Intracellular Ca2+ release and reuptake are necessary for normal contraction and relaxation of the human heart. Intracellular Ca2+ transients were recorded with aequorin during isometric contraction of myocardium from patients with end-stage heart failure. In contrast to controls, contractions and Ca2+ transients of muscles from failing hearts were markedly prolonged, and the Ca2+ transients exhibited two distinct components. Muscles from the failing hearts showed a diminished capacity to restore a low resting Ca2+ level during diastole. These data obtained in actively contracting human myocardium suggest that intracellular Ca2+ handling is abnormal and might cause both systolic and diastolic dysfunction in heart failure. The inotropic effectiveness of drugs that act to increase intracellular levels of cyclic adenosine monophosphate (AMP), such as beta-adrenergic agonists and phosphodiesterase inhibitors, was markedly reduced in muscles from patients with heart failure. In contrast, the effectiveness of inotropic stimulation with drugs that act by cyclic AMP-independent mechanisms, such as the cardiotonic steroids and DPI 201-106, were preserved. Stimulation of intracellular cyclic AMP production by the adenylate cyclase activator forskolin restored the inotropic response to phosphodiesterase inhibitors. These studies indicate that an abnormality in cyclic AMP production may be a fundamental defect in patients with end-stage heart failure that may markedly diminish the effectiveness of agents that depend on generation of this nucleotide for a positive inotropic effect. Moreover, deficient production of cyclic AMP seems, at least in part, to account for the reversal of the force-frequency relation that characterizes failing myocardium. Of interest, direct measurement of total cellular cyclic AMP content and protein kinase activity did not reveal significant differences between the control and myopathic tissue, suggesting the presence in human ventricular muscle of physiologically distinct compartmentalized pools of cyclic AMP. Finally, changes in the sensitivity of the contractile apparatus to Ca2+ also seem to play an important role in the differential responsiveness to drugs of myopathic versus normal human myocardium.

Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure.

To assess their comparative effects on hemodynamics and myocardial energetics, we administered nitroprusside (1.5 +/- 0.6 microgram/kg-min), dobutamine (10 +/- 3 micrograms/kg-min), and milrinone (67 +/- 13 micrograms/kg-min) sequentially to 10 patients with severe (NYHA class III or IV) congestive heart failure. Each agent led to a significant (p = .001) increase in cardiac index (1.9 +/- 0.5 to 2.7 +/- 0.6 liters/min/m2; 1.7 +/- 0.4 to 2.6 +/- 0.6 liters/min/m2; and 1.8 +/- 0.5 to 2.7 +/- 0.5 liters/min/m2, for nitroprusside, dobutamine, and milrinone, respectively). Dobutamine did not produce a significant change in the pulmonary capillary wedge pressure (27 +/- 5 to 24 +/- 6 mm Hg, NS) nor in mean arterial pressure (83 +/- 9 to 86 +/- 10 mm Hg, NS), but caused a significant rise in heart rate (85 +/- 16 to 99 +/- 17 beats/min, p = .001) and in myocardial oxygen consumption (8.7 +/- 2.1 to 11.1 +/- 3.8 ml O2/min, p = .03). In contrast, nitroprusside and milrinone each caused a significant (p = .001) fall in the pulmonary capillary wedge pressure (27 +/- 6 to 19 +/- 7 mm Hg and 26 +/- 6 to 19 +/- 9 mm Hg, respectively), without significantly increasing either the heart rate (87 +/- 18 to 85 +/- 17 beats/min and 86 +/- 17 to 89 +/- 17 beats/min, respectively) or myocardial oxygen consumption (8.8 +/- 2.3 to 7.6 +/- 2.1 ml O2/min and 8.8 +/- 2.1 to 8.4 +/- 2.1 ml O2/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Milrinone, dobutamine, and nitroprusside: comparative effects on hemodynamics and myocardial energetics in patients with severe congestive heart failure.

Cyclic adenosine monophosphate effects on the myocardium: a man who blows hot and cold with one breath.

There is substantial, although not yet conclusive, evidence that the failing heart is in an energy-depleted state Such an imbalance between energy production and energy utilization would have important implications for the management of patients with congestive heart failure (CHF), most important of which is that therapeutic measures that increase myocardial energy demand could have long-term detrimental effects on the heart By increasing energy expenditure, vasoconstrictors and positive inotropic agents could worsen cell damage, exacerbate relaxation abnormalities and promote arrhythmias Conversely, therapy that improved the balance between energy delivery and energy expenditure might be expected to improve prognosis in CHF For this reason, vasodilators and reduced inotropic drive to the failing heart could prolong survival in these patients Further understanding of the energetics of the failing heart will be of considerable importance in the formulation of hypotheses regarding long-term therapy that could be evaluated in controlled clinical trials

Cellular mechanisms in congestive heart failure.

Heart failure with normal systolic function.

Cardiac pumping action is governed by two interdependent systems: those that govern contraction and the emptying of the heart (inotropic) and those that control its relaxation and filling (lusitropic). The signs and symptoms of ‘heart failure’ can be caused by abnormalities of either or both of these systems. Major technological advances in the evaluation of the cardiac patient, especially those that utilize measurements of ventricular volume, coupled with potent new drugs that can modify differently the inotropic and lusitropic properties of the myocardium, make it necessary to understand the role that each plays in the genesis of the clinical syndrome of heart failure.

Inotropic and lusitropic abnormalities in the genesis of heart failure

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Inotropic and lusitropic abnormalities in the genesis of heart failure