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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

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

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

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

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

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

https://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,
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:
  1. CYP27B1,
  2. CYP24A1,
  3. VDR,
  4. REN and
  5. 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

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
  1. glycolysis and glucose oxidation
  2. 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
  1. opening of the permeability transition pore, leading to
  2. loss of inner membrane integrity and
  3. 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:
  1. vascular endothelial growth factor (10-200 ng/mL)
  2. 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
  1. the calcium calmodulin complex activates the constitutive NO synthase that releases NO,
  2. 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
  1. ATP production
  2. oxidative phosphorylation
  3. 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.

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.

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.
REFERENCES
Zachman AL, Page JM, Prabhakar G, Guelcher SA, and Sung HJ, “Elucidation of adhesion-dependent spontaneous apoptosis in macrophages using phase separated PEG/polyurethane films.”
Acta Biomater. 2012 Nov 2.    http://dx.doi.org/pii: S1742-7061(12)00530-2. 10.1016/j.actbio.2012.10.038.    http://www.ncbi.nlm.nih.gov/pubmed/23128157

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). https://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

https://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
https://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
https://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

https://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
https://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
https://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
https://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
https://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
https://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

https://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

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/

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

https://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

https://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

https://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

https://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

https://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

https://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

https://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

https://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

https://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

https://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

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

Mitochondrial metabolism and cardiac function, L H Bernstein, MD, FACP
Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects, L H Bernstein, MD, FACP
Lp(a) Gene Variant Association, L H Bernstein, MD, FACP

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

Amyloidosis with Cardiomyopathy, L H Bernstein, MD, FACP

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

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

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

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

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

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

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

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

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Curator:  Aviva Lev-Ari, PhD,RN

Cancer Diagnostics by Genomic Sequencing: ‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

How to Tailor Cancer Therapy to the particular Genetics of a patient’s Cancer

THIS IS A SERIES OF FOUR POINTS OF VIEW IN SUPPORT OF the Paradigm Shift in Human Genomics

‘No’ to Sequencing Patient’s DNA, ‘No’ to Sequencing Patient’s Tumor, ‘Yes’ to focus on Gene Mutation Aberration & Analysis of Gene Abnormalities

PRESENTED in the following FOUR PARTS. Recommended to be read in its entirety for completeness and arrival to the End Point of Present and Future Frontier of Research in Genomics

Part 1:

Research Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine

https://pharmaceuticalintelligence.com/2013/01/13/paradigm-shift-in-human-genomics-predictive-biomarkers-and-personalized-medicine-part-1/

Part 2:

LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment

https://pharmaceuticalintelligence.com/2013/01/13/leaders-in-genome-sequencing-of-genetic-mutations-for-therapeutic-drug-selection-in-cancer-personalized-treatment-part-2/

Part 3:

Personalized Medicine: An Institute Profile – Coriell Institute for Medical Research

https://pharmaceuticalintelligence.com/2013/01/13/personalized-medicine-an-institute-profile-coriell-institute-for-medical-research-part-3/

Part 4:

The Consumer Market for Personal DNA Sequencing

https://pharmaceuticalintelligence.com/2013/01/13/consumer-market-for-personal-dna-sequencing-part-4/

 

Part 2:

LEADERS in the Competitive Space of Genome Sequencing of Genetic Mutations for Therapeutic Drug Selection in Cancer Personalized Treatment

 

  • Foundation Medicine, a Cambridge, Mass.-based company that sells a $5,800 diagnostic test that uses DNA sequencing to help doctors guess which cancer drugs would be helpful in fighting a particular patient’s tumor.

CAMBRIDGE, Mass., January 8, 2013 – Foundation Medicine, Inc. today announced an expansion of its Series B financing, raising an additional $13.5 million and bringing the total raised in the round to $56 million. The new investors include Bill Gates, Evan Jones and Yuri Milner.

“Advances in understanding the human genome are having a dramatic impact on almost every area of medicine,” said Bill Gates. “Foundation Medicine’s approach in harnessing the power of genomic data to improve care for cancer patients could represent an extremely important step forward in improving routine cancer care. I’m happy to be supporting this quite promising approach.”

http://www.foundationmedicine.com/pdf/news-releases/2013_01_08_FMI_Series_B_Ext_FINAL.pdf

Foundation, which previously listed Kleiner Perkins Caulfield & Byers and Google Ventures, raised $13.5 million in the series B round in which Gates participated, bringing its total take to $56 million. The other investors were Facebook billionaire Yuri Milner, who also recently invested in the personal genomics company 23andMe, and Evan Jones, the diagnostics industry legend who founded DiGene, which was sold to Qiagen for $1.6 billion in 2007. Jones will also join Foundation’s board.

http://www.forbes.com/sites/matthewherper/2013/01/08/bill-gates-invests-in-cancer-dna-sequencing-firm/

It now costs as little as $1,000 to get a fairly accurate readout of the 6 billion letters of DNA code for any single person.

