Correspondence
The Failing Heart
N Engl J Med 2007; 356:2544-2546June 14, 2007
- Article
To the Editor:
The review article by Neubauer (March 15 issue),1 which focuses on myocardial energetics, states that the use of fatty acids and glucose is decreased and insulin resistance develops in advanced heart failure. Neubauer also suggests some new drug targets for the treatment of heart failure in the peroxisome proliferator–activated receptor (PPAR) family, including PPARα and PPARγ coactivator 1. We want to add PPARδ to the list. PPARδ is another isotype of the PPAR family.2 Cheng et al.3 discovered that a heart that is deficient in PPARδ has decreased fatty acid oxidation and lipotoxic cardiomyopathy, and Planavila et al.4 showed that activation of PPARδ inhibits hypertrophy in cardiomyocytes. A PPARδ agonist may increase the oxidation and use of fatty acids and inhibit the remodeling process leading to hypertrophy, cardiomyopathy, and heart failure.
4 ReferencesJaewon Oh, M.D.
Ji-Hyung Chung, Ph.D.
Seok-Min Kang, M.D., Ph.D.
Yonsei University College of Medicine, Seoul 120-752, South Korea1
Neubauer S . The failing heart -- an engine out of fuel. N Engl J Med 2007;356:1140-1151
Full Text | Web of Science | Medline2
Barish GD ,Narkar VA ,Evans RM . PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 2006;116:590-597
CrossRef | Web of Science | Medline3
Cheng L ,Ding G ,Qin Q , et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat Med 2004;10:1245-1250
CrossRef | Web of Science | Medline4
Planavila A ,Rodriguez-Calvo R ,Jove M , et al. Peroxisome proliferator-activated receptor beta/delta activation inhibits hypertrophy in neonatal rat cardiomyocytes. Cardiovasc Res 2005;65:832-841
CrossRef | Web of Science | Medline
To the Editor:
The review of the biochemical mechanisms of the failing heart did not mention thiamine deficiency and thiamine supplementation in the management of heart failure. Limited studies in patients with heart failure, especially those receiving high-dose loop-diuretic therapy, which can lead to thiamine wasting, have shown that thiamine deficiency occurs in heart failure. Moreover, small randomized trials have shown a benefit of thiamine supplementation at a dose of 200 mg per day.1-4 In light of the data already available, it is prudent to provide thiamine supplementation in patients with heart failure, and it is important to conduct further studies of its efficacy and safety.
4 ReferencesStephen W. Smith, M.D.
Hennepin County Medical Center, Minneapolis, MN 55415
smith253@umn.edu 1
Hanninen SA ,Darling PB ,Sole MJ ,Barr A ,Keith ME . The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure. J Am Coll Cardiol 2006;47:354-361
CrossRef | Web of Science | Medline2
Leslie D ,Gheorghiade M . Is there a role for thiamine supplementation in the management of heart failure? Am Heart J 1996;131:1248-1250
CrossRef | Web of Science | Medline3
Shimon I ,Almog S ,Vered Z , et al. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy. Am J Med 1995;98:485-490
CrossRef | Web of Science | Medline4
Witte KK ,Nikitin NP ,Parker AC , et al. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Eur Heart J 2005;26:2238-2244
CrossRef | Web of Science | Medline
To the Editor:
In his report on the molecular interactions in cardiomyocytes during heart failure, Neubauer does not mention exercise training. Numerous convincing molecular studies have shown a slowed progression to heart failure by means of exercise training.1
1 ReferencesDavid Niederseer, M.B., B.S.
Medical University Innsbruck, 6020 Innsbruck, AustriaChristoph Thaler, M.D.
Josef Niebauer, M.D., Ph.D.
