The goals of this research were to carefully characterize the phenomenology of impaired myocardial contractile reserve in failing hearts and to explore the mechanisms responsible for this phenomenology. For these studies, we utilized failing and non-failing myocardium from human hearts and from a large animal model that mimics human myocardial failure. We examined responses to changes in stimulation frequency and adrenergic stimulation and the effects of changes in preload on these responses. We also examined the direct inotropic effects of urotensin-II (U-II), an endogenous peptide hormone that is activated in the failing heart. In all studies, isometric contractile force was measured in right ventricular trabeculae and several studies employed rapid cooling contractures (RCC) to associate contractile responses with changes in sarcoplasmic reticulum (SR) Ca²⁺ load.

In non-failing human myocardium, increased stimulation frequency and adrenergic stimulation elicited potent increases in force generation. In failing human myocardium, responses to increased stimulation frequency were severely blunted but responses to adrenergic stimulation were relatively intact. Failing and non-failing feline myocardium exhibited similar responses and demonstrated that changes in contractility are closely paralleled by changes in RCC amplitude and changes in the abundance and phosphorylation of key Ca²⁺ handling proteins. Studies in feline myocardium also demonstrated that preload is a powerful modulator of other modulators of contractile reserve. Recognizing known species differences, responses to exogenous U-II were examined in human myocardium. These studies demonstrated that exogenous U-II reveals particularly sharp distinctions between failing and non-failing myocardium in that positive inotropic responses were seen in non-failing myocardium compared with negative inotropic responses in failing myocardium. Here again, contractile responses to U-II were paralleled by changes in RCCs suggesting the importance of SR Ca²⁺ load. Collectively, the findings of these studies indicate that a reduced ability to increase SR Ca²⁺ load is the primary mechanism of reduced contractile reserve in failing myocardium. The similarity of impaired contractile reserve phenomenology in the feline pulmonary artery banding model and transplanted human hearts suggests mechanistic relevance to human myocardial failure. U-II directly modulates contractility independent of vasoconstriction with opposite effects in failing and non-failing hearts.