Allopurinol has no discernable effects on LV contractile function or adrenergic responsiveness in normal, conscious animals. In pacing-induced CHF, however, allopurinol improves LV systolic function at rest and during adrenergic stimulation and exercise.

The new myofilament Ca 2ϩ sensitizer levosimendan (LSM) is a positive inotropic and vasodilatory agent. Its beneficial effects have been demonstrated at rest in congestive heart failure (CHF). However, its effect during exercise (Ex) in CHF is unknown. We assessed the effects of LSM on left ventricular (LV) dynamics at rest and during Ex in eight conscious, instrumented dogs with pacing-induced CHF. After CHF, with dogs at rest, LSM decreased arterial elastance (E a) and increased LV contractile performance as assessed by the slope of LV pressure-volume (P-V) relation. LSM caused a Ͼ60% increase in the peak rate of mitral flow (dV/dtmax) due to decreases in minimal LV pressure and the time constant of LV relaxation (). LV arterial coupling, quantified as the ratio of end-systolic elastance (E es) to Ea, was increased from 0.47 to 0.85%. LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, was improved from 0.54 Ϯ 0.09 to 0.61 Ϯ 0.07. These beneficial effects persisted during Ex after CHF. Compared with CHF Ex dogs, treatment with LSM prevented Ex-induced abnormal increases in mean left atrial pressure and end-diastolic pressure and decreased E es/Ea. With LSM treatment during CHF Ex, the early diastolic portion of the LV P-V loop was shifted downward with decreased minimal LV pressure and values and a further augmented dV/dtmax. Ees/Ea improved, and mechanical efficiency further increased from 0.61 Ϯ 0.07 to 0.67 Ϯ 0.07, which was close to the value reached during normal Ex. After CHF, LSM produced arterial vasodilatation; improved LV relaxation and diastolic filling; increased contractility, LV arterial coupling, and mechanical efficiency; and normalized the response to Ex.congestive heart failure; left ventricular dynamics; filling; contractility; mechanical efficiency IMPORTANT GOALS IN THE TREATMENT of patients with congestive heart failure (CHF) are to prolong survival and improve the patient's quality of life. The major symptom and cause of disability in CHF patients is exercise (Ex) intolerance (5,32,45). Observational work in the general healthy population has shown that Ex capacity is a more powerful prognostic indicator than traditional risk factors for cardiovascular disease (36, 44). However, despite enormous advances in the understanding and treatment of CHF that have taken place during the last 50 years, CHF remains a serious and, in fact, growing health problem. Present treatment of Ex intolerance is unsatisfactory in CHF patients (45,63). The ␤-adrenergic agonist dobutamine and phosphodiesterase inhibitor milrinone were associated with worse survival and clinical outcomes and did not improve quality of life for severe CHF patients (42, 48). Angiotensinconverting enzyme inhibitor therapy and ␤-blockade treatment improve survival in patients with CHF but do not always enhance Ex tolerance (37). Recently myofilament Ca 2ϩ sensitizers, which are a new class of nonglycosidic, nonadrenergic, positive inotropic agents, have been studied in patients with CHF. Because impair...

The purpose of the present study was to investigate the effects of long-term renal denervation (RD) on heart failure due to myocardial infarction (MI). Wistar rats were anesthetized and the bilateral renal nerves were surgically denervated 2 days before MI was induced by coronary artery ligation. Four weeks later, left ventricular (LV) function and sodium excretion were determined. In MI rats, RD improved the reduced sodium excretion. MI + RD rats revealed lower LV end-diastolic pressure and greater maximum dP/dt as compared with those of MI+ innervation (INN) rats. LV end-diastolic and end-systolic dimensions were significantly smaller and LV fractional shortening was greater in MI + RD rats than in MI + INN rats (20.9% +/- 3.2% vs 14.9% +/- 3.0%). In rats without MI, RD did not affect either sodium excretion or LV function and dimensions. The present results suggest that the long-term RD reduces LV filling pressure and improves LV function after MI, probably due to a restoration of impaired natriuresis. Increased renal sympathetic nerve activity might contribute to the progression of heart failure after MI.

Plasma vitamin E levels were significantly lower in patients with active variant angina than in subjects without coronary spasm, suggesting an association between vitamin E deficiency and coronary artery spasm.

The diastolic dysfunction present at rest in congestive heart failure (CHF) is exacerbated during exercise (Ex). Increases in circulating ANG II and endothelin-1 (ET-1) during Ex may contribute to this response. We assessed the effect of Ex on circulating plasma levels of ANG II and ET-1 and left ventricular (LV) dynamics before and after pacing-induced CHF at rest and during Ex in nine conscious, instrumented dogs. Before CHF, there were modest increases in circulating levels of ANG II (but not ET-1) during Ex. LV diastolic performance was enhanced during Ex with decreases in the time constant of LV relaxation (tau), LV end-systolic volume (V(ES)), and LV minimum pressure with a downward shift of the LV early diastolic portion of the pressure-volume (P-V) loop. This produced an increase in peak LV filling rate without an increase in mean left atrial (LA) pressure. After CHF, the resting values of ANG II and ET-1 were elevated and increased to very high levels during Ex. After CHF, mean LA pressure, tau, and LV minimum pressure were elevated at rest and increased further during Ex. Treatment with L-754,142, a potent ET-1 antagonist, or losartan, an ANG II AT(1)-receptor blocker, decreased these abnormal Ex responses in CHF more effectively than an equally vasodilatory dose of sodium nitroprusside. Combined treatment with both ANG II- and ET-1-receptor blockers was more effective than either agent alone. We conclude that in CHF, circulating ANG II and ET-1 increase to very high levels during Ex and exacerbate the diastolic dysfunction present at rest.

In patients routinely treated with metoprolol, influences of CYP2D6 genotype on the response of heart rate to isoproterenol (IP) were studied at its peak and trough concentrations and were compared with those of bisoprolol. In 72 patients treated with metoprolol or bisoprolol, CYP2D6 genotype (ie, CYP2D6*1, *2, *4, *5, *10, and *14) was determined. No patients except one who was heterozygous for CYP2D6*5 carried the null alleles of CYP2D6. The homozygote frequency for CYP2D6*10 was relatively high (19.4%) and these patients had greater peak and trough plasma concentrations of metoprolol than the other patients. Isoproterenol-induced percentage increases in heart rate were 58% and 38% less at the low and high rate of isoproterenol infusion (0.02 and 0.04 microg/kg/min), respectively, in patients homozygous for CYP2D6*10 than in the other patients at the trough, but not at the peak concentrations. In contrast, CYP2D6 genotype did not affect plasma concentrations of bisoprolol and the extent of its beta-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant beta-adrenergic inhibition independent of CYP2D6 genotype.

No abstract

The present results indicate that cardiac sympathetic neuronal function is relatively preserved at the compensated, hypertrophic stage of DS rats but deteriorates in association with beta-receptor downregulation at the failing stage. The cardiac neuronal dysfunction occurs heterogeneously. A combination of scintigraphic portrayal of beta-receptors with MIBG should provide valuable information regarding sympathetic nerve signaling in living hearts.