefront of clinical concern, whereas the safety of statins has come to be regarded as largely favorable. Statin intolerance is defined as any adverse symptoms, signs, or laboratory abnormalities attributed by the patient or physician to the statin and in most cases perceived by the patient to interfere unacceptably with activities of daily living, leading to a decision to stop or reduce statin therapy. The physician might also decide to stop or reduce statin therapy on the basis of clinical/laboratory assessment [abnormal liver function tests, creatine phosphokinase values (CPK)] suggesting undue risk. Adverse events are more common at higher doses of statins, and often contribute to patients low adherence to treatment. For this reason, researchers are testing alternative strategies for lipid treatment when statin intolerance is recognized. One strategy to reduce the risk of statin-induced adverse events includes using a low-dose of statin combined with nonstatin drugs in order to achieve the goals of therapy. Nonstatin drugs include nutraceuticals; in the latest years relatively large number of dietary supplements and nutraceuticals have been studied for their supposed or demonstrated ability to reduce cholesterolemia in humans, in particular Berberis Aristata, has been studied in randomized clinical trials and proved to be effective in improving lipid profile. In particular, B. aristata acts up-regulating LDL-receptor (LDL-R) expression independent of sterol regulatory element binding proteins, but dependent on extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) activation leading to total cholesterol (TC) and LDL-C reduction of about 30 and 25%, respectively. Hwever, B. aristata is a problem in terms of oral bioavailability, affected by a P-glycoprotein (P-gp) mediated gut extrusion process. P-gp seems to reduce by about 90% the amount of B. aristata able to cross the enterocytes, but the use of a potential P-gp inhibitor could ameliorate its oral poor bioavailability improving its effectiveness. Among the potential Pgp inhibitors, silymarin from S. marianum, an herbal drug used as liver protectant, could be considered a good candidate due to its high safety profile.

Analyzing the results of our study, it can appear, at a first glance, that B. aristata/S. marianum has a neutral effect of lipid profile that did not change during the study after the addition of the nutraceutical combination. This lack of effect, however, is only apparent, because, when we analyzed what happens in placebo group, we observed a worsening of lipid profile after statin dose reduction. In other words, the addition of B. aristata/S. marianum neutralized the worsening of lipid profile observed with placebo after statins dose reduction. These results are in line with what was reported by Kong et al., who evaluated the effects of a combination of berberine and simvastatin in sixty-three outpatients diagnosed with hypercholesterolemia. As compared with monotherapies, the combination showed an improved lipid lowering effect with 31.8% reduction of serum LDL-C, and similar efficacies were observed in the reduction of TC as well as Tg in patients. Considering the results of this study, B. aristata/S. marianum can be considered as addition to statins in patients not tolerating high dose of these drugs.

CETP inhibitors downregulate hepatic LDL receptor and PCSK9 expression in vitro and in vivo through a SREBP2 dependent mechanism

Bin Dong, Amar Bahadur Singh, Chin Fung, Kelvin Kan, Jingwen Liu
Atherosclerosis 235 (2014) 449-462
http://dx.doi.org/10.1016/j.atherosclerosis.2014.05.931

Background: CETP inhibitors block the transfer of cholesteryl ester from HDL-C to VLDL-C and LDL-C, thereby raising HDL-C and lowering LDL-C. In this study, we explored the effect of CETP inhibitors on hepatic LDL receptor (LDLR) and PCSK9 expression and further elucidated the underlying regulatory mechanism. Results: We first examined the effect of anacetrapib (ANA) and dalcetrapib (DAL) on LDLR and PCSK9 expression in hepatic cells in vitro. ANA exhibited a dose-dependent inhibition on both LDLR and PCSK9 expression in CETP-positive HepG2 cells and human primary hepatocytes as well as CETP-negative mouse primary hepatocytes (MPH). Moreover, the induction of LDLR protein expression by rosuvastatin in MPH was blunted by cotreatment with ANA. In both HepG2 and MPH ANA treatment reduced the amount of mature form of SREBP2 (SREBP2-M). In vivo, oral administration of ANA to dyslipidemic C57BL/6J mice at a daily dose of 50 mg/kg for 1 week elevated serum total cholesterol by approximately 24.5% (p < 0.05%) and VLDL-C by 70% (p < 0.05%) with concomitant reductions of serum PCSK9 and liver LDLR/SREBP2-M protein. Finally, we examined the in vitro effect of two other strong CETP inhibitors evacetrapib and torcetrapib on LDLR/PCSK9 expression and observed a similar inhibitory effect as ANA in a concentration range of 1-10 µM. Conclusion: Our study revealed an unexpected off-target effect of CETP inhibitors that reduce the mature form of SREBP2, leading to attenuated transcription of hepatic LDLR and PCSK9. This negative regulation of SREBP pathway by ANA manifested in mice where CETP activity was absent and affected serum cholesterol metabolism.

Effect of Eclipta prostrata on lipid metabolism in hyperlipidemic animals

Yun Zhao, Lu Peng, Wei Lu, Yiqing Wang, Xuefeng Huang, et al.
Experimental Gerontology 62 (2015) 37–44
http://dx.doi.org/10.1016/j.exger.2014.12.017

Eclipta prostrata (Linn.) Linn. is a traditional Chinese medicine and has previously been reported to have hypolipidemic effects. However, its mechanism of action is not well understood. This study was conducted to identify the active fraction of Eclipta, its toxicity, its effect on hyperlipidemia, and its mechanism of action. The ethanol extract (EP) of Eclipta and fractions EPF1–EPF4, obtained by eluting with different concentrations of ethanol from a HPD-450 macroporous resin column chromatography of the EP, were screened in hyperlipidemic mice for lipid lowering activity, and EPF3 was the most active fraction. The LD50 of EPF3 was undetectable because no mice died with administration of EPF3 at 10.4 g/kg. Then, 48 male hamsters were used and randomly assigned to normal chow diet, high-fat diet, high-fat diet with Xuezhikang (positive control) or EPF3 (75, 150 and 250 mg/kg) groups. We evaluated the effects of EPF3 on body weight gain, liver weight gain, serum lipid concentration, antioxidant enzyme activity, and the expression of genes involved in lipid metabolism in hyperlipidemic hamsters. The results showed that EPF3 significantly decreased body-weight gain and liver-weight gain and reduced the serum lipid levels in hyperlipidemic hamsters. EPF3 also increased the activities of antioxidant enzymes; upregulated the mRNA expression of peroxisome proliferator-activated receptor α (PPARα), low density lipoprotein receptor (LDLR), lecithin-cholesterol transferase (LCAT) and scavenger receptor class B type Ι receptor (SR-BI); and down-regulated the mRNA expression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR) in the liver. These results indicate that EPF3 ameliorates hyperlipidemia, in part, by reducing oxidative stress and modulating the transcription of genes involved in lipid metabolism.

Although Eclipta has long been used as a food additive, no studies or reports have clearly shown any liver or kidney toxicity from its use. Therefore, E. prostrata is safe and beneficial for preventing hyperlipidemia in experimental animals and can be used as an alternative medicine for the regulation of dyslipidemia.

Effect of high fiber products on blood lipids and lipoproteins in hamsters

HE Martinez-Floresa, Y Kil Chang, F Martinez-Bustosc, V Sgarbieri
Nutrition Research 24 (2004) 85–93
http://dx.doi.org:/10.1016/S0271-5317(03)00206-9

Serum and liver lipidemic responses in hamsters fed diets containing 2% cholesterol and different dietary fiber sources were studied. The following diets were made from: a) the control diet made from extruded cassava starch (CSH) contained 9.3% cellulose, b) cassava starch extruded with 9.7% resistant starch (CS-RS), c) cassava starch extruded with 9.9% oat fiber (CS-OF), d) the reference diet contained 9.5% cellulose, and no cholesterol was added. Total cholesterol, LDLVLDL-cholesterol and triglycerides were significantly lower (P < 0.05) in serum of hamsters fed on the CS-RS (17.87%, 62.92% and 9.17%, respectively) and CS-OF (15.12%, 67.41% and 18.35%, respectively) diets, as compared to hamster fed with the CSH diet. Similar results were found in the livers of hamsters fed on the CS-RS and CS-OF diets, as compared to hamsters fed with the CSH diet. The diets containing these fibers could be used as active ingredients in human diets to improve the human health.

A new piece in the puzzling effect of n-3 fatty acids on atherosclerosis?

Wilfried Le Goff
Atherosclerosis 235 (2014) 358-362
http://dx.doi.org/10.1016/j.atherosclerosis.2014.03.038

Omega-3 fatty acids (ω-3) FA are reported to be protective against cardiovascular disease (CVD), notably through their beneficial action on atherosclerosis development. In this context dietary intake of long chain marine eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is recommended and randomised trials largely support that EPA and DHA intake is associated with a reduction of CVD. However, mechanisms governing the atheroprotective action of ω-3 FA are still unclear and numerous studies using mouse models conducted so far do not allow to reach a precise view of the cellular and molecular effects of ω-3 FA on atherosclerosis. In the current issue of Atherosclerosis, Chang et al. provide important new information on the anti-atherogenic properties of ω-3 FA by analyzing the incremental replacement of saturated FA by pure fish oil as a source of EPA and DHA in Ldlr -/- mice fed a high fat/high cholesterol diet.

Cardiovascular disease (CVD) is the leading causes of death in the world and is frequently associated with atherosclerosis, a pathology characterized by the accumulation of lipids, mainly cholesterol in the arterial wall. Among major risk factors for CVD, circulating levels of lipids and more especially those originating from diets are closely linked to development of atherosclerosis. In this context, not only cholesterol, but also dietary fatty acids (FA) may appear particularly deleterious in regards to atherosclerosis and associated CVD. However, although saturated fats are proatherogenic, omega-3 fatty acids (ω-3 FA), and more especially long-chain marine eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exert atheroprotective properties through several potential underlying mechanisms. Therefore, the intake of EPA and DHA is recommended around the world and randomised trials with ω-3 FA confirmed that EPA and DHA intake reduced risk for CVD events. However benefits of ω-3 FA intake were challenged by recent clinical trials that failed to replicate protective effects of EPA + DHA on CVD, raising the controversy on the healthy side of marine ω-3 FA.

Animal models are commonly employed in order to decipher mechanisms by which ω-3 FA exert their beneficial actions regarding lipid metabolism and atherosclerosis. Since the last past 20 years, mouse models, and more especially genetically modified mouse models, became the reference model to evaluate the effects of dietary fatty acids, especially ω-3 FA, on atherosclerosis development [7-20]. However, the use of different mouse models of atherosclerosis (Apoe-/-, Ldlr-/-, double Apoe-/- x Ldlr-/- , Ldlr-/- x hApoB mice), as well as diet composition (chow, high cholesterol, high fat, high cholesterol/high fat), source of ω-3 FA supplementation (fish oil, perilla seed oil, flaxseed, pure ALA, EPA or DHA), duration of the diet (from 4 to 32 weeks), size of atherosclerotic lesions in control animals (from 51 to 700.103 mm2) in

those studies led to heterogeneous results and therefore to a partial understanding of the effects of ω-3 FA on atherosclerosis.

Contrary to what observed in Apoe-/- mice, dietary supplementation of Ldlr-/- mice with ω-3 FA led to a reproducible reduction of aortic atherosclerosis, although to various degrees, confirming that Ldlr-/- mice constitute the most appropriate model for studying the atheroprotective effects of ω-3 FA. When evaluated, the decrease of atherosclerosis upon ω-3 FA-rich diet was accompanied by a reduction in the macrophage content as well as inflammation in aortic lesions highlighting the major impact of ω-3 FA on monocyte recruitment and subsequent macrophage accumulation in the arterial wall. However, although supplementation with ω-3 FA allows an efficacious lowering of plasma lipid levels in humans, studies in mouse models suggest that the antiatherogenic action of ω-3 FA is independent of any effects on plasma cholesterol or triglyceride levels. However, that must be asserted with caution as lipid metabolism is quite different in mouse in comparison to humans, highlighting the need to study in the future the effects of ω-3 FA on atherosclerosis in a mouse model exhibiting a more “humanized” lipid metabolism as achieved in hApoB/CETP mice.

In a previous issue of Atherosclerosis, Chang et al. reevaluate the impact of fish oil ω-3 FA on atherosclerosis development by operating an incremental replacement of saturated fats (SAT) by ω-3 FA (pure fish oil, EPA- and DHA-rich) in Ldlr-/- mice fed a high-fat (21%, w/w)/high-cholesterol (0.2%, w/w) diet for a 12-week period. This experimental approach is quite pertinent as dietary fat intake in developed countries, as in United States, derived mostly from saturated FA and is poor in ω-3 FA. Then, using this strategy the authors were able to evaluate the potential beneficial effects of a supplementation with fish oil ω-3 FA in a dietary context for which ω-3 FA intake is relevant.

Here, Chang et al. demonstrated that the progressive increase of dietary intake of fish oil ω-3 FA (EPA and DHA) abrogated the deleterious effects of a SAT diet, thereby suggesting that a dietary ω-3 FA intake on a SAT background is potentially efficient to decrease CVD in humans. Indeed, replacement of SAT by fish oil ω-3 FA markedly reduced plasma cholesterol and triglycerides levels and abolished diet-induced atherosclerosis mediated by SAT in Ldlr-/-mice. To note that in the present study, Ldlr-/- mice only developed small atherosclerosic lesions (~100.103 mm2) after 12 weeks of diet with SAT.

As previously reported, decreased atherosclerotic lesions were accompanied by a reduced content of aortic macrophages and inflammation. Based on their previous works, the authors proposed that the reduction of atherosclerosis upon ω-3 FA resulted from an impairment of cholesterol uptake by arterial macrophages consecutive to the decrease of Lipoprotein Lipase (LPL) expression in those cells. Indeed, beyond its lipolysis action on triglycerides, LPL was reported to promote lipid accumulation, in particular in macrophages, by binding to lipoproteins and cell surface proteoglycans and then acting as a bridging molecule that facilitates cellular lipid uptake. Coherent with this mechanism, macrophage LPL expression was reported to promote foam cell formation and atherosclerosis. In the present study, replacement of SAT by ω-3 FA both decreased expression and altered distribution of arterial LPL. Such a mechanism for ω-3 FA (EPA and DHA) was proposed by this group in earlier studies to favor reduction of arterial LDL-cholesterol. It is noteworthy that lipid rafts alter distribution of LPL at the cell surface and subsequently the LPL dependent accumulation of lipids in macrophages and foam cell formation. As incorporation of ω-3 FA, such as DHA, into cell membrane phospholipids disrupts lipid rafts organization, it cannot be exclude that reduction of lipid accumulation in arterial macrophages upon addition of ω-3 FA results in part from an impairment of the localization and of the anchoring function of LPL at the cell surface of macrophages. Indeed Chang et al. observed that progressive replacement of SAT by ω-3 FA affected aortic FA composition leading to a pronounced increase of arterial EPA and DHA, then suggesting that content of ω-3 FA in macrophage membrane may be equally altered. However, the implication of LPL in the atheroprotective effects of ω-3 FA need to be validated using an appropriate mouse model for which LPL expression may be controlled.

Among the various mechanisms by which ω-3 FA exert anti-inflammatory properties, EPA and DHA repressed inflammation by shutting down NF-kB activation in macrophages. Since expression of TLR-4 and NF-kB target genes, IL-6 and TNFα, in aorta from mice fed diets containing ω-3 FA were decreased when compared to SAT, those results strongly support the contention that ω-3 FA repress inflammation by inhibiting the TLR4/NF-kB signaling cascade likely through the macrophage ω-3 FA receptor GPR120.

Although further studies are needed to explore the complete spectrum of actions of ω-3 FA on atherosclerosis development and CVD, this study provides important information that supports that ω-3 FA intake is a pertinent strategy to reduce risk of CVD.

Effects of dietary hull-less barley β-glucan on the cholesterol metabolism of hypercholesterolemic hamsters

Li-Tao Tong, Kui Zhong, Liya Liu, Xianrong Zhou, Ju Qiu, Sumei Zhou
Food Chemistry 169 (2015) 344–349
http://dx.doi.org/10.1016/j.foodchem.2014.07.157

The aim of the present study is to investigate the hypocholesterolemic effects of dietary hull-less barley β-glucan (HBG) on cholesterol metabolism in hamsters which were fed a hypercholesterolemic diet. The hamsters were divided into 3 groups and fed experimental diets, containing 5‰ HBG or 5‰ oat β-glucan (OG), for 30 days. The HBG, as well as OG, lowered the concentration of plasma LDL-cholesterol significantly. The excretion of total lipids and cholesterol in feces were increased in HBG and OG groups compared with the control group. The activity of 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) reductase in liver was reduced significantly in the HBG group compared with the control and OG groups. The activity of cholesterol 7-α hydroxylase (CYP7A1) in the liver, in the HBG and OG groups, was significantly increased compared with the control group. The concentrations of acetate, propionate and total short chain fatty acids (SCFAs) were not significantly different between the HBG and control groups. These results indicate that dietary HBG reduces the concentration of plasma LDL cholesterol by promoting the excretion of fecal lipids, and regulating the activities of HMG-CoA reductase and CYP7A1 in hypercholesterolemic hamsters.

Effects of dietary wheat bran arabinoxylans on cholesterolmetabolism of hypercholesterolemic hamsters

Li-Tao Tong, Kui Zhong, Liya Liu, Ju Qiu, Lina Guo, et al.
Carbohydrate Polymers 112 (2014) 1–5
http://dx.doi.org/10.1016/j.carbpol.2014.05.061

The aim of the present study is to investigate the effects of dietary wheat bran arabinoxylans (AXs) on cholesterol metabolism in hypercholesterolemic hamsters. The hamsters were divided into 3 groups and fed the experimental diets containing AXs or oat β-glucan at a dose of 5 g/kg for 30 days. As the results,the AXs lowered plasma total cholesterol and LDL-cholesterol concentrations, and increased excretions of total lipids, cholesterol and bile acids, as well as oat β-glucan. The AXs reduced the activity of 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) reductase, and increased the activity of cholesterol 7-α hydroxylase (CYP7A1) in liver. Moreover, the AXs increased propionate and the total short-chain fatty acids (SCFAs) concentrations. These results indicated that dietary AXs reduced the plasma total cholesterol and LDL-cholesterol concentrations by promoting the excretion of fecal lipids, regulating the activities of HMG-CoA reductase and CYP7A1, and increasing colonic SCFAs in hamsters.

High-fructose feeding promotes accelerated degradation of hepatic LDL receptor and hypercholesterolemia in hamsters via elevated circulating PCSK9 levels

Bin Dong, Amar Bahadur Singh, Salman Azhar, Nabil G. Seidah, Jingwen Liu
Atherosclerosis 239 (2015) 364-374
http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.013

Background: High fructose diet (HFD) induces dyslipidemia and insulin resistance in experimental animals and humans with incomplete mechanistic understanding. By utilizing mice and hamsters as in vivo models, we investigated whether high fructose consumption affects serum PCSK9 and liver LDL receptor (LDLR) protein levels. Results: Feeding mice with an HFD increased serum cholesterol and reduced serum PCSK9 levels as compared with the mice fed a normal chow diet (NCD). In contrast to the inverse relationship in mice, serum PCSK9 and cholesterol levels were co-elevated in HFD-fed hamsters. Liver tissue analysis revealed that PCSK9 mRNA and protein levels were both reduced in mice and hamsters by HFD feeding, however, liver LDLR protein levels were markedly reduced by HFD in hamsters but not in mice. We further showed that circulating PCSK9 clearance rates were significantly lower in hamsters fed an HFD as compared with the hamsters fed NCD, providing additional evidence for the reduced hepatic LDLR function by HFD consumption. The majority of PCSK9 in hamster serum was detected as a 53 kDa N-terminus cleaved protein. By conducting in vitro studies, we demonstrate that this 53 kDa truncated hamster PCSK9 is functionally active in promoting hepatic LDLR degradation. Conclusion: Our studies for the first time demonstrate that high fructose consumption increases serum PCSK9 concentrations and reduces liver LDLR protein levels in hyper-lipidemic hamsters. The positive correlation between circulating cholesterol and PCSK9 and the reduction of liver LDLR protein in HFD-fed hamsters suggest that hamster is a better animal model than mouse to study the modulation of PCSK9/LDLR pathway by atherogenic diets.

High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans

Peter J.H. Jones, Dylan S. MacKay, Vijitha K. Senanayake, Shuaihua Pu, et al.
Atherosclerosis 238 (2015) 231-238
http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.010

Oleic acid consumption is considered cardio-protective according to studies conducted examining effects of the Mediterranean diet. However, animal models have shown that oleic acid consumption increases LDL particle cholesteryl oleate content which is associated with increased LDL-proteoglycan binding and atherosclerosis. The objective was to examine effects of varying oleic, linoleic and docosahexaenoic acid consumption on human LDL-proteoglycan binding in a non-random subset of the Canola Oil Multi-center Intervention Trial (COMIT) participants. COMIT employed a randomized, double-blind, five-period, crossover trial design. Three of the treatment oil diets: 1) a blend of corn/safflower oil (25:75); 2) high oleic canola oil; and 3) DHA-enriched high oleic canola oil were selected for analysis of LDL-proteoglycan binding in 50 participants exhibiting good compliance. LDL particles were isolated from frozen plasma by gel filtration chromatography and LDL cholesteryl esters quantified by mass-spectrometry. LDL-proteoglycan binding was assessed using surface plasmon resonance. LDL particle cholesterol ester fatty acid composition was sensitive to the treatment fatty acid compositions, with the main fatty acids in the treatments increasing in the LDL cholesterol esters. The corn/safflower oil and high-oleic canola oil diets lowered LDL-proteoglycan binding relative to their baseline values (p < 0.0005 and p < 0.0012, respectively). At endpoint, high-oleic canola oil feeding resulted in lower LDL-proteoglycan binding than corn/safflower oil (p < 0.0243) and DHA-enriched high oleic canola oil (p < 0.0249), although high-oleic canola oil had the lowest binding at baseline (p < 0.0344). Our findings suggest that high-oleic canola oil consumption in humans increases cholesteryl oleate percentage in LDL, but in a manner not associated with a rise in LDL-proteoglycan binding.

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Lipid Metabolism


Lipid Metabolism

Reporter and Curator: Larry H. Bernstein, MD, FCAP 

 

This is fourth of a series of articles, lipid metabolism, that began with signaling and signaling pathways. These discussion lay the groundwork to proceed in later discussions that will take on a somewhat different approach. These are critical to develop a more complete point of view of life processes.  I have indicated that many of the protein-protein interactions or protein-membrane interactions and associated regulatory features have been referred to previously, but the focus of the discussion or points made were different.  The role of lipids in circulating plasma proteins as biomarkers for coronary vascular disease can be traced to the early work of Frederickson and the classification of lipid disorders.  The very critical role of lipids in membrane structure in health and disease has had much less attention, despite the enormous importance, especially in the nervous system.

