Unlocking the Secrets of Mitochondria in the Cardiovascular System: Path to a Cure in Heart Failure—A Report from the 2018 National Heart, Lung, and Blood Institute Workshop

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Abstract

Mitochondria have emerged as a central factor in the pathogenesis and progression of heart failure (HF), as well as other cardiovascular diseases (CVD), but no therapies are available to treat mitochondrial dysfunction. The National Heart, Lung, and Blood Institute (NHLBI) convened a group of leading experts in HF, CVD, and mitochondria research in August 2018. These experts reviewed the current state of science and identified key gaps and opportunities in basic, translational and clinical research focusing on the potential of mitochondria-based therapeutic strategies in HF. The workshop provided short- and long-term recommendations for moving the field toward clinical strategies for the prevention and treatment of HF and CVD using mitochondria-based approaches.

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Mitochondrial dysfunction in pathophysiology of heart failure

Bo Zhou, Rong Tian (2018)

Mitochondrial dysfunction has been implicated in the development of heart failure. Oxidative metabolism in mitochondria is the main energy source of the heart, and the inability to generate and transfer energy has long been considered the primary mechanism linking mitochondrial dysfunction and contractile failure. However, the role of mitochondria in heart failure is now increasingly recognized to be beyond that of a failed power plant. In this Review, we summarize recent evidence demonstrating vicious cycles of pathophysiological mechanisms during the pathological remodeling of the heart that drive mitochondrial contributions from being compensatory to being a suicide mission. These mechanisms include bottlenecks of metabolic flux, redox imbalance, protein modification, ROS-induced ROS generation, impaired mitochondrial Ca 2+ homeostasis, and inflammation. The interpretation of these findings will lead us to novel avenues for disease mechanisms and therapy.

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Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.

S Yusuf, G. Dagenais, J Pogue … (2000)

Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis. We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer. A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E. In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.

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Effects of purifying and adaptive selection on regional variation in human mtDNA.

Eduardo Ruiz-Pesini, Dan Mishmar, Martin Brandon … (2004)

A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.

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Author and article information

Journal

Title: Circulation

Abbreviated Title: Circulation

Publisher: Ovid Technologies (Wolters Kluwer Health)

ISSN (Print): 0009-7322

ISSN (Electronic): 1524-4539

Publication date Created: October 2019

Publication date (Print): October 2019

Volume: 140

Issue: 14

Pages: 1205-1216

Affiliations

[1 ]Mitochondria and Metabolism Center, Department of Anesthesiology and Pain Medicine (R.T.), University of Washington, Seattle.

[2 ]Department of Medicine, Boston University, MA (W.S.C., M.M.B.).

[3 ]Department of Medicine, University of Pennsylvania, Philadelphia (Z.A., D.B.K.).

[4 ]Department of Pathology, University of Alabama at Birmingham (S.W.B.).

[5 ]Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City (S.B.).

[6 ]Department of Genome Sciences (J.E.B.), University of Washington, Seattle.

[7 ]Department of Pharmacology, Tulane University, New Orleans, LA (D.W.B.).

[8 ]Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (S.D.).

[9 ]Center for Pharmacogenomics, Department of Internal Medicine, Washington University, St. Louis, MO (G.W.D.).

[10 ]National, Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (Z.S.G., D.L., M.N.S., Y.S., R.W., L.S.L.).

[11 ]Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.A.G.).

[12 ]Department of Medicine, Department of Cell Biology, Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, NY (R.N.K.).

[13 ]Departments of Environmental Health and Engineering (M.J.K.), The Johns Hopkins University, Baltimore, MD.

[14 ]Department of Internal Medicine, The Ohio State University, Columbus (E.D.L.).

[15 ]Department of Physiology, East Carolina University, Greenville, NC (J.M.M.).

[16 ]Department of Chemical and Systems Biology, Stanford University, CA (D.M.-R.).

[17 ]Medicine (B.O., R.G.W.), The Johns Hopkins University, Baltimore, MD.

[18 ]Department of Kinesiology, Temple University, Philadelphia, PA (J.-Y.P.).

[19 ]Department of Physiology and Department of Medicine, University of California, Los Angeles (P.P.).

[20 ]Department of Medicine, Thomas Jefferson University, Philadelphia, PA (S.-S.S.).

[21 ]Department of Pharmacology and Chemical Biology and Vascular Medicine Institute, University of Pittsburgh, PA (S.S.).

[22 ]Center for Mitochondrial and Epigenomic Medicine, Children’s Hospital of Philadelphia Research Institute, PA (D.C.W.).

[23 ]Genetic Medicine (H.J.V.), The Johns Hopkins University, Baltimore, MD.

Article

DOI: 10.1161/CIRCULATIONAHA.119.040551

PMC ID: 6880654

PubMed ID: 31769940

SO-VID: cb0e38a1-3502-4890-a1db-31693fd358ad

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Unlocking the Secrets of Mitochondria in the Cardiovascular System : Path to a Cure in Heart Failure—A Report from the 2018 National Heart, Lung, and Blood Institute Workshop

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Most cited references 50

Mitochondrial dysfunction in pathophysiology of heart failure

Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.

Effects of purifying and adaptive selection on regional variation in human mtDNA.

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