Mitochondrial Dysfunction and Cardiac Disorders

« Reversal of Cardiac Mitochondrial Dysfunction

Mitochondrial Dysfunction and Cardiac Disorders

April 14, 2013 by larryhbern

Mitochondrial Dysfunction and Cardiac Disorders

Curator: Larry H Bernstein, MD, FACP

This article is the THIRD in a four-article Series covering the topic of the Roles of the Mitochondria in Cardiovascular Diseases. They include the following;

Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing, Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/chapter-5-mitochondria-and-cardiovascular-disease/

Mitochondrial Metabolism and Cardiac Function, Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

Mitochondrial Dysfunction and Cardiac Disorders, Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-dysfunction-and-cardiac-disorders/

Reversal of Cardiac mitochondrial dysfunction, Larry H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/reversal-of-cardiac-mitochondrial-dysfunction/

Mitochondrial Metabolism in Impaired Cardiac Function

Mitochondrial Dysfunction and the Heart

Chronically elevated plasma free fatty acid levels in heart failure are associated with

decreased metabolic efficiency and cellular insulin resistance.

The mitochondrial theory of aging (MTA) and the free-radical theory of aging (FRTA) are closely related.
They were in fact proposed by the same researcher about 20 years apart. MTA adds

the mitochondria and its production of free radicals
into the concept that free-radicals damage DNA over time.

Tissue hypoxia, resulting from low cardiac output with or independent of endothelial impairment,

increases oxidative stress and leads to apoptosis and mitochondrial DNA damage.

This dysfunctional state causes loss of mitochondrial mass. Therapies aimed at protecting mitochondrial function

have shown promise in patients and animal models with heart failure that will be the subject of Chapter III.

Myocardial function in hypertension

Genetic variation in vitamin D-dependent signaling

is associated with congestive heart failure in human subjects with hypertension.

Functional polymorphisms were selected from five candidate genes:

CYP27B1,
CYP24A1,
VDR,
REN and
ACE.

Using the Marshfield Clinic Personalized Medicine Research Project,

205 subjects with hypertension and congestive heart failure,
206 subjects with hypertension alone and
206 controls (frequency matched by age and gender) were genotyped.

In the context of hypertension, a SNP in CYP27B1 was associated with congestive heart failure

(odds ratio: 2.14 for subjects homozygous for the C allele; 95% CI: 1.05–4.39).

Genetic variation in vitamin D biosynthesis is associated with increased risk of heart failure.

RA Wilke, RU Simpson, BN Mukesh, SV Bhupathi, et al. Genetic variation in CYP27B1 is associated

with congestive heart failure in patients with hypertension. Pharmacogenomics 2009; 10(11): 1789-1797. http://dx.doi.org/10.2217/pgs.09.101

Heart Failure and Coronary Circulation

There is a decrease in resting and peak stress myocardial function in chronic heart failure patients,

with recovery of skeletal muscle phosphocreatine following exercise induced by perhexiline treatment.

This suggested that mitochondrial deﬁciencies, caused by excessive free fatty acids (FFAs)

underlie a common cardiac and skeletal muscle myopathy in heart failure patients.

Tissue hypoxia in chronic heart failure from inadequate circulation in heart failure

increases the oxidative stress in lean body mass and in the heart itself.

The heterodimeric transcription factor hypoxia-inducible factor (HIF)-1

induces changes in the transcription of genes that encode proteins involved in the adaptation to hypoxia.

HIF-1 activity depends on levels of the HIF-1a subunit, which has a short half-life.

HIF-1a increases in rats with experimentally induced myocardial infarction together with elevated levels of

GLUT1 and haemoxygenase-1 in the peri-infarct region of the heart

The cardiac metabolic response to hypoxia is considered to be

a return to a pattern of fetal metabolism, in which
carbohydrates predominate as substrates for energy metabolism.

The reliance on carbohydrate energy source is thought to be a result of the downregulation of PPARa with a decreased activity of

The sarcolemmal fatty acid transporter protein (FATP) levels are also decreased with palmitate oxidation,

transitioning away from fatty acid metabolism proportional to the degree of cardiac impairment.

The hypoxic changes of heart failure drives a switch toward

glycolysis and glucose oxidation
restriction of myocardial fatty acid uptake.

Nevertheless, late in the progression of heart failure, substrate metabolism is insufﬁcient to support cardiac function, because

the hypoxic failing heart is no longer able to oxidize fats and may also be insulin resistant.