  1. Signaling and signaling pathways
  2. Signaling transduction tutorial.
  3. Carbohydrate metabolism

3.1  Selected References to Signaling and Metabolic Pathways in Leaders in Pharmaceutical Intelligence

  1. Lipid metabolism
  2. Protein synthesis and degradation
  3. Subcellular structure
  4. Impairments in pathological states: endocrine disorders; stress hypermetabolism; cancer.

 

Lipid Metabolism

http://www.elmhurst.edu/~chm/vchembook/622overview.html

Overview of Lipid Catabolism:

The major aspects of lipid metabolism are involved with

  • Fatty Acid Oxidationto produce energy or
  • the synthesis of lipids which is called Lipogenesis.

The metabolism of lipids and carbohydrates are related by the conversion of lipids from carbohydrates. This can be seen in the diagram. Notice the link through actyl-CoA, the seminal discovery of Fritz Lipmann. The metabolism of both is upset by diabetes mellitus, which results in the release of ketones (2/3 betahydroxybutyric acid) into the circulation.

 

metabolism of fats

metabolism of fats

 

http://www.elmhurst.edu/~chm/vchembook/images/590metabolism.gif

The first step in lipid metabolism is the hydrolysis of the lipid in the cytoplasm to produce glycerol and fatty acids.

Since glycerol is a three carbon alcohol, it is metabolized quite readily into an intermediate in glycolysis, dihydroxyacetone phosphate. The last reaction is readily reversible if glycerol is needed for the synthesis of a lipid.

The hydroxyacetone, obtained from glycerol is metabolized into one of two possible compounds. Dihydroxyacetone may be converted into pyruvic acid, a 3-C intermediate at the last step of glycolysis to make energy.

In addition, the dihydroxyacetone may also be used in gluconeogenesis (usually dependent on conversion of gluconeogenic amino acids) to make glucose-6-phosphate for glucose to the blood or glycogen depending upon what is required at that time.

Fatty acids are oxidized to acetyl CoA in the mitochondria using the fatty acid spiral. The acetyl CoA is then ultimately converted into ATP, CO2, and H2O using the citric acid cycle and the electron transport chain.

There are two major types of fatty acids – ω-3 and ω-6.  There are also saturated and unsaturated with respect to the existence of double bonds, and monounsaturated and polyunsatured.  Polyunsaturated fatty acids (PUFAs) are important in long term health, and it will be seen that high cardiovascular risk is most associated with a low ratio of ω-3/ω-6, the denominator being from animal fat. Ω-3 fatty acids are readily available from fish, seaweed, and flax seed. More can be said of this later.

Fatty acids are synthesized from carbohydrates and occasionally from proteins. Actually, the carbohydrates and proteins have first been catabolized into acetyl CoA. Depending upon the energy requirements, the acetyl CoA enters the citric acid cycle or is used to synthesize fatty acids in a process known as LIPOGENESIS.

The relationships between lipid and carbohydrate metabolism are
summarized in Figure 2.

 

fattyacidspiral

fattyacidspiral

http://www.elmhurst.edu/~chm/vchembook/images/620fattyacidspiral.gif

 

 Energy Production Fatty Acid Oxidation:

Visible” ATP:

In the fatty acid spiral, there is only one reaction which directly uses ATP and that is in the initiating step. So this is a loss of ATP and must be subtracted later.

A large amount of energy is released and restored as ATP during the oxidation of fatty acids. The ATP is formed from both the fatty acid spiral and the citric acid cycle.

 

Connections to Electron Transport and ATP:

One turn of the fatty acid spiral produces ATP from the interaction of the coenzymes FAD (step 1) and NAD+ (step 3) with the electron transport chain. Total ATP per turn of the fatty acid spiral is:

Electron Transport Diagram – (e.t.c.)

Step 1 – FAD into e.t.c. = 2 ATP
Step 3 – NAD+ into e.t.c. = 3 ATP
Total ATP per turn of spiral = 5 ATP

In order to calculate total ATP from the fatty acid spiral, you must calculate the number of turns that the spiral makes. Remember that the number of turns is found by subtracting one from the number of acetyl CoA produced. See the graphic on the left bottom.

Example with Palmitic Acid = 16 carbons = 8 acetyl groups

Number of turns of fatty acid spiral = 8-1 = 7 turns

ATP from fatty acid spiral = 7 turns and 5 per turn = 35 ATP.

This would be a good time to remember that single ATP that was needed to get the fatty acid spiral started. Therefore subtract it now.

NET ATP from Fatty Acid Spiral = 35 – 1 = 34 ATP

Review ATP Summary for Citric Acid Cycle:The acetyl CoA produced from the fatty acid spiral enters the citric acid cycle. When calculating ATP production, you have to show how many acetyl CoA are produced from a given fatty acid as this controls how many “turns” the citric acid cycle makes.Starting with acetyl CoA, how many ATP are made using the citric acid cycle? E.T.C = electron transport chain

 Step  ATP produced
7  1
Step 4 (NAD+ to E.T.C.) 3
Step 6 (NAD+ to E.T.C.)  3
Step10 (NAD+ to E.T.C.)  3
Step 8 (FAD to E.T.C.) 2
 NET 12 ATP

 

 

 ATP Summary for Palmitic Acid – Complete Metabolism:The phrase “complete metabolism” means do reactions until you end up with carbon dioxide and water. This also means to use fatty acid spiral, citric acid cycle, and electron transport as needed.Starting with palmitic acid (16 carbons) how many ATP are made using fatty acid spiral? This is a review of the above panel E.T.C = electron transport chain

 Step  ATP (used -) (produced +)
Step 1 (FAD to E.T.C.) +2
Step 4 (NAD+ to E.T.C.) +3
Total ATP  +5
 7 turns  7 x 5 = 35
initial step  -1
 NET  34 ATP

The fatty acid spiral ends with the production of 8 acetyl CoA from the 16 carbon palmitic acid.

Starting with one acetyl CoA, how many ATP are made using the citric acid cycle? Above panel gave the answer of 12 ATP per acetyl CoA.

E.T.C = electron transport chain

 Step  ATP produced
One acetyl CoA per turn C.A.C. +12 ATP
8 Acetyl CoA = 8 turns C.A.C. 8 x 12 = 96 ATP
Fatty Acid Spiral 34 ATP
GRAND TOTAL  130 ATP

 

Fyodor Lynen

Feodor Lynen was born in Munich on 6 April 1911, the son of Wilhelm Lynen, Professor of Mechanical Engineering at the Munich Technische Hochschule. He received his Doctorate in Chemistry from Munich University under Heinrich Wieland, who had won the Nobel Prize for Chemistry in 1927, in March 1937 with the work: «On the Toxic Substances in Amanita». in 1954 he became head of the Max-Planck-Institut für Zellchemie, newly created for him as a result of the initiative of Otto Warburg and Otto Hahn, then President of the Max-Planck-Gesellschaft zur Förderung der Wissenschaften.

Lynen’s work was devoted to the elucidation of the chemical details of metabolic processes in living cells, and of the mechanisms of metabolic regulation. The problems tackled by him, in conjunction with German and other workers, include the Pasteur effect, acetic acid degradation in yeast, the chemical structure of «activated acetic acid» of «activated isoprene», of «activated carboxylic acid», and of cytohaemin, degradation of fatty acids and formation of acetoacetic acid, degradation of tararic acid, biosynthesis of cysteine, of terpenes, of rubber, and of fatty acids.

In 1954 Lynen received the Neuberg Medal of the American Society of European Chemists and Pharmacists, in 1955 the Liebig Commemorative Medal of the Gesellschaft Deutscher Chemiker, in 1961 the Carus Medal of the Deutsche Akademie der Naturforscher «Leopoldina», and in 1963 the Otto Warburg Medal of the Gesellschaft für Physiologische Chemie. He was also a member of the U>S> National Academy of Sciences, and shared the Nobel Prize in Physiology and Medicine with Konrad Bloch in 1964, and was made President of the Gesellschaft Deutscher Chemiker (GDCh) in 1972.

This biography was written at the time of the award and first published in the book series Les Prix Nobel. It was later edited and republished in Nobel Lectures, and shortened by myself.

The Pathway from “Activated Acetic Acid” to the Terpenes and Fatty Acids

My first contact with dynamic biochemistry in 1937 occurred at an exceedingly propitious time. The remarkable investigations on the enzyme chain of respiration, on the oxygen-transferring haemin enzyme of respiration, the cytochromes, the yellow enzymes, and the pyridine proteins had thrown the first rays of light on the chemical processes underlying the mystery of biological catalysis, which had been recognised by your famous countryman Jöns Jakob Berzelius. Vitamin B2 , which is essential to the nourishment of man and of animals, had been recognised by Hugo Theorell in the form of the phosphate ester as the active group of an important class of enzymes, and the fermentation processes that are necessary for Pasteur’s “life without oxygen”

had been elucidated as the result of a sequence of reactions centered around “hydrogen shift” and “phosphate shift” with adenosine triphosphate as the phosphate-transferring coenzyme. However, 1,3-diphosphoglyceric acid, the key substance to an understanding of the chemical relation between oxidation and phosphorylation, still lay in the depths of the unknown. Never-

theless, Otto Warburg was on its trail in the course of his investigations on the fermentation enzymes, and he was able to present it to the world in 1939.

 

This was the period in which I carried out my first independent investigation, which was concerned with the metabolism of yeast cells after freezing in liquid air, and which brought me directly into contact with the mechanism of alcoholic fermentation. This work taught me a great deal, and yielded two important pieces of information.

 

  • The first was that in experiments with living cells, special attention must be given to the permeability properties of the cell membranes, and
  • the second was that the adenosine polyphosphate system plays a vital part in the cell,
    • not only in energy transfer, but
    • also in the regulation of the metabolic processes.

 

.

This investigation aroused by interest in problems of metabolic regulation, which led me to the investigation of the Pasteur effects, and has remained with me to the present day.

 

My subsequent concern with the problem of the acetic acid metabolism arose from my stay at Heinrich Wieland’s laboratory. Workers here had studied the oxidation of acetic acid by yeast cells, and had found that though most of the acetic acid undergoes complete oxidation, some remains in the form of succinic and citric acids.

 

The explanation of these observations was provided-by the Thunberg-Wieland process, according to which two molecules of acetic acid are dehydrogenated to succinic acid, which is converted back into acetic acid via oxaloacetic acid, pyruvic acid, and acetaldehyde, or combines at the oxaloacetic acid stage with a further molecule of acetic acid to form citric acid (Fig. 1). However, an experimental check on this view by a Wieland’s student Robert Sonderhoffs brought a surprise. The citric acid formed when trideuteroacetic acid was supplied to yeast cells contained the expected quantity of deuterium, but the succinic acid contained only half of the four deuterium atoms required by Wieland’s scheme.

 

This investigation aroused by interest in problems of metabolic regulation, which led me to the investigation of the Pasteur effects, and has remained with me to the present day. My subsequent concern with the problem of the acetic acid metabolism arose from my stay at Heinrich Wieland’s laboratory. Workers here had studied the oxidation of acetic acid by yeast cells, and had found that though most of the acetic acid undergoes complete oxidation, some remains in the form of succinic and citric acid

The answer provided by Martius was that citric acid  is in equilibrium with isocitric acid and is oxidised to cr-ketoglutaric acid, the conversion of which into succinic acid had already been discovered by Carl Neuberg (Fig. 1).

It was possible to assume with fair certainty from these results that the succinic acid produced by yeast from acetate is formed via citric acid. Sonderhoff’s experiments with deuterated acetic acid led to another important discovery.

In the analysis of the yeast cells themselves, it was found that while the carbohydrate fraction contained only insignificant quantities of deuterium, large quantities of heavy hydrogen were present in the fatty acids formed and in the sterol fraction. This showed that

  • fatty acids and sterols were formed directly from acetic acid, and not indirectly via the carbohydrates.

As a result of Sonderhoff’s early death, these important findings were not pursued further in the Munich laboratory.

  • This situation was elucidated only by Konrad Bloch’s isotope experiments, on which he reports.

My interest first turned entirely to the conversion of acetic acid into citric acid, which had been made the focus of the aerobic degradation of carbohydrates by the formulation of the citric acid cycle by Hans Adolf Krebs. Unlike Krebs, who regarded pyruvic acid as the condensation partner of acetic acid,

  • we were firmly convinced, on the basis of the experiments on yeast, that pyruvic acid is first oxidised to acetic acid, and only then does the condensation take place.

Further progress resulted from Wieland’s observation that yeast cells that had been “impoverished” in endogenous fuels by shaking under oxygen were able to oxidise added acetic acid only after a certain “induction period” (Fig. 2). This “induction period” could be shortened by addition of small quantities of a readily oxidisable substrate such as ethyl alcohol, though propyl and butyl alcohol were also effective. I explained this by assuming that acetic acid is converted, at the expense of the oxidation of the alcohol, into an “activated acetic acid”, and can only then condense with oxalacetic acid.

In retrospect, we find that I had come independently on the same group of problems as Fritz Lipmann, who had discovered that inorganic phosphate is indispensable to the oxidation of pyruvic acid by lactobacilli, and had detected acetylphosphate as an oxidation product. Since this anhydride of acetic acid and phosphoric acid could be assumed to be the “activated acetic acid”.

I learned of the advances that had been made in the meantime in the investigation of the problem of “activated acetic acid”. Fritz Lipmann has described the development at length in his Nobel Lecture’s, and I need not repeat it. The main advance was the recognition that the formation of “activated acetic acid” from acetate involved not only ATP as an energy source, but also the newly discovered coenzyme A, which contains the vitamin pantothenic acid, and that “activated acetic acid” was probably an acetylated coenzyme  A.

http://www.nobelprize.org/nobel_prizes/medicine/laureates/1964/lynen-bio.html

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Fyodor Lynen

Lynen’s most important research at the University of Munich focused on intermediary metabolism, cholesterol synthesis, and fatty acid biosynthesis. Metabolism involves all the chemical processes by which an organism converts matter and energy into forms that it can use. Metabolism supplies the matter—the molecular building blocks an organism needs for the growth of new tissues. These building blocks must either come from the breakdown of molecules of food, such as glucose (sugar) and fat, or be built up from simpler molecules within the organism.

Cholesterol is one of the fatty substances found in animal tissues. The human body produces cholesterol, but this substance also enters the body in food. Meats, egg yolks, and milk products, such as butter and cheese, contain cholesterol. Such organs as the brain and liver contain much cholesterol. Cholesterol is a type of lipid, one of the classes of chemical compounds essential to human health. It makes up an important part of the membranes of each cell in the body. The body also uses cholesterol to produce vitamin D and certain hormones.

All fats are composed of an alcohol called glycerol and substances called fatty acids. A fatty acid consists of a long chain of carbon atoms, to which hydrogen atoms are attached. There are three types of fatty acids: saturated, monounsaturated, and polyunsaturated.

Living cells manufacture complicated chemical compounds from simpler substances through a process called biosynthesis. For example, simple molecules called amino acids are put together to make proteins. The biosynthesis of both fatty acids and cholesterol begins with a chemically active form of acetate, a two-carbon molecule. Lynen discovered that the active form of acetate is a coenzyme, a heat-stabilized, water-soluble portion of an enzyme, called acetyl coenzyme A. Lynen and his colleagues demonstrated that the formation of cholesterol begins with the condensation of two molecules of acetyl coenzyme A to form acetoacetyl coenzyme A, a four-carbon molecule.

http://science.howstuffworks.com/dictionary/famous-scientists/biologists/feodor-lynen-info.htm

Fyodor Lynen

Fyodor Lynen

 

SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver

Jay D. Horton1,2, Joseph L. Goldstein1 and Michael S. Brown1

1Department of Molecular Genetics, and
2Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA

J Clin Invest. 2002;109(9):1125–1131.
http://dx.doi.org:/10.1172/JCI15593
Lipid homeostasis in vertebrate cells is regulated by a family of membrane-bound transcription factors designated sterol regulatory element–binding proteins (SREBPs). SREBPs directly activate the expression of more than 30 genes dedicated to the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids, as well as the NADPH cofactor required to synthesize these molecules (14). In the liver, three SREBPs regulate the production of lipids for export into the plasma as lipoproteins and into the bile as micelles. The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice. These studies form the subject of this review.

SREBPs: activation through proteolytic processing

SREBPs belong to the basic helix-loop-helix–leucine zipper (bHLH-Zip) family of transcription factors, but they differ from other bHLH-Zip proteins in that they are synthesized as inactive precursors bound to the endoplasmic reticulum (ER) (1, 5). Each SREBP precursor of about 1150 amino acids is organized into three domains: (a) an NH2-terminal domain of about 480 amino acids that contains the bHLH-Zip region for binding DNA; (b) two hydrophobic transmembrane–spanning segments interrupted by a short loop of about 30 amino acids that projects into the lumen of the ER; and (c) a COOH-terminal domain of about 590 amino acids that performs the essential regulatory function described below.

In order to reach the nucleus and act as a transcription factor, the NH2-terminal domain of each SREBP must be released from the membrane proteolytically (Figure 1). Three proteins required for SREBP processing have been delineated in cultured cells, using the tools of somatic cell genetics (see ref. 5for review). One is an escort protein designated SREBP cleavage–activating protein (SCAP). The other two are proteases, designated Site-1 protease (S1P) and Site-2 protease (S2P). Newly synthesized SREBP is inserted into the membranes of the ER, where its COOH-terminal regulatory domain binds to the COOH-terminal domain of SCAP (Figure 1).

 

Figure 1

Model for the sterol-mediated proteolytic release of SREBPs from membranes JCI0215593.f1

Model for the sterol-mediated proteolytic release of SREBPs from membranes JCI0215593.f1

 

Model for the sterol-mediated proteolytic release of SREBPs from membranes. SCAP is a sensor of sterols and an escort of SREBPs. When cells are depleted of sterols, SCAP transports SREBPs from the ER to the Golgi apparatus, where two proteases, Site-1 protease (S1P) and Site-2 protease (S2P), act sequentially to release the NH2-terminal bHLH-Zip domain from the membrane. The bHLH-Zip domain enters the nucleus and binds to a sterol response element (SRE) in the enhancer/promoter region of target genes, activating their transcription. When cellular cholesterol rises, the SCAP/SREBP complex is no longer incorporated into ER transport vesicles, SREBPs no longer reach the Golgi apparatus, and the bHLH-Zip domain cannot be released from the membrane. As a result, transcription of all target genes declines. Reprinted from ref. 5 with permission.

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SCAP is both an escort for SREBPs and a sensor of sterols. When cells become depleted in cholesterol, SCAP escorts the SREBP from the ER to the Golgi apparatus, where the two proteases reside. In the Golgi apparatus, S1P, a membrane-bound serine protease, cleaves the SREBP in the luminal loop between its two membrane-spanning segments, dividing the SREBP molecule in half (Figure 1). The NH2-terminal bHLH-Zip domain is then released from the membrane via a second cleavage mediated by S2P, a membrane-bound zinc metalloproteinase. The NH2-terminal domain, designated nuclear SREBP (nSREBP), translocates to the nucleus, where it activates transcription by binding to nonpalindromic sterol response elements (SREs) in the promoter/enhancer regions of multiple target genes.

 

Figure 1

 

When the cholesterol content of cells rises, SCAP senses the excess cholesterol through its membranous sterol-sensing domain, changing its conformation in such a way that the SCAP/SREBP complex is no longer incorporated into ER transport vesicles. The net result is that SREBPs lose their access to S1P and S2P in the Golgi apparatus, so their bHLH-Zip domains cannot be released from the ER membrane, and the transcription of target genes ceases (1, 5). The biophysical mechanism by which SCAP senses sterol levels in the ER membrane and regulates its movement to the Golgi apparatus is not yet understood. Elucidating this mechanism will be fundamental to understanding the molecular basis of cholesterol feedback inhibition of gene expression.

SREBPs: two genes, three proteins

The mammalian genome encodes three SREBP isoforms, designated SREBP-1a, SREBP-1c, and SREBP-2. SREBP-2 is encoded by a gene on human chromosome 22q13. Both SREBP-1a and -1c are derived from a single gene on human chromosome 17p11.2 through the use of alternative transcription start sites that produce alternate forms of exon 1, designated 1a and 1c (1). SREBP-1a is a potent activator of all SREBP-responsive genes, including those that mediate the synthesis of cholesterol, fatty acids, and triglycerides. High-level transcriptional activation is dependent on exon 1a, which encodes a longer acidic transactivation segment than does the first exon of SREBP-1c. The roles of SREBP-1c and SREBP-2 are more restricted than that of SREBP-1a. SREBP-1c preferentially enhances transcription of genes required for fatty acid synthesis but not cholesterol synthesis. Like SREBP-1a, SREBP-2 has a long transcriptional activation domain, but it preferentially activates cholesterol synthesis (1). SREBP-1a and SREBP-2 are the predominant isoforms of SREBP in most cultured cell lines, whereas SREBP-1c and SREBP-2 predominate in the liver and most other intact tissues (6).

When expressed at higher than physiologic levels, each of the three SREBP isoforms can activate all enzymes indicated in Figure 2, which shows the biosynthetic pathways used to generate cholesterol and fatty acids. However, at normal levels of expression, SREBP-1c favors the fatty acid biosynthetic pathway and SREBP-2 favors cholesterologenesis. SREBP-2–responsive genes in the cholesterol biosynthetic pathway include those for the enzymes HMG-CoA synthase, HMG-CoA reductase, farnesyl diphosphate synthase, and squalene synthase. SREBP-1c–responsive genes include those for ATP citrate lyase (which produces acetyl-CoA) and acetyl-CoA carboxylase and fatty acid synthase (which together produce palmitate [C16:0]). Other SREBP-1c target genes encode a rate-limiting enzyme of the fatty acid elongase complex, which converts palmitate to stearate (C18:0) (ref.7); stearoyl-CoA desaturase, which converts stearate to oleate (C18:1); and glycerol-3-phosphate acyltransferase, the first committed enzyme in triglyceride and phospholipid synthesis (3). Finally, SREBP-1c and SREBP-2 activate three genes required to generate NADPH, which is consumed at multiple stages in these lipid biosynthetic pathways (8) (Figure 2).

