Chronic Sildenafil Treatment in Heart Failure

Heart failure (HF) is a significant health care concern that is evolving to epidemic proportions. Development of new forms of interventions remains a challenging task. An abnormal nitric oxide (NO) pathway is involved in several basic pathophysiological abnormalities encountered in HF syndrome and NO overexpression may represent a desirable therapeutic target in the cure of the disease.

PDE5-inhibition is an intriguing pharmacological strategy to enhance in vivo nitric oxide (NO) signaling by increasing the cyclic guanosine monophosphate (cGMP). availability. A number of theoretical backgrounds support the use of PDE5-inhibitors in HF and an increasing number of clinical studies have been testing PDE5-inhibition as a potential valid adjunct in the management of HF patients.

In failing hearts of animal models, PDE5-inhibition has also provided the attractive therapeutic properties to reverse left ventricular chamber remodelling by preventing and reversing LV cardiac hypertrophy and fibrosis and by protecting the myocardium from ischemia-reperfusion injury and apoptosis. There is also evidence that a defective NO activity plays an important role in the excitation-relaxation process of the failing heart, an effect explained by a defective cGMP-induced phosphorylation of troponin I, which facilitates calcium-independent diastolic cross-bridge cycling and concomitant myocardium diastolic stiffening.

No report has so far investigated whether cardiac function and, primarily, diastolic LV function may be a target of chronic PDE5-inhibition and whether any improvement in diastolic function is related to a reverse effect in cardiac geometry in patients with HF. Furthermore, it is undefined whether a favourable effect on left ventricular function may be involved in the reported changes in important clinical correlates such as functional status and quality of life. We tested these hypotheses, by addressing the effects of chronic sildenafil administration (50 mg three times/day) on diastolic function and clinical status by Tissue Doppler imaging, cardiopulmonary exercise testing and quality of life score.

Inclusion criteria

• consent to participate in the study after detailed information about procedures, possible clinical benefits and risks;
• negative exercise stress test prior to study initiation;
• forced expiratory volume in 1 sec/forced vital capacity ratio>70%;
• left ventricular ejection fraction < 45%, determined by echocardiography.

Exclusion criteria

• subjects unable to complete a maximal exercise test
• systolic blood pressure > 140 and <110 mmHg
• diabetes mellitus
• therapy with nitrate preparations
• history of sildenafil intolerance
• significant lung or valvular diseases
• neuromuscular disorders, claudication
• peripheral vascular disease