Cardiac Uses of Phosphodiesterase-5 Inhibitors

Mechanism of Action

Vascular tone and blood flow is primarily regulated by endothelial-dependent vasodilation whereby endothelial cells produce nitric oxide (NO) that diffuses to the adjacent smooth muscle cells and enhances the production of cyclic guanosine monophosphate (cGMP), which relaxes smooth muscle, resulting in vasodilation. The cGMP is broken down by PDE5; thus, PDE5Is inhibit the breakdown of cGMP, resulting in enhanced vasodilation. By taking advantage of PDE5 located within the systemic and pulmonary vasculature, PDE5Is might benefit cardiovascular diseases. In addition to enhancing vasodilation, PDE5Is protect myocytes directly through complex mechanisms described in the following text.

CHF

The PDE5Is improved hemodynamic and clinical parameters in patients with CHF in a number of small trials (Table 1), although efficacy has not been tested in large-scale, long-term placebo-controlled trials. In small placebo-controlled trials of patients with CHF, sildenafil increased oxygen uptake (3,4), increased cardiac index (4,5), reduced systemic vascular resistance (5), reduced aorta stiffness (5), and improved exercise time (3), 6-min walk distance (4), depression scores (6), and quality of life (6). The hemodynamic improvements of Sildenafil were maintained at 4 weeks (7), and the benefits of sildenafil on pulmonary arterial pressure, breathlessness score, and aerobic efficiency persisted at 6 months with a trend to greater improvement (8).

Small trials in patients with CHF demonstrated the greatest benefit of PDE5Is in patients with secondary PAH and right ventricular failure (4,9). The utility of PDE5Is in CHF patients without PAH is less clear, emphasizing the lack of large-scale testing.

In normal myocardium the presence of PDE5 is minimal to none. PDE5 expression, however, seems to be increased in a number of myocardial disease states, including chronic myopathies involving myocyte or ventricular hypertrophy. Histologic examination of myocardium from 6 patients with CHF and 6 normal donor hearts revealed PDE5 within the myocardium only in CHF hearts (10). Myocardial PDE5 expression correlated with markers of oxidative stress (10). In mouse (10) and rat (11) models, pressure overload resulted in increased myocardial PDE5 levels. Superoxide dismutase blunted the increase in PDE5 and protected against left ventricular hypertrophy and CHF, suggesting that oxidative stress increases PDE5 expression leading to hypertrophy (10). In human surgical specimens, PDE5 was not expressed in normal myocardium; however, PDE5 and PDE5 messenger ribonucleic acid was upregulated in hypertrophied myocardium, but only in the chamber with pressure overload (11). Furthermore, sildenafil increased the contractility of hypertrophied myocytes in cell-shortening experiments and in hypertrophied right ventricles in a Langendorff model (11).

PDE5Is increase cGMP levels, which under normal circumstances would activate protein kinase G, decrease intracellular calcium levels, and reduce contractility. However, in hypertrophied myocardium, protein kinase G activity is inhibited, so cGMP preferentially shifts to its other pathway: inhibition of phosphodiesterase-3 (11). Thus, in hypertrophied myocardium, PDE5Is increase cGMP—which inhibits phosphodiesterase-3—thereby increasing cyclic adenosine monophosphate (cAMP), which activates protein kinase A; this, in turn, increases intracellular calcium and contractility (11).

Sildenafil seems to induce additional mechanisms that prevent adverse remodeling (12). To assess the effects of sildenafil on remodeling independent of infarct size, randomized treatment began 3 days after permanent coronary occlusion in a mouse model of myocardial infarction (12). Compared with placebo, sildenafil preserved left ventricular function and reduced left ventricular dilation. Mice randomized to sildenafil demonstrated significantly less fibrosis, apoptosis, and ventricular hypertrophy. Moreover, sildenafil increased protein kinase G activation (from increased NO availability and cGMP levels), increased the Bcl-2/Bcl-2–associated X protein ratio, and inhibited the RhoA/Rho-kinase pathway (this effect was abolished by a protein kinase G inhibitor). The Rho kinase pathway is pathogenic, and Rho kinase inhibition has previously improved atherosclerosis, post-infarction remodeling, and cardiac hypertrophy (12). The authors concluded that sildenafil reduced myocardial apoptosis, fibrosis, and hypertrophy through a mechanism that involves protein kinase G activation, Rho kinase inhibition, and increased Blc-2 (anti-apoptotic, see following text) (12).