 

Figure 2

 

major metabolic intermediates in the pathways for synthesis of cholesterol, fatty acids, and triglycerides JCI0215593.f2

major metabolic intermediates in the pathways for synthesis of cholesterol, fatty acids, and triglycerides JCI0215593.f2

 

 

 

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Genes regulated by SREBPs. The diagram shows the major metabolic intermediates in the pathways for synthesis of cholesterol, fatty acids, and triglycerides. In vivo, SREBP-2 preferentially activates genes of cholesterol metabolism, whereas SREBP-1c preferentially activates genes of fatty acid and triglyceride metabolism. DHCR, 7-dehydrocholesterol reductase; FPP, farnesyl diphosphate; GPP, geranylgeranyl pyrophosphate synthase; CYP51, lanosterol 14α-demethylase; G6PD, glucose-6-phosphate dehydrogenase; PGDH, 6-phosphogluconate dehydrogenase; GPAT, glycerol-3-phosphate acyltransferase.

Genes regulated by SREBPs. The diagram shows the major metabolic intermediates in the pathways for synthesis of cholesterol, fatty acids, and triglycerides. In vivo, SREBP-2 preferentially activates genes of cholesterol metabolism, whereas SREBP-1c preferentially activates genes of fatty acid and triglyceride metabolism. DHCR, 7-dehydrocholesterol reductase; FPP, farnesyl diphosphate; GPP, geranylgeranyl pyrophosphate synthase; CYP51, lanosterol 14α-demethylase; G6PD, glucose-6-phosphate dehydrogenase; PGDH, 6-phosphogluconate dehydrogenase; GPAT, glycerol-3-phosphate acyltransferase.

Knockout and transgenic mice

Ten different genetically manipulated mouse models that either lack or overexpress a single component of the SREBP pathway have been generated in the last 6 years (916). The key molecular and metabolic alterations observed in these mice are summarized in Table 1.

 

Table 1
Alterations in hepatic lipid metabolism in gene-manipulated mice overexpressing or lacking SREBPs

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Knockout mice that lack all nSREBPs die early in embryonic development. For instance, a germline deletion of S1p, which prevents the processing of all SREBP isoforms, results in death before day 4 of development (15, 17). Germline deletion of Srebp2 leads to 100% lethality at a later stage of embryonic development than does deletion of S1p (embryonic day 7–8). In contrast, germline deletion of Srebp1, which eliminates both the 1a and the 1c transcripts, leads to partial lethality, in that about 15–45% of Srebp1–/– mice survive (13). The surviving homozygotes manifest elevated levels of SREBP-2 mRNA and protein (Table 1), which presumably compensates for the loss of SREBP-1a and -1c. When the SREBP-1c transcript is selectively eliminated, no embryonic lethality is observed, suggesting that the partial embryonic lethality in the Srebp1–/– mice is due to the loss of the SREBP-1a transcript (16).

To bypass embryonic lethality, we have produced mice in which all SREBP function can be disrupted in adulthood through induction of Cre recombinase. For this purpose, loxP recombination sites were inserted into genomic regions that flank crucial exons in the Scap or S1p genes (so-called floxed alleles) (14, 15). Mice homozygous for the floxed gene and heterozygous for a Cre recombinase transgene, which is under control of an IFN-inducible promoter (MX1-Cre), can be induced to delete Scap or S1p by stimulating IFN expression. Thus, following injection with polyinosinic acid–polycytidylic acid, a double-stranded RNA that provokes antiviral responses, the Cre recombinase is produced in liver and disrupts the floxed gene by recombination between the loxP sites.

Cre-mediated disruption of Scap or S1p dramatically reduces nSREBP-1 and nSREBP-2 levels in liver and diminishes expression of all SREBP target genes in both the cholesterol and the fatty acid synthetic pathways (Table 1). As a result, the rates of synthesis of cholesterol and fatty acids fall by 70–80% in Scap- and S1p-deficient livers.

In cultured cells, the processing of SREBP is inhibited by sterols, and the sensor for this inhibition is SCAP (5). To learn whether SCAP performs the same function in liver, we have produced transgenic mice that express a mutant SCAP with a single amino acid substitution in the sterol-sensing domain (D443N) (12). Studies in tissue culture show that SCAP(D443N) is resistant to inhibition by sterols. Cells that express a single copy of this mutant gene overproduce cholesterol (18). Transgenic mice that express this mutant version of SCAP in the liver exhibit a similar phenotype (12). These livers manifest elevated levels of nSREBP-1 and nSREBP-2, owing to constitutive SREBP processing, which is not suppressed when the animals are fed a cholesterol-rich diet. nSREBP-1 and -2 increase the expression of all SREBP target genes shown in Figure 2, thus stimulating cholesterol and fatty acid synthesis and causing a marked accumulation of hepatic cholesterol and triglycerides (Table 1). This transgenic model provides strong in vivo evidence that SCAP activity is normally under partial inhibition by endogenous sterols, which keeps the synthesis of cholesterol and fatty acids in a partially repressed state in the liver.

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Function of individual SREBP isoforms in vivo

To study the functions of individual SREBPs in the liver, we have produced transgenic mice that overexpress truncated versions of SREBPs (nSREBPs) that terminate prior to the membrane attachment domain. These nSREBPs enter the nucleus directly, bypassing the sterol-regulated cleavage step. By studying each nSREBP isoform separately, we could determine their distinct activating properties, albeit when overexpressed at nonphysiologic levels.

Overexpression of nSREBP-1c in the liver of transgenic mice produces a triglyceride-enriched fatty liver with no increase in cholesterol (10). mRNAs for fatty acid synthetic enzymes and rates of fatty acid synthesis are elevated fourfold in this tissue, whereas the mRNAs for cholesterol synthetic enzymes and the rate of cholesterol synthesis are not increased (8). Conversely, overexpression of nSREBP-2 in the liver increases the mRNAs only fourfold. This increase in cholesterol synthesis is even more remarkable when encoding all cholesterol biosynthetic enzymes; the most dramatic is a 75-fold increase in HMG-CoA reductase mRNA (11). mRNAs for fatty acid synthesis enzymes are increased to a lesser extent, consistent with the in vivo observation that the rate of cholesterol synthesis increases 28-fold in these transgenic nSREBP-2 livers, while fatty acid synthesis increases one considers the extent of cholesterol overload in this tissue, which would ordinarily reduce SREBP processing and essentially abolish cholesterol synthesis (Table 1).

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We have also studied the consequences of overexpressing SREBP-1a, which is expressed only at low levels in the livers of adult mice, rats, hamsters, and humans (6). nSREBP-1a transgenic mice develop a massive fatty liver engorged with both cholesterol and triglycerides (9), with heightened expression of genes controlling cholesterol biosynthesis and, still more dramatically, fatty acid synthesis (Table 1). The preferential activation of fatty acid synthesis (26-fold increase) relative to cholesterol synthesis (fivefold increase) explains the greater accumulation of triglycerides in their livers. The relative representation of the various fatty acids accumulating in this tissue is also unusual. Transgenic nSREBP-1a livers contain about 65% oleate (C18:1), markedly higher levels than the 15–20% found in typical wild-type livers (8) — a result of the induction of fatty acid elongase and stearoyl-CoA desaturase-1 (7). Considered together, the overexpression studies indicate that both SREBP-1 isoforms show a relative preference for activating fatty acid synthesis, whereas SREBP-2 favors cholesterol.

The phenotype of animals lacking the Srebp1 gene, which encodes both the SREBP-1a and -1c transcripts, also supports the notion of distinct hepatic functions for SREBP-1 and SREBP-2 (13). Most homozygous SREBP-1 knockout mice die in utero. The surviving Srebp1–/– mice show reduced synthesis of fatty acids, owing to reduced expression of mRNAs for fatty acid synthetic enzymes (Table 1). Hepatic nSREBP-2 levels increase in these mice, presumably in compensation for the loss of nSREBP-1. As a result, transcription of cholesterol biosynthetic genes increases, producing a threefold increase in hepatic cholesterol synthesis (Table 1).

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The studies in genetically manipulated mice clearly show that, as in cultured cells, SCAP and S1P are required for normal SREBP processing in the liver. SCAP, acting through its sterol-sensing domain, mediates feedback regulation of cholesterol synthesis. The SREBPs play related but distinct roles: SREBP-1c, the predominant SREBP-1 isoform in adult liver, preferentially activates genes required for fatty acid synthesis, while SREBP-2 preferentially activates the LDL receptor gene and various genes required for cholesterol synthesis. SREBP-1a and SREBP-2, but not SREBP-1c, are required for normal embryogenesis.

Transcriptional regulation of SREBP genes

Regulation of SREBPs occurs at two levels — transcriptional and posttranscriptional. The posttranscriptional regulation discussed above involves the sterol-mediated suppression of SREBP cleavage, which results from sterol-mediated suppression of the movement of the SCAP/SREBP complex from the ER to the Golgi apparatus (Figure 1). This form of regulation is manifest not only in cultured cells (1), but also in the livers of rodents fed cholesterol-enriched diets (19).

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The transcriptional regulation of the SREBPs is more complex. SREBP-1c and SREBP-2 are subject to distinct forms of transcriptional regulation, whereas SREBP-1a appears to be constitutively expressed at low levels in liver and most other tissues of adult animals (6). One mechanism of regulation shared by SREBP-1c and SREBP-2 involves a feed-forward regulation mediated by SREs present in the enhancer/promoters of each gene (20, 21). Through this feed-forward loop, nSREBPs activate the transcription of their own genes. In contrast, when nSREBPs decline, as in Scap or S1p knockout mice, there is a secondary decline in the mRNAs encoding SREBP-1c and SREBP-2 (14, 15).

Three factors selectively regulate the transcription of SREBP-1c: liver X-activated receptors (LXRs), insulin, and glucagon. LXRα and LXRβ, nuclear receptors that form heterodimers with retinoid X receptors, are activated by a variety of sterols, including oxysterol intermediates that form during cholesterol biosynthesis (2224). An LXR-binding site in the SREBP-1c promoter activates SREBP-1c transcription in the presence of LXR agonists (23). The functional significance of LXR-mediated SREBP-1c regulation has been confirmed in two animal models. Mice that lack both LXRα and LXRβ express reduced levels of SREBP-1c and its lipogenic target enzymes in liver and respond relatively weakly to treatment with a synthetic LXR agonist (23). Because a similar blunted response is found in mice that lack SREBP-1c, it appears that LXR increases fatty acid synthesis largely by inducing SREBP-1c (16). LXR-mediated activation of SREBP-1c transcription provides a mechanism for the cell to induce the synthesis of oleate when sterols are in excess (23). Oleate is the preferred fatty acid for the synthesis of cholesteryl esters, which are necessary for both the transport and the storage of cholesterol.

LXR-mediated regulation of SREBP-1c appears also to be one mechanism by which unsaturated fatty acids suppress SREBP-1c transcription and thus fatty acid synthesis. Rodents fed diets enriched in polyunsaturated fatty acids manifest reduced SREBP-1c mRNA expression and low rates of lipogenesis in liver (25). In vitro, unsaturated fatty acids competitively block LXR activation of SREBP-1c expression by antagonizing the activation of LXR by its endogenous ligands (26). In addition to LXR-mediated transcriptional inhibition, polyunsaturated fatty acids lower SREBP-1c levels by accelerating degradation of its mRNA (27). These combined effects may contribute to the long-recognized ability of polyunsaturated fatty acids to lower plasma triglyceride levels.

SREBP-1c and the insulin/glucagon ratio

The liver is the organ responsible for the conversion of excess carbohydrates to fatty acids to be stored as triglycerides or burned in muscle. A classic action of insulin is to stimulate fatty acid synthesis in liver during times of carbohydrate excess. The action of insulin is opposed by glucagon, which acts by raising cAMP. Multiple lines of evidence suggest that insulin’s stimulatory effect on fatty acid synthesis is mediated by an increase in SREBP-1c. In isolated rat hepatocytes, insulin treatment increases the amount of mRNA for SREBP-1c in parallel with the mRNAs of its target genes (28, 29). The induction of the target genes can be blocked if a dominant negative form of SREBP-1c is expressed (30). Conversely, incubating primary hepatocytes with glucagon or dibutyryl cAMP decreases the mRNAs for SREBP-1c and its associated lipogenic target genes (30, 31).

In vivo, the total amount of SREBP-1c in liver and adipose tissue is reduced by fasting, which suppresses insulin and increases glucagon levels, and is elevated by refeeding (32, 33). The levels of mRNA for SREBP-1c target genes parallel the changes in SREBP-1c expression. Similarly, SREBP-1c mRNA levels fall when rats are treated with streptozotocin, which abolishes insulin secretion, and rise after insulin injection (29). Overexpression of nSREBP-1c in livers of transgenic mice prevents the reduction in lipogenic mRNAs that normally follows a fall in plasma insulin levels (32). Conversely, in livers of Scap knockout mice that lack all nSREBPs in the liver (14) or knockout mice lacking either nSREBP-1c (16) or both SREBP-1 isoforms (34), there is a marked decrease in the insulin-induced stimulation of lipogenic gene expression that normally occurs after fasting/refeeding. It should be noted that insulin and glucagon also exert a posttranslational control of fatty acid synthesis though changes in the phosphorylation and activation of acetyl-CoA carboxylase. The posttranslational regulation of fatty acid synthesis persists in transgenic mice that overexpress nSREBP-1c (10). In these mice, the rates of fatty acid synthesis, as measured by [3H]water incorporation, decline after fasting even though the levels of the lipogenic mRNAs remain high (our unpublished observations).

Taken together, the above evidence suggests that SREBP-1c mediates insulin’s lipogenic actions in liver. Recent in vitro and in vivo studies involving adenoviral gene transfer suggest that SREBP-1c may also contribute to the regulation of glucose uptake and glucose synthesis. When overexpressed in hepatocytes, nSREBP-1c induces expression of glucokinase, a key enzyme in glucose utilization. It also suppresses phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme (35, 36).

SREBPs in disease

Many individuals with obesity and insulin resistance also have fatty livers, one of the most commonly encountered liver abnormalities in the US (37). A subset of individuals with fatty liver go on to develop fibrosis, cirrhosis, and liver failure. Evidence indicates that the fatty liver of insulin resistance is caused by SREBP-1c, which is elevated in response to the high insulin levels. Thus, SREBP-1c levels are elevated in the fatty livers of obese (ob/ob) mice with insulin resistance and hyperinsulinemia caused by leptin deficiency (38, 39). Despite the presence of insulin resistance in peripheral tissues, insulin continues to activate SREBP-1c transcription and cleavage in the livers of these insulin-resistant mice. The elevated nSREBP-1c increases lipogenic gene expression, enhances fatty acid synthesis, and accelerates triglyceride accumulation (31, 39). These metabolic abnormalities are reversed with the administration of leptin, which corrects the insulin resistance and lowers the insulin levels (38).

Metformin, a biguanide drug used to treat insulin-resistant diabetes, reduces hepatic nSREBP-1 levels and dramatically lowers the lipid accumulation in livers of insulin-resistant ob/ob mice (40). Metformin stimulates AMP-activated protein kinase (AMPK), an enzyme that inhibits lipid synthesis through phosphorylation and inactivation of key lipogenic enzymes (41). In rat hepatocytes, metformin-induced activation of AMPK also leads to decreased mRNA expression of SREBP-1c and its lipogenic target genes (41), but the basis of this effect is not understood.

The incidence of coronary artery disease increases with increasing plasma LDL-cholesterol levels, which in turn are inversely proportional to the levels of hepatic LDL receptors. SREBPs stimulate LDL receptor expression, but they also enhance lipid synthesis (1), so their net effect on plasma lipoprotein levels depends on a balance between opposing effects. In mice, the plasma levels of lipoproteins tend to fall when SREBPs are either overexpressed or underexpressed. In transgenic mice that overexpress nSREBPs in liver, plasma cholesterol and triglycerides are generally lower than in control mice (Table 1), even though these mice massively overproduce fatty acids, cholesterol, or both. Hepatocytes of nSREBP-1a transgenic mice overproduce VLDL, but these particles are rapidly removed through the action of LDL receptors, and they do not accumulate in the plasma. Indeed, some nascent VLDL particles are degraded even before secretion by a process that is mediated by LDL receptors (42). The high levels of nSREBP-1a in these animals support continued expression of the LDL receptor, even in cells whose cholesterol concentration is elevated. In LDL receptor–deficient mice carrying the nSREBP-1a transgene, plasma cholesterol and triglyceride levels rise tenfold (43).

Mice that lack all SREBPs in liver as a result of disruption of Scap or S1p also manifest lower plasma cholesterol and triglyceride levels (Table 1).

http://dm5migu4zj3pb.cloudfront.net/manuscripts/15000/15593/small/JCI0215593.t1.gif

In these mice, hepatic cholesterol and triglyceride synthesis is markedly reduced, and this likely causes a decrease in VLDL production and secretion. LDL receptor mRNA and LDL clearance from plasma is also significantly reduced in these mice, but the reduction in LDL clearance is less than the overall reduction in VLDL secretion, the net result being a decrease in plasma lipid levels (15). However, because

humans and mice differ substantially with regard to LDL receptor expression, LDL levels, and other aspects of lipoprotein metabolism,

it is difficult to predict whether human plasma lipids will rise or fall when the SREBP pathway is blocked or activated.

SREBPs in liver: unanswered questions

The studies of SREBPs in liver have exposed a complex regulatory system whose individual parts are coming into focus. Major unanswered questions relate to the ways in which the transcriptional and posttranscriptional controls on SREBP activity are integrated so as to permit independent regulation of cholesterol and fatty acid synthesis in specific nutritional states. A few clues regarding these integration mechanisms are discussed below.

Whereas cholesterol synthesis depends almost entirely on SREBPs, fatty acid synthesis is only partially dependent on these proteins. This has been shown most clearly in cultured nonhepatic cells such as Chinese hamster ovary cells. In the absence of SREBP processing, as when the Site-2 protease is defective, the levels of mRNAs encoding cholesterol biosynthetic enzymes and the rates of cholesterol synthesis decline nearly to undetectable levels, whereas the rate of fatty acid synthesis is reduced by only 30% (44). Under these conditions, transcription of the fatty acid biosynthetic genes must be maintained by factors other than SREBPs. In liver, the gene encoding fatty acid synthase (FASN) can be activated transcriptionally by upstream stimulatory factor, which acts in concert with SREBPs (45). The FASN promoter also contains an LXR element that permits a low-level response to LXR ligands even when SREBPs are suppressed (46). These two transcription factors may help to maintain fatty acid synthesis in liver when nSREBP-1c is low.

Another mechanism of differential regulation is seen in the ability of cholesterol to block the processing of SREBP-2, but not SREBP-1, under certain metabolic conditions. This differential regulation has been studied most thoroughly in cultured cells such as human embryonic kidney (HEK-293) cells. When these cells are incubated in the absence of fatty acids and cholesterol, the addition of sterols blocks processing of SREBP-2, but not SREBP-1, which is largely produced as SREBP-1a in these cells (47). Inhibition of SREBP-1 processing requires an unsaturated fatty acid, such as oleate or arachidonate, in addition to sterols (47). In the absence of fatty acids and in the presence of sterols, SCAP may be able to carry SREBP-1 proteins, but not SREBP-2, to the Golgi apparatus. Further studies are necessary to document this apparent independent regulation of SREBP-1 and SREBP-2 processing and to determine its mechanism.

 

Acknowledgments

Support for the research cited from the authors’ laboratories was provided by grants from the NIH (HL-20948), the Moss Heart Foundation, the Keck Foundation, and the Perot Family Foundation. J.D. Horton is a Pew Scholar in the Biomedical Sciences and is the recipient of an Established Investigator Grant from the American Heart Association and a Research Scholar Award from the American Digestive Health Industry.

References

  1. Brown, MS, Goldstein, JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997. 89:331-340.

View this article via: PubMed

  1. Horton, JD, Shimomura, I. Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis. Curr Opin Lipidol 1999. 10:143-150.

View this article via: PubMed

  1. Edwards, PA, Tabor, D, Kast, HR, Venkateswaran, A. Regulation of gene expression by SREBP and SCAP. Biochim Biophys Acta 2000. 1529:103-113.

View this article via: PubMed

  1. Sakakura, Y, et al. Sterol regulatory element-binding proteins induce an entire pathway of cholesterol synthesis. Biochem Biophys Res Commun 2001. 286:176-183.

View this article via: PubMed

  1. Goldstein, JL, Rawson, RB, Brown, MS. Mutant mammalian cells as tools to delineate the sterol regulatory element-binding protein pathway for feedback regulation of lipid synthesis. Arch Biochem Biophys 2002. 397:139-148.

View this article via: PubMed

  1. Shimomura, I, Shimano, H, Horton, JD, Goldstein, JL, Brown, MS. Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and cultured cells. J Clin Invest 1997. 99:838-845.

View this article via: JCI.org PubMed

  1. Moon, Y-A, Shah, NA, Mohapatra, S, Warrington, JA, Horton, JD. Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins. J Biol Chem 2001. 276:45358-45366.

View this article via: PubMed

  1. Shimomura, I, Shimano, H, Korn, BS, Bashmakov, Y, Horton, JD. Nuclear sterol regulatory element binding proteins activate genes responsible for entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J Biol Chem 1998. 273:35299-35306.

View this article via: PubMed

  1. Shimano, H, et al. Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. J Clin Invest 1996. 98:1575-1584.

View this article via: JCI.org PubMed

  1. Shimano, H, et al. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 1997. 99:846-854.

View this article via: JCI.org PubMed

  1. Horton, JD, et al. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2. J Clin Invest 1998. 101:2331-2339.

View this article via: JCI.org PubMed

  1. Korn, BS, et al. Blunted feedback suppression of SREBP processing by dietary cholesterol in transgenic mice expressing sterol-resistant SCAP(D443N). J Clin Invest 1998. 102:2050-2060.

View this article via: JCI.org PubMed

  1. Shimano, H, et al. Elevated levels of SREBP-2 and cholesterol synthesis in livers of mice homozygous for a targeted disruption of the SREBP-1 gene. J Clin Invest 1997. 100:2115-2124.

View this article via: JCI.org PubMed

  1. Matsuda, M, et al. SREBP cleavage-activating protein (SCAP) is required for increased lipid synthesis in liver induced by cholesterol deprivation and insulin elevation. Genes Dev 2001. 15:1206-1216.

View this article via: PubMed

  1. Yang, J, et al. Decreased lipid synthesis in livers of mice with disrupted Site-1 protease gene. Proc Natl Acad Sci USA 2001. 98:13607-13612.

