Heart and Metabolism

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Abstracts and commentaries

Combination treatment in stable effort angina using trimetazidine and
metoprolol. Results of a randomized, double-blind, multicentre study (TRIMPOL II)
Szwed H, Sadowski Z, Elikowski W, et al. Eur Heart J. 2001;22:2267–2274.

Commentary
Combination therapy for treating stable angina using conventional hemodynamic agents
(b-blockers, calcium antagonists, and oral nitrates) confers no advantage over optimal dose of a single agent, eg, atenolol 100 mg daily. The search for an alternative strategy explored the mechanism behind ischemia at both the cellular (metabolic) and hemodynamic levels. Trimetazidine is free of any hemodynamic actions, but by partially inhibiting long-chain 3-ketoacyl-coenzyme A-thiolase it reduces fatty acid oxidation and increases myocardial glucose oxidation. These anti-ischemic properties have been confirmed both experimentally and clinically. The TRIMPOL II study was designed to assess the anti-ischemic efficacy and tolerability of trimetazidine as a form of metabolic combination therapy using the hemodynamic agent metoprolol.
TRIMPOL II was a randomized, multicenter, double-blind, placebo-controlled, parallel-group study of patients with stable angina and documented myocardial ischemia. Metoprolol 50 mg bid was combined with trimetazidine 20 mg tid or identical placebo for a 12-week period. The primary outcome measure was time to 1-mm ST-segment depression at 12 weeks. Secondary outcome measures included exercise duration, time to angina onset, maximal ST depression, and the subjective markers of weekly anginal attack rate and nitrate consumption. In total, 347 patients completed the study (179 taking trimetazidine and 168 taking placebo).
After 12 weeks the trimetazidine group had a significant (P < 0.01) improvement in time to 1-mm ST-segment depression, time to onset of angina, degree of ST depression, anginal attack rate, and nitrate consumption; total exercise duration was also significantly prolonged (P < 0.05). The acceptability was excellent since no drug-attributable adverse effects were reported. Of interest, the rate–pressure product was the same in both groups, suggesting a nonhemodynamic benefit of trimetazidine therapy.
This study complements other studies and confirms the validity, both theoretically and clinically, of the concept of a metabolic approach. TRIMPOL II specifically addresses the issue of combination therapy: when conventional monotherapy with a b-blocker insufficiently controls anginal symptoms, a metabolic agent such as trimetazidine is of particular value. Its fully additive benefit in combination therapy has been demonstrated both subjectively and objectively.

Graham Jackson

An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with heart failure
Taylor M, Wallhaus TR, Degrado TR, et al.
J Nucl Med. 2001;42:55–62.

Understanding the metabolic consequences of heart failure is important in evaluating potential mechanisms for disease progression and assessing targets for therapies designed to improve myocardial metabolism in patients with heart failure. PET is uniquely suited to noninvasively evaluate myocardial metabolism. In this study, we investigated the kinetics of 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) and [18F]fluoro-2-deoxy-glucose (FDG) in patients with stable NYHA functional class III congestive heart failure and a left ventricular ejection fraction of no more than 35%. Twelve fasting patients underwent dynamic PET studies using [18F]FTHA and [18F]FDG. From the dynamic image data, the fractional uptake rates (Ki) were determined for [18F]FTHA and [18F]FDG. Subsequently, serum FFA and glucose concentrations were used to calculate the myocardial FFA and glucose uptake rates, respectively. Uptake rates were compared with reported values for [18F]FTHA and [18F]FDG in subjects with normal left ventricular function. The average Ki for [18F]FTHA was 19.7 ± 9.3 mL 100 g-1 min-1 (range, 7.2–36.0 mL 100 g-1 min-1). The
average myocardial fatty acid use was 19.3 ± 2.3 mmol 100 g-1 min-1. The average Ki for [18F]FDG was 1.5 ± 0.37 mL 100 g-1 min-1 (range, 0.1–3.3 mL 100 g-1 min-1), and the average myocardial glucose use was 12.3 ± 2.3 mmol 100 g-1 min-1. Myocardial FFA and glucose use in heart failure can be quantitatively assessed using PET with [18F]FTHA and [18F]FDG. Myocardial fatty acid uptake rates in heart failure are higher than expected for the normal heart, whereas myocardial glucose uptake rates are lower. This shift in myocardial substrate use may be an indication of impaired energy efficiency in the failing heart, providing a target for therapies directed at improving myocardial energy efficiency.

Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure
Wallhaus TR, Taylor M, DeGrado TR, et al. Circulation. 2001;103:2441–2446.

Use of b-adrenoceptor blockade in the treatment of heart failure has been associated with a reduction in myocardial oxygen consumption and an improvement in myocardial energy efficiency. One potential mechanism for this beneficial effect is a shift in myocardial substrate use from increased FFA oxidation to increased glucose oxidation. We studied the effect of carvedilol therapy on myocardial FFA and glucose use in nine patients with stable NYHA functional class III ischemic cardiomyopathy (left ventricular ejection fraction £35%) using myocardial PET studies and resting echocardiograms before and 3 months after carvedilol treatment. Myocardial uptake of the novel long-chain fatty acid metabolic tracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid (FTHA) was used to determine myocardial FFA use, and [18F]fluoro-2-deoxy-glucose (FDG) was used to determine myocardial glucose use. After carvedilol treatment, the mean myocardial uptake rate for [18F]FTHA decreased (from 20.4 ± 8.6 to 9.7 ± 2.3 mL 100 g-1 min-1; P < 0.005), mean fatty acid use decreased (from 19.3 ± 7.0 to 8.2 ± 1.8 mmol 100 g-1 min-1; P < 0.005), mean myocardial uptake rate for [18F]FDG was unchanged (from 1.4 ± 0.4 to 2.4 ± 0.8 mL 100 g-1 min-1; P = 0.14), and mean glucose use was unchanged (from 11.1 ± 3.1 to 18.7 ± 6.0 mmol 100 g-1 min-1; P = 0.12). Serum FFA and glucose concentrations were unchanged, and mean left ventricular ejection fraction improved (from 26 ± 2% to 37 ± 4%; P < 0.05). Carvedilol treatment in patients with heart failure results in a 57% decrease in myocardial FFA use without a significant change in glucose use. These metabolic changes could contribute to the observed improvements in energy efficiency seen in patients with heart failure.

The effects of ‚1-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: a double-blind, placebo-controlled, ositron-emission tomography study
Beanlands RS, Nahmias C, Gordon E, et al. Circulation. 2000;102:2070–2075.

The mechanism for the beneficial effect of b-blocker therapy in patients with left ventricular dysfunction is unclear, but it may relate to an energy-sparing effect that results in improved cardiac efficiency. C-11 acetate kinetics, measured using PET, are a proven noninvasive marker of oxidative metabolism and myocardial oxygen consumption (MVO2). This approach can be used to measure the work–metabolic index, which is a noninvasive estimate of cardiac efficiency. The aim of this study was to determine the effect of metoprolol on oxidative metabolism and the work–metabolic index in patients with left ventricular dysfunction. Forty patients (29 with ischemic and 11 with nonischemic heart disease; left ventricular ejection fraction <40%) were randomized to receive metoprolol or placebo in a treatment protocol of titration plus 3 months of stable therapy. Seven patients were not included in the analysis because of withdrawal from the study, incomplete follow-up, or nonanalyzable PET data. The rate of oxidative metabolism (k) was measured using C-11 acetate PET, and stoke volume index (SVI) was measured using echocardiography. The work–metabolic index was calculated as follows: (systolic blood pressure ´ SVI ´ heart rate)/k. No significant change in oxidative metabolism occurred with placebo (k = 0.061 ± 0.022 to 0.054 ± 0.012 per min). Metoprolol reduced oxidative metabolism (k = 0.062 ± 0.024 to 0.045 ± 0.015 per min; P = 0.002). The work–metabolic index did not change with placebo (from 5.29 ± 2.46 ´ 106 to 5.14 ± 2.06 ´ 106 mm Hg mL/m2), but it increased with metoprolol (from 5. 31 ± 2.15 ´ 106 to 7.08 ± 2.36 ´ 106 mm Hg mL/m2; P < 0.001). Selective b-blocker therapy with metoprolol leads to a reduction in oxidative metabolism and an improvement in cardiac efficiency in patients with left ventricular dysfunction. It is likely that this energy-sparing effect contributes to the clinical benefits observed with b-blocker therapy in this patient population.