The author surmises that mitochondrial dysfunction caused by tissue hypoxia might be mediated by the

proapoptotic protein BCL2/adenovirus E1B 19kDa interacting protein (Bnip)3.

It is strongly upregulated in response to hypoxia. In the isolated, perfused rat heart, Bnip3 expression was

induced after 1h of hypoxia, with Bnip3 integrating into the mitochondria of hypoxic ventricular myocytes.

This resulted in mitochondrial defects associated with

opening of the permeability transition pore, leading to
loss of inner membrane integrity and
loss of mitochondrial mass.

Mitochondrial Dysfunction caused by Bnip3 Precedes Cell Death.

Experimentally induced myocardial ischemia had evidence of contractile dysfunction but preserved viability. A progressive

decline in circulating levels of endothelial progenitor cells was documented 3 months following instrumentation (P<0.001).

Quantitative polymerase chain reaction analysis revealed that

chronic myocardial ischemia produced a biphasic response in both
- hypoxic-inducible factor 1 and
- stromal-derived factor 1 mRNA expression.

While initially unregulated, a gradual decline was observed over time (from day 45 to 90), in

hypoxic-inducible factor 1 and
stromal-derived factor 1 mRNA expression .

On serial assessment, endothelial progenitor cell migration was progressively impaired in response to chemo-attractant gradients of:

vascular endothelial growth factor (10-200 ng/mL)
and stromal cell-derived factor-1 (10-100 ng/mL) .

Decreased circulating levels and migratory dysfunction of bone marrow derived endothelial progenitor cells

were documented in a reproducible clinically relevant model of myocardial ischemia.

Nitric Oxide (NO) in Myocardial Ischemia and Infarct

Nitric oxide (NO) is a free radical with an unpaired electron; it is an important physiologic messenger,

produced by nitric oxide synthases, which catalyze the reaction l-arginine to citrulline and NO.

The constitutive isoforms exists in neuronal and endothelial cells and is calcium dependent. Calcium binds to calmodulin and

the calcium calmodulin complex activates the constitutive NO synthase that releases NO,
relaxing smooth muscle cells through activation of guanylate cyclase and the production cGMP.

Therefore, the NO produced has a negative inotropic effect on the heart and is instrumental in the autoregulation of the coronary circulation.

The inducible form of NO synthase (iNOS), mostly produced in macrophages, is activated by cytokines and endotoxin. It eliminates intracellular pathogens,

damaging cells by inhibiting

ATP production
oxidative phosphorylation
DNA synthesis.

In infection, lipopolysaccharide released from bacterial walls, stimulates production of iNOS. The large amount of NO produced

causes extensive vasodilation and hypotension.

We sought to assess whether oxidation products of

nitric oxide (NO), nitrite (NO2−) and nitrate (NO3−), referred to as NOx,
are released by the heart of patients after acute myocardial infarction (AMI) and
whether NOx can be determined in peripheral blood of these patients.

Previously we reported that in experimental myocardial infarction (rabbits) NOx is released mainly by inflammatory cells

(macrophages) in the myocardium 3 days after onset of ischemia.

NOx is formed in heart muscle from NO; It originates through the activity of the inducible form of nitric oxide synthase (iNOS).

Eight patients with acute anterior MI and an equal number of controls were studied. Coronary venous blood was obtained by

coronary sinus catheterization; NOx concentrations in coronary sinus, in arterial and peripheral venous plasma were measured.

Left ventricular end-diastolic pressure was determined. Measurements were carried out 24, 48 and 72 h after onset of symptoms.

The type and location of coronary arterial lesions were determined by coronary angiography. Plasma NO3− was reduced to NO2−

by nitrate reductase before determination of NO2− concentration by chemiluminescence.

The results provided evidence that in patients with acute anterior MI, the myocardial production of nitrite and nitrate (NOx) was increased,

as well as the coronary arterial–venous difference.

Increased NOx production by the infarcted heart accounted for the increase of NOx concentration in arterial and the peripheral venous plasma.

The peak elevation of NOx occurred on days 2 and 3 after onset of the symptoms, suggesting that NOx production was at least in part the result of

production of NO by inflammatory cells (macrophages) in the heart.

The appearance of oxidative products of NO (NO2− and NO3−) in peripheral blood of patients with acute MI is

the result of their increased release from infarcted heart during the inflammatory phase of myocardial ischemia.

Further studies are needed to define the clinical value of these observations.