Paracelsus Medical University, 5020 Salzburg, Austria
j.niebauer@salk. at 1
Piepoli MF ,Davos C ,Francis DP ,Coats AJ . Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 2004;328:189-195
CrossRef | Web of Science | Medline
To the Editor:
Neubauer does not mention the role of oxidative stress, which has many effects on myocardial structure and function.1 Accumulating evidence suggests that mitochondria are the main source of reactive oxygen species in heart failure.2 Oxidation-induced damage may play an important role in the dysfunction of mitochondrial oxidative phosphorylation in heart failure.
2 ReferencesPanagiotis Korantzopoulos, M.D., Ph.D.
John A. Goudevenos, M.D.
University of Ioannina Medical School, 45110 Ioannina, Greece
p.korantzopoulos@yahoo. gr 1
Sawyer DB, Colucci WS. Oxidative stress in heart failure. In: Mann DL, ed. Heart failure: a companion to Braunwald's Heart Disease. New York: Elsevier, 2004:181-92.
2
Sheeran FL ,Pepe S . Energy deficiency in the failing heart: linking increased reactive oxygen species and disruption of oxidative phosphorylation rate. Biochim Biophys Acta 2006;1757:543-552
CrossRef | Web of Science | Medline
To the Editor:
Neubauer proposes the use of phosphorus-31 magnetic resonance (31P-MR) spectroscopy as a tool to assess myocardial energetics and to monitor therapeutic interventions. We concur, but the article omits the clinical value of noninvasive quantification of oxidative metabolism and, more important, the efficiency of cardiac work in heart failure.1 Recent advances in positron-emission tomography (PET) have permitted the noninvasive assessment of these measures,2 making this technique suitable for clinical studies.3,4 Furthermore, since 31P-MR spectroscopy and PET give information pertaining to different components of cardiac energy metabolism, the combination of the two imaging studies could be complementary in investigating myocardial energetics in heart failure.
4 ReferencesPaul Knaapen, M.D., Ph.D.
VU University Medical Center, 1081 HV Amsterdam, the Netherlands
p.knaapen@vumc. nl Juhani Knuuti, M.D., Ph.D.
Turku PET Center, FIN-20521 Turku, FinlandAlbert C. van Rossum, M.D., Ph.D.
VU University Medical Center, 1081 HV Amsterdam, the Netherlands1
Kim IS ,Izawa H ,Sobue T , et al. Prognostic value of mechanical efficiency in ambulatory patients with idiopathic dilated cardiomyopathy in sinus rhythm. J Am Coll Cardiol 2002;39:1264-1268
CrossRef | Web of Science | Medline2
Knaapen P ,Germans T ,Knuuti J , et al. Myocardial energetics and efficiency: current status of the noninvasive approach. Circulation 2007;115:918-927
CrossRef | Web of Science | Medline3
Beanlands RS ,Nahmias C ,Gordon E , et al. The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: a double-blind, placebo-controlled, positron-emission tomography study. Circulation 2000;102:2070-2075
Web of Science | Medline4
Tuunanen H ,Engblom E ,Naum A , et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 2006;114:2130-2137
CrossRef | Web of Science | Medline
To the Editor:
Neubauer deserves credit for sorting through various defects in energy metabolism in the failing heart. This is an exceedingly difficult topic, but three points should make it easier to understand. In contrast to the title of the article (“The Failing Heart — An Engine Out of Fuel”), the failing heart never runs out of fuel. Unless the coronary circulation is severely compromised, the heart fails in the midst of plenty.1 Beginning with the circulation and ending with the cross-bridge cycling of the sarcomere, energy transfer in the heart occurs through a series of component conserved cycles.2 In biology, as in physics, cycles improve efficiency.3 The dilemma of impaired energy transfer in the failing heart is our inability (in most cases) to distinguish between cause and consequence. For the time being, the term “cardiac burnout syndrome”4 seems quite appropriate.