Commentary
The three abovementioned articles give some insight into the alterations of
oxidative metabolism in patients with heart failure. The study by Taylor et al shows that in patients with heart failure, fatty acid uptake is increased and glucose uptake is decreased in comparison with normal healthy volunteers. This is surprising as it is generally assumed (from animal data) that fatty acid oxidation is decreased and glucose oxidation is increased in heart failure [1]. However, the data are in line with previous clinical studies in patients with heart failure (see the original paper for references). Importantly, the FTHA and FDG measurements were performed in myocardial segments with relatively preserved contractile function. Possibly, this remodeled tissue may have other metabolic characteristics than failing (post)ischemic tissue. Thus, further studies are needed to unravel the seemingly contradictory changes of metabolism in heart failure.
Patients with heart failure may have elevated levels of catecholamines, leading to an increased and inefficient oxygen use of the myocardium. This inefficient use of oxygen and energy substrates was studied by the same group (Wallhaus et al). These authors studied the effect of b-blocker treatment in patients with heart failure and demonstrated that carvedilol treatment reduced fatty acid (FTHA) uptake, while glucose (FDG) uptake remained unaltered. Despite the fact that fatty acid uptake was decreased, the ejection fraction and stroke volume were increased. This indicates that the heart more efficiently uses the energy substrates (glucose and fatty acids) for contraction. This may well be one of the protective mechanisms of b-blocker therapy in heart failure.
The relation between cardiac work and metabolic efficiency was particularly studied in the third abstract by Beanlands et al using C-11 acetate. In a double-blind placebo-controlled study they clearly demonstrated that the efficiency of oxidative metabolism was increased during b-blocker treatment in patients with heart failure. Similarly to Wallhaus et al, they found that the oxidation rate of C-11 acetate was reduced after metoprolol treatment, but at the same time the efficiency (hemodynamics parameters divided by the oxidation rate of C-11 acetate) increased.
To summarize, there are clear changes in fatty acid and glucose metabolism in patients with heart failure. The exact nature of the changes in relation to the type of dysfunctional tissue needs further study. It is clear that metabolic studies need to be linked to hemodynamics. Further, the failing heart inefficiently uses metabolic substrates and this inefficiency can be improved by therapeutic interventions such as b-blockade.

REFERENCE
1. Montessuit C, Rosenblatt-Velin N, Lerch R. Metabolic changes in cardiac hypertrophy. Heart Metab. 2000;9:3–8.

Frans C. Visser

Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle
Perreault M, Marette A. Nat Med. 2001;7:1138–1143.

The authors investigated whether genetic disruption of iNOS expression could protect against obesity-linked insulin resistance. iNOS expression was increased in skeletal muscle of genetic and dietary models of obesity. Moreover, mice in which the gene encoding iNOS was disrupted (Nos2–/– mice) are protected from high-fat-induced insulin resistance. Whereas both wild-type and Nos2-/- mice developed obesity on the high-fat diet, obese Nos2-/- mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo, and normal insulin-stimulated glucose uptake in muscles. iNOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase activation by insulin in muscle. These defects were fully prevented in obese Nos2-/- mice. These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity.

