Keiichi Nagami

Abnormalities in sympathoneuronal regulation are localized to failing myocardium in rabbit heart.

OBJECTIVES This study investigated the differences in sympathoneuronal regulation between acute left ventricular failure and chronic biventricular failure to determine whether an increase in plasma norepinephrine concentration plays a primary role in the genesis of the desensitization phenomenon in heart failure. BACKGROUND It remains to be determined whether plasma norepinephrine plays a primary role in the pathogenesis of sympathetic desensitization in heart failure in vivo. METHODS Acute left ventricular failure was induced by aortic regurgitation in seven rabbits. Chronic heart failure was induced by adriamycin treatment in another seven rabbits. RESULTS Cardiac output was lower in rabbits with aortic regurgitation than in seven sham-operated rabbits. Left ventricular end-diastolic pressure was higher in rabbits with aortic regurgitation, but no significant difference in right ventricular end-diastolic pressure was observed. Beta-adrenoceptor density and norepinephrine concentration in the left ventricular myocardium were lower in rabbits with aortic regurgitation; no such differences were observed for the right ventricular myocardium. Cardiac output was lower in adriamycin-treated rabbits than in seven control rabbits. Both left and right ventricular end-diastolic pressures were higher in experimental rabbits than in control rabbits. Myocardial beta-adrenoceptor density and norepinephrine content were reduced in both ventricles. CONCLUSIONS In chronic heart failure induced by adriamycin, sympathoneuronal activity was altered in both ventricles, whereas in acute left ventricular failure induced by aortic regurgitation, sympathoneuronal activity was affected only in the left ventricle despite a similar increase in plasma norepinephrine concentration in both animal models. Local abnormalities in sympathoneuronal regulation in failing myocardium therefore appear to be responsible for these phenomena.

Effectiveness of carvedilol alone versus carvedilol + pimobendan for severe congestive heart failure ∗

Pimobendan is a new inotropic agent with phosphodiesterase-inhibiting and calcium-sensitizing effects that increase contractility with minimal increase in oxygen consumption.1‐5 We hypothesized that short-term administration of pimobendan in the early phase of b-blocker therapy would be beneficial in alleviating exacerbation of congestive heart failure (CHF) resulting in withdrawal for patients with severe CHF. The present study investigated the effects of short-term coadministration of pimobendan during introduction of carvedilol therapy on the clinical outcome, left ventricular contractile function, and neurohormone and cytokine levels compared with conventional carvedilol therapy in a randomized fashion in patients with severe CHF. ••• For the present study patients with New York Heart Association (NYHA) class III/IV symptomatic CHF who had multiple episodes of decompensated heart failure and a left ventricular ejection fraction of ,40% on radionuclide ventriculography or contrast ventriculography were enrolled. They were treated with conventional medical treatment including digitalis glycosides, diuretics, and angiotensin-converting enzyme (ACE) inhibitors. Exclusion criteria included a heart rate of ,50 beats/min, systolic blood pressure of ,90 mm Hg, significant bradyarrhythmias or atrioventricular block, serum creatinine of .3.0 mg/dl, and the presence of stenotic valvular heart disease, alcohol abuse, active myocarditis, or hypertrophic obstructive cardiomyopathy. Plasma creatinine phosphokinase level determination and scintigraphic assessment were performed to exclude myocarditis in the absence of biopsy samples. The study protocol was approved by an institutional review committee, and informed consent was obtained from all patients who participated in the study.

Effects of methylprednisolone on hemodynamics and β-adrenergic receptor signaling in rabbits with acute left ventricular failure

SummaryStudies suggest that corticosteroids may restore the responsiveness to catecholamines in hypotensive patients. Since the significance of this promising intervention in congestive heart failure remains to be explored, we determined the effects of methylprednisolone, a potent activator of β-adrenergic receptor signaling, on hemodynamics and β-adrenergic receptor regulation in an animal model of heart failure. Acute left ventricular overloading was produced by aortic regurgitation (AR) in 22 Japanese white rabbits. Eleven animals received an intravenous administration of methylprednisolone (AR+PSL), while 11 received saline (AR+C) for 1 week. A sham operation was performed on 10 other rabbits (S). There was no difference between the AR+C and AR+PSL groups in the decrease in aortic diastolic pressure immediately after the production of AR. The aortic diastolic pressure and regurgitant fractions were also similar in the two groups. The left ventricular end-diastolic and end-systolic dimensions were both larger, and the left ventricular end-diastolic pressure was higher in AR+C or AR+PSL than in S rabbits. Between the AR+C and AR+PSL, there were no differences in any of these variables. Cardiac output was lower in AR+C, but not in AR+PSL, than in S. Cardiac output in AR+PSL was significantly higher than in AR+C. The myocardial concentration of norepinephrine and the number of β-adrenergic receptors were both lower in the AR+C and AR+PSL than in the S groups. The number of receptors in AR+PSL was higher than in AR+C. Maximal isoproterenol-stimulated adenylyl cyclase activity was similar in the AR+C and AR+PSL groups. Results suggest methylprednisolone yielded some benefits, including an increase in cardiac output and in total β-adrenergic receptor number, in this animal model of heart failure.

Beta-blockade prevents ventricular failure following aortic regurgitation in rabbits

This study investigated the effects of chronic beta-blockade on the pathophysiology of heart failure following induction of aortic regurgitation (AR). Nine rabbits with AR were administered propranolol continuously for 7 days (AR+P), 8 rabbits with AR received vehicle for the same period (AR+C), and 7 rabbits underwent sham operation. Cardiac output was lower and the left-ventricular end-diastolic pressure was higher in AR+C than in sham-operated rabbits, but there was no difference in the right-ventricular end-diastolic pressure between the two groups. Down-regulation of beta-adrenoceptors was observed in the left ventricle, but not in the right ventricle. All of these variables were reversed in AR+P. In left-ventricular failure produced by AR, (1) the augmentation of adrenergic drive occurred selectively in the left ventricle, and (2) propranolol blunted adrenergic drive and played a protective role against myocardial damage.