Skip Navigation

Cardiovascular Research 2000 45(4):805-806; doi:10.1016/S0008-6363(99)00419-8
© 2000 by European Society of Cardiology
This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Stanley, W. C
Right arrow Articles by Hoppel, C. L
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stanley, W. C
Right arrow Articles by Hoppel, C. L
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2000, European Society of Cardiology

Mitochondrial dysfunction in heart failure: potential for therapeutic interventions?

William C Stanleya,* and Charles L Hoppelb,c

aDepartment of Physiology and Biophysics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA
bDepartments of Pharmacology and Medicine, Case Western Reserve University, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4970, USA
cVeterans Affairs Medical Center, Cleveland, OH, USA

* Corresponding author. Tel.: +1-216-368-5585; fax: +1-216-368-3952 wcs4{at}po.cwru.edu

Received 7 December 1999; accepted 7 December 1999

KEYWORDS Cardiomyopathy; Heart failure; Mitochondria

See article by Jarreta et al. [4] (pages 860–865) in this issue.

Cardiac work is supported by a high rate of ATP hydrolysis, matched by ATP production through mitochondrial oxidative phosphorylation (Fig. 1). Low ATP content in cardiac tissue was observed in patients with chronic heart failure despite the absence of myocardial ischaemia [1]. Mitochondrial function in cardiac tissue from the failing heart demonstrated that the capacity of the mitochondria for oxygen consumption and oxidative phosphorylation are significantly reduced compared to the normal heart [2]. Furthermore, morphological examination of the failing heart by electron microscopy revealed that the mitochondria are disrupted and damaged [3]. The paper by Jarreta et al. in this issue of Cardiovascular Research shows in both idiopathic dilated cardiomyopathy (IDC) and heart failure patients with a history of ischaemic coronary disease (IC) that the activity of complex III of the electron transport chain is reduced, without changes in the activities of complexes I, II or IV, or in the mitochondrial marker enzyme citrate synthase [4]. Evidence for a causal link between impaired mitochondrial metabolic function and cardiac failure was found in several cases of inherited cardiomyopathies [5], presenting as classic IDC. Surprisingly little is known about the molecular aspects of mitochondrial pathology in the failing heart. While point mutations in key mitochondrial enzymes could significantly impair the ability of the mitochondria to generate ATP, Jarreta et al. [4] found only neutral polymorphisms in the mitochondrial cytochrome b gene, suggesting that the complex III defect is not a primary mitochondrial disease.


Figure 1
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Schematic depiction of myocardial energy metabolism. Abbreviations: PDH, pyruvate dehydrogenase; I, II, III, IV and V, complexes I through V; CAC, citric acid cycle; SR, sarcoplasmic reticulum.

 
A myriad of good questions is raised by the work of Jarreta et al. [4]. Are there functional consequences of the complex III defect? Is a 35% reduction in activity enough to result in a decrease in the rate of oxidative phosphorylation and a meaningful drop in the ATP content? Of interest, cardiomyopathy is not a presentation in patients with a congenital complex III defect [6]. The molecular cause of this decrease in complex III activity in heart failure is not known. Complex III contains 11 subunits, and the only one that is encoded on mitochondrial DNA, cytochrome b, has been shown by Jarreta et al. [4] to be normal. The status of the other subunits needs to be determined before the molecular mechanism(s) can be fully understood. Additionally, the mitochondria in the heart exist as two populations (interfibrillar and subsarcolemmal) which respond differently to inherited cardiomyopathy [7], ischaemic injury [8], and aging [9]. Is there a selective decrease in complex III in only one population? Also, is there a greater production of free radicals due to the decreased complex III activity?

