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• decreased metabolic efficiency and cellular insulin resistance.

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

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

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

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

1. CYP27B1,
2. CYP24A1,
3. VDR,
4. REN and
5. ACE.

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

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

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

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

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

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

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

1. medium-chain acyl-CoA dehydrogenase,
2. CPT-1 and
3. malonyl-CoA decarboxylase

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

1. glycolysis and glucose oxidation
2. restriction of myocardial fatty acid uptake.

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

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

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

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

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

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

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

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

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

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

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.

1. ATP production
2. oxidative phosphorylation
3. DNA synthesis.

• causes extensive vasodilation and hypotension.

• 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.

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

• as well as the coronary arterial–venous difference.

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

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

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

• manifest until the development of blindness.

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

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

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

• should be screened for abnormalities of cardiac function.

• superoxide,
• hydroxyl radicals and
• hydrogen peroxide,

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

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

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

• developed progressive congestive heart failure
• with defects in mitochondrial respiration.

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

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

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

• functional impairment and
• morphological disorganization

• the modulation of mitochondrial electron transport itself.

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

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

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

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

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

• preproendothelin-1 gene expression and apoptosis.

• increase in DNA laddering, an indication of apoptosis.

• 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.

• the progression of congestive heart failure (CHF).

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

• substrate utilization and
• oxidative phosphorylation,

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/

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