K Akiyama, A Kimura, H Suzuki, Y Takeyama, …. R Bing. Production of oxidative products of nitric oxide in infarcted human heart. J Am Coll Cardiol. 1998;32(2):373-379. http://dx.doi.org/10.1016/S0735-1097(98)00270-8

OPA1 Mutation and Late-Onset Cardiomyopathy

No cardiac disorders have been described in patients with OPA1 or similar mutations

involving the fission/fusion genes as seen in inherited maladies like Charcot–Marie–Tooth disease.

Our results indicate that, at least for OPA1, cardiac abnormalities are not completely

manifest until the development of blindness.

The OPA1-mutant mice survived more than 1 year and appeared healthy.

In patients with these diseases, reduced cardiac function may go undetected

secondary to reduced physical activity secondary to loss of vision.

It would be expected that patients with such mutations would have impaired cardiac reserve with

reduced ability to respond to high-stress disease states such as myocardial infarction and sepsis.

The OPA1-mutant mice have reduced cardiac reserve, as shown by

the lack of response to isoproterenol or to ischemia/reperfusion injury,

This suggests that patients with OPA1 and related inherited mitochondrial diseases

should be screened for abnormalities of cardiac function.

Le Chen; T Liu; A Tran; Xiyuan Lu; …AA. Knowlton. OPA1 Mutation and Late-Onset Cardiomyopathy:
Mitochondrial Dysfunction and mtDNA Instability. http://jaha.ahajournals.org/content/1/5/e003012.full

Oxidative Stress and Mitochondria in the Failing Heart

The major problem in tissue hypoxia in the failing heart is oxidative stress. Reactive oxygen species (ROS), including

superoxide,
hydroxyl radicals and
hydrogen peroxide,

are generated by a number of cellular processes, including

mitochondrial electron transport,
NADPH oxidase and
xanthine dehydrogenase/xanthine oxidase.

The low availability of oxygen, the ﬁnal receptor of mitochondrial electron transport (ET), results in

electron accumulation in the ET chain as the complexes become highly reduced.

A number of experimental and clinical studies have suggested that ROS generation is

enhanced in heart failure because of electron leak, and complexes I and II
are implicated as the primary sites of this loss.

Prolonged oxidative stress in cardiac failure results in damage to mitochondrial DNA.

The continued ROS generation and consequent cellular injury leads to functional decline.

Thus, mitochondria are both the sources and targets of a cycle of ROS-mediated injury in the failing heart.

Mice with a cardiac/skeletal muscle speciﬁc deﬁciency in the scavenger enzyme superoxide dismutase

developed progressive congestive heart failure
with defects in mitochondrial respiration.

Oxidative stress in these mice also caused speciﬁc morphological changes in cardiac mitochondria

characterized by decreased ATP levels,
impaired contractility,
dramatically restricted exercise capacity and
decreased survival.

This was in part corrected by treatment with the antioxidant superoxide dismutase mimetic, namely

manganese5,10,15,20-tetrakis-(4-benzoic acid)-porphyrin.

EUK-8, a superoxide dismutase and catalase mimetic improved survival and contractile parameters in a mutant mouse model

of pressure overload-induced oxidative stress and heart failure and in wild-type mice subjected to pressure overload.

In addition, mitochondria show

functional impairment and
morphological disorganization

in the left ventricle of Hypertrophic Cardiomyopathy (HCM) patients without baseline systolic dysfunction.

These mitochondrial changes were associated with impaired myocardial contractile and relaxation reserves.

A strategy to protect the heart against oxidative stress could lie with

the modulation of mitochondrial electron transport itself.

Mild mitochondrial uncoupling may offer a potential cardioprotective effect by decreasing ROS production

preventing electron accumulation at complex III and
the Fe–S centres of complex I, and may therefore

mtDNA, Autophagy, and Heart Failure

Mitochondria are evolutionary endosymbionts derived from bacteria and contain DNA similar to bacterial DNA.

Mitochondria damaged by external haemodynamic stress are degraded by the autophagy/lysosome system in cardiomyocytes.

Mitochondrial DNA (mtDNA) that escapes from autophagy cell-autonomously leads to Toll-like receptor (TLR) 9-mediated

inflammatory responses in cardiomyocytes and
is capable of inducing myocarditis and dilated cardiomyopathy.

