Number 32, 2006
Metabolic profile in heart disease

Understanding the metabolic phenotype of heart disease

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Rong Tian
NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
Correspondence: Dr Rong Tian, 221 Longwood Ave, Room 252, Boston, MA 02115, USA.
Tel: +1 617 732 6729; fax: +1 617 732 6990; e-mail: rtian@rics.bwh.harvard.edu

Introduction
Cardiovascular disease is the leading cause of death in developed countries. Improved survival after an acute ischemic episode in recent years has, paradoxically, resulted in an increased diagnosis of heart failure in patients post-myocardial infarction. Despite the success of neurohormonal inhibition, many patients with heart failure still experience progression of their disease, and heart failure remains the number one killer in the USA [1]. The recent failure of trials of treatment with endothelin-1 receptor blockers and cytokine antibodies has fueled the search for alternative options in chronic therapy in order to achieve further improvement in the limited prognosis of patients with heart failure.
Targeting energy metabolism for heart failure therapy is worth considering, not only because the heart is an organ with high energy consumption, but also because failing hearts are energy-deprived. Studies in animal models and in patients have shown a significant decrease in myocardial content of the energy reserve compound, phosphocreatine, which can rapidly regenerate ATP in case of abrupt increases in energy demand [2–4], followed by the eventual depletion of myocardial ATP content at the end-stage of heart failure [4]. Long-term follow-up studies in patients with idiopathic dilated cardiomyopathy have demonstrated that decreased phosphocreatine is an independent predictor of mortality [3], suggesting that impaired myocardial energetics contributes significantly to the progression of heart failure. This notion is further supported by consistent observations in clinical trials in patients with heart failure showing that energy-costly treatments such as positive inotropic agents (β-receptor mimetic drugs, phosphodiesterase inhibitors) increase mortality, whereas energy-sparing treatments such as angiotensin-converting enzyme inhibitors, angiotensin II blockers or β-receptor blockers reduce mortality. These observations collectively suggest that myocardial energy metabolism plays an important part in the progression of heart failure. Thus a better understanding of the metabolic phenotype may offer new opportunities to mend the failing heart.

Energy metabolism in animal models of heart failure
An important change in energy metabolism observed in animal models of cardiac hypertrophy and failure is a shift in the preference of substrates for energy generation. Although the heart is able to utilize a variety of substrates, preference in substrate utilization has been documented and it can change in response to altered substrate availability or altered regulation of metabolic pathways. As illustrated in Figure 1, substrate preference of the heart changes under several physiological and pathological situations. For example, glucose and lactate (collectively referred to as carbohydrates) are the primary carbon substrates for fetal hearts, whereas fatty acids become the predominant fuel in adult hearts, supporting more than 67% of the total ATP synthesized [5–7]. In contrast, hypertrophied and failing hearts demonstrate increased reliance on glucose as a fuel while decreasing its fatty acid utilization, an apparent recurrence of the fetal metabolic profile [8–10].

Functional consequences of the altered substrate metabolism
Is the shift in substrate preference beneficial or detrimental, or of no functional significance for the heart? To address such a question, it is necessary to alter substrate preference by a mechanism that is independent of heart failure. This is made possible by studying transgenic mouse hearts in which substrate preference has been altered by genetic manipulations. In mouse hearts deficient in PPARα, increased glucose utilization has been observed and it was sufficient to compensate for the decrease in fatty acid oxidation at baseline workload [13,16,17]. However, these hearts showed impaired energetics and contractile function when challenged with high workloads [17,18]. In contrast, myocardial glucose utilization increased by overexpression of an insulin-independent glucose transporter, GLUT 1, was not associated with an adverse phenotype [17,19], and the overexpression of GLUT 1 was able to correct the energetic and contractile defects in PPARα-deficient hearts [17]. Analysis of substrate oxidation profiles using a carbon-13 nuclear magnetic resonance technique showed that the compensatory increases in glucose oxidation in hearts that were deficient in PPARα at baseline had exhausted the reserve for a further increase at high workload, thus depleting the metabolic reserve and consequently the contractile reserve of the heart. Subsequent overexpression of GLUT 1 restored the ability to achieve a further increase in the contribution of glucose to oxidative metabolism [17].
An important lesson learned from these studies is that increased reliance on glucose per se is not harmful for the heart. However, the intrinsic adaptation to impaired fatty acid oxidation through an increase in glucose utilization is limited in the adult heart and comes with the cost of depleting the functional reserve of the heart. Such a scenario is clearly unfavorable for failing hearts that constantly struggle to accomplish their workload. This is even more problematic when one considers that heart failure is often associated with insulin insensitivity [20,21], thus further compromising the glucose utilization of the heart. Therefore, altered substrate metabolism, which is part of the myocardial remodeling process after an initial pathological event such as myocardial infarction or pressure or volume overload of the heart, may ultimately fail to satisfy the high energy demand of the heart coping with mechanical overload caused by the underlying diseases. The mismatch of energy supply and demand thus drives a vicious cycle that contributes to the ultimate failure of the heart.

Developing therapeutic concepts based on phenotyping
How do we restore the supply of energy to the overloaded heart? Several hypotheses derived from the metabolic phenotype discussed above have been tested (Figure 2). One obvious approach is to restore substrate preference by reactivating PPARα. Although systemic benefits of the lipid-decreasing and anti-inflammatory effects of PPARα agonists have been noted in several studies [22,23], increased myocardial fatty acid oxidation that results from reactivation of PPARα is apparently detrimental to hypertrophied hearts [24,25]. Decreased fatty acid oxidation is probably beneficial for hearts with compromised perfusion, because of its oxygen-sparing effect [26]. Furthermore, a recent study showed that decreased PPARα activity in ischemic cardiomyopathy protected the heart from lipotoxicity by shifting the fuel preference away from fatty acids [25]. This is consistent with earlier observations that partial inhibition of fatty acid utilization is cardioprotective [27].

Summary
The use of animal models as “proofs-of-concept” in understanding of the metabolic phenotype has generated valuable evidence for the therapeutic potential of manipulating cardiac metabolism. We anticipate that the concept will be further tested by clinical studies and eventually in large-scale clinical trials; however, in addition, basic research leading to the development of novel compounds that have high efficacy in myocardial metabolism and few side effects is urgently needed to advance the practice of metabolic therapy.

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