Sildenafil: Mechanism of Action
Sildenafil is the prototypical agent in a class of selective inhibitors of phosphodiesterase type 5 (PDE5), which are known to enhance nitric oxide-mediated vasodilation in patients with and without heart failure by inhibiting degradation of cyclic GMP, a key intracellular second messenger.[1] Whereas inhibitors of the cyclic AMP-specific phosphodiesterase type 3 (PDE3, including inotropic drugs such as milrinone, vesnarinone, and enoximone) augment intracellular levels of cyclic AMP and increase mortality in patients with heart failure,[2] sildenafil is highly selective (>4000-fold) for human PDE5, does not increase cyclic AMP, and lacks inotropic effects; it is thus not thought to share the toxicity associated with PDE3 inhibition.[3]
The vascular effects of PDE5 have been well recognized since its initial identification as a therapeutic target. Inhibition of PDE5 in the vascular smooth muscle of the penile corpus cavernosum has been a major breakthrough in the treatment of erectile dysfunction.[4] However, emerging data indicate that PDE5 is also present within cardiac myocytes and may play a role in modulating cyclic GMP activity in cardiovascular disease.[5] Indeed, upregulation of cyclic GMP has been reported in a variety of cardiovascular conditions including pulmonary hypertension,[6] congestive heart failure,[7] and right ventricular hypertrophy,[8] suggesting a therapeutic opportunity for using sildenafil to treat patients with heart failure and its sequelae.
Sildenafil and Heart Failure
Several observations from preclinical and short-term clinical studies support a role for sildenafil in the treatment of heart failure patients. The following discussion briefly considers each of these in turn.
Effects of Sildenafil on Pulmonary Vascular Resistance. Right ventricular performance is an important determinant of prognosis and effort tolerance in patients with heart failure, and accordingly, reduction in pulmonary vascular resistance has emerged as an important target for therapy. In patients with primary pulmonary hypertension (PAH), sildenafil has selective vasodilatory effects in the pulmonary vasculature comparable to those of inhaled nitric oxide (NO).[9] As well, sildenafil has been shown to improve exercise capacity, resting hemodynamics, and functional capacity in patients with idiopathic PAH and PAH associated with connective tissue disease or repaired congenital systemic-to-pulmonary shunts.[10] Data from small, acute hemodynamic studies suggest that in chronic heart failure (with our without associated pulmonary hypertension), sildenafil lowers resting pulmonary vascular resistance and pulmonary capillary wedge pressure and increases cardiac index without causing systemic hypotension.[11-13] Acute improvements in right ventricular ejection fraction and ventilatory efficiency during exercise appear most pronounced in patients with heart failure and associated mean pulmonary artery pressure > 25 mm Hg.[14] Though data examining long-term use of sildenafil in heart failure patients is limited, effects on pulmonary artery pressure and aerobic efficiency appear to be sustained at 6 months.[15]
Effects of Sildenafil on Cardiac Response to Stress. Evolving data suggest that inhibition of PDE5 may have important antihypertrophic, anti-apoptotic, and ischemic preconditioning effects that may limit myocardial remodeling in response to stress and attenuate the substrate for heart failure development. In murine models of myocardial pressure overload induced by aortic banding, inhibition of PDE-5 is associated with reduction of cardiac and myocyte hypertrophy, reduction in interstitial fibrosis, preservation of cardiac function, and the deactivation of various hypertrophy signaling cascades.[16] PDE5 inhibition also promotes opening of mitochondrial KATP channels,[17] a putative target of reactive oxygen species generated in response to both ischemia/reperfusion (IR) and doxorubicin treatment, and reduces doxorubicin or ischemia/reperfusion-induced apoptosis.[18,19] Accordingly, administration of sildenafil appears both to limit the size of myocardial infarction generated during ischemia/reperfusion, and to attenuate the development of left ventricular dysfunction in murine models of doxorubicin cardiotoxicity.[5,19-21]
Effects of Sildenafil on the Cardiac Response to Neurohormonal Activation. Resistance to the actions of natriuretic peptides is the hallmark of pathological states of sodium retention such as cirrhosis, heart failure, and the nephrotic syndrome.[22,23] Enhanced degradation of cyclic GMP by PDE5 in response to angiotensin II stimulation may be an important mechanism of this attenuated natriuretic peptide response.[7] The circulating ratio of plasma B-type natriuretic peptide to cyclic GMP, a marker of natriuretic peptide desensitization, rises markedly in heart failure, but is restored to normal levels following PDE5 inhibition.[24] Accordingly, in a canine model of heart failure, exposure to chronic PDE5 inhibition appears to improve the acute renal responsiveness to natriuretic peptides.[25] Although these observations await validation in human subjects, they suggest that inhibion of PDE5 with sildenafil may mimic or enhance natriuretic peptide effects in the failing heart.
PDE5 may also play a role in modulating the response to sympathetic stimulation. Acute PDE5 inhibition has been associated with blunting of the inotropic and lusitropic response to acute beta-adrenergic stimulation with dobutamine in normal human and canine subjects.[5,26] Despite this observation, however, sildenafil does not appear to alter resting cardiac contractility or relaxation in patients with heart failure and actually improves exercise capacity when administered chronically to heart failure patients with systolic dysfunction.[15] These observations argue against any relevant clinical effect on contractile reserve.
Effects of Sildenafil on Vascular Function. Abnormal endothelial function is a hallmark of heart failure and may contribute to enhanced systemic vascular tone, reduced vasodilator reserve, and abnormal skeletal muscle perfusion that in turn promotes early transition to anaerobic metabolism and exaggerated ventilatory response to exercise.[27,28] Increased ventilatory drive contributes to hyperventilation and a perception of dyspnea in heart failure patients and is associated with poor prognosis independent of ejection fraction.[29-31] Inhibition of PDE5 has been associated with improvements in endothelial function in patients with heart failure due to systolic dysfunction[32] that are highly correlated with improvements in skeletal muscle perfusion, reduction in exercise-induced hyperventilation (VE/VCO2), and increased aerobic efficiency.[28] Associated reductions in large artery stiffness observed during sildenafil treatment may further contribute to improved baroreceptor function and enhanced heart rate recovery in patients with heart failure.[33] Tandem improvements in vascular function and pulmonary vascular resistance may account for the overall improvements in exercise capacity and health-related quality of life that have been observed during chronic administration of sildenafil to heart failure patients.[34]
Conclusions
In summary, multiple lines of pre-clinical evidence support a therapeutic role for PDE5 inhibition with sildenafil in the management of heart failure patients. However, human trials to date are limited to small physiologic studies of patients with heart failure and reduced ejection fraction (most with associated pulmonary hypertension) followed for relatively short periods of time. Since many of the observed benefits of PDE5 inhibition with regard to left ventricular hypertrophy, ventricular-vascular stiffening, renal dysfunction, and pulmonary hypertension may be particularly relevant to the pathophysiology heart failure in patients with preserved ejection fraction, there is compelling rationale for extending the preliminary physiologic benefits of sildenafil seen in 'systolic' heart failure to the population with 'diastolic' heart failure. The RELAX trial, funded by the National Institutes of Health, is currently in progress, and proposes to address this question by randomizing 190 patients with a clinical diagnosis of heart failure and left ventricular ejection fraction ≥50% to treatment with sildenafil or placebo for 24 weeks, focusing on the primary endpoint of exercise capacity. At present, however, despite an established role in the management of patients with PAH and promising initial data, longer-term randomized trials will be necessary to define the safety, tolerability, and efficacy of sildenafil for the management of heart failure across the spectrum of ejection fraction.
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