Sildenafil’s protective effect against cardiac hypertrophy

Left ventricular hypertrophy is a leading contributor to cardiovascular morbidity and mortality, increasing the risk of heart failure, myocardial infarction and stroke by threeto ten-fold [1]. Moreover, the prevalence of cardiac hypertrophy is increasing, probably ref lecting the advancing age of the world’s population and the global epidemics of diabetes, obesity and hypertension. Hypertrophy occurs in nearly a third of patients with arterial hypertension and is common to most forms of valvular and ischemic heart disease [2,3]. Although hypertrophy has been viewed as providing some initial functional compensation to increased pressure or volume stress, studies increasingly suggest that the response is never really adaptive when the stress imposed is pathologic. Prolonged hypertrophic stimulation can lead to frank heart failure, and even short-term exposure to pathologic versus physiologic stress triggers maladaptive signaling cascades [4]. Recent antihypertension clinical trials have found that the reversal of hypertrophy independently predicts lower cardiovascular mortality risk [5,6], while mice harboring genetic mutations that suppress hypertrophy often respond more favorably to pressure stress [7,8]. The evolution of hypertrophy involves a broad array of signaling modifications, involving kinases, phosphatases, transcription factors and miRNAs, and virtually all of these pathways are presently being pursued as potential therapeutic targets [2]. Hypertrophy is also negatively regulated by a variety of enzymes and, among these, one that has gained particular attention, owing in part to the availability of clinically effective, smallmolecule modulators, is that related to cyclic guanosine monophosphate (cGMP) and its primary target kinase, protein kinase-G (PKG) [2,9].