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Right arrow Cardiac - pharmacology

Ann Thorac Surg 2004;78:1496-1506
© 2004 The Society of Thoracic Surgeons

Review

Sildenafil: Emerging Cardiovascular Indications

Shahzad G. Raja, MRCSa,*, Suneela H. Nayak, MRCPCHb

a Department of Paediatric Cardiac Surgery, Alder Hey Children's Hospital, Liverpool, United Kingdom
b Department of Paediatric Cardiology, Alder Hey Children's Hospital, Liverpool, United Kingdom

* Address reprint requests to Dr Raja, Department of Paediatric Cardiac Surgery, Alder Hey Children's Hospital, Eaton Rd, West Derby, Liverpool L12 2AP, UK
drrajashahzad{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Phosphodiesterase-5 and...
 Cardiovascular Effects of...
 Emerging Therapeutic Indications
 References
 
The discovery in 1989 of sildenafil, a highly selective inhibitor of phosphodiesterase-5 (PDE-5), was the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Initial clinical studies on sildenafil in the early 1990s were not promising with respect to its antianginal potential. However, the incidental discovery of its antiimpotence effect led to its approval of for the treatment of erectile dysfunction. Thereafter, several reports of adverse cardiac events in patients on sildenafil raised concerns about its safety in cardiovascular disorders. Novel therapeutic indications are emerging for sildenafil with the recent discovery that PDE-5 is expressed in various other tissues such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, platelets, and visceral and tracheobronchial muscles. In this review we briefly summarize the pharmacology of sildenafil and the current available evidence on its potential therapeutic applications in cardiovascular disorders.


   Introduction
Top
 Abstract
 Introduction
Phosphodiesterase-5 and...
 Cardiovascular Effects of...
 Emerging Therapeutic Indications
 References
 
Sildenafil belongs to a class of compounds called phosphodiesterase (PDE) inhibitors. PDEs comprise a diverse family of enzymes that hydrolyze the cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) and therefore have a critical role in the modulation of second-messenger signaling pathways [1]. Initial reports of myocardial infarction and sudden death in men with erectile dysfunction who had taken sildenafil (sometimes in conjunction with nitrates) raised concerns that sildenafil may increase the risk of cardiovascular events in men with erectile dysfunction and vascular disease [2].

A significant body of evidence now indicates that sildenafil generally has a good safety profile in men with erectile dysfunction and cardiovascular disease [3]. Sildenafil therapy does not appear to be associated with ischemic events either at the time of introduction of therapy or during longer-term use [2]. Rates of discontinuation from sildenafil therapy that are due to adverse events are similar to placebo in men with cardiovascular disease [2]. Sildenafil does not interact in a potentially hazardous way with antihypertensive or antianginal therapy, with the exception of nitrates [2]. This information has prompted researchers to prescribe sildenafil for cardiovascular disorders.


   Phosphodiesterase-5 and Mechanism of Action of Sildenafil
Top
 Abstract
 Introduction
 Phosphodiesterase-5 and...
Cardiovascular Effects of...
 Emerging Therapeutic Indications
 References
 
Several families of PDEs, the enzymes that catalyze hydrolysis of the cyclic nucleoside monophosphates 3'5'-cAMP and 3'5'-cGMP, have been identified and characterized in recent years [1]. In addition, at least 11 isoforms of PDE have been discovered (Table 1), and the differential distribution of PDE isoforms in various tissues, as well as the selectivity of pharmacologic agents, is the basis for potential tissue-specific effects of PDE inhibitors [4]. Apart from corpus cavernosum, PDE-5 is expressed in various other tissues, such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, visceral and tracheobronchial muscles, brain, retina, and platelets [1, 4–7].


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  		Table 1. Isoforms of Human Cyclic Phosphodiesterase

 
Sildenafil is a potent and selective inhibitor of cGMP-specific PDE-5 [4]. This isozyme metabolizes cGMP, which is the second messenger of nitric oxide (NO) and a principal mediator of smooth muscle relaxation and vasodilatation. By inhibiting the hydrolytic breakdown of cGMP, sildenafil prolongs the action of cGMP. This results in augmented smooth muscle relaxation [4].