Further evidence of sildenafil's benefits on reverse remodeling comes from a mouse model of cardiomyopathy induced by pressure overload with aortic banding (13). Despite sustained pressure overload, sildenafil reversed pre-established maladaptive responses to pressure overload, including eccentric remodeling, maladaptive molecular signaling, hypertrophy, fibrosis, and depression of function (13,14). In addition, sildenafil improved endothelial-mediated vasodilation in patients with CHF (15).

In conclusion, in patients with CHF, sildenafil improves numerous hemodynamic and clinical parameters both acutely and chronically. In experimental models, sildenafil also benefits cardiac remodeling, apoptosis, fibrosis, and hypertrophy. The heterogeneous nature of CHF requires large scale, long-term placebo-controlled trials with clinical endpoints to determine efficacy. To date, no studies powered to assess mortality have been completed, and the clinical utility of PDE5Is in CHF remains unclear.

Doxorubicin Cardiotoxicity

In a model of chronic (8 weeks) doxorubicin cardiotoxicity, sildenafil protected against doxorubicin-induced apoptosis and preserved left ventricular function (16). In a mouse model, compared with doxorubicin alone, treatment with doxorubicin plus tadalafil significantly improved survival, fractional shortening, ejection fraction, and hypertrophy (17). Moreover, tadalafil reduced the incidence of apoptosis and preserved the expression of Bcl-2, which blocks the mitochondrial pathway of apoptosis. Tadalafil also increased cardiac cGMP levels and protein kinase G activity, upregulated mitochondrial superoxide dismutase, and prevented lipid peroxidation. The authors concluded that “tadalafil activated mitochondrial antioxidative and anti-apoptotic mechanisms through up-regulation of cGMP, protein kinase G activity, and mitochondrial superoxide dismutase level without interfering with the chemotherapeutic benefits of doxorubicin” (17). Therefore, prophylactic PDE5Is for patients treated with doxorubicin seems promising and deserves further clinical investigation.

Cardioprotection

Mechanisms similar to those involved in preventing doxorubicin cardiotoxicity also seem to protect the heart from acute infarction, as reviewed elsewhere (18). Briefly, NO synthesis by endothelial- and especially inducible-NO synthase is an essential component of cardioprotection (19,20). Numerous stimuli, including PDE5Is, initiate the NO synthase signaling cascade by first activating protein kinase C or extracellular-signal-regulated kinase, which mediates survival pathways in many cell types—including the delayed cardioprotective effect of sildenafil (18). Nitric oxide directly mediates early cardioprotection (21–24) and also triggers delayed cardioprotection by increasing cGMP levels and protein kinase G activity (25–27). Mitochondrial adenosine triphosphate (ATP)-dependent potassium channels are a critical downstream target of cardioprotection pathways. Mitochondrial integrity is essential to cell survival, by maintaining ATP synthesis and calcium homeostasis. Nitric oxide acts directly and indirectly through protein kinase G to open mitochondrial ATP potassium channels, which protect myocytes by compensating for the altered membrane potential and enabling protons to be pumped out of the mitochondria, which maintains the electrochemical gradient necessary for ATP synthesis and calcium transport (18). Additionally, PDE5Is also seem to promote cardioprotection through NO-dependent up-regulation of Bcl-2, which promotes cell survival by inhibiting the mitochondrial permeability transition pore (18).

Numerous studies have reported a reduction in infarct size in animals treated with sildenafil compared with placebo (19–22,25,26). Sildenafil provided cardioprotection when administered immediately (25), 30 min (21), 24 h (21,22), or chronically for 4 weeks (19) before a coronary occlusion or during coronary reperfusion (26). Likewise, tadalafil (27,28) and vardenafil (24) reduced infarct size when given 30 to 120 min before coronary occlusion. The duration of cardioprotection from tadalafil remained until 36 to 40 h after a single dose, and repeat administration at 36 and 72 h extended protection until 108 h (23). In addition to reducing infarct size, administration of PDE5Is before coronary occlusion in animal models increased endothelial- and inducible-NO synthase, (19,20) reduced cardiac hypertrophy (19), reduced apoptosis (19), preserved fractional shortening (27), and improved survival (19,27). In a dog model mimicking cardiopulmonary bypass, vardenafil improved recovery of the ventricular end-systolic pressure volume relationship, increased coronary blood flow, and preserved endothelial function (29). At least 1 study reported that sildenafil had no effect on infarct size but did improve coronary vascular resistance and certain hemodynamic parameters during experimental myocardial infarction (30).

