Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: A randomized, double-blind, placebo-controlled study

Eichhorn, Eric J.; Heesch, Christian M.; Barnett, James H.; Álvarez, Luis; Fass, Steven M.; Grayburn, Paul A.; Hatfield, Barbara A.; Marcoux, Lucille; Malloy, Craig R.

doi:10.1016/0735-1097(94)90114-7

Cited by 290 publications

(130 citation statements)

References 53 publications

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“…2,20 The consistent observation in previous studies in which diastolic relaxation properties have been investigated and in the present investigation is the improvement in early, active isovolumic relaxation with ␤-adrenergic blocking therapy. However, Eichhorn and colleagues did not report a significant improvement in late, passive relaxation properties on bucindolol 2 or metoprolol.…”

Section: Discussionsupporting

confidence: 70%

“…However, Eichhorn and colleagues did not report a significant improvement in late, passive relaxation properties on bucindolol 2 or metoprolol. 20 This is important because, in a retrospective analysis, they concluded 21 that cardiomyopathy patients with a higher LV end-diastolic pressure, among other indicators, were more likely to experience a hemodynamic improvement with metoprolol. Our observation that cardiomyopathy patients who have the most markedly increased LV end-diastolic pressures and late, passive diastolic relaxation constants have the greatest improvement with metoprolol is consistent with this concept.…”

Section: Discussionmentioning

confidence: 99%

“…2,5,6,20 Waagstein and colleagues 1 initially reported improvement in LV end-diastolic pressure with metoprolol. Subsequently, the MDC Study Group evaluated LV diastolic filling using transmitral Doppler echocardiography.…”

Section: Discussionmentioning

confidence: 99%

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Effects of β-Adrenergic Blocking Therapy on Left Ventricular Diastolic Relaxation Properties in Patients With Dilated Cardiomyopathy

et al. 1999

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Background-The hemodynamic mechanism for the improvement in left ventricle (LV) end-diastolic pressure in cardiomyopathy patients treated with ␤-adrenergic blocking agents is controversial. We hypothesized that the salutary effect of this kind of therapy on LV end-diastolic pressure would be indicative of an improvement in late, passive diastolic relaxation properties. Methods and Results-We studied 14 cardiomyopathy patients in normal sinus rhythm with no arteriographic evidence of coronary artery disease and an LV ejection fraction of Յ40% by radionuclide angiography both before and after 6 months of metoprolol therapy with simultaneous micromanometry and biplane cineventriculography. Four comparable patients who were not treated with metoprolol were studied in a similar fashion and served as control subjects. In those receiving metoprolol, LV end-diastolic pressure decreased (Pϭ0.001). The isovolumic relaxation index, ln , shortened (Pϭ0.03). In a similar fashion, the LV chamber stiffness constant, , decreased (Pϭ0.02), LV volume elastance improved (Pϭ0.04), and the myocardial stiffness constant, e , decreased (Pϭ0.02). A multiple regression analysis revealed that the decrease in LV end-diastolic pressure was indicative of significant improvements in ln and e with the relationship: LV end-diastolic pressureϭϪ4.73ϩ0.27 ln ϩ0.54 e (rϭ0.81, PϽ0.0001). These LV diastolic relaxation properties did not change or worsened in the control cardiomyopathy patients. Conclusions-We conclude that the decrease in LV end-diastolic pressure in cardiomyopathy patients treated with metoprolol is an indicator of improvement in LV diastolic properties resulting from more complete myocardial relaxation. (Circulation. 1999;100:729-735.)

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Effects of β-Adrenergic Blocking Therapy on Left Ventricular Diastolic Relaxation Properties in Patients With Dilated Cardiomyopathy

et al. 1999

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“…Ten flies were monitored in each of six vials (N) per treatment c Two-tailed unpaired t tests were used to determine the significance of the differences between the vehicle and treatment groups of cardiac glucose oxidation (reviewed in Sharma and McNeill 2011). Metoprolol and other βAR blockers also have been shown to induce a switch from fatty acid to glucose oxidation in the heart of nondiabetic patients with heart failure, perhaps through inhibition of carnitine palmitoyltransferase (Andersson et al 1991;Eichhorn et al 1994;Panchal et al 1998;Sharma and McNeill 2011). The longevity benefits of β-blockers reported here are likely to involve organs other than just smooth and cardiac muscle.…”

Section: Discussionmentioning

confidence: 99%

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

Spindler

Mote

et al. 2013

AGE

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Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease allcause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality.Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively (P< 0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans.

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“…42 More recently, epinephrine was shown to increase glucose oxidation rates by approximately 400% without significant increases in fatty acid oxidation rates in isolated working rat hearts. 43 Although adrenergic stimulation has been shown to increase glucose oxidation rates, β-blockers widely used in the treatment of heart failure have been shown to inhibit fat oxidation and result in an increase in glucose oxidation, 44 an effect that could be attributed to carnitine palmitoyltransferase I (CPT1) inhibition. 45 …”

Section: Adrenergic Signaling In Heartmentioning

confidence: 99%

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

Sankaralingam

Lopaschuk

2015

Pulm. circ.

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Pressure overload of the heart, such as seen with pulmonary hypertension and/or systemic hypertension, can result in cardiac hypertrophy and the eventual development of heart failure. The development of hypertrophy and heart failure is accompanied by numerous molecular changes in the heart, including alterations in cardiac energy metabolism. Under normal conditions, the high energy (adenosine triphosphate [ATP]) demands of the heart are primarily provided by the mitochondrial oxidation of fatty acids, carbohydrates (glucose and lactate), and ketones. In contrast, the hypertrophied failing heart is energy deficient because of its inability to produce adequate amounts of ATP. This can be attributed to a reduction in mitochondrial oxidative metabolism, with the heart becoming more reliant on glycolysis as a source of ATP production. If glycolysis is uncoupled from glucose oxidation, a decrease in cardiac efficiency can occur, which can contribute to the severity of heart failure due to pressure-overload hypertrophy. These metabolic changes are accompanied by alterations in the enzymes that are involved in the regulation of fatty acid and carbohydrate metabolism. It is now becoming clear that optimizing both energy production and the source of energy production are potential targets for pharmacological intervention aimed at improving cardiac function in the hypertrophied failing heart. In this review, we will focus on what alterations in energy metabolism occur in pressure overload induced left and right heart failure. We will also discuss potential targets and pharmacological approaches that can be used to treat heart failure occurring secondary to pulmonary hypertension and/or systemic hypertension.

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Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: A randomized, double-blind, placebo-controlled study

Cited by 290 publications

References 53 publications

Effects of β-Adrenergic Blocking Therapy on Left Ventricular Diastolic Relaxation Properties in Patients With Dilated Cardiomyopathy

Effects of β-Adrenergic Blocking Therapy on Left Ventricular Diastolic Relaxation Properties in Patients With Dilated Cardiomyopathy

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

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