View this article via: PubMed

Liang, G, et al. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c. J Biol Chem 2002. 277:9520-9528.

http://www.jci.org/articles/view/15593

 

Structural Biochemistry/Lipids/Membrane Lipids

< Structural Biochemistry‎ | Lipids

Membrane proteins rely on their interaction with membrane lipids to uphold its structure and maintain its functions as a protein. For membrane proteins to purify and crystallize, it is essential for the membrane protein to be in the appropriate lipid environment. Lipids assist in crystallization and stabilize the protein and provide lattice contacts. Lipids can also help obtain membrane protein structures in a native conformation. Membrane protein structures contain bound lipid molecules. Biological membranes are important in life, providing permeable barriers for cells and their organelles. The interaction between membrane proteins and lipids facilitates basic processes such as respiration, photosynthesis, transport, signal transduction and motility. These basic processes require a diverse group of proteins, which are encoded by 20-30% of an organism’s annotated genes.

There exist a great number of membrane lipids. Specifically, eukaryotic cells have a very complex collection of lipids that rely on many of the cell’s resources for its synthesis. Interactions between proteins and lipids can be very specific. Specific types of lipids can make a structure stable, provide control in insertion and folding processes, and help to assemble multisubunit complexes or supercomplexes, and most importantly, can significantly affect a membrane protein’s functions. Protein and lipid interactions are not sufficiently tight, meaning that lipids are retained during membrane protein purification. Since cellular membranes are fluid arrangements of lipids, some lipids affect interesting changes to membrane due to their characteristics. Glycosphigolipids and cholesterol tend to form small islands within the membranes, called lipid rafts, due to their physical properties. Some proteins also tend to cluster in lipid raft, while others avoid being in lipid rafts. However, the existence of lipid rafts in cells seems to be transitory.

Recent progress in determining membrane protein structure has brought attention to the importance of maintaining a favorable lipid environment so proteins to crystallize and purify successfully. Lipids assist in crystallization by stabilizing the protein fold and the relationships between subunits or monomers. The lipid content in protein-lipid detergent complexes can be altered by adjusting solubilisation and purification protocols, also by adding native or non-native lipids.

There are three type of membrane lipids: 1. Phospholipids: major class of membrane lipids. 2. glycolipids. 3. Cholesterols. Membrane lipids were started with eukaryotes and bacteria.

http://en.wikibooks.org/wiki/Structural_Biochemistry/Lipids/Membrane_Lipids

Types of Membrane Lipids

Lipids are often used as membrane constituents. The three major classes that membrane lipids are divided into are phospholipids, glycolipids, and cholesterol. Lipids are found in eukaryotes and bacteria. Although the lipids in archaea have many features that are related to the membrane formation that is similar with lipids of other organisms, they are still distinct from one another. The membranes of archaea differ in composition in three major ways. Firstly, the nonpolar chains are joined to a glycerol backbone by ether instead of esters, allowing for more resistance to hydrolysis. Second, the alkyl chains are not linear, but branched and make them more resistant to oxidation. The ability of archaeal lipids to resist hydrolysis and oxidation help these types of organisms to withstand the extreme conditions of high temperature, low pH, or high salt concentration. Lastly, the stereochemistry of the central glycerol is inverted. Membrane lipids have an extensive repertoire, but they possess a critical common structural theme in which they are amphipathic molecules, meaning they contain both a hydrophilic and hydrophobic moiety.

Membrane lipids are all closed bodies or boundaries separating substituent parts of the cell. The thickness of membranes is usually between 60 and 100 angstroms. These bodies are constructed from non-covalent assemblies. Their polar heads align with each other and their non-polar hydrocarbon tails align as well. The resulting stability is credited to hydrophobic interaction which proves to be quite stable due to the length of their hydrocarbon tails.

 

Membrane Lipids

Lipid Vesicles

Lipid vesicles, also known as liposomes, are vesicles that are essentially aqueous vesicles that are surrounded by a circular phospholipid bilayer. Like the other phospholipid structures, they have the hydrocarbon/hydrophobic tails facing inward, away from the aqueous solution, and the hydrophilic heads facing towards the aqueous solution. These vesicles are structures that form enclosed compartments of ions and solutes, and can be utilized to study the permeability of certain membranes, or to transfer these ions or solutes to certain cells found elsewhere.

Liposomes as vesicles can serve various clinical uses. Injecting liposomes containing medicine or DNA (for gene therapy) into patients is a possible method of drug delivery. The liposomes fuse with other cells’ membranes and therefore combine their contents with that of the patient’s cell. This method of drug delivery is less toxic than direct exposure because the liposomes carry the drug directly to cells without any unnecessary intermediate steps.

Because of the hydrophobic interactions among several phospholipids and glycolipids, a certain structure called the lipid bilayer or bimolecular sheet is favored. As mentioned earlier, phospholipids and glycolipids have both hydrophilic and hydrophobic moieties; thus, when several phospholipids or glycolipids come together in an aqueous solution, the hydrophobic tails interact with each other to form a hydrophobic center, while the hydrophilic heads interact with each other forming a hydrophilic coating on each side of the bilayer.

http://upload.wikimedia.org/wikibooks/en/b/ba/Liposome_final%2A.png

http://upload.wikimedia.org/wikibooks/en/f/fa/Membrane_bilayer.jpg

 

Liposome_

Liposome_

 

 

Membrane_bilayer

Membrane_bilayer

 

 

 

Evidence Report/Technology Assessment   Number 89

 

Effects of Omega-3 Fatty Acids on Lipids and Glycemic Control in Type II Diabetes and the Metabolic Syndrome and on Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal Disease, Systemic Lupus Erythematosus, and Osteoporosis

 

Prepared for:

Agency for Healthcare Research and Quality

U.S. Department of Health and Human Services

540 Gaither Road

Rockville, MD 20850

http://www.ahrq.gov

Contract No. 290-02-0003

 

Chapter 1. Introduction

This report is one of a group of evidence reports prepared by three Agency for Healthcare Research and Quality (AHRQ)-funded Evidence-Based Practice Centers (EPCs) on the role of omega-3 fatty acids (both from food sources and from dietary supplements) in the prevention or treatment of a variety of diseases. These reports were requested and funded by the Office of Dietary Supplements, National Institutes of Health. The three EPCs – the Southern California EPC (SCEPC, based at RAND), the Tufts-New England Medical Center (NEMC) EPC, and the University of Ottawa EPC – have each produced evidence reports. To ensure consistency of approach, the three EPCs collaborated on selected methodological elements, including literature search strategies, rating of evidence, and data table design.

The aim of these reports is to summarize the current evidence on the effects of omega-3 fatty acids on prevention and treatment of cardiovascular diseases, cancer, child and maternal health, eye health, gastrointestinal/renal diseases, asthma, immune- mediated diseases, tissue/organ transplantation, mental health, and neurological diseases and conditions. In addition to informing the research community and the public on the effects of omega-3 fatty acids on various health conditions, it is anticipated that the findings of the reports will also be used to help define the agenda for future research.

This report focuses on the effects of omega-3 fatty acids on immune- mediated diseases, bone metabolism, and gastrointestinal/renal diseases. Subsequent reports from the SCEPC will focus on cancer and neurological diseases and conditions.

This chapter provides a brief review of the current state of knowledge about the metabolism, physiological functions, and sources of omega-3 fatty acids.

 

The Recognition of Essential Fatty Acids

Dietary fat has long been recognized as an important source of energy for mammals, but in the late 1920s, researchers demonstrated the dietary requirement for particular fatty acids, which came to be called essential fatty acids. It was not until the advent of intravenous feeding, however, that the importance of essential fatty acids was widely accepted: Clinical signs of essential fatty acid deficiency are generally observed only in patients on total parenteral nutrition who received mixtures devoid of essential fatty acids or in those with malabsorption syndromes.

These signs include dermatitis and changes in visual and neural function. Over the past 40 years, an increasing number of physiological functions, such as immunomodulation, have been attributed to the essential fatty acids and their metabolites, and this area of research remains quite active.1, 2

Fatty Acid Nomenclature

The fat found in foods consists largely of a heterogeneous mixture of triacylglycerols (triglycerides)–glycerol molecules that are each combined with three fatty acids. The fatty acids can be divided into two categories, based on chemical properties: saturated fatty acids, which are usually solid at room temperature, and unsaturated fatty acids, which are liquid at room temperature. The term “saturation” refers to a chemical structure in which each carbon atom in the fatty acyl chain is bound to (saturated with) four other atoms, these carbons are linked by single bonds, and no other atoms or molecules can attach; unsaturated fatty acids contain at least one pair of carbon atoms linked by a double bond, which allows the attachment of additional atoms to those carbons (resulting in saturation). Despite their differences in structure, all fats contain approximately the same amount of energy (37 kilojoules/gram, or 9 kilocalories/gram).

The class of unsaturated fatty acids can be further divided into monounsaturated and polyunsaturated fatty acids. Monounsaturated fatty acids (the primary constituents of olive and canola oils) contain only one double bond. Polyunsaturated fatty acids (PUFAs) (the primary constituents of corn, sunflower, flax seed and many other vegetable oils) contain more than one double bond. Fatty acids are often referred to using the number of carbon atoms in the acyl chain, followed by a colon, followed by the number of double bonds in the chain (e.g., 18:1 refers to the 18-carbon monounsaturated fatty acid, oleic acid; 18:3 refers to any 18-carbon PUFA with three double bonds).

PUFAs are further categorized on the basis of the location of their double bonds. An omega or n notation indicates the number of carbon atoms from the methyl end of the acyl chain to the first double bond. Thus, for example, in the omega-3 (n-3) family of PUFAs, the first double bond is 3 carbons from the methyl end of the molecule. The trivial names, chemical names and abbreviations for the omega-3 fatty acids are detailed in Table 1.1.  Finally, PUFAs can be categorized according to their chain length. The 18-carbon n-3 and n-6 short-chain PUFAs are precursors to the longer 20- and 22-carbon PUFAs, called long-chain PUFAs (LCPUFAs).

Fatty Acid Metabolism

Mammalian cells can introduce double bonds into all positions on the fatty acid chain except the n-3 and n-6 position. Thus, the short-chain alpha- linolenic acid (ALA, chemical abbreviation: 18:3n-3) and linoleic acid (LA, chemical abbreviation: 18:2n-6) are essential fatty acids.

No other fatty acids found in food are considered ‘essential’ for humans, because they can all be synthesized from the short chain fatty acids.

Following ingestion, ALA and LA can be converted in the liver to the long chain, more unsaturated n-3 and n-6 LCPUFAs by a complex set of synthetic pathways that share several enzymes (Figure 1). LC PUFAs retain the original sites of desaturation (including n-3 or n-6). The omega-6 fatty acid LA is converted to gamma-linolenic acid (GLA, 18:3n-6), an omega- 6 fatty acid that is a positional isomer of ALA. GLA, in turn, can be converted to the longerchain omega-6 fatty acid, arachidonic acid (AA, 20:4n-6). AA is the precursor for certain classes of an important family of hormone- like substances called the eicosanoids (see below).

The omega-3 fatty acid ALA (18:3n-3) can be converted to the long-chain omega-3 fatty acid, eicosapentaenoic acid (EPA; 20:5n-3). EPA can be elongated to docosapentaenoic acid (DPA 22:5n-3), which is further desaturated to docosahexaenoic acid (DHA; 22:6n-3). EPA and DHA are also precursors of several classes of eicosanoids and are known to play several other critical roles, some of which are discussed further below.

The conversion from parent fatty acids into the LC PUFAs – EPA, DHA, and AA – appears to occur slowly in humans. In addition, the regulation of conversion is not well understood, although it is known that ALA and LA compete for entry into the metabolic pathways.

Physiological Functions of EPA and AA

As stated earlier, fatty acids play a variety of physiological roles. The specific biological functions of a fatty acid are determined by the number and position of double bonds and the length of the acyl chain.

Both EPA (20:5n-3) and AA (20:4n-6) are precursors for the formation of a family of hormone- like agents called eicosanoids. Eicosanoids are rudimentary hormones or regulating – molecules that appear to occur in most forms of life. However, unlike endocrine hormones, which travel in the blood stream to exert their effects at distant sites, the eicosanoids are autocrine or paracrine factors, which exert their effects locally – in the cells that synthesize them or adjacent cells. Processes affected include the movement of calcium and other substances into and out of cells, relaxation and contraction of muscles, inhibition and promotion of clotting, regulation of secretions including digestive juices and hormones, and control of fertility, cell division, and growth.3

The eicosanoid family includes subgroups of substances known as prostaglandins, leukotrienes, and thromboxanes, among others. As shown in Figure 1.1, the long-chain omega-6 fatty acid, AA (20:4n-6), is the precursor of a group of eicosanoids that include series-2 prostaglandins and series-4 leukotrienes. The omega-3 fatty acid, EPA (20:5n-3), is the precursor to a group of eicosanoids that includes series-3 prostaglandins and series-5 leukotrienes. The AA-derived series-2 prostaglandins and series-4 leukotrienes are often synthesized in response to some emergency such as injury or stress, whereas the EPA-derived series-3 prostaglandins and series-5 leukotrienes appear to modulate the effects of the series-2 prostaglandins and series-4 leukotrienes (usually on the same target cells). More specifically, the series-3 prostaglandins are formed at a slower rate and work to attenuate the effects of excessive levels of series-2 prostaglandins. Thus, adequate production of the series-3 prostaglandins seems to protect against heart attack and stroke as well as certain inflammatory diseases like arthritis, lupus, and asthma.3.

EPA (22:6 n-3) also affects lipoprotein metabolism and decreases the production of substances – including cytokines, interleukin 1ß (IL-1ß), and tumor necrosis factor a (TNF-a) – that have pro-inflammatory effects (such as stimulation of collagenase synthesis and the expression of adhesion molecules necessary for leukocyte extravasation [movement from the circulatory system into tissues]).2 The mechanism responsible for the suppression of cytokine production by omega-3 LC PUFAs remains unknown, although suppression of omega-6-derived eicosanoid production by omega-3 fatty acids may be involved, because the omega-3 and omega-6 fatty acids compete for a common enzyme in the eicosanoid synthetic pathway, delta-6 desaturase.

DPA (22:5n-3) (the elongation product of EPA) and its metabolite DHA (22:6n-3) are frequently referred to as very long chain n-3 fatty acids (VLCFA). Along with AA, DHA is the major PUFA found in the brain and is thought to be important for brain development and function. Recent research has focused on this role and the effect of supplementing infant formula with DHA (since DHA is naturally present in breast milk but not in formula).

Dietary Sources and Requirements

Both ALA and LA are present in a variety of foods. LA is present in high concentrations in many commonly used oils, including safflower, sunflower, soy, and corn oil. ALA is present in some commonly used oils, including canola and soybean oil, and in some leafy green vegetables. Thus, the major dietary sources of ALA and LA are PUFA-rich vegetable oils. The proportion of LA to ALA as well as the proportion of those PUFAs to others varies considerably by the type of oil. With the exception of flaxseed, canola, and soybean oil, the ratio of LA to ALA in vegetable oils is at least 10 to 1. The ratios of LA to ALA for flaxseed, canola, and soy are approximately 1: 3.5, 2:1, and 8:1, respectively; however, flaxseed oil is not typically consumed in the North American diet. It is estimated that on average in the U.S., LA accounts for 89% of the total PUFAs consumed, and ALA accounts for 9%. Another estimate suggests that Americans consume 10 times more omega-6 than omega-3 fatty acids.4 Table 1.2 shows the proportion of omega 3 fatty acids for a number of foods.

Syntheis and Degradation

Source of Acetyl CoA for Fatty Acid Synthesis

Source of Acetyl CoA for Fatty Acid Synthesis

step 1

step 1

condensation reaction with malonyl ACP

ACP (acyl carrier protein)

ACP (acyl carrier protein)

synthesis requires acetyl CoA from citrate shuttle

synthesis requires acetyl CoA from citrate shuttle

conversion to fatty acyl co A in cytoplasm

conversion to fatty acyl co A in cytoplasm

ACP (acyl carrier protein)

ACP (acyl carrier protein)

FA synthesis not exactly reverse of catabolism

FA synthesis not exactly reverse of catabolism

 

Fatty Acid Synthase

Fatty Acid Synthase

complete FA synthesis

complete FA synthesis

Desaturation

Desaturation

Elongation and Desaturation of Fatty Acids

Elongation and Desaturation of Fatty Acids

release of FAs from adiposites

release of FAs from adiposites

Fatty acid beta oxidation and Krebs cycle produce NAD, NADH, FADH2

Fatty acid beta oxidation and Krebs cycle produce NAD, NADH, FADH2

ketone bodies

ketone bodies

metabolism of ketone bodies

metabolism of ketone bodies

Arachidonoyl-mimicking

Arachidonoyl-mimicking

Arachidonate pathways

Arachidonate pathways

arachidonic acid derivatives

arachidonic acid derivatives

major metabolic intermediates in the pathways for synthesis of cholesterol, fatty acids, and triglycerides

major metabolic intermediates in the pathways for synthesis of cholesterol, fatty acids, and triglycerides

Model for the sterol-mediated proteolytic release of SREBPs from membrane

Model for the sterol-mediated proteolytic release of SREBPs from membrane

hormone regulation

hormone regulation

 insulin receptor and and insulin receptor signaling pathway (IRS)

insulin receptor and and insulin receptor signaling pathway (IRS)

 islet brain glucose signaling

islet brain glucose signaling

 

 

 

 

 

 

 

 

Fish source

Fish source

omega FAs

omega FAs

 

Excessive omega 6s

Excessive omega 6s

omega 6s

omega 6s

diet and cancer

diet and cancer

Patients at risk of FA deficiency

Patients at risk of FA deficiency

PPAR role

PPAR role

PPAR role

PPAR role

Omega 6_3 pathways

Omega 6_3 pathways

n3 vs n6 PUFAs

n3 vs n6 PUFAs

triene-teraene ratio

triene-teraene ratio

arachidonic acid, leukotrienes, PG and thromboxanes

arachidonic acid, leukotrienes, PG and thromboxanes

Cox 2 and cancer

Cox 2 and cancer

Lipidomics of atherosclerotic plaques

Lipidomics of atherosclerotic plaques

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Effect of TPN on EFAD

Effect of TPN on EFAD

benefits of omega 3s

benefits of omega 3s

food consumption

food consumption

 

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Summary – Volume 4, Part 2: Translational Medicine in Cardiovascular Diseases


Summary – Volume 4, Part 2:  Translational Medicine in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

 

We have covered a large amount of material that involves

  • the development,
  • application, and
  • validation of outcomes of medical and surgical procedures

that are based on translation of science from the laboratory to the bedside, improving the standards of medical practice at an accelerated pace in the last quarter century, and in the last decade.  Encouraging enabling developments have been:

1. The establishment of national and international outcomes databases for procedures by specialist medical societies

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

On Devices and On Algorithms: Prediction of Arrhythmia after Cardiac Surgery and ECG Prediction of an Onset of Paroxysmal Atrial Fibrillation
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC
https://pharmaceuticalintelligence.com/2013/05/07/on-devices-and-on-algorithms-arrhythmia-after-cardiac-surgery-prediction-and-ecg-prediction-of-paroxysmal-atrial-fibrillation-onset/

Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/

Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions
Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) /Coronary Angioplasty
Larry H. Bernstein, MD, Writer And Aviva Lev-Ari, PhD, RN, Curator
https://pharmaceuticalintelligence.com/2013/06/23/comparison-of-cardiothoracic-bypass-and-percutaneous-interventional-catheterization-survivals/

Revascularization: PCI, Prior History of PCI vs CABG
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB
Reporter and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2012/08/27/outcomes-in-high-cardiovascular-risk-patients-prasugrel-effient-vs-clopidogrel-plavix-aliskiren-tekturna-added-to-ace-or-added-to-arb/

Endovascular Lower-extremity Revascularization Effectiveness: Vascular Surgeons (VSs), Interventional Cardiologists (ICs) and Interventional Radiologists (IRs)
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

and more

2. The identification of problem areas, particularly in activation of the prothrombotic pathways, infection control to an extent, and targeting of pathways leading to progression or to arrythmogenic complications.

Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

Anticoagulation genotype guided dosing
Larry H. Bernstein, MD, FCAP, Author and Curator
https://pharmaceuticalintelligence.com/2013/12/08/anticoagulation-genotype-guided-dosing/

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

The Effects of Aprotinin on Endothelial Cell Coagulant Biology
Co-Author (Kamran Baig, MBBS, James Jaggers, MD, Jeffrey H. Lawson, MD, PhD) and Curator
https://pharmaceuticalintelligence.com/2013/07/20/the-effects-of-aprotinin-on-endothelial-cell-coagulant-biology/

Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB
Reporter and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2012/08/27/outcomes-in-high-cardiovascular-risk-patients-prasugrel-effient-vs-clopidogrel-plavix-aliskiren-tekturna-added-to-ace-or-added-to-arb/

Pharmacogenomics – A New Method for Druggability  Author and Curator: Demet Sag, PhD
https://pharmaceuticalintelligence.com/2014/04/28/pharmacogenomics-a-new-method-for-druggability/

Advanced Topics in Sepsis and the Cardiovascular System at its End Stage    Author: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-Sepsis-and-the-Cardiovascular-System-at-its-End-Stage/

3. Development of procedures that use a safer materials in vascular management.

Stent Design and Thrombosis: Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization
Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/05/05/bioengineering-of-vascular-and-tissue-models/

Vascular Repair: Stents and Biologically Active Implants
Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, RN, PhD
https://pharmaceuticalintelligence.com/2013/05/04/stents-biologically-active-implants-and-vascular-repair/

Drug Eluting Stents: On MIT’s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES
Author: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN
http://PharmaceuticalIntelligence.com/2013/04/25/Contributions-to-vascular-biology/

MedTech & Medical Devices for Cardiovascular Repair – Curations by Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/04/17/medtech-medical-devices-for-cardiovascular-repair-curation-by-aviva-lev-ari-phd-rn/

4. Discrimination of cases presenting for treatment based on qualifications for medical versus surgical intervention.

Treatment Options for Left Ventricular Failure – Temporary Circulatory Support: Intra-aortic balloon pump (IABP) – Impella Recover LD/LP 5.0 and 2.5, Pump Catheters (Non-surgical) vs Bridge Therapy: Percutaneous Left Ventricular Assist Devices (pLVADs) and LVADs (Surgical)
Author: Larry H Bernstein, MD, FCAP And Curator: Justin D Pearlman, MD, PhD, FACC
https://pharmaceuticalintelligence.com/2013/07/17/treatment-options-for-left-ventricular-failure-temporary-circulatory-support-intra-aortic-balloon-pump-iabp-impella-recover-ldlp-5-0-and-2-5-pump-catheters-non-surgical-vs-bridge-therapy/

Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI
Writer and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/06/30/mayo-risk-score-for-percutaneous-coronary-intervention/

ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery Reporter: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/11/05/accaha-guidelines-for-coronary-artery-bypass-graft-surgery/

Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/ 

5.  This has become possible because of the advances in our knowledge of key related pathogenetic mechanisms involving gene expression and cellular regulation of complex mechanisms.