4 ReferencesHeinrich Taegtmeyer, M.D., D.Phil.
University of Texas Medical School at Houston, Houston, TX 77030
heinrich.taegtmeyer@uth. tmc. edu 1
Taegtmeyer H . Myocardial energetics: still only the tip of an iceberg. Heart Lung Circ 2003;12:3-6
CrossRef | Medline2
Taegtmeyer H . Energy metabolism of the heart: from basic concepts to clinical applications. Curr Probl Cardiol 1994;19:59-113
CrossRef | Web of Science | Medline3
Racker E . Energy cycles in health and disease. Curr Top Cell Regul 1981;18:361-375
Medline4
van Bilsen M ,Smeets PJ ,Gilde AJ ,van der Vusse GJ . Metabolic remodelling of the failing heart: the cardiac burn-out syndrome? Cardiovasc Res 2004;61:218-226
CrossRef | Web of Science | Medline
To the Editor:
Neubauer provides an excellent summary of cardiac energy metabolism in the normal heart but has a problem summarizing it in the failed heart. Heart failure has many causes (e.g., hypertension, coronary artery disease, and hypertrophic cardiomyopathy), and there is no reason to believe that the changes in cardiac energy metabolism are the same in all of them. To find out, we will have to study each cause separately. It is not good enough to lump them all together and simply indicate the directional changes without providing units, as Neubauer does in Figure 3 of his article. Separate studies might explain the conflicting changes in one or more of the three components of cardiac energy metabolism: substrate utilization, oxidative phosphorylation, and high-energy phosphate metabolism. For example, a separate study might explain the conflicting and inconsistent findings on fatty acid and glucose utilization in heart failure that Neubauer mentions. The findings might not be inconsistent if categorized according to disease states as a function of time.
Francis J. Haddy, M.D., Ph.D.
Mayo Clinic College of Medicine, Rochester, MN 55905
tbhaddy@aol.com Author/Editor Response
An unavoidable challenge for a space-restricted review article is that many interesting potential mechanisms and treatment strategies (e.g., adenine nucleotide translocase, adenylate kinase, AMP-activated protein kinase, intracellular hypoxia, allopurinol, ranolazine, statins, and coenzyme Q10), as well as those raised by Oh et al. (PPARδ), Smith (thiamine), and Niederseer et al. (exercise training), cannot be covered. The systematic exploration of these mechanisms and therapies would be worthwhile. Korantzopoulos and Goudevenos note the important role of oxidative stress, which was not the focus of my article; it would be an excellent topic for a separate review.
Knaapen et al. point out that PET methods for the noninvasive assessment of cardiac metabolism are complementary to MR spectroscopy. I agree, and in my article I therefore cite three references (38, 39, and 40) that mention the use of PET. I thank Taegtmeyer for his thoughtful comments. There is, however, a discrepancy between what he and I consider the “fuel” to be. For him, the fuel is the substrates, whereas for me it is the ATP delivered to the myofibrils for work. My article describes in detail why the failing heart is an engine out of fuel on the basis of this definition.
Finally, Haddy suggests that there is no reason to believe that changes in energy metabolism are similar for all causes of heart failure. I agree, and I state in my review that there are many reasons why a human heart can fail. However, for the most common causes of heart failure (remodeling after myocardial infarction, dilated cardiomyopathy, and chronic pressure and volume overload), changes in energy metabolism are remarkably similar. The purpose of Figure 3 was to summarize this. Some simplification (e.g., omission of units) is unavoidable in a general review article.
I would like to take this opportunity to draw attention to the important historical contribution of Dr. Richard Bing to the field. In his Harvey lecture of 1956, he stated that the failing heart would appear to be deficient in its ability to use energy for effective muscular contraction.1
1 ReferencesStefan Neubauer, M.D., F.R.C.P.
University of Oxford, Oxford OX3 9DU, United Kingdom
stefan.neubauer@cardiov. ox. ac. uk 1
Blain JM ,Schafer H ,Siegel AL ,Bing RJ . Studies on myocardial metabolism. VI. Myocardial metabolism in congestive failure. Am J Med 1956;20:820-833
CrossRef | Web of Science | Medline
