Springer Science and Business Media LLC

The energetic demands imposed upon the heart vary dramatically over the course of the day. In the face of equally commanding oscillations in the neurohumoral mileu, the heart must respond both rapidly and appropriately to its diurnal environment, for the survival of the organism. A major response of the heart to alterations in workload, nutrients, and various neurohumoral stimuli is at the level of metabolism. Failure of the heart to achieve adequate metabolic adaptation results in contractile dysfunction. Substantial evidence is accumulating which suggests that a transcriptionally based timekeeping mechanism known as the circadian clock plays a role in mediating myocardial metabolic rhythms. Here, we provide an overview of our current knowledge regarding the interplay between the circadian clock within the cardiomyocyte and myocardial metabolism. This includes a particular focus on circadian clock mediated regulation of endogenous energy stores, as well as those mechanisms orchestrating circadian rhythms in metabolic gene expression. An essential need to elucidate fully the functions of this molecular mechanism in the heart remains.

We evaluated the effect of cholesterol reduction on atherosclerotic coronary artery lesions using diet and simvastatin, a potent HMG CoA reductase inhibitor. Fifteen subjects aged 28–69 years (mean 44), each of whom demonstrated significant (>50%) narrowing of a coronary artery and a baseline cholesterol level greater than 278 mg/dl, were studied. Coronary arteriography was performed prior to and after 20±2.5 months of therapy. A 42% reduction in total serum cholesterol, a 52% reduction in LDL cholesterol, and an 87% increase in the HDL/LDL cholesterol ratio (p<0.01) were achieved. Pretreatment and posttreatment angiograms were reviewed by three experienced angiographers with temporal order masked. Improvement in the overall status of coronary atherosclerotic lesions was demonstrated in two patients (13%), while deterioration occurred in one patient (7%). No overall change was found in the remaining 12 patients (80%). We conclude that a cholesterol-lowering regimen using a nonatherogenic diet and simvastatin therapy may at least stabilize coronary atherosclerosis.

Patients treated with beta-blocking agents often complain of fatigue during exercise. Exercise capacity is decreased under this condition. Nebivolol is a new beta1-adrenoceptor antagonist with a particular hemodynamic profile, which might be due to an ancillary property. Five milligrams once daily seems the optimal dose for antihypertensive treatment. In a double-blind, placebo-controlled crossover study, the effects of nebivolol on maximal and endurance exercise capacity are compared with those of atenolol in healthy volunteers. The hemodynamic and metabolic effects during exercise are also studied. Nebivolol 5 mg once daily and atenolol 100 mg once daily decrease blood pressure at rest similarly. At these dosages nebivolol shows a smaller decrease in heart rate than atenolol. During exercise, the rise in systolic blood pressure and heart rate is less depressed with nebivolol than with atenolol. In contrast to atenolol, nebivolol does not decrease maximal and endurance exercise capacity, and does not increase perceived exertion significantly. Changes in hemodynamics influence maximal exercise capacity. Since nebivolol has less effect on exercise hemodynamics than atenolol, this might explain why maximal work capacity is not changed during nebivolol. During endurance exercise metabolic effects are thought to be more important. Under nebivolol glycerol and NEFA production is less depressed during exercise and might explain the preserved endurance capacity. These data suggest less beta blockade during nebivolol than during atenolol at the dosages used in this study. In conclusion, at a dose known to be antihypertensive, nebivolol does not alter exercise capacity significantly in healthy volunteers.

The hemodynamic and cardiac effects of the new angiotensin-converting enzyme inhibitor, benazepril, were studied in 28 hypertensives in a double blind, placebo-controlled, between-patient study. Hemodynamic studies were performed noninvasively by means of M-mode echo (central hemodynamics and left ventricular systolic function), 2-D echo-Doppler (left ventricular diastolic function), and pulsed Doppler flowmetry (forearm circulation). Examinations were done at the end of a placebo run-in period and 3 hours after benazepril administration, both on the first day and after 6 weeks of treatment (10 or 20 mg once daily, according to patient response). In comparison with placebo, benazepril reduced systolic (p=0.04) and diastolic (p=0.003) blood pressure, because of a significant reduction in systemic vascular resistance (p=0.03), while cardiac output was unchanged. Forearm vascular resistance was reduced and brachial artery compliance increased, although not to a statistically significant level (both p=0.07). Both systolic and diastolic left ventricular function were positively influenced by the afterload reduction: End-systolic stress was reduced by 12% (p=0.07), as was the late diastolic peak flow velocity (p=0.02). All hemodynamic changes were evident after acute benazepril administration, and no difference was observed between acute and repeated treatment. We conclude that, similar to other ACE-inhibitors, benazepril reduces blood pressure through a reduction in vascular resistance, while cardiac output and heart rate are unaffected. These hemodynamic effects occur as early as after the first administration and exert a favorable influence on left ventricular dynamics.