High-Altitude Pulmonary Edema and High-Altitude Pulmonary Hypertension

High altitudes can cause pulmonary disease acutely (high-altitude pulmonary edema [HAPE]) and chronically (high-altitude pulmonary hypertension [HAPH]). Upon ascent to altitudes >2,500 m, the lungs respond to hypoxia by reducing NO availability, which precipitates pulmonary artery vasoconstriction and increased pulmonary artery pressure. Depending upon altitude and ascent rate, 0.1% to 4% of climbers develop HAPE consisting of pulmonary edema and restricted gas exchange (31,32). In populations living at ≥3,200 m, HAPH occurs in 5% to 18% (33). At high altitudes, sustained hypoxia can lead to pulmonary endothelial dysfunction, muscularization, and deposition of connective tissue in the pulmonary arteries and PAH leading to right ventricular hypertrophy and potentially culminating in right heart failure and premature death. The PDE5Is seem ideally suited to prevent and treat HAPE and HAPH, because PDE5Is increase NO availability, improve endothelial function, and reduce pulmonary arterial resistance and pressure (Table 2).

In fact, in climbers with a history of HAPE, prophylactic tadalafil significantly and markedly reduced the incidence of HAPE compared with placebo in 2 separate studies (34,35). In 10 healthy volunteers, sildenafil almost abolished the 56% increase in pulmonary arterial pressure induced by breathing 11% oxygen for 30 min (36). Sildenafil was investigated in 10 trained male cyclists studied at sea-level and at simulated high altitude (breathing 12.8% oxygen) (37). At sea-level, sildenafil did not affect any hemodynamic or performance parameters. In contrast, while breathing 12.8% oxygen sildenafil increased stroke volume, cardiac output, and arterial oxygen saturation during set-work-rate exercise, and sildenafil lowered 6-km time-trial time by 15% (37). Sildenafil was investigated in 14 healthy volunteers assessed at rest and during maximal exercise capacity while breathing 10% oxygen both at low altitude and at high altitude (Mount Everest base camp) (38). At low altitude, sildenafil increased oxygen saturation during exercise, reduced systolic pulmonary arterial pressure during rest and exercise, and increased maximum workload (38). At high altitude, sildenafil had no effect on oxygen saturation at rest but did reduce pulmonary arterial pressure during rest and exercise and increased maximum workload and cardiac output. Thus, sildenafil and tadalafil seem to reduce pulmonary arterial pressure, increase maximum workload, and reduce the incidence of HAPE, during exercise while breathing air with reduced oxygen content and during ascent to high altitude.

To investigate sildenafil as a therapy for HAPH, 689 subjects living >2,500 m were screened by examination and electrocardiogram, revealing 188 subjects (27%) with right ventricular hypertrophy, of which 44 underwent cardiac catheterization (39). Twenty-nine of 44 subjects (66%) had resting mean pulmonary arterial pressure >25 mm Hg. Twenty-two of these patients with HAPH were then randomized to placebo or sildenafil. Sildenafil reduced pulmonary arterial pressure and improved 6-min walk distance, after 12 weeks of therapy (39). Moreover, sildenafil reduced right ventricular systolic pressure, reduced right ventricular hypertrophy, and inhibited pulmonary vascular remodeling, in mice given placebo or sildenafil for 3 weeks during exposure to 10% oxygen (36). In cultured human pulmonary artery smooth muscle cells exposed to platelet-derived growth factor, sildenafil reduced smooth muscle cell proliferation and DNA synthesis through pathways involving cGMP, protein kinase G, cAMP (sildenafil increased cAMP through cGMP inhibition of phosphodiesterase type 3), and protein kinase A (40). In conclusion, initial evidence suggests that PDE5Is might prevent and improve HAPE and HAPH.

Hypertension

Effects of PDE5I on systemic vascular resistance might be useful for treating patients with hypertension. This was investigated in 25 patients with untreated hypertension randomized to placebo or sildenafil 50 mg 3× daily (41). Sildenafil decreased average daytime blood pressure (by −8/−6 mm Hg) and clinic blood pressure (by −5/−5 mm Hg) (41). Numerous studies of PDE5Is in a variety of patients generally reported only small reductions in blood pressure (Table 3) (1). In most healthy subjects, blood pressure returned to baseline values within 6 h of sildenafil administration (42), so multiple daily dosing would be necessary and would not cover the morning rise in blood pressure. Longer-acting tadalafil decreased diastolic blood pressure for 12 h but did not affect systolic blood pressure in healthy volunteers (43).