What is the key method to harness Inflammation to close the doors for many complex diseases?
Author and Curator: Larry H Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/03/03/cvd-prevention-and-evaluation-of-cardiovascular-imaging-modalities-coronary-calcium-score-by-ct-scan-screening-to-justify-or-not-the-use-of-statin/

Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension
Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/03/03/richard-lifton-md-phd-of-yale-university-and-howard-hughes-medical-institute-recipient-of-2014-breakthrough-prizes-awarded-in-life-sciences-for-the-discovery-of-genes-and-biochemical-mechanisms-tha/

Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)
Curator:  Larry H. Bernstein, MD, FCAP
https://pharmaceuticalintelligence.com/2014/01/15/pathophysiological-effects-of-diabetes-on-ischemic-cardiovascular-disease-and-on-chronic-obstructive-pulmonary-disease-copd/

Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))
Reviewer and Co-Curator: Larry H Bernstein, MD, CAP and Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/12/21/genetic-polymorphisms-of-ion-channels-have-a-role-in-the-pathogenesis-of-coronary-microvascular-dysfunction-and-ischemic-heart-disease/

Notable Contributions to Regenerative Cardiology  Author and Curator: Larry H Bernstein, MD, FCAP and Article Commissioner: Aviva Lev-Ari, PhD, RD
https://pharmaceuticalintelligence.com/2013/10/20/notable-contributions-to-regenerative-cardiology/

As noted in the introduction, any of the material can be found and reviewed by content, and the eTOC is identified in attached:

http://wp.me/p2xfv8-1W

 

This completes what has been presented in Part 2, Vol 4 , and supporting references for the main points that are found in the Leaders in Pharmaceutical Intelligence Cardiovascular book.  Part 1 was concerned with Posttranslational Modification of Proteins, vital for understanding cellular regulation and dysregulation.  Part 2 was concerned with Translational Medical Therapeutics, the efficacy of medical and surgical decisions based on bringing the knowledge gained from the laboratory, and from clinical trials into the realm opf best practice.  The time for this to occur in practice in the past has been through roughly a generation of physicians.  That was in part related to the busy workload of physicians, and inability to easily access specialty literature as the volume and complexity increased.  This had an effect of making access of a family to a primary care provider through a lifetime less likely than the period post WWII into the 1980s.

However, the growth of knowledge has accelerated in the specialties since the 1980’s so that the use of physician referral in time became a concern about the cost of medical care.  This is not the place for or a matter for discussion here.  It is also true that the scientific advances and improvements in available technology have had a great impact on medical outcomes.  The only unrelated issue is that of healthcare delivery, which is not up to the standard set by serial advances in therapeutics, accompanied by high cost due to development costs, marketing costs, and development of drug resistance.

I shall identify continuing developments in cardiovascular diagnostics, therapeutics, and bioengineering that is and has been emerging.

1. Mechanisms of disease

REPORT: Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures 

Science 11 April 2014:
Vol. 344 no. 6180 pp. 208-211
http://dx.doi.org/10.1126/science.1250217

Abstract: Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small molecules affects biology and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compound in vivo to profile 3250 small molecules in a systematic and unbiased manner. We identified 317 compounds that specifically perturb the function of 121 genes and characterized the mechanism of specific compounds. Global analysis revealed that the cellular response to small molecules is limited and described by a network of 45 major chemogenomic signatures. Our results provide a resource for the discovery of functional interactions among genes, chemicals, and biological processes.

Yeasty HIPHOP

Laura Zahn
Sci. Signal. 15 April 2014; 7(321): ec103.   http://dx.doi.org/10.1126/scisignal.2005362

In order to identify how chemical compounds target genes and affect the physiology of the cell, tests of the perturbations that occur when treated with a range of pharmacological chemicals are required. By examining the haploinsufficiency profiling (HIP) and homozygous profiling (HOP) chemogenomic platforms, Lee et al.(p. 208) analyzed the response of yeast to thousands of different small molecules, with genetic, proteomic, and bioinformatic analyses. Over 300 compounds were identified that targeted 121 genes within 45 cellular response signature networks. These networks were used to extrapolate the likely effects of related chemicals, their impact upon genetic pathways, and to identify putative gene functions

Key Heart Failure Culprit Discovered

A team of cardiovascular researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai, Sanford-Burnham Medical Research Institute, and University of California, San Diego have identified a small, but powerful, new player in thIe onset and progression of heart failure. Their findings, published in the journal Nature  on March 12, also show how they successfully blocked the newly discovered culprit.
Investigators identified a tiny piece of RNA called miR-25 that blocks a gene known as SERCA2a, which regulates the flow of calcium within heart muscle cells. Decreased SERCA2a activity is one of the main causes of poor contraction of the heart and enlargement of heart muscle cells leading to heart failure.

Using a functional screening system developed by researchers at Sanford-Burnham, the research team discovered miR-25 acts pathologically in patients suffering from heart failure, delaying proper calcium uptake in heart muscle cells. According to co-lead study authors Christine Wahlquist and Dr. Agustin Rojas Muñoz, developers of the approach and researchers in Mercola’s lab at Sanford-Burnham, they used high-throughput robotics to sift through the entire genome for microRNAs involved in heart muscle dysfunction.

Subsequently, the researchers at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai found that injecting a small piece of RNA to inhibit the effects of miR-25 dramatically halted heart failure progression in mice. In addition, it also improved their cardiac function and survival.

“In this study, we have not only identified one of the key cellular processes leading to heart failure, but have also demonstrated the therapeutic potential of blocking this process,” says co-lead study author Dr. Dongtak Jeong, a post-doctoral fellow at the Cardiovascular Research Center at Icahn School of  Medicine at Mount Sinai in the laboratory of the study’s co-senior author Dr. Roger J. Hajjar.

Publication: Inhibition of miR-25 improves cardiac contractility in the failing heart.Christine Wahlquist, Dongtak Jeong, Agustin Rojas-Muñoz, Changwon Kho, Ahyoung Lee, Shinichi Mitsuyama, Alain Van Mil, Woo Jin Park, Joost P. G. Sluijter, Pieter A. F. Doevendans, Roger J. :  Hajjar & Mark Mercola.     Nature (March 2014)    http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13073.html

 

“Junk” DNA Tied to Heart Failure

Deep RNA Sequencing Reveals Dynamic Regulation of Myocardial Noncoding RNAs in Failing Human Heart and Remodeling With Mechanical Circulatory Support

Yang KC, Yamada KA, Patel AY, Topkara VK, George I, et al.
Circulation 2014;  129(9):1009-21.
http://dx.doi.org/10.1161/CIRCULATIONAHA.113.003863              http://circ.ahajournals.org/…/CIRCULATIONAHA.113.003863.full

The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

Junk DNA was long thought to have no important role in heredity or disease because it doesn’t code for proteins. But emerging research in recent years has revealed that many of these sections of the genome produce noncoding RNA molecules that still have important functions in the body. They come in a variety of forms, some more widely studied than others. Of these, about 90% are called long noncoding RNAs (lncRNAs), and exploration of their roles in health and disease is just beginning.

The Washington University group performed a comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied nonfailing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.

In their study, the researchers found that unlike other RNA molecules, expression patterns of long noncoding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.

“The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support,” wrote the researchers. “These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.”

‘Junk’ Genome Regions Linked to Heart Failure

In a recent issue of the journal Circulation, Washington University investigators report results from the first comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied nonfailing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.

“We took an unbiased approach to investigating which types of RNA might be linked to heart failure,” said senior author Jeanne Nerbonne, the Alumni Endowed Professor of Molecular Biology and Pharmacology. “We were surprised to find that long noncoding RNAs stood out.

In the new study, the investigators found that unlike other RNA molecules, expression patterns of long noncoding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.

“We don’t know whether these changes in long noncoding RNAs are a cause or an effect of heart failure,” Nerbonne said. “But it seems likely they play some role in coordinating the regulation of multiple genes involved in heart function.”

Nerbonne pointed out that all types of RNA molecules they examined could make the obvious distinction: telling the difference between failing and nonfailing hearts. But only expression of the long noncoding RNAs was measurably different between heart failure associated with a heart attack (ischemic) and heart failure without the obvious trigger of blocked arteries (nonischemic). Similarly, only long noncoding RNAs significantly changed expression patterns after implantation of left ventricular assist devices.

Comment

Decoding the noncoding transcripts in human heart failure

Xiao XG, Touma M, Wang Y
Circulation. 2014; 129(9): 958960,  http://dx.doi.org/10.1161/CIRCULATIONAHA.114.007548 

Heart failure is a complex disease with a broad spectrum of pathological features. Despite significant advancement in clinical diagnosis through improved imaging modalities and hemodynamic approaches, reliable molecular signatures for better differential diagnosis and better monitoring of heart failure progression remain elusive. The few known clinical biomarkers for heart failure, such as plasma brain natriuretic peptide and troponin, have been shown to have limited use in defining the cause or prognosis of the disease.1,2 Consequently, current clinical identification and classification of heart failure remain descriptive, mostly based on functional and morphological parameters. Therefore, defining the pathogenic mechanisms for hypertrophic versus dilated or ischemic versus nonischemic cardiomyopathies in the failing heart remain a major challenge to both basic science and clinic researchers. In recent years, mechanical circulatory support using left ventricular assist devices (LVADs) has assumed a growing role in the care of patients with end-stage heart failure.3 During the earlier years of LVAD application as a bridge to transplant, it became evident that some patients exhibit substantial recovery of ventricular function, structure, and electric properties.4 This led to the recognition that reverse remodeling is potentially an achievable therapeutic goal using LVADs. However, the underlying mechanism for the reverse remodeling in the LVAD-treated hearts is unclear, and its discovery would likely hold great promise to halt or even reverse the progression of heart failure.

 

Efficacy and Safety of Dabigatran Compared With Warfarin in Relation to Baseline Renal Function in Patients With Atrial Fibrillation: A RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) Trial Analysis

Circulation. 2014; 129: 951-952     http://dx.doi.org/10.1161/​CIR.0000000000000022

In patients with atrial fibrillation, impaired renal function is associated with a higher risk of thromboembolic events and major bleeding. Oral anticoagulation with vitamin K antagonists reduces thromboembolic events but raises the risk of bleeding. The new oral anticoagulant dabigatran has 80% renal elimination, and its efficacy and safety might, therefore, be related to renal function. In this prespecified analysis from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY) trial, outcomes with dabigatran versus warfarin were evaluated in relation to 4 estimates of renal function, that is, equations based on creatinine levels (Cockcroft-Gault, Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) and cystatin C. The rates of stroke or systemic embolism were lower with dabigatran 150 mg and similar with 110 mg twice daily irrespective of renal function. Rates of major bleeding were lower with dabigatran 110 mg and similar with 150 mg twice daily across the entire range of renal function. However, when the CKD-EPI or MDRD equations were used, there was a significantly greater relative reduction in major bleeding with both doses of dabigatran than with warfarin in patients with estimated glomerular filtration rate ≥80 mL/min. These findings show that dabigatran can be used with the same efficacy and adequate safety in patients with a wide range of renal function and that a more accurate estimate of renal function might be useful for improved tailoring of anticoagulant treatment in patients with atrial fibrillation and an increased risk of stroke.

Aldosterone Regulates MicroRNAs in the Cortical Collecting Duct to Alter Sodium Transport.

Robert S Edinger, Claudia Coronnello, Andrew J Bodnar, William A Laframboise, Panayiotis V Benos, Jacqueline Ho, John P Johnson, Michael B Butterworth

Journal of the American Society of Nephrology (Impact Factor: 8.99). 04/2014;     http://dx. DO.org/I:10.1681/ASN.2013090931

Source: PubMed

ABSTRACT A role for microRNAs (miRs) in the physiologic regulation of sodium transport in the kidney has not been established. In this study, we investigated the potential of aldosterone to alter miR expression in mouse cortical collecting duct (mCCD) epithelial cells. Microarray studies demonstrated the regulation of miR expression by aldosterone in both cultured mCCD and isolated primary distal nephron principal cells.

Aldosterone regulation of the most significantly downregulated miRs, mmu-miR-335-3p, mmu-miR-290-5p, and mmu-miR-1983 was confirmed by quantitative RT-PCR. Reducing the expression of these miRs separately or in combination increased epithelial sodium channel (ENaC)-mediated sodium transport in mCCD cells, without mineralocorticoid supplementation. Artificially increasing the expression of these miRs by transfection with plasmid precursors or miR mimic constructs blunted aldosterone stimulation of ENaC transport.

Using a newly developed computational approach, termed ComiR, we predicted potential gene targets for the aldosterone-regulated miRs and confirmed ankyrin 3 (Ank3) as a novel aldosterone and miR-regulated protein.

A dual-luciferase assay demonstrated direct binding of the miRs with the Ank3-3′ untranslated region. Overexpression of Ank3 increased and depletion of Ank3 decreased ENaC-mediated sodium transport in mCCD cells. These findings implicate miRs as intermediaries in aldosterone signaling in principal cells of the distal kidney nephron.

 

2. Diagnostic Biomarker Status

A prospective study of the impact of serial troponin measurements on the diagnosis of myocardial infarction and hospital and 6-month mortality in patients admitted to ICU with non-cardiac diagnoses.

Marlies Ostermann, Jessica Lo, Michael Toolan, Emma Tuddenham, Barnaby Sanderson, Katie Lei, John Smith, Anna Griffiths, Ian Webb, James Coutts, John hambers, Paul Collinson, Janet Peacock, David Bennett, David Treacher

Critical care (London, England) (Impact Factor: 4.72). 04/2014; 18(2):R62.   http://dx.doi.org/:10.1186/cc13818

Source: PubMed

ABSTRACT Troponin T (cTnT) elevation is common in patients in the Intensive Care Unit (ICU) and associated with morbidity and mortality. Our aim was to determine the epidemiology of raised cTnT levels and contemporaneous electrocardiogram (ECG) changes suggesting myocardial infarction (MI) in ICU patients admitted for non-cardiac reasons.
cTnT and ECGs were recorded daily during week 1 and on alternate days during week 2 until discharge from ICU or death. ECGs were interpreted independently for the presence of ischaemic changes. Patients were classified into 4 groups: (i) definite MI (cTnT >=15 ng/L and contemporaneous changes of MI on ECG), (ii) possible MI (cTnT >=15 ng/L and contemporaneous ischaemic changes on ECG), (iii) troponin rise alone (cTnT >=15 ng/L), or (iv) normal. Medical notes were screened independently by two ICU clinicians for evidence that the clinical teams had considered a cardiac event.
Data from 144 patients were analysed [42% female; mean age 61.9 (SD 16.9)]. 121 patients (84%) had at least one cTnT level >=15 ng/L. A total of 20 patients (14%) had a definite MI, 27% had a possible MI, 43% had a cTNT rise without contemporaneous ECG changes, and 16% had no cTNT rise. ICU, hospital and 180 day mortality were significantly higher in patients with a definite or possible MI.Only 20% of definite MIs were recognised by the clinical team. There was no significant difference in mortality between recognised and non-recognised events.At time of cTNT rise, 100 patients (70%) were septic and 58% were on vasopressors. Patients who were septic when cTNT was elevated had an ICU mortality of 28% compared to 9% in patients without sepsis. ICU mortality of patients who were on vasopressors at time of cTNT elevation was 37% compared to 1.7% in patients not on vasopressors.
The majority of critically ill patients (84%) had a cTnT rise and 41% met criteria for a possible or definite MI of whom only 20% were recognised clinically. Mortality up to 180 days was higher in patients with a cTnT rise.

 

Prognostic performance of high-sensitivity cardiac troponin T kinetic changes adjusted for elevated admission values and the GRACE score in an unselected emergency department population.

Moritz BienerMatthias MuellerMehrshad VafaieAllan S JaffeHugo A Katus,Evangelos Giannitsis

Clinica chimica acta; international journal of clinical chemistry (Impact Factor: 2.54). 04/2014;   http://dx.doi.org/10.1016/j.cca.2014.04.007

Source: PubMed

ABSTRACT To test the prognostic performance of rising and falling kinetic changes of high-sensitivity cardiac troponin T (hs-cTnT) and the GRACE score.
Rising and falling hs-cTnT changes in an unselected emergency department population were compared.
635 patients with a hs-cTnT >99th percentile admission value were enrolled. Of these, 572 patients qualified for evaluation with rising patterns (n=254, 44.4%), falling patterns (n=224, 39.2%), or falling patterns following an initial rise (n=94, 16.4%). During 407days of follow-up, we observed 74 deaths, 17 recurrent AMI, and 79 subjects with a composite of death/AMI. Admission values >14ng/L were associated with a higher rate of adverse outcomes (OR, 95%CI:death:12.6, 1.8-92.1, p=0.01, death/AMI:6.7, 1.6-27.9, p=0.01). Neither rising nor falling changes increased the AUC of baseline values (AUC: rising 0.562 vs 0.561, p=ns, falling: 0.533 vs 0.575, p=ns). A GRACE score ≥140 points indicated a higher risk of death (OR, 95%CI: 3.14, 1.84-5.36), AMI (OR,95%CI: 1.56, 0.59-4.17), or death/AMI (OR, 95%CI: 2.49, 1.51-4.11). Hs-cTnT changes did not improve prognostic performance of a GRACE score ≥140 points (AUC, 95%CI: death: 0.635, 0.570-0.701 vs. 0.560, 0.470-0.649 p=ns, AMI: 0.555, 0.418-0.693 vs. 0.603, 0.424-0.782, p=ns, death/AMI: 0.610, 0.545-0.676 vs. 0.538, 0.454-0.622, p=ns). Coronary angiography was performed earlier in patients with rising than with falling kinetics (median, IQR [hours]:13.7, 5.5-28.0 vs. 20.8, 6.3-59.0, p=0.01).
Neither rising nor falling hs-cTnT changes improve prognostic performance of elevated hs-cTnT admission values or the GRACE score. However, rising values are more likely associated with the decision for earlier invasive strategy.

 

Troponin assays for the diagnosis of myocardial infarction and acute coronary syndrome: where do we stand?

Arie Eisenman

ABSTRACT: Under normal circumstances, most intracellular troponin is part of the muscle contractile apparatus, and only a small percentage (< 2-8%) is free in the cytoplasm. The presence of a cardiac-specific troponin in the circulation at levels above normal is good evidence of damage to cardiac muscle cells, such as myocardial infarction, myocarditis, trauma, unstable angina, cardiac surgery or other cardiac procedures. Troponins are released as complexes leading to various cut-off values depending on the assay used. This makes them very sensitive and specific indicators of cardiac injury. As with other cardiac markers, observation of a rise and fall in troponin levels in the appropriate time-frame increases the diagnostic specificity for acute myocardial infarction. They start to rise approximately 4-6 h after the onset of acute myocardial infarction and peak at approximately 24 h, as is the case with creatine kinase-MB. They remain elevated for 7-10 days giving a longer diagnostic window than creatine kinase. Although the diagnosis of various types of acute coronary syndrome remains a clinical-based diagnosis, the use of troponin levels contributes to their classification. This Editorial elaborates on the nature of troponin, its classification, clinical use and importance, as well as comparing it with other currently available cardiac markers.

Expert Review of Cardiovascular Therapy 07/2006; 4(4):509-14.   http://dx.doi.org/:10.1586/14779072.4.4.509 

 

Impact of redefining acute myocardial infarction on incidence, management and reimbursement rate of acute coronary syndromes.

Carísi A Polanczyk, Samir Schneid, Betina V Imhof, Mariana Furtado, Carolina Pithan, Luis E Rohde, Jorge P Ribeiro

ABSTRACT: Although redefinition for acute myocardial infarction (AMI) has been proposed few years ago, to date it has not been universally adopted by many institutions. The purpose of this study is to evaluate the diagnostic, prognostic and economical impact of the new diagnostic criteria for AMI. Patients consecutively admitted to the emergency department with suspected acute coronary syndromes were enrolled in this study. Troponin T (cTnT) was measured in samples collected for routine CK-MB analyses and results were not available to physicians. Patients without AMI by traditional criteria and cTnT > or = 0.035 ng/mL were coded as redefined AMI. Clinical outcomes were hospital death, major cardiac events and revascularization procedures. In-hospital management and reimbursement rates were also analyzed. Among 363 patients, 59 (16%) patients had AMI by conventional criteria, whereas additional 75 (21%) had redefined AMI, an increase of 127% in the incidence. Patients with redefined AMI were significantly older, more frequently male, with atypical chest pain and more risk factors. In multivariate analysis, redefined AMI was associated with 3.1 fold higher hospital death (95% CI: 0.6-14) and a 5.6 fold more cardiac events (95% CI: 2.1-15) compared to those without AMI. From hospital perspective, based on DRGs payment system, adoption of AMI redefinition would increase 12% the reimbursement rate [3552 Int dollars per 100 patients evaluated]. The redefined criteria result in a substantial increase in AMI cases, and allow identification of high-risk patients. Efforts should be made to reinforce the adoption of AMI redefinition, which may result in more qualified and efficient management of ACS.

International Journal of Cardiology 03/2006; 107(2):180-7. · 5.51 Impact Factor   http://www.sciencedirect.com/science/article/pii/S0167527305005279

 

3. Biomedical Engineerin3g

Safety and Efficacy of an Injectable Extracellular Matrix Hydrogel for Treating Myocardial Infarction 

Sonya B. Seif-Naraghi, Jennifer M. Singelyn, Michael A. Salvatore,  et al.
Sci Transl Med 20 February 2013 5:173ra25  http://dx.doi.org/10.1126/scitranslmed.3005503

Acellular biomaterials can stimulate the local environment to repair tissues without the regulatory and scientific challenges of cell-based therapies. A greater understanding of the mechanisms of such endogenous tissue repair is furthering the design and application of these biomaterials. We discuss recent progress in acellular materials for tissue repair, using cartilage and cardiac tissues as examples of application with substantial intrinsic hurdles, but where human translation is now occurring.