Sildenafil is highly selective for the cGMP-hydrolyzing isoform PDE-5, with a half-maximal inhibition (IC50) of PDE-5 activity at a concentration of 3.5 nmol/L, followed by IC50 values of 34 to 38 nmol/L for PDE-6 (cGMP-hydrolyzing PDE in the retina) and 280 nmol/L for PDE-1 (cAMP- and cGMP-hydrolyzing PDE isoform) [4, 5, 7]. The cAMP-hydrolyzing PDE-3 and PDE-4, and the cAMP- and cGMP-hydrolyzing isoform PDE-2, as well as PDE-7 to PDE-11, are inhibited by sildenafil with an IC50 of more than 2600 nmol/L [4].


   Cardiovascular Effects of Sildenafil
Top
 Abstract
 Introduction
 Phosphodiesterase-5 and...
 Cardiovascular Effects of...
Emerging Therapeutic Indications
 References
 
Sildenafil has a variety of cardiovascular effects, which are summarized in Table 2.


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  		Table 2. Cardiovascular Effects of Sildenafil

 
Effects on Cardiac Contractility
Unlike cAMP-specific PDE-3 inhibitors (milrinone, vesnarinone, and enoximone) that increase long-term mortality in patients with heart failure [19, 20], sildenafil is highly selective (> 4000-fold) for human PDE-5 over human PDE-3 and has not been found to elevate cAMP [21]. The cardiotoxic effects of PDE-3 inhibitors are thought to be related to increases in intracellular cAMP in the myocardium [1, 20, 22].

In a study published in 2003, Corbin and colleagues demonstrated that sildenafil does not have any direct inotropic effect on segments from dog or human heart [8]. These findings agree with other animal and clinical studies. For example, in anesthetized dogs, no changes in cardiac output were found at therapeutically relevant sildenafil concentrations [23]; similarly, in patients with severe coronary artery disease [9] or stable ischemic heart disease [24], no or small decreases in cardiac output were observed after oral (100 mg) or intravenous (40 mg) sildenafil administration, respectively.

Similar to the findings of Senzaki and colleagues [6], Corbin and colleagues found PDE-5 activity in extracts from human heart. However, the absolute amounts were lower than in other tissues. This information, combined with the lack of inotropic effect of sildenafil in heart strips, prompted the Corbin group to suggest that most of the PDE-5 activity was derived from coronary vascular smooth muscle cells within the preparation. The authors indicated that this was to be expected, as the atrial tissue used in this study consisted of multiple cell types, including cardiac myocytes, connective tissue, and smooth muscle cells.

Other studies that have detected only low intracellular concentrations of PDE-5 in human heart support this conclusion. For example, Parums and colleagues [25], using a polyclonal antibody against PDE-5 and immunohistochemistry, did not detect PDE-5 in human cardiac myocytes. In contrast, reports of PDE-5 in cardiac myocytes from other species suggest contamination of homogenized tissue with vascular smooth muscle cells or, for immunohistochemical studies, the use of nonspecific antibodies and the occurrence of false-positive signals resulting from epifluorescence [8].

Stief and colleagues [26] have suggested that cross-talk may be occurring between cGMP- and cAMP-dependent signal transduction pathways in human cavernous and cardiac muscle, but the Corbin group's data [8] in cardiac tissue do not support this claim. According to them [8], there is currently no evidence for intercompartmentalization that would allow the type of PDE cross-talk suggested by Stief and colleagues [26].

Considering the available evidence, it can be said that the effect of sildenafil on cardiac contractility has yet to be fully elucidated.

Effects on Blood Pressure and Heart Rate
A number of studies in healthy volunteers (18 to 81 years) have examined the effect of sildenafil on blood pressure and heart rate. Both intravenous dose escalation (20, 40, and 80 mg) and oral dose escalation studies (1.25 to 800 mg) have been performed [9, 10]. A dose–response relationship is not evident from these studies [10]. The mean maximum reduction in supine blood pressure is 8/6 mm Hg, occurring 1 to 2 hours after oral dosing, and not different from placebo after 8 hours. The maximum blood pressure response after oral dosing was achieved with 50 mg, with little additional effect evident at higher doses in healthy volunteers. The effects on heart rate were not consistent. This blood pressure-lowering effect is not associated with clinically significant adverse events [9].

These small, transient decreases in blood pressure were confirmed in other oral administration studies, including trials that enrolled elderly subjects, and were not dose related within the dose range studied. In all studies, there were no consistent orthostatic effects and no significant differences in the blood pressure response between the young and elderly. Healthy volunteers (19 to 30 years) were given intravenous infusions of sildenafil (40 and 80 mg) that exceeded 40 minutes, which resulted in plasma levels similar to those achieved after a 200-mg oral dose. This resulted in both mean supine systolic and diastolic blood pressures that were statistically significantly reduced compared with placebo at the end of the infusion period (difference between the means ± 10 mm Hg systolic/7 mm Hg diastolic). No effect on heart rate was observed [9].