In addition to defects in the electron transport chain, the failing heart has important, clinically relevant mitochondrial abnormalities in the metabolism of carbon substrates for the generation of reducing equivalents (NADH and FADH2) (Fig. 1). The oxidation of fatty acids normally supplies approximately two thirds of the energy for oxidative phosphorylation [10]. Heart failure patients may have impaired oxidation of glucose and lactate and enhanced fatty acid oxidation that contributes to contractile dysfunction [11]. Thus pharmacotherapies aimed at increasing myocardial oxidation of pyruvate (derived from glucose and lactate) (Fig. 1) could be beneficial for the failing heart [12]. In line with this, pharmacological activation of pyruvate dehydrogenase (the key site regulating the oxidation of carbohydrate) results in a significant improvement in left ventricular function without an increase in myocardial oxygen consumption [13]. The enhanced pyruvate oxidation lowers lactate accumulation and efflux from the cell, and helps maintain myocyte pH and ion homeostasis [10]. This would allow more efficient use of ATP for contractile work by myosin ATPases, and for relaxation by the Ca2+ ATPase on the sarcoplasmic reticulum, and a greater rate of left ventricular power for a given rate of myocardial oxygen consumption. Pyruvate oxidation also can be increased by partially inhibiting fatty acid oxidation, which removes product inhibition on pyruvate dehydrogenase [10]. The partial fatty acid oxidation inhibitors trimetazidine and ranolazine have been used successfully for the treatment of stable angina [10], without eliciting any of the classic anti-ischaemic effects of traditional therapies (e.g. decrease heart rate, coronary vasodilation, decreased arterial blood pressure). This approach remains to be tested in heart failure patients.

A switch to greater carbohydrate oxidation and less fatty acid oxidation is observed with chronic treatment with the beta-adrenergic receptor antagonist metoprolol, and is associated with improvement in left ventricular function [14]. This may be due to down-regulation of carnitine palmitoyl transferase-I (a key enzyme regulating fatty acid β-oxidation in the mitochondria), as observed with long-term treatment with metoprolol in dogs with progressive heart failure [15]. In addition, progression of heart failure following a myocardial infarction in the rat is prevented with ACE inhibitors, as is the fall in state III respiration in isolated cardiac mitochondria [16]. Perhaps the suppression of heart failure induced neural–hormonal activation prevents the decline in complex III activity observed by Jarreta et al. [4].

Clearly the failing heart has mitochondrial abnormalities that impair the ability of the tissue to synthesize ATP. Future work will attempt to identify the causes of these abnormalities, and determine the role they play in the progression of heart failure. Congestive heart failure is a malignant disease and drugs that can stop the progression of the disease are sorely needed. Therapies aimed at preserving mitochondrial function and optimizing substrate metabolism appear to be worthwhile pursuits in the effort to stop the progression of heart failure.