In cancer, the approach right now is usually not to sequence all a patient’s DNA or that of his tumor, but instead to focus on particular genetic mutations in the tumor that might provide clues as to what medicines to try. Major cancer centers are using this approach with patients for whom it’s not obvious which medicine represents the best bet. Foundation’s approach has been to provide that kind of testing to a larger audience. To do so, it uses the DNA sequencing machines made by Illumina and other companies.

“What we want to do is take this testing to the community practices to treat patients where they live,” Michael Pellini, Foundation’s chief executive, 2011.

There is some evidence backing up that test. In a study conducted with the Dana-Farber Cancer Institute and published in Nature Medicine, found that more than half of patients with lung and colon cancer might benefit from the test.  from high-speed tests that detect DNA flaws doctors can target with existing medicines, a study found.

Researchers used a gene test made by closely held Foundation Medicine Inc. to sequence 145 cancer-associated genes in 40 colon tumor samples and 24 lung tumors.

They found that

53 percent of colon tumors and

71 percent of lung tumors

had mutations that may be attacked with cancer medicines on the market or in human trials, according to the study published in Nature Medicine. In some cases, the results revealed what drugs wouldn’t work against the tumors.

The study from researchers at Foundation Medicine and the Dana-Farber Cancer Institute in Boston, shows the value of using DNA sequencing machines to optimize treatment by matching drugs against specific gene abnormalities inside a patient’s tumor, said Pasi Janne, a study co-author.

Finding Gene Abnormalities

Maureen Cronin, a study co-author and molecular pharmacologist at Cambridge, Massachusetts-based Foundation Medicine, said her company was finding new gene abnormalities at a much higher rate than they expected as it performs DNA scans on tumors.

“We expected to find new things, but not at the frequency we are finding them,” she said in a telephone interview. The results “are very surprising.

The study also suggests cancer researchers may need to rethink the way they classify and treat the disease, Cronin said. The particular genetic abnormality inside tumor DNA may matter as much as what organ the tumor came from, she said.

Pfizer is aware of the new lung cancer gene finding and “believes the data are interesting,” said Jenifer Antonacci, a company spokeswoman, in an e-mail.

Laura Woodin, a spokeswoman for London-based AstraZeneca, said the company “is constantly alert to new developments and research in the science of oncology and we review relevant, peer reviewed studies for what they might mean for patients and drug development.”

Foundation Medicine performs a $5,800 test that takes tumor samples and sequences DNA from 200 genes relevant to cancer. It is funded with $33.5 million in venture capital from Third Rock Ventures, Kleiner Perkins Caufield & Byers and Google Ventures, according to its website. $56 Millions on January 8, 2013.

It is difficult to analyze DNA data, Foundation’s test is anything but a full genome, it’s a $6,000 .02% of the genome, showing how much of the problem of using genetic information will need to coming from solving computational and analytical problems — exactly the kind of thing that Bill Gates has always been interested in both at Microsoft and in his work getting lifesaving vaccines to children all around the world.

http://www.bloomberg.com/news/2012-02-12/high-speed-dna-scans-help-most-lung-cancer-patients-study-finds.html

Physicians need to incorporate the latest molecular diagnostic tests to help guide treatment of cancer patients due to the growing number of molecular subtypes that are understood across tumor types.

As more targeted therapies are approved for new molecular subtypes, the number of tests that need to be performed on each patient to determine their subtype increases and very quickly exhausts the very small amount of tumor tissue that is available in routine, clinical samples

Importantly, as patients’ molecular subtypes are more broadly incorporated into physician treatment decisions, we continue to further our understanding of a pathway view of cancer. Patients with different tumor types can have same molecular subtype – often, these therapies are applicable across tumor types since they are targeting the same pathway.

Comprehensive cancer genome analysis to routine cancer care. The company’s initial clinical assay, FoundationOneTM, is a fully informative genomic profile to identify a patient’s individual molecular alterations and match them with relevant targeted therapies and clinical trials.

http://www.foundationmedicine.com/diagnostics.php

The DNA sequencing field has drawn increased interest from pharmaceutical makers focused on developing gene-targeted therapies. Roche Holding AG (ROG), the world’s biggest maker of cancer medicines, last month began a $5.7 billion hostile takeover offer for Illumina Inc., the maker of gene sequencing machines that Foundation Medicine uses in its tests.