Cardiac-specific deletion of lysosomal deoxyribonuclease (DNase) II showed no cardiac phenotypes under baseline conditions,

but increased mortality and caused severe myocarditis and dilated cardiomyopathy 10 days after treatment with pressure overload.

Early in the pathogenesis, DNase II-deficient hearts showed

infiltration of inflammatory cells
increased messenger RNA expression of inflammatory cytokines
accumulation of mitochondrial DNA deposits in autolysosomes in the myocardium.

Administration of inhibitory oligodeoxynucleotides against TLR9, which is known to be activated by bacterial DNA6, or ablation of Tlr9

attenuated the development of cardiomyopathy in DNase II-deficient mice.

Furthermore, Tlr9 ablation

improved pressure overload-induced cardiac dysfunction and
inflammation even in mice with wild-type Dnase2a alleles.

These data provide new perspectives on the mechanism of genesis of chronic inflammation in failing hearts.

T Oka, S Hikoso, O Yamaguchi, M Taneike, T Takeda, T Tamai, et al. Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure.

Nature 485, 251–255 (10 May 2012) http://dx.doi.org/10.1038/nature10992

Mitochondrial Dysfunction Increases Expression of Endothelin-1 and Induces Apoptosis

We developed an in vitro model of mitochondrial dysfunction using rotenone, a mitochondrial respiratory chain complex I inhibitor, and studied

preproendothelin-1 gene expression and apoptosis.

Rotenone greatly increased the gene expression of preproendothelin-1 in cardiomyocytes.

This result suggests that the gene expression of preproendothelin-1 is induced by the mitochondrial dysfunction.

Furthermore, treatment of cardiomyocytes with rotenone induced an elevation of caspase-3 activity, and caused a marked

increase in DNA laddering, an indication of apoptosis.

In conclusion, it is suggested that mitochondrial impairment in primary cultured cardiomyocytes induced by rotenone in vitro,

mimics some of the pathophysiological features of heart failure in vivo, and that ET-1 may have a role in myocardial dysfunction
- with impairment of mitochondria in the failing heart.

Yuki, K; Miyauchi, T; Kakinuma, Y; Murakoshi, N; Suzuki, T; et al. Mitochondrial Dysfunction Increases Expression of Endothelin-1 and Induces Apoptosis through Caspase-3 Activation in Rat Cardiomyocytes In Vitro. Journal of Cardiovascular Pharmacology: 2000; 36 VASCULAR EFFECTS: PDF Only http://journals.lww.com/cardiovascularpharm/Abstract/2000/36001/Mitochondrial_Dysfunction_Increases_Expression_of.62.aspx

Summary

This review focused on the evidence accumulated to the effect that mitochondria are key players in

the progression of congestive heart failure (CHF).

Mitochondria are the primary source of energy in the form of adenosine triphosphate that fuels the contractile apparatus,

essential for the mechanical activity and the Starling Effect of the heart.

We evaluate changes in mitochondrial morphology and alterations in the main components of mitochondrial energetics, such as

substrate utilization and
oxidative phosphorylation,

in the context of their contribution to the chronic energy deficit and mechanical dysfunction in HF.

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symptomatic patients with hypertrophic cardiomyopathy. European Heart Journal 2009; 30:1853–1862.

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De Haan JB, Crack PJ, Flentjar N, Iannello RC, Hertzog PJ, Kola I. An imbalance in antioxidant defense affects cellular function: the pathophysiological consequences of a reduction in antioxidant defense in the glutathione peroxidase-1 (Gpx1) knockout mouse. Redox Rep. 2003;8(2):69-79. http://dx.doi.org/10.1179/135100003125001378

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Other Related articles published on this Open Access Scientific Journal, include the following:

Perspectives on Nitric Oxide in Disease Mechanisms: The Nitric Oxide Discovery, Function, and Targeted Therapy Opportunities, 2013, Aviral Vatsa, PhD and Larry H Bernstein, MD, FACP, Editors, Amazon e-Books (forthcoming). http://pharmaceuticalintelligence.com/biomed-e-books/perspectives-on-nitric-oxide-in-disease-mechanisms-v2/

Mitochondria: More than just the “powerhouse of the cell” Ritu Saxena, Ph.D. Consultants: Aviva Lev-Ari, PhD, RN and Pnina G. Abir-Am, PhD 7/9/2012

http://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

Mitochondrial dynamics and cardiovascular diseases, Ritu Saxena, PhD 11/14/2012
http://pharmaceuticalintelligence.com/2012/11/14/mitochondrial-dynamics-and-cardiovascular-diseases/