Although PDE5Is are contraindicated with any nitrate medication, because of potentially severe hypotension, this drug combination might be beneficial for patients with treatment-resistant hypertension and was investigated in a crossover trial including 6 such subjects continued on their previous medications (44). Compared with sildenafil alone and with isosorbide mononitrate alone, the combination of sildenafil and isosorbide mononitrate produced the largest blood pressure decrease (placebo-subtracted maximum decrease −26/−18 mm Hg) without significant side effects (44). The combination of PDE5Is and nitrates requires further investigation to ensure safety.

Raynaud's Phenomenon

The effects of PDE5Is on systemic vasodilation and endothelial function might benefit patients with Raynaud's phenomenon. In an open-label pilot study in 40 patients with Raynaud's disease, vardenafil 10 mg twice daily improved digital blood flow in 70% of patients and improved clinical symptoms in 68% (45). In a crossover study, sildenafil reduced the frequency and duration of Raynaud's attacks and markedly increased capillary blood flow velocity (46). Moreover, visible healing was noted in all 6 patients with chronic digital ulcerations, all 16 patients correctly identified the double-blinded pills as either sildenafil or placebo, and 89% of patients requested to continue sildenafil as off-label therapy after the conclusion of the study (46). Furthermore, in 19 patients with systemic sclerosis and digital ulcers refractory to treatment, the number of digital ulcers decreased from 3.1 to 1.1 ulcers/patient during sildenafil therapy for a mean of 5.2 months (47). Approximately one-half of patients developed new ulcers during sildenafil therapy, suggesting that sildenafil does not prevent new ulcerations (47). Previously, bosentan, an endothelin-1 receptor antagonist, failed to heal digital ulcers but was effective in preventing them (47). Thus, different mechanisms might be involved in preventing and healing digital ulcers, and combination therapy might be beneficial. Two other crossover studies did not demonstrate a benefit with tadalafil therapy; however, it was noted that placebo response was a factor (48,49). In a double-blind, randomized study accepted for publication, sildenafil significantly reduced the frequency of Raynaud's attacks compared with placebo (50). In conclusion, PDE5Is are promising for the treatment of Raynaud's patients, and additional placebo-controlled trials are needed to clarify dosing and subsets of patients most likely to benefit from PDE5I therapy.

Other Cardiovascular Uses

The PDE5Is are hypothesized to benefit but have not been tested in preeclampsia (51) and in patients undergoing cardiac surgery (52). Sildenafil (53) and vardenafil (54) were each studied in a mouse model of unilateral hindlimb ischemia mimicking peripheral arterial disease. In each study, the PDE5I enhanced ischemia-induced angiogenesis as measured by vascular perfusion, tissue blood flow and vascular density (53,54).

Conclusions

PDE5 is expressed throughout the human body, including the pulmonary and systemic vasculature and hypertrophied myocardium. The effects of PDE5Is on pulmonary circulation and the hypertrophied right ventricle have made these agents first-line therapy for many patients with PAH. The PDE5Is also benefit hemodynamic and clinical parameters in patients with CHF, especially those with secondary PAH and right ventricular failure. The clinical utility of PDE5Is in CHF patients requires large-scale clinical testing. The PDE5Is are ideally suited for and have demonstrated benefit in preventing and treating HAPE and HAPH. Cardioprotection has been reported in numerous animal models where PDE5Is reduced infarct size. In some but not all randomized trials, PDE5Is improved clinical parameters in patients with Raynaud's phenomenon. The PDE5Is might be beneficial in combination with nitrates in patients with treatment-resistant hypertension if proven to be safe. Mechanisms of benefit of PDE5Is include pulmonary and systemic vasodilation, increased myocardial contractility, improved endothelial function, and reduced apoptosis, fibrosis, and hypertrophy through mechanisms involving NO, cGMP, protein kinase G, Bcl-2, and Rho kinase inhibition. Further investigation is warranted to verify benefit in the conditions described and might discover a benefit of PDE5Is in other cardiovascular diseases.