In attempting to explain the lack of a dose response on blood pressure in healthy volunteers, it is useful to consider the degree of PDE-5 inhibition. In vitro isolated enzyme data can be used to estimate the percentage of inhibition in humans by making a number of assumptions when the data is extrapolated, one of which is that the inhibition of the enzyme is sigmoid with respect to inhibitor concentration. The estimated degree of PDE-5 inhibition in humans after oral dosing would be as follows: 25 mg ({approx}11 nmol/L free drug) would give approximately 76% inhibition; 50 mg ({approx}22 nmol/L free drug) approximately 86% inhibition; and 100 mg ({approx}47 nmol/L free drug) approximately 93% inhibition [10]. At a dose of 50 mg, PDE-5 is already significantly inhibited and, as far as a clinically measurable effect on blood pressure is concerned, further increments in dose are unlikely to have any additional effect.

Sildenafil's blood pressure-lowering effect is modest and therefore unlikely to trigger a reflex heart rate response [27]. Indeed, a mild sympathetic response directly to the vasculature may be responsible for the maintenance of blood pressure without triggering a reflex tachycardia [28]. However, with pharmacologic drives resulting in a greater reduction of blood pressure, as seen with the nitrate interaction studies, a small reflex response in heart rate occurs in order to maintain blood pressure [10].

A paucity of data is available on the blood pressure-lowering effects of sildenafil in hypertensive subjects. An independent study has been performed in 8 hypertensive subjects (57 to 76 years) on background antihypertensive therapy enrolled in a placebo-controlled, crossover study with sildenafil (50 mg) [29]. Subjects were evaluated at baseline and every 15 minutes after ingestion of the study drug. Blood pressure and heart rate were measured, and arterial pulse wave analysis was performed. The maximum reductions from baseline in systolic (24 ± 10 vs 6 ± 8; p < 0.05) and diastolic pressure (8 ± 5 vs 3 ± 2, p < 0.05) occurred after treatment with sildenafil and placebo, respectively. At 1-hour post dose, blood pressure was lower after treatment with sildenafil (systolic blood pressure, 135 ± 18 vs 144 ± 14, p < 0.05; diastolic blood pressure, 81 ± 7.8 vs 88 ± 6, p= NS). The greatest reductions were seen in those with the highest baseline blood pressure. Heart rate did not change significantly.

Of interest is that it has been shown that sildenafil is well tolerated in combination with a wide range of antihypertensive drugs (with the exclusion of NO donors), such as calcium-channel blockers, ß-blockers, angiotensin-converting enzyme (ACE) inhibitors, or ß1-antagonists [30].

Effects on Central Hemodynamics and Peripheral Vasculature
In healthy volunteers, no significant changes in cardiac index were evident up to 12 hours after the dose for oral sildenafil (100 to 200 mg) or intravenous sildenafil (20 to 80 mg) [21]. Significant decreases in the systemic vascular resistance index were reported at the end of intravenous sildenafil infusion (20 to 80 mg), when plasma concentrations were highest [21]. Sildenafil has both arteriodilator and venodilator effects on the peripheral vasculature [21]. In 8 patients with stable angina, intravenous sildenafil reduced systemic and pulmonary arterial pressures and cardiac output by 8%, 25%, and 7%, respectively, consistent with its mixed arterial (systemic and pulmonary hypotension) and venous (drop in stroke volume secondary to decreased preload) vasodilator effects [9].

In conclusion, consistent with the anticipated effects resulting from an increase in cGMP levels in vascular smooth muscle, sildenafil possesses vasodilatory properties that result in mild, generally clinically insignificant decreases in blood pressure when taken alone.

Effects on the Sympathetic Nervous System
Sildenafil induces heightened levels of sympathetic activity, both at rest and during physical, mental, and metabolic stress, as measured by intraneural recordings of muscle sympathetic nerve activity and by plasma catecholamine levels [28]. It is conceivable that sildenafil may have direct central effects on sympathetic outflow. This potential mechanism is supported, in part, by evidence that sildenafil crosses the blood–brain barrier and that PDE-5 is present in the brain [1, 31].