Mitochondrial Damage and Repair under Oxidative Stress, Larry H Bernstein, MD, FACP 10/28/2012
http://pharmaceuticalintelligence.com/2012/10/28/mitochondrial-damage-and-repair-under-oxidative-stress/

Mitochondria: Origin from oxygen free environment, role in aerobic glycolysis, metabolic adaptation, Larry H Bernstein, MD, FACP 9/26/2012

http://pharmaceuticalintelligence.com/2012/09/26/mitochondria-origin-from-oxygen-free-environment-role-in-aerobic-glycolysis-metabolic-adaptation/

Ca2+ signaling: transcriptional control, Larry H Bernstein, MD, FACP 3/6/2-13
http://pharmaceuticalintelligence.com/2013/03/06/ca2-signaling-transcriptional-control/

MIT Scientists on Proteomics: All the Proteins in the Mitochondrial Matrix identified, Aviva Lev-Ari, PhD, RN 2/3/2013
http://pharmaceuticalintelligence.com/2013/02/03/mit-scientists-on-proteomics-all-the-proteins-in-the-mitochondrial-matrix-identified/

Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function, Larry H Bernstein, MD, FACP 9/16/2012
http://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

Ubiquinin-Proteosome pathway, autophagy, the mitochondrion, proteolysis and cell apoptosis, Larry H Bernstein, MD, FACP 2/14/2013
http://pharmaceuticalintelligence.com/2013/02/14/ubiquinin-proteosome-pathway-autophagy-the-mitochondrion-proteolysis-and-cell-apoptosis-reconsidered/

Low Bioavailability of Nitric Oxide due to Misbalance in Cell Free Hemoglobin in Sickle Cell Disease – A Computational Model Anamika Sarkar, PhD 11/9/2012
http://pharmaceuticalintelligence.com/2012/11/09/low-bioavailability-of-nitric-oxide-due-to-misbalance-in-cell-free-hemoglobin-in-sickle-cell-disease-a-computational-model/

The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure, , Larry H Bernstein, MD, FACP 8/20/2012

http://pharmaceuticalintelligence.com/2012/08/20/the-rationale-and-use-of-inhaled-no-in-pulmonary-artery-hypertension-and-right-sided-heart-failure/

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination? Aviva Lev-Ari, PhD, RN 10/19/2012

http://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/

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation, Aviva Lev-Ari, PhD, RN 10/4/2012

http://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography, Aviva Lev-Ari, PhD, RN 10/4/2012

http://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013, L H Bernstein, MD, FACP and Aviva Lev-Ari,PhD, RN 3/7/2013

http://pharmaceuticalintelligence.com/2013/03/07/genomics-genetics-of-cardiovascular-disease-diagnoses-a-literature-survey-of-ahas-circulation-cardiovascular-genetics-32010-32013/

Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production, Aviva Lev-Ari, PhD, RN 7/19/2012

http://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

Aviva Lev-Ari, PhD, RN 10/30/2012

http://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD, Aviva Lev-Ari, PhD, RN 4/7/2013

http://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/

Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients, Aviva Lev-Ari, PhD, RN 4/4/2013

http://pharmaceuticalintelligence.com/2013/04/04/hypertriglyceridemia-concurrent-hyperlipidemia-vertical-density-gradient-ultracentrifugation-a-better-test-to-prevent-undertreatment-of-high-risk-cardiac-patients/

Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore, Aviva Lev-Ari, PhD, RN 4/3/2013

http://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk, Aviva Lev-Ari, PhD, RN 3/31/2013

http://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes, Aviva Lev-Ari, PhD, RN 11/13/2012

http://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

Sulfur-Deficiciency and Hyperhomocysteinemia, L H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/04/sulfur-deficiency-and-hyperhomocusteinemia/

Mitochondrial metabolism and cardiac function, L H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/14/mitochondrial-metabolism-and-cardiac-function/

Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects, L H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/04/11/cardiotoxicity-and-cardiomyopathy-related-to-drugs-adverse-effects/

Lp(a) Gene Variant Association, L H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/03/06/10447/

Predicting Drug Toxicity for Acute Cardiac Events, L H Bernstein, MD, FACP

http://pharmaceuticalintelligence.com/2013/03/15/predicting-drug-toxicity-for-acute-cardiac-events/

Amyloidosis with Cardiomyopathy, L H Bernstein, MD, FACP