ESPVRs can be reliably estimated in humans from single cardiac cycles by a new method that has a potential for noninvasive application.

No abstract

Recent studies implicate increased cGMP synthesis as a postreceptor contributor to reduced cardiac sympathetic responsiveness. Here we provide the first evidence that modulation of this interaction by cGMP-specific phosphodiesterase PDE5A is also diminished in failing hearts, providing a novel mechanism for blunted beta-adrenergic signaling in this disorder. In normal conscious dogs chronically instrumented for left ventricular pressure-dimension analysis, PDE5A inhibition by EMD82639 had modest basal effects but markedly blunted dobutamine-enhanced systolic and diastolic function. In failing hearts (tachypacing model), however, EMD82639 had negligible effects on either basal or dobutamine-stimulated function. Whole myocardium from failing hearts had 50% lower PDE5A protein expression and 30% less total and EMD92639-inhibitable cGMP-PDE activity. Although corresponding myocyte protein and enzyme activity was similar among groups, the proportion of EMD82639-inhibitable activity was significantly lower in failure cells. Immunohistochemistry confirmed PDE5A expression in both the vasculature and myocytes of normal and failing hearts, but there was loss of z-band localization in failing myocytes that suggested altered intracellular localization. Thus, PDE5A regulation of cGMP in the heart can potently modulate beta-adrenergic stimulation, and alterations in enzyme localization and reduced synthesis may blunt this pathway in cardiac failure, contributing to dampening of the beta-adrenergic response.

Abstract-Allopurinol, an inhibitor of xanthine oxidase, increases myofilament calcium responsiveness and blunts calcium cycling in isolated cardiac muscle. We sought to extend these observations to conscious dogs with and without pacing-induced heart failure and tested the prediction that allopurinol would have a positive inotropic effect without increasing energy expenditure, thereby increasing mechanical efficiency. In control dogs (nϭ10), allopurinol (200 mg IV) caused a small positive inotropic effect; (dP/dt) max increased from 3103Ϯ162 to 3373Ϯ225 mm Hg/s (ϩ8.3Ϯ3.2%; Pϭ0.01), but preload-recruitable stroke work and ventricular elastance did not change. In heart failure (nϭ5), this effect was larger; (dP/dt) max rose from 1602Ϯ190 to 1988Ϯ251 mm Hg/s (ϩ24.4Ϯ8.7%; Pϭ0.03), preload-recruitable stroke work increased from 55.8Ϯ9.1 to 84.9Ϯ12.2 mm Hg (ϩ28.1Ϯ5.3%; Pϭ0.02), and ventricular elastance rose from 6.0Ϯ1.6 to 10.5Ϯ2.2 mm Hg/mm (Pϭ0.03). Allopurinol did not affect myocardial lusitropic properties either in control or heart failure dogs. In heart failure dogs, but not controls, allopurinol decreased myocardial oxygen consumption (-49Ϯ4.6%; Pϭ0.002) and substantially increased mechanical efficiency (stroke work/myocardial oxygen consumption; ϩ122Ϯ42%; Pϭ0.04). Moreover, xanthine oxidase activity was Ϸ4-fold increased in failing versus control dog hearts (387Ϯ125 versus 78Ϯ72 pmol/min ⅐ mg -1 ; Pϭ0.04) but was not detectable in plasma. These data indicate that allopurinol possesses unique inotropic properties, increasing myocardial contractility while simultaneously reducing cardiac energy requirements. The resultant boost in myocardial contractile efficiency may prove beneficial in the treatment of congestive heart failure. (Circ Res. 1999;85:437-445.)

Because normal ventricular-vascular interaction and augmentation of cardiac performance during increased HR and adrenergic stimulation are important for maintaining cardiac output and exercise capacity, the present results may have important implications for the mechanisms underlying adverse outcome after Fontan surgery. Thus, improvement of long-term prognosis of patients after Fontan surgery requires the development of medical interventions that can overcome such limitations inherent in Fontan circulation.