   References
Top
 References
 

  1. Bashore T.M., Magorien D.J., Letterio J., Shaffer P., Unverferth D.V. Histologic and biochemical correlates of left ventricular chamber dynamics in man. J Am Col Cardiol (1987) 9:734–742.[Abstract]
  2. Sharov V.G., Sabbah H.N., Cook J.M., Silverman N., Lesch M., Goldstein S. Abnormal mitochondrial respiration in failed human and dog myocardium. J Mol Cell Cardiol (1998) 30:1757–1762.[CrossRef][Web of Science][Medline]
  3. Sabbah H.N., Sharov V.G., Riddle J.M., Kono T., Lesch M., Goldstein S. Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J. Mol. Cell Cardiol. (1992) 24:1333–1347.[CrossRef][Web of Science][Medline]
  4. Jarreta D., Orius J., Barrientos A., et al. Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy. Cardiovasc Res (2000) 45:860–865.[Abstract/Free Full Text]
  5. Kelly D.P., Strauss A.W. Inherited cardiomyopathies. N Engl J Med (1994) 330:913–919.[Free Full Text]
  6. Moourmans J., Wendel U., Bentlage H.A.C.M., et al. Clinical heterogeneity in respiratory chain complex III deficiency in childhood. J Neurol Sci (1997) 149:111–117.[CrossRef][Web of Science][Medline]
  7. Hoppel C.L., Tandler B., Parland W., Turkaly J.S., Albers L.D. Hamster cardiomyopathy: a defect in oxidative phosphorylation in the cardiac interfibrillar mitochondria. J Biol Chem (1982) 257:1540–1548.[Free Full Text]
  8. Lesnefsky E.J., Tandler B., Ye J., Slabe T.J., Turkaly J., Hoppel C.L. Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria. Am J Physiol (1997) 273:H1544–H1554.[Web of Science][Medline]
  9. Fannin S.W., Lesnefsky E.J., Slabe T.J., Hassan M.O., Hoppel C.L. Aging selectively decreases oxidative capacity in rat heart interfibrillar mitochondria. Arch Biochem Biophys (2000) 372:1.[CrossRef][Web of Science]
  10. Stanley W.C., Lopaschuk G.D., Hall J.H., McCormack J.G. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions: Potential for pharmacological interventions. Cardiovasc Res (1997) 33:243–257.[Free Full Text]
  11. Paolisso G., Gambardella A., Galzerano D., et al. Total body and myocardial substrate oxidation in congestive heart failure. Metabolism (1994) 43:174–178.[CrossRef][Web of Science][Medline]
  12. From A.H.L. Should manipulation of myocardial substrate utilization patterns be a component of the congestive heart failure therapeutic paradigm? J Cardiac Failure (1998) 4:127–129.[CrossRef][Medline]
  13. Bersin R.M., Wolfe C., Kwasman M., et al. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol (1994) 23:1617–1624.[Abstract]
  14. Eichhorn E.J., Heesch C.M., Barnett J.H., et al. Effect of metoprolol on myocardial function and energetics in patients with non-ischemic dilated cardiomyopathy: a randomized, double-blind, placebo controlled study. J Am Coll Cardiol (1994) 24:1310–1320.[Abstract]
  15. Panchal A.R., Stanley W.C., Kerner J., Sabbah H.N. Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure. J Cardiac Failure (1998) 4:121–126.[CrossRef][Medline]
  16. Sanbe A., Tanonake K., Kobayasi R., Takeo S. Effect of long-term therapy with ACE inhibitors on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol (1995) 27:2209–2222.[CrossRef][Web of Science][Medline]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cardiovasc ResHome page
M. K. Duda, K. M. O'Shea, and W. C. Stanley
{omega}-3 polyunsaturated fatty acid supplementation for the treatment of heart failure: mechanisms and clinical potential
Cardiovasc Res, October 1, 2009; 84(1): 33 - 41.
[Abstract] [Full Text] [PDF]

Home page
 J CARDIOVASC PHARMACOL THERHome page
B.-q. Zhu, U. Simonis, G. Cecchini, H.-z. Zhou, L. Li, J. R. Teerlink, and J. S. Karliner
Comparison of Pyrroloquinoline Quinone and/or Metoprolol on Myocardial Infarct Size and Mitochondrial Damage in a Rat Model of Ischemia/Reperfusion Injury
Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2006; 11(2): 119 - 128.
[Abstract] [PDF]

Home page
 Physiol. Rev.Home page
W. C. Stanley, F. A. Recchia, and G. D. Lopaschuk
Myocardial Substrate Metabolism in the Normal and Failing Heart
Physiol Rev, July 1, 2005; 85(3): 1093 - 1129.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
M. P. Chandler, J. Kerner, H. Huang, E. Vazquez, A. Reszko, W. Z. Martini, C. L. Hoppel, M. Imai, S. Rastogi, H. N. Sabbah, et al.
Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation
Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1538 - H1543.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
H. N. Sabbaha and W. C. Stanley
Partial fatty acid oxidation inhibitors: a potentially new class of drugs for heart failure
Eur J Heart Fail, January 1, 2002; 4(1): 3 - 6.
[Full Text] [PDF]

This Article
Right arrow Extract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Stanley, W. C
Right arrow Articles by Hoppel, C. L
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stanley, W. C
Right arrow Articles by Hoppel, C. L
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?