 Acellular Biomaterials: An Evolving Alternative to Cell-Based Therapies

J. A. Burdick, R. L. Mauck, J. H. Gorman, R. C. Gorman,
Sci. Transl. Med. 2013; 5, (176): 176 ps4    http://stm.sciencemag.org/content/5/176/176ps4

Acellular biomaterials can stimulate the local environment to repair tissues without the regulatory and scientific challenges of cell-based therapies. A greater understanding of the mechanisms of such endogenous tissue repair is furthering the design and application of these biomaterials. We discuss recent progress in acellular materials for tissue repair, using cartilage and cardiac tissues as examples of applications with substantial intrinsic hurdles, but where human translation is now occurring.


Instructive Nanofiber Scaffolds with VEGF Create a Microenvironment for Arteriogenesis and Cardiac Repair

Yi-Dong Lin, Chwan-Yau Luo, Yu-Ning Hu, Ming-Long Yeh, Ying-Chang Hsueh, Min-Yao Chang, et al.
Sci Transl Med 8 August 2012; 4(146):ra109.   http://dx.doi.org/ 10.1126/scitranslmed.3003841

Angiogenic therapy is a promising approach for tissue repair and regeneration. However, recent clinical trials with protein delivery or gene therapy to promote angiogenesis have failed to provide therapeutic effects. A key factor for achieving effective revascularization is the durability of the microvasculature and the formation of new arterial vessels. Accordingly, we carried out experiments to test whether intramyocardial injection of self-assembling peptide nanofibers (NFs) combined with vascular endothelial growth factor (VEGF) could create an intramyocardial microenvironment with prolonged VEGF release to improve post-infarct neovascularization in rats. Our data showed that when injected with NF, VEGF delivery was sustained within the myocardium for up to 14 days, and the side effects of systemic edema and proteinuria were significantly reduced to the same level as that of control. NF/VEGF injection significantly improved angiogenesis, arteriogenesis, and cardiac performance 28 days after myocardial infarction. NF/VEGF injection not only allowed controlled local delivery but also transformed the injected site into a favorable microenvironment that recruited endogenous myofibroblasts and helped achieve effective revascularization. The engineered vascular niche further attracted a new population of cardiomyocyte-like cells to home to the injected sites, suggesting cardiomyocyte regeneration. Follow-up studies in pigs also revealed healing benefits consistent with observations in rats. In summary, this study demonstrates a new strategy for cardiovascular repair with potential for future clinical translation.

Manufacturing Challenges in Regenerative Medicine

I. Martin, P. J. Simmons, D. F. Williams.
Sci. Transl. Med. 2014; 6(232): fs16.   http://dx.doi.org/10.1126/scitranslmed.3008558

Along with scientific and regulatory issues, the translation of cell and tissue therapies in the routine clinical practice needs to address standardization and cost-effectiveness through the definition of suitable manufacturing paradigms.

 

 

 

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MedTech (Cardiac Imaging) and Medical Devices for Cardiovascular Repair – Curations, Co-Curations and Reporting by Aviva Lev-Ari, PhD, RN


MedTech (Cardiac Imaging) and Medical Devices for Cardiovascular Repair – Curations, Co-Curations and Reporting by Aviva Lev-Ari, PhD, RN

Cardiac Imaging and Cardiovascular Medical Devices in use for

Cardiac Surgery, Cardiothoracic Surgical Procedures and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

List of Publications updated on 8/13/2018

 

Single-Author Curation by Aviva Lev-Ari, PhD, RN

 

42c       Experimental Therapy (Left inter-atrial shunt implant device) for Heart Failure: Expert Opinion on a Preliminary Study on Heart Failure with preserved Ejection Fraction

Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/05/09/experimental-therapy-left-inter-atrial-shunt-implant-device-for-heart-failure-expert-opinion-on-a-preliminary-study-on-heart-failure-with-preserved-ejection-fraction/

 

41c       Spectranetics, a Technology Leader in Medical Devices for Coronary Intervention, Peripheral Intervention, Lead Management to be acquired by Philips for 1.9 Billion Euros

Reporter and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/06/28/spectranetics-a-technology-leader-in-medical-devices-for-coronary-intervention-peripheral-intervention-lead-management-to-be-acquired-by-philips-for-1-9-billion-euros/

 

40c       Moderate Ischemic Mitral Regurgitation: Outcomes of Surgical Treatment during CABG vs CABG without Mitral Valve Repair

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/04/moderate-ischemic-mitral-regurgitation-outcomes-of-surgical-treatment-during-cabg-vs-cabg-without-mitral-valve-repair/

 

39c       Patients with Heart Failure & Left Ventricular Dysfunction: Life Expectancy Increased by coronary artery bypass graft (CABG) surgery: Medical Therapy alone and had Poor Outcomes

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/04/patients-with-heart-failure-left-ventricular-dysfunction-life-expectancy-increased-by-coronary-artery-bypass-graft-cabg-surgery/

 

38c       Mapping the Universe of Pharmaceutical Business Intelligence: The Model developed by LPBI and the Model of Best Practices LLC

Author and Curator of Model A: Aviva Lev-Ari, PhD, RN and Reporter on Model B: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/13/mapping-the-universe-of-pharmaceutical-business-intelligence-the-model-developed-by-lpbi-and-the-model-of-best-practices-llc/

 

37c     MedTech & Medical Devices for Cardiovascular Repair – Curations by

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/17/medtech-medical-devices-for-cardiovascular-repair-curation-by-aviva-lev-ari-phd-rn/

 

36c     Stem Cells and Cardiac Repair: Scientific Reporting by: Aviva Lev-Ari, PhD, RN

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/17/stem-cells-and-cardiac-repair-content-curation-scientific-reporting-aviva-lev-ari-phd-rn/

 

35c       CVD Prevention and Evaluation of Cardiovascular Imaging Modalities: Coronary Calcium Score by CT Scan Screening to justify or not the Use of Statin

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/03/03/cvd-prevention-and-evaluation-of-cardiovascular-imaging-modalities-coronary-calcium-score-by-ct-scan-screening-to-justify-or-not-the-use-of-statin/

 

34c       “Sudden Cardiac Death,” SudD is in Ferrer inCode’s Suite of Cardiovascular Genetic Tests to be Commercialized in the US

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/10/sudden-cardiac-death-sudd-is-in-ferrer-incodes-suite-of-cardiovascular-genetic-tests-to-be-commercialized-in-the-us/

 

33c       Transcatheter Valve Competition in the United States: Medtronic CoreValve infringes on Edwards Lifesciences Corp. Transcatheter Device Patents

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/26/transcatheter-valve-competition-in-the-united-states-medtronic-corevalve-infringes-on-edwards-lifesciences-corp-transcatheter-device-patents/

 

32c       Developments on the Frontier of Transcatheter Aortic Valve Replacement (TAVR) Devices

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/26/developments-on-the-frontier-of-transcatheter-aortic-valve-replacement-tavr-devices/

 

31c       Market Impact on Global Suppliers of Renal Denervation Systems by Pivotal US Trial: Metronics’ Symplicity Renal Denervation System FAILURE at Efficacy Endpoint

Curator and Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/09/market-impact-on-global-suppliers-of-renal-denervation-systems-by-pivotal-us-trial-metronics-symplicity-renal-denervation-system-failure-at-efficacy-endpoint/

 

30c     Stenting for Proximal LAD Lesions

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/18/stenting-for-proximal-lad-lesions/

 

29c       Stent Design and Thrombosis:  Bifurcation Intervention, Drug Eluting Stents (DES) and Biodegrable Stents

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/06/stent-design-and-thrombosis-bifurcation-intervention-drug-eluting-stents-des-and-biodegrable-stents/

 

28c       Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

 

27c       Call for the abandonment of the Off-pump CABG surgery (OPCAB) in the On-pump / Off-pump Debate, +100 Research Studies

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/31/call-for-the-abandonment-of-the-off-pump-cabg-surgery-opcab-in-the-on-pump-off-pump-debate-100-research-studies/

 

26c       3D Cardiovascular Theater – Hybrid Cath Lab/OR Suite, Hybrid Surgery, Complications Post PCI and Repeat Sternotomy

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/19/3d-cardiovascular-theater-hybrid-cath-labor-suite-hybrid-surgery-complications-post-pci-and-repeat-sternotomy/

 

25c       Vascular Surgery: International, Multispecialty Position Statement on Carotid Stenting, 2013 and Contributions of a Vascular Surgeon at Peak Career – Richard Paul Cambria, MD

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/14/vascular-surgery-position-statement-in-2013-and-contributions-of-a-vascular-surgeon-at-peak-career-richard-paul-cambria-md-chief-division-of-vascular-and-endovascular-surgery-co-director-thoracic/

 

24c       Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/09/research-programs-george-m-linda-h-kaufman-center-for-heart-failure-cleveland-clinic/

 

23c       Becoming a Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater and through Scientific Publications 

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/08/becoming-a-cardiothoracic-surgeon-an-emerging-profile-in-the-surgery-theater-and-through-scientific-publications/

 

22c       Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools (Software Validation) for Endovascular Lower-extremity Revascularization Effectiveness: Vascular Surgeons (VSs), Interventional Cardiologists (ICs) and Interventional Radiologists (IRs)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/01/endovascular-lower-extremity-revascularization-effectiveness-vascular-surgeons-vss-interventional-cardiologists-ics-and-interventional-radiologists-irs/

 

21c       No Early Symptoms – An Aortic Aneurysm Before It Ruptures – Is There A Way To Know If I Have it?

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/10/no-early-symptoms-an-aortic-aneurysm-before-it-ruptures-is-there-a-way-to-know-if-i-have-it/

 

20c       Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

 

19c       Revascularization: PCI, Prior History of PCI vs CABG

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/

 

18c       Minimally Invasive Structural CVD Repairs: FDA grants 510(k) Clearance to Philips’ EchoNavigator – X-ray and 3-D Ultrasound Image Fused.

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/03/21/minimally-invasive-structural-cvd-repairs-fda-grants-510k-to-philips-echonavigator-x-ray-and-3-d-ultrasound-image-fused/

 

17c       Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

 

16c       Clinical Trials on Transcatheter Aortic Valve Replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/12/american-college-of-cardiologys-and-the-society-of-thoracic-surgeons-entrance-into-clinical-trials-is-noteworthy-read-more-two-medical-societies-jump-into-clinical-trial-effort-for-tavr-tech-f/

 

15c       FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/28/fda-pending-510k-for-the-latest-cardiovascular-imaging-technology/

 

14c       The ACUITY-PCI score: Will it Replace Four Established Risk Scores — TIMI, GRACE, SYNTAX, and Clinical SYNTAX

Curator: Aviva Lev-Ari, PhD, RN   https://pharmaceuticalintelligence.com/2013/01/03/the-acuity-pci-score-will-it-replace-four-established-risk-scores-timi-grace-syntax-and-clinical-syntax/

13c       Renal Sympathetic Denervation: Updates on the State of Medicine

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/31/renal-sympathetic-denervation-updates-on-the-state-of-medicine/

 

12c       Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

 

11c       CABG or PCI: Patients with Diabetes – CABG Rein Supreme

Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2012/11/05/cabg-or-pci-patients-with-diabetes-cabg-rein-supreme/

 

10c       Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

 

9c         Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

 

8c         New Drug-Eluting Stent Works Well in STEMI

Curator: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2012/08/22/new-drug-eluting-stent-works-well-in-stemi/

 

7c         Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

 

6c         DELETED, identical to 7r

 

5c         Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

 

4c         Global Supplier Strategy for Market Penetration &amp; Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology &amp; Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/06/22/global-supplier-strategy-for-market-penetration-partnership-options-niche-suppliers-vs-national-leaders-in-the-massachusetts-cardiology-vascular-surgery-tools-and-devices-market-for-car/

 

3c         Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/

 

2c         Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/06/19/executive-compensation-and-comparator-group-definition-in-the-cardiac-and-vascular-medical-devices-sector-a-bright-future-for-edwards-lifesciences-corporation-in-the-transcatheter-heart-valve-replace/

 

1c         Treatment of Refractory Hypertension via Percutaneous Renal Denervation

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/06/13/treatment-of-refractory-hypertension-via-percutaneous-renal-denervation/

 

Lev-Ari, A. (2006b). First-In-Man Stent Implantation Clinical Trials & Medical Ethical Dilemmas.

Bouve College of Health Sciences, Northeastern University, Boston, MA 02115

 

Co-Curation Articles on MedTech and Cardiac Medical Devices by LPBI Group’s Team Members and Aviva Lev-Ari, PhD, RN

67co     ATP – the universal energy carrier in the living cell: Reflections on the discoveries and applications in Medicine

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/27/atp-the-universal-energy-carrier-in-the-living-cell-reflections-on-the-discoveries-and-applications-in-medicine/

66co     Eric Topol, M.D.

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/09/22/eric-topol-m-d/

 

65co     Summary of Translational Medicine – e-Series A: Cardiovascular Diseases, Volume Four – Part 1

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/28/summary-of-translational-medicine-cardiovascular-diseases-part-1/

 

64co     Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/27/larryhbernintroduction_to_cardiovascular_diseases-translational_medicine-part_2/

 

63co     Epilogue: Volume 4 – Translational, Post-Translational and Regenerative Medicine in Cardiology

Larry H Bernstein, MD, FCAP, Author and Curator, Consultant for Series B,C,D,E

Justin Pearlman, MD, PhD, FACC, Content Consultant for Series A: Cardiovascular Diseases

Aviva Lev-Ari, PhD, RN, Co-Editor and Editor-in-Chief, BioMed e-Series

https://pharmaceuticalintelligence.com/2014/05/12/epilogue-volume-4-post-translational-and-transformative-cardiology/

 

62co     Introduction to Translational Medicine (TM) – Part 1: Translational Medicine

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/25/introduction-to-translational-medicine-tm-part-1/

 

61co     Acute Myocardial Infarction: Curations of Cardiovascular Original Research A Bibliography

Curators: Aviva Lev-Ari, PhD, RN and Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/01/22/acute-myocardial-infarction-curations-of-cardiovascular-original-research-a-bibliography/

60co     Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/

 

59co     Coronary Circulation Combined Assessment: Optical Coherence Tomography (OCT), Near-Infrared Spectroscopy (NIRS) and Intravascular Ultrasound (IVUS) – Detection of Lipid-Rich Plaque and Prevention of Acute Coronary Syndrome (ACS)

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/25/coronary-circulation-combined-assessment-optical-coherence-tomography-oct-near-infrared-spectroscopy-nirs-and-intravascular-ultrasound-ivus-detection-of-lipid-rich-plaque-and-prevention-of-a/

 

58co     Normal and Anomalous Coronary Arteries: Dual Source CT in Cardiothoracic Imaging

Reporters: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/18/normal-and-anomalous-coronary-arteries-dual-source-ct-in-cardiothoracic-imaging/

 

57co     Alternative Designs for the Human Artificial Heart: Patients in Heart Failure –  Outcomes of Transplant (donor)/Implantation (artificial) and Monitoring Technologies for the Transplant/Implant Patient in the Community

Authors and Curators: Larry H Bernstein, MD, FCAP and Justin D Pearlman, MD, PhD, FACC and Article Curator and Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/05/alternative-designs-for-the-human-artificial-heart-the-patients-in-heart-failure-outcomes-of-transplant-donorimplantation-artificial-and-monitoring-technologies-for-the-transplantimplant-pat/

 

56co     Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions

Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC, and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

 

55co     The Cardiorenal Syndrome in Heart Failure: Cardiac? Renal? syndrome?

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/the-cardiorenal-syndrome-in-heart-failure/

 

54co     Mechanical Circulatory Assist Devices as a Bridge to Heart Transplantation or as “Destination Therapy“: Options for Patients in Advanced Heart Failure

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/advanced-heart-failure/

 

53co     Heart Transplantation: NHLBI’s Ten year Strategic Research Plan to Achieving Evidence-based Outcomes

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/heart-transplantation-research-in-the-next-decade-a-goal-to-achieving-evidence-based-outcomes/

 

52co     After Cardiac Transplantation: Sirolimus acts as immunosuppressant Attenuates Allograft Vasculopathy

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/sirolimus-as-primary-immunosuppression-attenuates-allograft-vasculopathy/

51co     Orthotropic Heart Transplant (OHT): Effects of Autonomic Innervation / Denervation on Atrial Fibrillation (AF) Genesis and Maintenance

Author and Curator: Larry H. Bernstein, MD, FCAP and

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/decreased-postoperative-atrial-fibrillation-following-cardiac-transplantation/

 

50co     CABG Survival in Multivessel Disease Patients: Comparison of Arterial Bypass Grafts vs Saphenous Venous Grafts

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/multiple-arterial-grafts-improve-late-survival-of-patients-with-multivessel-disease/

49co     Coronary Reperfusion Therapies: CABG vs PCI – Mayo Clinic preprocedure Risk Score (MCRS) for Prediction of in-Hospital Mortality after CABG or PCI

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/mayo-risk-score-for-percutaneous-coronary-intervention/

 

48co     Pre-operative Risk Factors and Clinical Outcomes Associated with Vasoplegia in Recipients of Orthotopic Heart Transplantation in the Contemporary Era

Writer and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/30/vasoplegia-in-orthotopic-heart-transplants/

 

47co     Carotid Endarterectomy (CEA) vs. Carotid Artery Stenting (CAS): Comparison of CMMS high-risk criteria on the Outcomes after Surgery:  Analysis of the Society for Vascular Surgery (SVS) Vascular Registry Data

Writer and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/28/effect-on-endovascular-carotid-artery-repair-outcomes-of-the-cmms-high-risk-criteria/

 

46co     Improved Results for Treatment of Persistent type 2 Endoleak after Endovascular Aneurysm Repair: Onyx Glue Embolization

Author and Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/28/onyx-glue-for-the-treatment-of-persistent-type-2-endoleak/

 

45co     DELETED, was identical to 47co

 

44co     Open Abdominal Aortic Aneurysm (AAA) repair (OAR) vs. Endovascular AAA Repair (EVAR) in Chronic Kidney Disease (CKD) Patients – Comparison of Surgery Outcomes

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/28/the-effect-of-chronic-kidney-disease-on-outcomes-after-abdominal-aortic-aneurysm-repair/

 

43co     Effect of Hospital Characteristics on Outcomes of Endovascular Repair of Descending Aortic Aneurysms in US Medicare Population

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/27/effect-of-hospital-characteristics-on-outcomes-of-endovascular-repair-of-descending-aortic-aneurysms-in-us-medicare-population/

 

42co     First case in the US: Valve-in-Valve (Aortic and  Mitral) Replacements with Transapical Transcatheter Implants – The Use of Transfemoral Devices

Author: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/23/valve-in-valve-replacements-with-transapical-transcatheter-implants/

 

41co     Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/23/comparison-of-cardiothoracic-bypass-and-percutaneous-interventional-catheterization-survivals/

 

40co     Ventricular Assist Device (VAD): A Recommended Approach to the Treatment of Intractable Cardiogenic Shock

Author: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/18/a-recommended-approach-to-the-treatmnt-of-intractable-cardiogenic-shock/

39co     Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD)

Author: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/17/management-of-difficult-trans-apical-transcatheter-aortic-valve-replacement-in-a-patient-with-severe-and-complex-arterial-disease/

 

38co     Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve

Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/17/postdilatation-to-reduce-paravalvular-regurgitation-during-transcatheter-aortic-valve-replacement/

 

37co     Acute and Chronic Myocardial Infarction: Quantification of Myocardial Perfusion Viability – FDG-PET/MRI vs. MRI or PET alone

Justin Pearlman, MD, PhD and Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/05/22/acute-and-chronic-myocardial-infarction-quantification-of-myocardial-viability-fdg-petmri-vs-mri-or-pet-alone/

 

36co     On Devices and On Algorithms: Arrhythmia after Cardiac SurgeryPrediction and ECG Prediction of Paroxysmal Atrial Fibrillation Onset

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/07/on-devices-and-on-algorithms-arrhythmia-after-cardiac-surgery-prediction-and-ecg-prediction-of-paroxysmal-atrial-fibrillation-onset/

 

35co     Vascular Repair: Stents and Biologically Active Implants

Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/04/stents-biologically-active-implants-and-vascular-repair/

 

34co     Drug Eluting Stents: On MIT‘s Edelman Lab’s Contributions to Vascular Biology and its Pioneering Research on DES

Author: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/25/contributions-to-vascular-biology/

 

33co     Mitral Valve Repair: Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC and Article Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/04/mitral-valve-repair-who-is-a-candidate-for-a-non-ablative-fully-non-invasive-procedure/

 

32co     Source of Stem Cells to Ameliorate Damaged Myocardium (Part 2)

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/29/source-of-stem-cells-to-ameliorate-damaged-myocardium/

 

31co     State of Cardiology on Wall Stress, Ventricular Workload and Myocardial Contractile Reserve: Aspects of Translational Medicine (TM)

Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/30/state-of-cardiology-on-wall-stress-ventricular-workload-and-myocardial-contractile-reserve-aspects-of-translational-medicine/

 

30co  DELETED identical to 58co

 

29co  DELETED identical to 58co

 

28co  DELETED identical to 57co

 

27co  DELETED identical to 47co

 

26co     Cardiac Resynchronization Therapy (CRT) to Arrhythmias: Pacemaker/Implantable Cardioverter Defibrillator (ICD) Insertion

Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/22/cardiac-resynchronization-therapy-crt-to-arrhythmias-pacemakerimplantable-cardioverter-defibrillator-icd-insertion/

 

25co     Emerging Clinical Applications for Cardiac CT: Plaque Characterization, SPECT Functionality, Angiogram’s and Non-Invasive FFR

Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/17/emerging-clinical-applications-for-cardiac-ct-plaque-characterization-spect-functionality-angiograms-and-non-invasive-ffr/

 

24co     Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools (Software Validation) for Ischemic Assessment (Diagnostics) – Change in Paradigm: The RIGHT vessel not ALL vessels

Reporters: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/04/fractional-flow-reserve-ffr-instantaneous-wave-free-rario-ifr-an-evaluation-of-catheterization-lab-tools-for-ischemic-assessment/

 

23co  DELETED identical to 24co

 

22co  DELETED identical to 49co

 

21co  DELETED identical to 52co

 

20co  DELETED identical to 50co

 

19co  DELETED identical to 57co

 

18co     Open Abdominal Aortic Aneurysm (AAA) repair (OAR) vs. Endovascular AAA Repair (EVAR) in Chronic Kidney Disease (CKD) Patients – Comparison of Surgery Outcomes

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/28/the-effect-of-chronic-kidney-disease-on-outcomes-after-abdominal-aortic-aneurysm-repair/

 

17co     Improved Results for Treatment of Persistent type 2 Endoleak after Endovascular Aneurysm Repair: Onyx Glue Embolization

Author & Curator: Larry H Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/28/onyx-glue-for-the-treatment-of-persistent-type-2-endoleak/

16co     Effect of Hospital Characteristics on Outcomes of Endovascular Repair of Descending Aortic Aneurysms in US Medicare Population

Author and Curator: Larry H. Bernstein, MD, FCAP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/27/effect-of-hospital-characteristics-on-outcomes-of-endovascular-repair-of-descending-aortic-aneurysms-in-us-medicare-population/

 

15co     Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/23/comparison-of-cardiothoracic-bypass-and-percutaneous-interventional-catheterization-survivals/

 

14co     First case in the US: Valve-in-Valve (Aortic and Mitral) Replacements with Transapical Transcatheter Implants – The Use of Transfemoral Devices.