Commentary
Nitric oxide (NO) has a pivotal role in the physiology and pathophysiology of the central nervous, cardiovascular, and immune systems. The reactivity of NO toward molecular oxygen and various biological targets enables it to act as a signal transduction molecule and to control diverse biological functions. However, excessive NO formation by the inducible member of the nitric oxide synthase family (iNOS) has also been shown to be a mediator of nonspecific tissue damage and is thought to be involved in the pathogenesis of inflammatory and autoimmune diseases. Recent studies also suggest that iNOS may be involved in the pathogenesis of metabolic disorders associated with a low-grade chronic inflammatory state, such as atherosclerosis and obesity-linked type 2 diabetes. These diseases are characterized by insulin resistance, as indicated by the inability of insulin to promote glucose disposal in peripheral tissues and to inhibit hepatic glucose production. It has been proposed that chronic iNOS induction may cause insulin resistance.
High-fat-mediated obesity likely causes iNOS induction by promoting the expression and secretion of TNFa* and other proinflammatory cytokine*. Because skeletal muscle is infiltrated with adipose tissue in obese subjects, enhanced production of cytokines by adipocytes may thus contribute to the development of muscle insulin resistance in obesity. Another potential factor that may be involved in iNOS induction in muscle of obese mice is an increased availability of circulating or intramyocellular free fatty acids. As NO is a low-molecular-weight, highly lipophilic molecule, and can diffuse rapidly to adjacent cells, it is possible that iNOS induction and NO production by local adipose cells also contribute to muscle insulin resistance in obesity. Recent studies have shown that iNOS is induced in the pancreatic b-cells and hearts of Zucker diabetic fatty rats, and suggested that NO production in these tissues caused impaired insulin secretion and cardiac dysfunction by promoting programmed cell death (apoptosis) [1, 2]. Together with those findings, the present data by Perreault and Marette strongly suggest that iNOS may have a pathogenic role not only in the development of skeletal muscle insulin resistance but also possibly in obesity-linked b-cell failure and cardiovascular dysfunction. This study also raises the possibility that agents that reduce iNOS expression or activity may have beneficial effects on obesity-linked insulin resistance and associated complications.

REFERENCES

1: Proc Natl Acad Sci U S A 1998 Mar 3;95(5):2498-502

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Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes.

Shimabukuro M, Zhou YT, Levi M, Unger RH.

Gifford Laboratories for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75235, USA.

Like obese humans, Zucker diabetic fatty (ZDF) rats exhibit early beta cell compensation for insulin resistance (4-fold beta cell hyperplasia) followed by decompensation (>50% loss of beta cells). In prediabetic and diabetic ZDF islets, apoptosis measured by DNA laddering is increased 3- and >7-fold, respectively, compared with lean ZDF controls. Ceramide, a fatty acid-containing messenger in cytokine-induced apoptosis, was significantly increased (P < 0.01) in prediabetic and diabetic islets. Free fatty acids (FFAs) in plasma are high (>1 mM) in prediabetic and diabetic ZDF rats; therefore, we cultured prediabetic islets in 1 mM FFA. DNA laddering rose to 19.6% vs. 4.6% in lean control islets, preceded by an 82% increase in ceramide. C2-Ceramide without FFA induced DNA laddering, but fumonisin B1, a ceramide synthetase inhibitor, completely blocked FFA-induced DNA laddering in cultured ZDF islets. [3H]Palmitate incorporation in [3H]ceramide in ZDF islets was twice that of controls, but [3H]palmitate oxidation was 77% less. Triacsin C, an inhibitor of fatty acyl-CoA synthetase, and troglitazone, an enhancer of FFA oxidation in ZDF islets, both blocked DNA laddering. These agents also reduced inducible nitric oxide (NO) synthase mRNA and NO production, which are involved in FFA-induced apoptosis. In ZDF obesity, beta cell apoptosis is induced by increased FFA via de novo ceramide formation and increased NO production.

PMID: 9482914 [PubMed - indexed for MEDLINE]

2: Proc Natl Acad Sci U S A 2000 Feb 15;97(4):1784-9