Myocardial infarction (MI) is a major cause of death. Nicotinamide adenine dinucleotide (NAD+) is a coenzyme in oxidative phosphorylation and substrate of sirtuins and poly-ADP ribose polymerases, enzymes critical for cardiac remodeling post-MI. Decreased NAD+ is reported in several heart failure models with paradoxically an upregulation of nicotinamide riboside kinase 2, which uses nicotinamide riboside (NR) as substrate in an NAD+ biosynthetic pathway. We hypothesized that stimulating nicotinamide riboside kinase 2 pathway by NR supplementation exerts cardioprotective effects. MI was induced by LAD ligation in 2–3-month-old male mice. NR was administered daily (1 µmole/g body weight) over 7 days. RT-PCR showed a 60-fold increase in nicotinamide riboside kinase 2 expression 4 days post-MI with a 60% drop in myocardial NAD+ and overall survival of 61%. NR restored NAD+ levels and improved survival to 92%. Assessment of respiration in cardiac fibers revealed mitochondrial dysfunction post-MI, and NR improved complexes II and IV activities and citrate synthase activity, a measure of mitochondrial content. Additionally, NR reduced elevated PARP1 levels and activated a type 2 cytokine milieu in the damaged heart, consistent with reduced early inflammatory and pro-fibrotic response. Our data show that nicotinamide riboside could be useful for MI management.

Nicorandil is a new coronary vasodilator possessing beneficial properties. However, its detailed cardiovascular effects, especially on left ventricular (LV) preload, have not yet been fully elucidated. The purpose of this study was to assess the effects of nicorandil on LV hemodynamics in conscious dogs and to examine the mechanisms of its anti-ischemic action. Nine mongrel dogs were instrumented for instantaneous and continuous measurements of LV diameters, and aortic and LV pressures. The effects of nicorandil (0.2 mg/kg, intravenously) were compared with those of nitroglycerin (15 μg/kg, intravenously) in conscious dogs. Mean aortic pressure decreased similarly with both nicorandil and nitroglycerin (−20.1±3.1% vs. 21.6±2.8%, ns). Heart rate was elevated with both drugs. Both nicorandil and nitroglycerin significantly decreased LV systolic pressure to the same extent (−11.3±0.5% vs.−10.5±11.6^, ns). LV max dp/dt was not significantly changed by either drug. Although both nicorandil and nitroglylerin significantly increased fractional shortening, nicorandil had a greater effect on fractional shortening than nitroglycerin (20.0±3.0% vs. 10.2±2.3%, p<0.05). In this study, nicorandil, administered intravenously, had a salutary effect on cardiac function. LV enddiastolic diameter decreased with nicorandil and nitroglycerin (−6.5±1.5% vs.−12.6±2.6%, p<0.01), respectively. In conclusion, nicorandil decreased LV end-diastolic diameter in conscious dogs, indicating a decrease in venous return and preload of the heart. In addition, nicorandil decreased LV afterload to the same extent as nitroglycerin. The decrease in preload and afterload on the heart is thought to be one of the mechanisms of the antiischemic action of nicorandil.

Coronary and systemic hemodynamic effects of verapamil have been investigated previously in detail. The acute impact of intracoronary verapamil on coronary hemodynamics has, however, not been correlated to simultaneously changes in myocardial metabolism or norepinephrine levels in humans. After bolus application of 1 mg verapamil into the left coronary artery of 52 patients scheduled for routine coronary angiography, heart rate (HR) remained unchanged, whereas mean arterial blood pressure (MAP) decreased (93.8 ± 14.9 mmHg to 85.1 ± 13.7 mmHg, p = 0.001). Coronary blood flow (CBF), calculated from intra-coronary Doppler measurements and quantitative coronary angiography, increased after verapamil administration (28.5 ± 16.7 ml/min to 66.2 ± 41.8 ml/min, p < 0.001), whereas coronary vascular resistance index (CVRI) decreased (1.43 ± 0.92 to 0.46 ± 0.23, p <0.001). Blood samples, taken simultaneously from the aorta (Ao) and coronary sinus (CS) at baseline and at maximal flow velocity, showed an increase in norepinephrine concentrations in Ao (209 ± 151 ng/I to 283 ± 195 ng/l, p <0.001) and CS (233 ± 162 ng/l to 323 ± 248 ng/l, p = 0.004). Myocardial metabolism of pyruvate and free fatty acids were not affected. Glucose release was augmented and initial lactate consumption changed to a net lactate release into the CS (Ao to CS differences: glucose: −1.92 ± 9.9 mg/dl to −12.8 ± 22.8 mg/dl, p < 0.001; lactate: 0.07 ± 0.2 mmol/l to −0.08 ± 0.3 mmol/l, p = 0.001). Similar results were obtained for the extraction ratios and flux of these metabolites. There was a weak correlation between the increase in CBF and lactate release into the CS. This is the first report of unexpected myocardial lactate release following intracoronary verapamil administration in humans. This lactate release was paralleled by an increased glucose release into the CS at an unchanged metabolism of free fatty acids and pyruvate. One explanation for this unexplained lactate release during increased coronary blood flow might be a wash out phenomenon of lactate from previous ischemic areas, other explanations might be the induction of paradox myocardial ischemia and/or a steal effect. Further studies are necessary to explain these unexpected findings of increased coronary flow and myocardial lactate release. Until reliable explanations are pending, studies using only lactate release as a marker of myocardial ischemia, without taken coronary and systemic hemodynamic parameters into account, should be interpreted with caution.