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/23/valve-in-valve-replacements-with-transapical-transcatheter-implants/

 

13co     Phrenic Nerve Stimulation in Patients with Cheyne-Stokes Respiration and Congestive Heart Failure

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/20/phrenic-nerve-stimulation-in-patients-with-cheyne-stokes-respiration-and-congestive-heart-failure/

 

12co  DELETED identical to 40co

11co  DELETED identical to 38co

10co  DELETED identical to 39co

 

9co       Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/24/imaging-biomarker-for-arterial-stiffness-pathways-in-pharmacotherapy-for-hypertension-and-hypercholesterolemia-management/

 

8co       DELETED identical to 37co

 

7co       Treatment, Prevention and Cost of Cardiovascular Disease: Current & Predicted Cost of Care and the Potential for Improved Individualized Care Using Clinical Decision Support Systems

Author, and Content Consultant to e-SERIES A: Cardiovascular Diseases: Justin Pearlman, MD, PhD, FACC, Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

 

6co       Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus

Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/11/arterial-elasticity-in-quest-for-a-drug-stabilizer-isolated-systolic-hypertension-caused-by-arterial-stiffening-ineffectively-treated-by-vasodilatation-antihypertensives/

 

5co       DELETED identical to 36co

 

4co       Biomaterials Technology: Models of Tissue Engineering for Reperfusion and Implantable Devices for Revascularization

Author and Curator: Larry H Bernstein, MD, FACP and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/05/bioengineering-of-vascular-and-tissue-models/

 

3co       Cardiovascular Diseases: Decision Support Systems for Disease Management Decision Making

Curators: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/04/cardiovascular-diseases-decision-support-systems-for-disease-management-decision-making/

 

2co    DELETED identical to 35co

 

1co    DELETED identical to 34co

 

Single-Author Reporting on MedTech and Cardiac Medical Devices by

Aviva Lev-Ari, PhD, RN

 

162r Rhythm Management Device Hardware (Dual-chamber Pacemaker) coupled with BackBeat’s Cardiac Neuromodulation Therapy (CNT) bioelectronic therapy for Lowering Systolic Blood Pressure for patients with Pacemakers

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/10/03/rhythm-management-device-hardware-dual-chamber-pacemaker-coupled-with-backbeats-cardiac-neuromodulation-therapy-cnt-bioelectronic-therapy-for-lowering-systolic-blood-pressure-for-patients-w/

 

161r Pulmonary Valve Replacement and Repair: Valvuloplasty Device – Tissue (bioprosthetic) or mechanical valve;  Surgery type – Transcatheter Pulmonary Valve Replacement (TPVR) vs Open Heart, Valve Repair – Commissurotomy, Valve-ring Annuloplasty

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/09/30/pulmonary-valve-replacement-and-repair-valvuloplasty-device-tissue-bioprosthetic-or-mechanical-valve-surgery-type-transcatheter-pulmonary-valve-replacement-tpvr-vs-open-heart-valve-re/

 

160r Are TAVR volume requirements limiting rural and minority access to this life-saving procedure, or are they still necessary for patient safety?

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/09/20/are-tavr-volume-requirements-limiting-rural-and-minority-access-to-this-life-saving-procedure-or-are-they-still-necessary-for-patient-safety/

159r Top 100 of 415 articles published on PubMed in 2018 on TAVR

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/14/top-100-of-415-articles-published-on-pubmed-in-2018-on-tavr/

158r Aortic Stenosis (AS): Managed Surgically by Transcatheter Aortic Valve Replacement (TAVR) – Search Results for “TAVR” on NIH.GOV website, Top 16 pages

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/14/aortic-stenosis-as-managed-surgically-by-transcatheter-aortic-valve-replacement-tavr-search-results-for-tavr-on-nih-gov-website-top-16-pages/

 

157r Comparison of four methods in diagnosing acute myocarditis: The diagnostic performance of native T1, T2, ECV to LLC

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/08/08/comparison-of-four-methods-in-diagnosing-acute-myocarditis-the-diagnostic-performance-of-native-t1-t2-ecv-to-llc/

 

156r   Left ventricular outflow tract (LVOT) obstruction (LVOTO): The Role of CT in TAVR and in TMVR

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/07/25/left-ventricular-outflow-tract-lvot-obstruction-lvoto-the-role-of-ct-in-tavr-and-in-tmvr/

 

155r   CABG: a Superior Revascularization Modality to PCI in Patients with poor LVF, Multivessel disease and Diabetes, Similar Risk of Stroke between 31 days and 5 years, post intervention

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/07/25/cabg-a-superior-revascularization-modality-to-pci-in-patients-with-poor-lvf-multivessel-disease-and-diabetes-similar-risk-of-stroke-between-31-days-and-5-years-post-intervention/

 

154r   Stanford University researchers have developed a scanner that unites optical, radioluminescence, and photoacoustic imaging to evaluate for Thin-Cap Fibro Atheroma (TCFA)

Reporter: Aviva Lev-Ari, RN

https://pharmaceuticalintelligence.com/2018/07/23/stanford-university-researchers-have-developed-a-scanner-that-unites-optical-radioluminescence-and-photoacoustic-imaging-to-evaluate-for-thin-cap-fibro-atheroma-tcfa/

 

153r   An Overview of the Heart Surgery Specialty: heart transplant, lung transplant, heart-lung transplantation, aortic valve surgery, bypass surgery, minimally invasive cardiac surgery, heart valve surgery, removal of cardiac tumors, reoperation valve surgery

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/07/11/the-heart-surgery-specialty-heart-transplant-lung-transplant-heart-lung-transplantation-aortic-valve-surgery-bypass-surgery-minimally-invasive-cardiac-surgery-heart-valve-surgery-removal-of-ca/

 

152r   PCI, CABG, CHF, AMI – Two Payment Methods: Bundled payments (hospitalization costs, up to 90 days of post-acute care, nursing home care, complications, and rehospitalizations) vs Diagnosis-related groupings cover only what happens in the hospital.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/07/10/pci-cabg-chf-ami-two-payment-methods-bundled-payments-hospitalization-costs-up-to-90-days-of-post-acute-care-nursing-home-care-complications-and-rehospitalizations-vs-diagnosis-related-gro/

 

151r   Expanded Stroke Thrombectomy Guidelines: FDA expands treatment window for use (Up to 24 Hours Post-Stroke) of clot retrieval devices (Stryker’s Trevo Stent) in certain stroke patients

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/27/expanded-stroke-thrombectomy-guidelines-fda-expands-treatment-window-for-use-up-to-24-hours-post-stroke-of-clot-retrieval-devices-strykers-trevo-stent-in-certain-stroke-patients/

 

150r   What is the Role of Noninvasive Diagnostic Fractional Flow Reserve (FFR) CT vs Invasive FFR for PCI?

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/27/what-is-the-role-of-noninvasive-diagnostic-fractional-flow-reserve-ffr-ct-vs-invasive-ffr-for-pci/

 

149r   Renowned Electrophysiologist Dr. Arthur Moss Died on February 14, 2018 at 86

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/27/renowned-electrophysiologist-dr-arthur-moss-died-on-february-14-2018-at-86/

 

148r   Mitral Valve Repair Global Leader: Edwards LifeSciences acquired Harpoon Medical for $250 in 12/2017 followed by $690 million buyout of Valtech Cardio 1/2017 and $400 million acquisition of CardiAQ Valve Technologies in 8/2017

Reporter: Aviva Lev-Ari, PhD

https://pharmaceuticalintelligence.com/2017/12/08/mitral-valve-repair-global-leader-edwards-lifesciences-acquired-harpoon-medical-for-250-in-12-2017-followed-by-690-million-buyout-of-valtech-cardio-1-2017-and-400-million-acquisitio/

 

147r   2017 American Heart Association Annual Meeting: Sunday’s Science at #AHA17 – Presidential Address

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/13/2017-american-heart-association-annual-meeting-sundays-science-at-aha17-presidential-address/

 

146r   Medical Devices Early Feasibility FDA’s Pathway – Accelerated Recruitment for Randomized Clinical Trials: Replacement and Repair of Mitral Valves

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/13/medical-devices-early-feasibility-fdas-pathway-accelerated-recruitment-for-randomized-clinical-trials-replacement-and-repair-of-mitral-valves/

 

145r   Arrhythmias Detection: Speeding Diagnosis and Treatment – New deep learning algorithm can diagnose 14 types of heart rhythm defects by sifting through hours of ECG data generated by some REMOTELY iRhythm’s wearable monitors

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/arrhythmias-detection-speeding-diagnosis-and-treatment-new-deep-learning-algorithm-can-diagnose-14-types-of-heart-rhythm-defects-by-sifting-through-hours-of-ecg-data-generated-by-some-remotely-irhy/

 

144r   Cleveland Clinic: Change at the Top, Tomislav “Tom” Mihaljevic, M.D., as its next CEO and President to succeed Toby Cosgrove, M.D., effective Jan. 1, 2018

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/09/01/cleveland-clinic-change-at-the-top-tomislay-tom-mihaljevic-m-d-as-its-next-ceo-and-president-to-succeed-toby-cosgrove-m-d-effective-jan-1-2018/

 

143r   Off-Label TAVR Procedures: 1 in 10 associated with higher in-hospital 30-day mortality, 1-year mortality was similar in the Off-Label and the On-Label groups

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/06/22/off-label-tavr-procedures-1-in-10-associated-with-higher-in-hospital-30-day-mortality-1-year-mortality-was-similar-in-the-off-lavel-and-the-on-label-groups/

 

142r   Right Internal Carotid Artery Clot Aspiration: 4.5 Minute Thrombectomy Using the ADAPT-FAST Technique and the ACE68 Catheter

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/17/right-internal-carotid-artery-clot-aspiration-4-5-minute-thrombectomy-using-the-adapt-fast-technique-and-the-ace68-catheter/

 

141r   Less is More: Minimalist Mitral Valve Repair: Expert Opinion of Prem S. Shekar, MD, Chief, Division of Cardiac Surgery, BWH – #7, 2017 Disruptive Dozen at #WMIF17

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/17/less-is-more-minimalist-mitral-valve-repair-expert-opinion-of-prem-s-shekar-md-chief-division-of-cardiac-surgery-bwh-7-2017-disruptive-dozen-at-wmif17/

140r   What is the history of STEMI? What is the current treatment for Cardiogenic Shock? The Case Study of Detroit Cardiogenic Shock Initiative

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/07/what-is-the-history-of-stemi-what-is-the-current-treatment-for-cardiogenic-shock-the-case-study-of-detroit-cardiogenic-shock-initiative/

 

139r   ACC 2017, 3/30/2017 – Poor Outcomes for Bioresorbable Stents in Small Coronary Arteries

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/04/02/acc-2017-3302017-poor-outcomes-for-bioresorbable-stents-in-small-coronary-arteries/

 

138r   Edwards Lifesciences closes $690m a buy of Valtech Cardio and most of the heart valve repair technologies it’s developing

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/25/edwards-lifesciences-closes-690m-a-buy-of-valtech-cardio-and-most-of-the-heart-valve-repair-technologies-its-developing/

 

137r   First U.S. TAVR Patients Treated With Temporary Pacing Lead (Tempo Lead)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/21/first-u-s-tavr-patients-treated-with-temporary-pacing-lead-tempo-lead/

 

136r   2017 World Medical Innovation Forum: Cardiovascular, May 1-3, 2017, Partners HealthCare, Boston, at the Westin Hotel, Boston

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/14/2017-world-medical-innovation-forum-cardiovascular-may-1-3-2017-partners-healthcare-boston-at-the-westin-hotel-boston/

 

135r   Advanced Peripheral Artery Disease (PAD): Axillary Artery PCI for Insertion and Removal of Impella Device

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/13/advanced-peripheral-artery-disease-pad-axillary-pci-for-insertion-and-removal-of-impella-device/

 

134r   CorPath robotic system for bifurcation lesions with placement of the Absorb GT1 Bioresorbable Vascular Scaffold (BVS) (Abbott Vascular)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/07/corpath-robotic-system-for-bifurcation-lesions-with-placement-of-the-absorb-gt1-bioresorbable-vascular-scaffold-bvs-abbott-vascular/

 

133r   Hadassah Opens Israel’s First Heart Valve Disease Clinic

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/06/hadassah-opens-israels-first-heart-valve-disease-clinic/

 

132r   Left Main Coronary Artery Disease (LMCAD): Stents vs CABG – The less-invasive option is Equally Safe and Effective

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/06/left-main-coronary-artery-disease-lmcad-stents-vs-cabg-the-less-invasive-option-is-equally-safe-and-effective/

 

131r   Advances and Future Directions for Transcatheter Valves – Mitral and tricuspid valve repair technologies now in development

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/06/advances-and-future-directions-for-transcatheter-valves-mitral-and-tricuspid-valve-repair-technologies-now-in-development/

 

130r   New method for performing Aortic Valve Replacement: Transmural catheter procedure developed at NIH, Minimally-invasive tissue-crossing – Transcaval access, abdominal aorta and the inferior vena cava

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/10/31/new-method-for-performing-aortic-valve-replacement-transmural-catheter-procedure-developed-at-nih-minimally-invasive-tissue-crossing-transcaval-access-abdominal-aorta-and-the-inferior-vena-cava/

 

129r   Robot-assisted coronary intervention program @MGH – The first CorPath Vascular Robotic System, lets Interventional Cardiologists position the right stent in the right place at reduces radiation exposure by 95%

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/10/17/robot-assisted-coronary-intervention-program-mgh-the-first-corpath-vascular-robotic-system-lets-interventional-cardiologists-position-the-right-stent-in-the-right-place-at-reduces-radiation-exposu/

 

128r   Second in the United States to implant Edwards Newly FDA-Approved Aortic Valve “Intuity Elite” Sutureless Valve at Northwestern Medicine

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/10/13/second-in-the-united-states-to-implant-edwards-newly-fda-approved-aortic-valve-intuity-elite-sutureless-valve-at-northwestern-medicine/

 

127r   First-in-Man Mitral Valve Repairs Device used for Tricuspid Valve Repair: Cardioband used by University Hospital Zurich Heart Team

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/10/13/first-in-man-mitral-valve-repairs-device-used-for-tricuspid-valve-repair-cardioband-used-by-university-hospital-zurich-heart-team/

 

126r   Inferior Vena Cava Filters: Device for Prevention of Pulmonary Embolism and Thrombosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/10/04/vena-caval-filters-device-for-prevention-of-pulmonary-embolism-and-thrombosis/

 

125r   Chest Radiation Therapy causes Collateral Damage to the Human Heart

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/28/chest-radiation-therapy-causes-collateral-damage-to-the-human-heart/

 

124r   Clinical Trials for Transcatheter Mitral Valves Annulus Repairs and TAVR: CT Structural Software for Procedural Planning and Anatomical Assessments

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/15/clinical-trials-for-transcatheter-mitral-valves-annulus-repairs-and-tavr-ct-structural-software-for-procedural-planning-and-anatomical-assessments/

 

123r   Lysyl Oxidase (LOX) gene missense mutation causes Thoracic Aortic Aneurysm and Dissection (TAAD) in Humans because of inadequate cross-linking of collagen and elastin in the aortic wall

Mutation carriers may be predisposed to vascular diseases because of weakened vessel walls under stress conditions.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/19/lysyl-oxidase-lox-gene-missense-mutation-causes-thoracic-aortic-aneurysm-and-dissection-taad-in-humans-because-of-inadequate-cross-linking-of-collagen-and-elastin-in-the-aortic-wall/

 

122r   SAPIEN 3 Transcatheter Aortic Valve Replacement in High-Risk and Inoperable Patients with Severe Aortic Stenosis: One-Year Clinical Outcomes

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/14/sapien-3-transcatheter-aortic-valve-replacement-in-high-risk-and-inoperable-patients-with-severe-aortic-stenosis-one-year-clinical-outcomes/

 

121r   Entire Family of Impella Abiomed Impella® Therapy Left Side Heart Pumps: FDA Approved To Enable Heart Recovery

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/06/entire-family-of-impella-abiomed-impella-therapy-left-side-heart-pumps-fda-approved-to-enable-heart-recovery/

 

120r   DELETED identical to 121r

 

119r   FDA approved Absorb GT1 Bioresorbable Vascular Scaffold System (BVS), Everolimus releasing and Absorbed by the body in 3 years

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/05/fda-approved-absorb-gt1-bioresorbable-vascular-scaffold-system-bvs-everolimus-releasing-and-absorbed-by-the-body-in-3-years/

 

118r   TAVR with Sapien 3: combined all-cause death & disabling stroke rate was 8.4% and 16.6% for the surgery arm

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/05/tavr-with-sapien-3-combined-all-cause-death-disabling-stroke-rate-was-8-4-and-16-6-for-the-surgery-arm/

 

117r   Boston Scientific implant designed to occlude the heart’s left atrial appendage implicated with embolization – Device Sales in Europe halts

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/05/boston-scientific-implant-designed-to-occlude-the-hearts-left-atrial-appendage-implicated-with-embolization-device-sales-in-europe-halts/

 

116r   Issue with Delivery System Deployment Process: MitraClip Clip Recalled by Abbott Vascular

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/03/21/issue-with-delivery-system-deployment-process-mitraclip-clip-recalled-by-abbott-vascular/

 

115r   Prospects for First-in-man Implantation of Transcatheter Mitral Valve by Direct Flow Medical

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/03/03/prospects-for-first-in-man-implantation-of-transcatheter-mitral-valve-by-direct-flow-medical/

 

114r   Steps to minimise replacement of cardiac implantable electronic devices

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/02/04/steps-to-minimise-replacement-of-cardiac-implantable-electronic-devices/

 

113r Atrial Fibrillation Surgery Market worth $1.73 Billion by 2020

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/12/15/atrial-fibrillation-surgery-market-worth-1-73-billion-by-2020/

 

112r   Abbott’s Bioabsorbable Stent met its Primary Endpoint in a U.S. Clinical Trial, applications for FDA Approval follows

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/10/13/abbotts-bioabsorbable-stent-met-its-primary-endpoint-in-a-u-s-clinical-trial-applications-for-fda-approval-follows/

 

111r   Low-dose and High-resolution Cardiac Imaging with Revolution™ CT

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/08/23/low-dose-and-high-resolution-cardiac-imaging-with-revolution-ct/

 

110r   Hybrid Imaging 3D Model of a Human Heart by Cardiac Imaging Techniques: CT and Echocardiography

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/08/03/hybrid-imaging-3d-model-of-a-human-heart-by-cardiac-imaging-techniques-ct-and-echocardiography/

 

109r   Premature Ventricular Contraction percentage predicts new Systolic Dysfunction and clinically diagnosed CHF and overall Mortality

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/14/premature-ventricular-contraction-percentage-predicts-new-systolic-dysfunction-and-clinically-diagnosed-chf-and-overall-mortality/

 

108r   ‘Mammogram for the heart’ can predict heart attack by Dr. James Min, Director of the Dalio Institute of Cardiovascular Imaging at New York-Presbyterian Hospital and Weill Cornell Medical College

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/07/mammogram-for-the-heart-can-predict-heart-attack-by-dr-james-min-director-of-the-dalio-institute-of-cardiovascular-imaging-at-new-york-presbyterian-hospital-and-weill-cornell-medic/

 

107r   Abbott’s percutaneous MitraClip mitral valve repair device SUPERIOR to Pacemaker or Implantable Cardioverter Defibrillator (ICD) for reduction of Ventricular Tachyarrhythmia (VT) episodes

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/05/19/abbotts-percutaneous-mitraclip-mitral-valve-repair-device-superior-to-pacemaker-or-implantable-cardioverter-defibrillator-for-reduction-of-ventricular-tachyarrhythmia-vt-episodes/

 

106r   No evidence to change current transfusion practices for adults undergoing complex cardiac surgery: RECESS evaluated 1,098 cardiac surgery patients received red blood cell units stored for short or long periods

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/08/no-evidence-to-change-current-transfusion-practices-for-adults-undergoing-complex-cardiac-surgery-recess-evaluated-1098-cardiac-surgery-patients-received-red-blood-cell-units-stored-for-short-or-lon/

 

105r   3-D BioPrinting in use to create Cardiac Living Tissue: Print Your Heart Out

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/03/16/3-d-bioprinting-in-use-to-create-cardiac-living-tissue-print-your-heart-out/

 

104r   Fractional Flow Reserve vs. Angiography in Non-ST-segment Elevation Myocardial Infarction

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/02/24/fractional-flow-reserve-vs-angiography-in-non-st-segment-elevation-myocardial-infarction/

 

103r   Transradial PCI Bests Transfemoral PCI in UK Analysis, regardless of Patient’s Age

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/02/24/transradial-pci-bests-transfemoral-pci-in-uk-analysis-regardless-of-patients-age/

 

102r   DELETED, identical to 101r

 

101r   Protein Clue to Sudden Cardiac Death: Research @Oxford University

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/02/19/protein-clue-to-sudden-cardiac-death-research-oxford-university/

 

100r   Culprit-Lesion Over Multivessel PCI in STEMI Patients

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/07/culprit-lesion-over-multivessel-pci-in-stemi-patients/

 

99r     Convergent Procedure addresses the progressive nature of A-Fib

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/29/convergent-procedure-addresses-the-progressive-nature-of-a-fib/

 

98r     Paul Zoll, MD: Originator of Modern Electrocardiac Therapy – A Biography by Stafford Cohen, MD, BIDMC

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/16/paul-zoll-md-originator-of-modern-electrocardiac-therapy-a-biography-by-stafford-cohen-md-bidmc/

 

 

97r     Surgical Options for Left Atrial Appendage (LAA) Removal for A-Fib Patients without Indication for Anticoagulant Therapy

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/15/surgical-options-for-left-atrial-appendage-laa-removal-for-a-fib-patients-without-indication-for-anticoagulant-therapy/

 

96r     Intracranial Vascular Stenosis: Comparison of Clinical Trials: Percutaneous Transluminal Angioplasty and Stenting (PTAS) vs. Clot-inhibiting Drugs: Aspirin and Clopidogrel (dual antiplatelet therapy) – more Strokes if Stenting