  • Pfizer’s Sutent

The researchers also spotted a previously unknown genetic flaw in 2 percent of 561 lung tumors tested. The flaw activates a growth-boosting protein targeted by Pfizer Inc. (PFE)’s kidney- cancer drug Sutent, hinting that the treatment from the New York-based drugmaker may also work in these lung patients, said Janne. He wants to begin a trial of Sutent in lung-cancer patients with the gene change by year end, he said.

Lev-Ari, A. (2012N). Sunitinib (Sutent) brings Adult acute lymphoblastic leukemia (ALL) to Remission – RNA Sequencing – FLT3 Receptor Blockade

https://pharmaceuticalintelligence.com/2012/07/09/sunitinib-brings-adult-all-to-remission-rna-sequencing/

Pfizer’s Kidney Cancer Drug Sutent Effectively caused REMISSION to Adult Acute Lymphoblastic Leukemia (ALL)

https://pharmaceuticalintelligence.com/2012/07/10/pfizers-kidney-cancer-drug-sutent-effectively-caused-remission-to-adult-acute-lymphoblastic-leukemia-all/REMISSION to Adult Acute Lymphoblastic Leukemia (ALL)

REMISSION to Adult Acute Lymphoblastic Leukemia (ALL): Pfizer’s Sutent blocks FLT3 Gene Receptors

https://pharmaceuticalintelligence.com/?s=Pfizer

Researchers in Japan also reported finding the same new genetic change in a fraction of lung tumors, according to two other studies published today in Nature Medicine. Until the three new studies, the genetic change had never been seen in any cancer, said Dr. Pasi Janne.

The change fuses two unrelated genes together to form KIF5B-RET, turning on a growth-driving protein called RET that is usually not active in lung cells.

When Pasi Janne and his collaborators treated cells with the aberrant gene using Pfizer’s Sutent or AstraZeneca Plc (AZN)’s thyroid-cancer drug Caprelsa, the cells died. Both drugs block RET.

http://www.google.com/search?q=pasi+janne+lab&hl=en&tbo=u&tbm=isch&source=univ&sa=X&ei=GzXzUMCyHYSK0QGouoCoAw&ved=0CD8QsAQ&biw=1140&bih=731

Pasi Antero Janne, M.D.,Ph.D.