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/15/intracranial-vascular-stenosis-comparison-of-clinical-trials-percutaneous-transluminal-angioplasty-and-stenting-ptas-vs-clot-inhibiting-drugs-aspirin-and-clopidogrel-dual-antiplatelet-therapy/

95r     New Era for PAD as FDA approval in the US of 1st Drug-coated Balloon (DCB) for PDA – CAD Indication for DCB will follow

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/15/new-era-for-pad-as-fda-approval-in-the-us-of-1st-drug-coated-balloon-dcb-for-pda-cad-indication-for-dcb-will-follow/

 

94r     Tethered–Liquid Perfluorocarbon surface (TLP): Biocoating Prevents Blood from Clotting on Implantables

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/13/tethered-liquid-perfluorocarbon-surface-tlp-biocoating-prevents-blood-from-clotting-on-implantables/

 

93r     Medtronic’s CoreValve System Sustains Positive Outcomes Through Two Years in Extreme Risk Patients

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/09/15/medtronics-corevalve-system-sustains-positive-outcomes-through-two-years-in-extreme-risk-patients/

 

92r     Thrombus Aspiration for Myocardial Infarction: What are the Outcomes One Year After

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/09/04/thrombus-aspiration-for-myocardial-infarction-what-are-the-outcomes-one-year-after/

 

91r     Fractional Flow Reserve–Guided PCI vs Drug Therapy for Stable Coronary Artery Disease

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/09/04/fractional-flow-reserve-guided-pci-vs-drug-therapy-for-stable-coronary-artery-disease/

90r     Capillaries: A Mapping Geometrical Method using Organ 3D Printing

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/08/22/capillaries-a-mapping-geometrical-method-using-organ-3d-printing/

 

89r     One year Post-Intervention Mortality Rate: TAVR and AVR – Aortic Valve Procedures 6.7% in AVR, 11.0% in AVR with CABG, 20.7 in Transvascular (TV-TAVT) and 28.0% in Transapical (TA-TAVR) Patients

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/08/04/one-year-post-intervention-mortality-rate-tavr-and-avr-aortic-valve-procedures-6-7-in-avr-11-0-in-avr-with-cabg-20-7-in-transvascular-tv-tavt-and-28-0-in-transapical-ta-tavr-patients/

 

88r     CEO of PolyNova: The Paradigm Shift in Heart Valve

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/06/16/ceo-of-polynova-the-paradigm-shift-in-heart-valve/

 

87r     An FDA advisory committee unanimously recommended approval of the Lutonix drug-coated balloon PTA catheter for the treatment of patients with femoropopliteal occlusive disease.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/06/16/an-fda-advisory-committee-unanimously-recommended-approval-of-the-lutonix-drug-coated-balloon-pta-catheter-for-the-treatment-of-patients-with-femoropopliteal-occlusive-disease/

 

86r     Patent Dispute over Heart Defect Repair Technology: Appeals court Upholds Gore win over St. Jude Medical – Helex septal occluder competes with the Amplatzer device made by AGA/St. Jude

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/06/12/patent-dispute-over-heart-defect-repair-technology-appeals-court-upholds-gore-win-over-st-jude-medical-helex-septal-occluder-competes-with-the-amplatzer-device-made-by-agast-jude/

85r     Chest Pain: Cardiac MRI provides the Picture of MI

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/06/03/chest-pain-cardiac-mri-provides-the-picture-of-mi/

 

84r     CardioMEMS sold to St. Jude Medical: Boston Millennia Partners announced that St. Jude Medical (NYSE: STJ) is acquiring the remaining 81 percent of CardioMEMS, Inc. it does not own for $375 million

Reporter: Aviva Lev-Ari,  PhD, RN

https://pharmaceuticalintelligence.com/2014/06/02/implantable-device-cardiomems-hf-system-for-heart-failure-patients-fda-approved/

 

83r     Cardiovascular Biology  – A Bibliography of Research @Technion

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/27/cardiovascular-biology-a-bibliography-of-research-technion/

 

82r     Asymptomatic Patients After Percutaneous Coronary Intervention: Low Yield of Stress Imaging – Population-Based Study

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/27/asymptomatic-patients-after-percutaneous-coronary-intervention-low-yield-of-stress-imaging-population-based-study/

 

 

81r     Transcatheter Mitral Valve (TMV) Procedures: Centers for Medicare & Medicaid Services (CMS) proposes to cover Transcatheter Mitral Valve Repair (TMVR)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/19/transcatheter-mitral-valve-tmv-procedures-centers-for-medicare-medicaid-services-cms-proposes-to-cover-transcatheter-mitral-valve-repair-tmvr/

 

80r     Minimally Invasive Valve Therapy Programs: Recommendations by SCAI, AATS, ACC, STS

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/19/minimally-invasive-valve-therapy-programs-recommendations-by-scai-aats-acc-sts/

 

79r     Among those 26 exams deemed low-value, 12 involve medical imaging, in tests that range from preoperative chest radiography to carotid artery screening for asymptomatic patients, imaging for back pain, and CT for headache and rhinosinusitis (JAMA Internal Medicine, May 12, 2014)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/13/among-26-exams-deemed-low-value-12-involve-medical-imaging-preoperative-chest-radiography-carotid-artery-screening-imaging-for-back-pain-and-ct-for-headache-and-rhinosinusitis-jama-im-may-12-2/

 

78r     FDA on Medical Devices: Part 1 – User Fee Act (MDUFA) III and Part 2 – Expedited Access Program for Medical Devices that Address Unmet Medical Needs

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/28/fda-on-medical-devices-part-1-user-fee-act-mdufa-iii-and-part-2-expedited-access-program-for-medical-devices-that-address-unmet-medical-needs/

 

77r     Settled Heart Valve Lawsuit: Medtronic to Pay Edwards: Edwards Lifesciences’ Sapien XT beat out Medtronic’s CoreValve

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/16/first-head-to-head-trial-finds-edwards-tavr-superior-to-medtronics/

 

76r     Replacement of the Mitral Valve: Using the Edwards’ Sapien Aortic Valve Device

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/10/replacement-of-the-mitral-valve-using-the-edwards-sapien-aortic-valve-device/

 

75r     Stem-Cell Therapy for Ischemic Heart Failure: Clinical Trial MSC Demonstrates Efficacy

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/08/stem-cell-therapy-for-ischemic-heart-failure-clinical-trial-msc-demonstrates-efficacy/

 

 

74r     ATVB (Arteriosclerosis, Thrombosis and Vascular Biology) 2014 Conference  5/1 – 5/3/2014, Sheraton Centre Toronto – Toronto, Ontario

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/03/05/atvb-arteriosclerosis-thrombosis-and-vascular-biology-2014-conference-51-532014-sheraton-centre-toronto-toronto-ontario/

 

73r     Endovascular Aortic Repair: A New Tool for Procedure Planning

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/25/endovascular-aortic-repair-a-new-tool-for-procedure-planning/

 

72r     Females and Non-Atherosclerotic Plaque: Spontaneous Coronary Artery Dissection – New Insights from Research and DNA Ongoing Study

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/female-and-non-atherosclerotic-plaque-spontaneous-coronary-artery-dissection-new-insights-from-research-and-dna-ongoing-study/

71r     Of the Cardiac-specific Deaths, Deaths from Heart Attack and Sudden Heart Rhythm Disturbances declined steeply, no decline in Deaths from Heart Failure in a 20,000 PCI patients Study @ Mayo Clinic

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/of-the-cardiac-specific-deaths-deaths-from-heart-attack-and-sudden-heart-rhythm-disturbances-declined-steeply-but-there-was-no-decline-in-deaths-from-heart-failure-in-a-20000-pci-patients-study/

 

70r     Cardiac Perfusion Exam, Rapid Heart Scanner, CT, MRI and PET imaging – Innovations in Radiology @ Beth Israel Deaconess Medical Center

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/cardiac-perfusion-exam-rapid-heart-scanner-ct-mri-and-pet-imaging-innovations-in-radiology-beth-israel-deaconess-medical-center/

 

69r     Maladaptive Vascular Remodeling found by four-dimensional (4D) flow MRI: Outflow Patterns, Wall Shear Stress, and Expression of Aortopathy are caused by Congenital bicuspid aortic valve (BAV) Cusp Fusion

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/maladaptive-vascular-remodeling-found-by-four-dimensional-4d-flow-mri-outflow-patterns-wall-shear-stress-and-expression-of-aortopathy-are-caused-by-congenital-bicuspid-aortic-valve-bav-cusp-fus/

 

68r     “Medicine Meets Virtual Reality” – NextMed-MMVR21 Conference 2/19 – 2/22/2014, Manhattan Beach Marriott, Manhattan Beach, CA

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/09/medicine-meets-virtual-reality-nextmed-mmvr21-conference-219-2222014-manhattan-beach-marriott-manhattan-beach-ca/

 

67r     Preserved vs Reduced Ejection Fraction: Available and Needed Therapies

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/03/preserved-vs-reduced-ejection-fraction-available-and-needed-therapies/

 

66r     Developments on the Frontier of Transcatheter Aortic Valve Replacement (TAVR) Devices

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/26/developments-on-the-frontier-of-transcatheter-aortic-valve-replacement-tavr-devices/

 

65r     On-Hours vs Off-Hours: Presentation to ER with Acute Myocardial Infarction – Lower Survival Rate if Off-Hours

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/22/on-hours-vs-off-hours-presentation-to-er-with-acute-myocardial-infarction-lower-survival-rate-if-off-hours/

 

64r     Elastin Arteriopathy: The Genetics of Supravalvular Aortic Stenosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/30/elastin-arteriopathy-the-genetics-of-supravalvular-aortic-stenosis/

 

63r     Abdominal Aortic Aneurysm: Matrix Metalloproteinase-9 Genotype as a Potential Genetic Marker

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/30/abdominal-aortic-aneurysm-matrix-metalloproteinase-9-genotype-as-a-potential-genetic-marker/

 

62r     Genetics of Aortic and Carotid Calcification: The Role of Serum Lipids

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/12/genetics-of-aortic-and-carotid-calcification-the-role-of-serum-lipids/

 

61r     St. Jude’s CEO is still betting on EnligHTN IV Study Renal Denervation System, despite Medtronic’s setback related to SYMPLICITY Phase IV

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/10/renal-denervation-enlightn-iv-study-called-off-and-potential-novel-indications-diastolic-heart-failure/

 

60r     Ischemic Stable CAD: Medical Therapy and PCI no difference in End Point: Meta-Analysis of Contemporary Randomized Clinical Trials

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/03/ischemic-stable-cad-ffr-in-5000-patients-medical-therapy-and-pci-no-difference-in-end-point-meta-analysis-of-contemporary-randomized-clinical-trials/

 

59r     Resistance Hypertension: Renal Artery Intervention using Stenting

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/02/pad-and-resistance-hypertension-renal-artery-intervention-using-stenting/

 

58r   For Accomplishments in Cardiology and Cardiovascular Diseases: 2015 The Arrigo Recordati International Prize for Scientific Research

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/22/for-accomplishments-in-cardiology-and-cardiovascular-diseases-the-arrigo-recordati-international-prize-for-scientific-research/

 

57r   Dalio Institute of Cardiovascular Imaging @ NewYork-Presbyterian Hospital and Weill Cornell Medical College

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/12/dalio-institute-of-cardiovascular-imaging-newyork-presbyterian-hospital-and-weill-cornell-medical-college/

 

56r   ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/11/05/accaha-guidelines-for-coronary-artery-bypass-graft-surgery/

 

55r     Risks for Patients’ and Physician’s Health in the Cath Lab

Reporter and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/17/risks-for-patients-contrast-induced-nephropathy-and-physicians-health-radiation-exposure-in-the-cath-lab/

 

54r     Myocardial Infarction: The New Definition After Revascularization

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/15/myocardial-infarction-the-new-definition-after-revascularization/

53r     Echocardiogram Quantification: Quest for Reproducibility and Dependability

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/10/12/echocardiogram-quantification-quest-for-reproducibility-and-dependability/

52r     Myocardial Strain and Segmental Synchrony: Age and Gender in Speckle-tracking-based Echocardiographic Study

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/05/myocardial-strain-and-segmental-synchrony-age-and-gender-in-speckle-tracking-based-echocardiographic-study/

51r   Hybrid Cath Lab/OR Suite’s da Vinci Surgical Robot of Intuitive Surgical gets FDA Warning Letter on Robot Track Record

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/19/hybrid-cath-labor-suites-da-vinci-surgical-robot-of-intuitive-surgical-gets-fda-warning-letter-on-robot-track-record/

 

50r     Abdominal Aortic Aneurysms (AAA): Albert Einstein’s Operation by Dr. Nissen

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/06/11/abdominal-aortic-aneurysms-aaa-albert-einsteins-operation-by-dr-nissen/

49r     Transposon-mediated Gene Therapy improves Pulmonary Hemodynamics and attenuates Right Ventricular Hypertrophy: eNOS gene therapy reduces Pulmonary vascular remodeling and Arterial wall hyperplasia

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/31/transposon-mediated-gene-therapy-improves-pulmonary-hemodynamics-and-attenuates-right-ventricular-hypertrophy-enos-gene-therapy-reduces-pulmonary-vascular-remodeling-and-arterial-wall-hyperplasia/

 

48r   First-of-Its-Kind FDA Approval for ‘AUI’ Device with Endurant II AAA Stent Graft: Medtronic Expands in Endovascular Aortic Repair in the United States

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/30/first-of-its-kind-fda-approval-for-aui-device-with-endurant-ii-aaa-stent-graft-medtronic-expands-in-endovascular-aortic-repair-in-the-united-states/

 

47r     Bioabsorbable Drug Coating Scaffolds, Stents and Dual Antiplatelet Therapy

Reporter: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2013/05/29/bioabsorbable-drug-coating-scaffolds-stents-and-dual-antiplatelet-therapy/

 

46r     Svelte Medical Systems’ Drug-Eluting Stent: 0% Clinically-Driven Events Through 12-Months in First-In-Man Study

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/28/svelte-medical-systems-drug-eluting-stent-0-clinically-driven-events-through-12-months-in-first-in-man-study/

 

45r   Echo vs Cardiac Magnetic Resonance Imaging (CMRI): CMRI may be a useful adjunct in Hypertrophic Cardiomyopathy (HCM) family screening in higher risk

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/20/echo-vs-cardiac-magnetic-resonance-imaging-cmri-cmri-may-be-a-useful-adjunct-in-hypertrophic-cardiomyopathy-hcm-family-screening-in-higher-risk/

 

44r   iElastance: Calculates Ventricular Elastance, Arterial Elastance and Ventricular-Arterial Coupling using Echocardiographic derived values in a single beat determination

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/19/ielastance-calculates-ventricular-elastance-arterial-elastance-and-ventricular-arterial-coupling-using-echocardiographic-derived-values-in-a-single-beat-determination/

 

43r   CT Angiography (CCTA) Reduced Medical Resource Utilization compared to Standard Care reported in JACC

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/16/ct-angiography-ccta-reduced-medical-resource-utilization-compared-to-standard-care-reported-in-jacc/

 

42r   Texas Heart Institute: 50 Years of Accomplishments

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/05/04/texas-heart-institute-50-years-of-accomplishments/

 

41r   Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States – A Policy Statement From the American Heart Association

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/25/economic-toll-of-heart-failure-in-the-us-forecasting-the-impact-of-heart-failure-in-the-united-states-a-policy-statement-from-the-american-heart-association/

 

40r   Sudden Cardiac Death invisible at Autopsy: Forensic Power of Postmortem MRI

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/18/sudden-cardiac-death-invisible-at-autopsy-forensic-power-of-postmortem-mri/

 

39r   Advanced CT Reconstruction: Plaque Estimation Algorithm for Fewer Errors and Semiautomation

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/04/18/advanced-ct-reconstruction-plaque-estimation-algorithm-for-fewer-errors-and-semiautomation/

 

38r     Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/03/10/dilated-cardiomyopathy-decisions-on-implantable-cardioverter-defibrillators-icds-using-left-ventricular-ejection-fraction-lvef-and-midwall-fibrosis-decisions-on-replacement-using-late-gadolinium/

 

37r     Clinical Trials on transcatheter aortic valve replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/12/american-college-of-cardiologys-and-the-society-of-thoracic-surgeons-entrance-into-clinical-trials-is-noteworthy-read-more-two-medical-societies-jump-into-clinical-trial-effort-for-tavr-tech-f/

 

36r     Direct Flow Medical Wins European Clearance for Catheter Delivered Aortic Valve

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/29/direct-flow-medical-wins-european-clearance-for-catheter-delivered-aortic-valve/

 

35r     DELETED, identical to 15c

 

34r     PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

 

33r     Cardiac Surgery Theatre in China vs. in the US: Cardiac Repair Procedures, Medical Devices in Use, Technology in Hospitals, Surgeons’ Training and Cardiac Disease Severity

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/08/cardiac-surgery-theatre-in-china-vs-in-the-us-cardiac-repair-procedures-medical-devices-in-use-technology-in-hospitals-surgeons-training-and-cardiac-disease-severity/

 

32r     DELETED, identical to 14c

31r     DELETED, identical to 12c

 

30r     Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/

 

29r     Ablation Devices Market to 2016 – Global Market Forecast and Trends Analysis by Technology, Devices & Applications

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/23/ablation-devices-market-to-2016-global-market-forecast-and-trends-analysis-by-technology-devices-applications/

 

28r     Abdominal Aortic Aneurysm: Endovascular repair and open repair resulted in similar long-term survival

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/03/abdominal-aortic-aneurysm-endovascular-repair-and-open-repair-resulted-in-similar-long-term-survival/

 

27r     Renal Denervation Technology of Vessix Vascular, Inc. been acquired by Boston Scientific Corporation (BSX) to pay up to $425 Million

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/08/renal-denervation-technology-of-vessix-vascular-inc-been-acquired-by-boston-scientific-corporation-bsx-to-pay-up-to-425-million/

 

26r     DELETED, identical to 11c

 

25r     To Stent or Not? A Critical Decision

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/23/to-stent-or-not-a-critical-decision/

 

24r     FDA Approval for Under-Skin Defibrillator goes to Boston Scientific Corporation

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/01/fda-approval-for-under-skin-defibrillator-goes-to-boston-scientific-corporation/

 

23r     Absorb™ Bioresorbable Vascular Scaffold: An International Launch by Abbott Laboratories

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/29/absorb-bioresorbable-vascular-scaffold-an-international-launch-by-abbott-laboratories/

 

22r     Carotid Stenting: Vascular surgeons have pointed to more minor strokes in the stenting group and cardiologists to more myocardial infarctions in the CEA cohort.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/21/carotid-stenting-vascular-surgeons-have-pointed-to-more-minor-strokes-in-the-stenting-group-and-cardiologists-to-more-myocardial-infarctions-in-the-cea-cohort/

 

21r     FDA: Strengthening Our National System for Medical Device Post-market Surveillance

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/07/fda-strengthening-our-national-system-for-medical-device-post-market-surveillance/

 

20r     Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic Stenosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/03/transcatheter-aortic-valve-replacement-for-inoperable-severe-aortic-stenosis/

 

19r     Evidence for Overturning the Guidelines in Cardiogenic Shock

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/03/evidence-for-overturning-the-guidelines-in-cardiogenic-shock/

 

18r     Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

17r     Intravascular Stimulation of Autonomics: A Letter from Dr. Michael Scherlag

Letter received by Aviva Lev-Ari, PhD, RN on September 1, 2012

https://pharmaceuticalintelligence.com/2012/09/02/intravascular-stimulation-of-autonomics-a-letter-from-dr-michael-scherlag/

 

16r     New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/27/new-definition-of-mi-unveiled-fractional-flow-reserve-ffrct-for-tagging-ischemia/

 

15r     DELETED, identical to 8c

 

14r     Expected New Trends in Cardiology and Cardiovascular Medical Devices

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/17/expected-new-trends-in-cardiology-and-cardiovascular-medical-devices/

 

13r     Patient Access to Medical Devices — A Comparison of U.S. and European Review Processes

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/09/patient-access-to-medical-devices-a-comparison-of-u-s-and-european-review-processes/

 

12r   Coronary CT Angiography versus Standard Evaluation in Acute Chest Pain

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/09/coronary-ct-angiography-versus-standard-evaluation-in-acute-chest-pain/

 

11r     Updated Transcatheter Aortic Valve Implantation (TAVI): risk for stroke and suitability for surgery

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/07/transcatheter-aortic-valve-implantation-tavi-risky-and-costly-2/

 

10r     Transcatheter Aortic Valve Implantation (TAVI): FDA approves expanded indication for two transcatheter heart valves for patients at intermediate risk for death or complications associated with open-heart surgery

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/02/transcatheter-aortic-valve-implantation-tavi-risky-and-costly/

 

9r      Early Surgery May Benefit Some With Heart Infection

Reporter: Aviva Lev-Ari, RN

https://pharmaceuticalintelligence.com/2012/08/02/early-surgery-may-benefit-some-with-heart-infection/

 

8r      Gaps, Tensions, and Conflicts in the FDA Approval Process: Implications for Clinical Practice

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/31/gaps-tensions-and-conflicts-in-the-fda-approval-process-implications-for-clinical-practice/

 

7r      Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/

 

6r      Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

 

5r      Implantable Synchronized Cardiac Assist Device Designed for Heart Remodeling: Abiomed’s Symphony

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/11/implantable-synchronized-cardiac-assist-device-designed-for-heart-remodeling-abiomeds-symphony/

 

4r      Percutaneous Transluminal Angioplasty and Stenting (PTAS) – Stenting versus Aggressive Medical Therapy for Intracranial Arterial Stenosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/07/05/percutaneous-transluminal-angioplasty-and-stenting-ptas-stenting-versus-aggressive-medical-therapy-for-intracranial-arterial-stenosis/

 

3r      The Centers for Medicare & Medicaid Services (CMS) covers transcatheter aortic valve replacement (TAVR) under Coverage with Evidence Development (CED)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/06/19/the-centers-for-medicare-medicaid-services-cms-covers-transcatheter-aortic-valve-replacement-tavr-under-coverage-with-evidence-development-ced/

 

2r     Investigational Devices: Edwards Sapien Transcatheter Aortic Heart Valve Replacement Transfemoral Deployment

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/06/10/investigational-devices-edwards-sapien-transcatheter-aortic-heart-valve-replacement-transfemoral-deployment/

 

1r     Investigational Devices: Edwards Sapien Transcatheter Aortic Valve Transapical Deployment

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/06/04/investigational-devices-edwards-sapien-transcatheter-heart-valve/

 

 

 

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