Harvard Catalyst Profiles

http://connects.catalyst.harvard.edu/profiles/profile/person/711

  1. Yuen HF, Abramczyk O, Montgomery G, Chan KK, Huang YH, Sasazuki T, Shirasawa S, Gopesh S, Chan KW, Fennell D, Janne P, El-Tanani M, Murray JT. Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells. Biosci Rep. 2012 Aug 1; 32(4):413-22.
    View in: PubMed
  2. Tanizaki J, Okamoto I, Takezawa K, Sakai K, Azuma K, Kuwata K, Yamaguchi H, Hatashita E, Nishio K, Janne PA, Nakagawa K. Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small-cell lung cancer cells. Br J Cancer. 2012 Feb 14; 106(4):763-7.
    View in: PubMed
  3. Vogelzang NJ, Benowitz SI, Adams S, Aghajanian C, Chang SM, Dreyer ZE, Janne PA, Ko AH, Masters GA, Odenike O, Patel JD, Roth BJ, Samlowski WE, Seidman AD, Tap WD, Temel JS, Von Roenn JH, Kris MG. Clinical cancer advances 2011: annual report on progress against cancer from the american society of clinical oncology. J Clin Oncol. 2012 Jan 1; 30(1):88-109.
    View in: PubMed
  4. Yuen HF, Chan KK, Grills C, Murray JT, Platt-Higgins A, Eldin OS, O’Byrne K, Janne P, Fennell DA, Johnston PG, Rudland PS, El-Tanani M. Ran Is a Potential Therapeutic Target for Cancer Cells with Molecular Changes Associated with Activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK Pathways. Clin Cancer Res. 2012 Jan 15; 18(2):380-91.
    View in: PubMed
  5. Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, Brace LE, Woods BA, Lin W, Zhang J, Deng X, Lim SM, Heynck S, Peifer M, Simard JR, Lawrence MS, Onofrio RC, Salvesen HB, Seidel D, Zander T, Heuckmann JM, Soltermann A, Moch H, Koker M, Leenders F, Gabler F, Querings S, Ansén S, Brambilla E, Brambilla C, Lorimier P, Brustugun OT, Helland A, Petersen I, Clement JH, Groen H, Timens W, Sietsma H, Stoelben E, Wolf J, Beer DG, Tsao MS, Hanna M, Hatton C, Eck MJ, Janne PA, Johnson BE, Winckler W, Greulich H, Bass AJ, Cho J, Rauh D, Gray NS, Wong KK, Haura EB, Thomas RK, Meyerson M. Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov. 2011 Jun; 1(1):78-89.
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  6. Weisberg E, Choi HG, Ray A, Barrett R, Zhang J, Sim T, Zhou W, Seeliger M, Cameron M, Azam M, Fletcher JA, Debiec-Rychter M, Mayeda M, Moreno D, Kung AL, Janne PA, Khosravi-Far R, Melo JV, Manley PW, Adamia S, Wu C, Gray N, Griffin JD. Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants. Blood. 2010 May 27; 115(21):4206-16.
    View in: PubMed
  7. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher JA, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M. The landscape of somatic copy-number alteration across human cancers. Nature. 2010 Feb 18; 463(7283):899-905.
    View in: PubMed
  8. Qin W, Kozlowski P, Taillon BE, Bouffard P, Holmes AJ, Janne P, Camposano S, Thiele E, Franz D, Kwiatkowski DJ. Ultra deep sequencing detects a low rate of mosaic mutations in tuberous sclerosis complex. Hum Genet. 2010 Mar; 127(5):573-82.
    View in: PubMed
  9. Rodig SJ, Mino-Kenudson M, Dacic S, Yeap BY, Shaw A, Barletta JA, Stubbs H, Law K, Lindeman N, Mark E, Janne PA, Lynch T, Johnson BE, Iafrate AJ, Chirieac LR. Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin Cancer Res. 2009 Aug 15; 15(16):5216-23.
    View in: PubMed
  10. Lynch TJ, Blumenschein GR, Engelman JA, Espinoza-Delgado I, Govindan R, Hanke J, Hanna NH, Heymach JV, Hirsch FR, Janne PA, Lilenbaum RC, Natale RB, Riely GJ, Sequist LV, Shapiro GI, Shaw A, Shepherd FA, Socinski M, Sorensen AG, Wakelee HA, Weitzman A. Summary statement novel agents in the treatment of lung cancer: Fifth Cambridge Conference assessing opportunities for combination therapy. J Thorac Oncol. 2008 Jun; 3(6 Suppl 2):S107-12.
    View in: PubMed

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Reported by: Dr. Venkat S. Karra, Ph.D.

 

Brain structures involved in dealing with fear...

 

Major depression or chronic stress can cause the loss of brain volume, a condition that contributes to both emotional and cognitive impairment. Now a team of researchers led by Yale University scientists has discovered one reason why this occurs—a single genetic switch that triggers loss of brain connections in humans and depression in animal models.

 

The findings, reported in Nature Medicine, show that the genetic switch known as a transcription factor represses the expression of several genes that are necessary for the formation of synaptic connections between brain cells, which in turn could contribute to loss of brain mass in the prefrontal cortex.

 

“We wanted to test the idea that stress causes a loss of brain synapses in humans,” said senior author Ronald Duman, the Elizabeth Mears and House Jameson Professor of Psychiatry and professor of neurobiology and of pharmacology. “We show that circuits normally involved in emotion, as well as cognition, are disrupted when this single transcription factor is activated.”

 

The research team analyzed tissue of depressed and non-depressed patients donated from a brain bank and looked for different patterns of gene activation. The brains of patients who had been depressed exhibited lower levels of expression in genes that are required for the function and structure of brain synapses. Lead author and postdoctoral researcher H.J. Kang discovered that at least five of these genes could be regulated by a single transcription factor called GATA1. When the transcription factor was activated, rodents exhibited depressive-like symptoms, suggesting GATA1 plays a role not only in the loss of connections between neurons but also in symptoms of depression.

 

Duman theorizes that genetic variations in GATA1 may one day help identify people at high risk for major depression or sensitivity to stress.

 

“We hope that by enhancing synaptic connections, either with novel medications or behavioral therapy, we can develop more effective antidepressant therapies,” Duman said.

 

source:

 

http://www.rdmag.com/News/2012/08/Life-Sciences-Team-Discovers-How-Stress-Depression-Can-Shrink-The-Brain/

 

 

 

 

 

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