Effects on Pulmonary Circulation
In human pulmonary circulation, the isoforms 1, 3, 4, and 5 of PDE seem to be involved in regulating pulmonary resistance [32, 33]. Thus, the blood pressure-lowering effects of sildenafil in the pulmonary circulation are of special interest. Sildenafil markedly reduces the rise in pulmonary arterial pressure in response to breathing 11% inspiratory oxygen in healthy volunteers [34]. Inhalation of nebulized sildenafil reduces pulmonary artery pressures significantly and has a synergistic effect with inhalation of NO [35]. Effect of sildenafil on pulmonary right-to-left shunt volume in pulmonary hypertension is controversial. The study by Ichinose and colleagues suggests that it does not increase after sildenafil [35]. On the other hand, Kleinsasser and colleagues describe an increase in right-to-left shunt volume and subsequently, a decrease of systemic arterial oxygen tension after sildenafil along with reduced pulmonary arterial pressure [36].

Effects on the Coronary Vasculature
The effects of sildenafil on the coronary vasculature have attracted significant interest. Sildenafil has been shown to selectively increase cGMP levels in the vascular smooth muscle of isolated canine coronary arteries. Sildenafil concentrations of 10 to 100 nmol/L demonstrated a dose response in increased levels of cGMP. However, sildenafil concentrations of more than 100 nmol/L did not further increase cCMP. It is important to note that tissue cAMP levels were not affected by sildenafil at any concentration [10].

Studies that used dog models have demonstrated a sildenafil-induced increase in coronary blood flow in normal coronary arteries at rest [37–39] and during exercise [37]. Traverse and colleagues studied the effects of sildenafil on coronary blood flow at rest and during exercise in chronically instrumented dogs and found that sildenafil caused a small increase in coronary blood flow at rest and during exercise in the normal heart [37]. This suggests a modest vasodilator activity in the coronary resistance vessels.

Myocardial hypoperfusion, induced by exercise in the presence of a left anterior descending coronary artery stenosis, was improved by a significant increase in coronary flow in the presence of sildenafil. This was achieved at the same distal coronary pressure before and after treatment with sildenafil, supporting an effect on the coronary microvasculature. It was concluded from this dog model that sildenafil caused the coronary resistance vessels to dilate, resulting in an increase in blood flow to the ischemic myocardium during exercise.

Another study assessed the effects of sildenafil on coronary perfusion in two canine models. One model was of stable hypoperfusion induced by a mechanical stenosis (mimicking hibernating myocardium), while the other was of unstable angina mediated through a damaged and stenotic coronary artery. There was no evidence that sildenafil exacerbated ischemia in either model [40].

Coronary blood flow was unchanged after treatment with sildenafil in a coronary artery with an artificially created critical stenosis that was not flow limiting and did not induce myocardial ischemia at rest despite an increase in flow in the normal coronary artery [39]. Similarly, in a model of hibernating myocardium induced by stable hypoperfusion, sildenafil did not affect coronary flow [40]. Furthermore, sildenafil increased coronary blood flow during exercise in a coronary artery with a mechanically induced critical stenosis, resulting in an improvement in the subendocardial/epicardial flow ratio and ameliorating the effects of myocardial ischemia noted under control conditions [37]. The increase in blood flow to the ischemic myocardium was transmurally uniform.

This is different than the effect seen after treatment with nitrates, in which the increase in blood flow is preferentially to the subendocardium. Traverse and colleagues suggest that PDE-5 activity may not be significantly involved in cGMP degradation in the penetrating coronary arteries [37], thus explaining this difference in flow distribution between nitrates and sildenafil.

Two studies to date report on the effect of sildenafil on coronary flow in humans [24, 41]. Dietz and colleagues have shown that in diabetic patients with erectile dysfunction, sildenafil did not alter coronary flow reserve [41]. In another study Herrmann and colleges noted that coronary blood flow was unchanged; however, the coronary flow reserve was significantly increased in both stenosed and reference arteries 45 minutes after treatment with oral sildenafil (100 mg) compared with baseline [24]. Taken together with the preclinical (canine) data, this would suggest that sildenafil is unlikely to cause coronary steal. Extending these findings into the patient population, Patrizi and colleagues reported that the acute administration of sildenafil (50 mg) did not reverse the beneficial effect of atenolol therapy on exercise-induced ischemia in 14 patients with chronic stable angina [42].

Effects on Cardiopulmonary Responses During Stress
In a 2003 study, Stanopoulos and colleagues evaluated the effects of sildenafil on cardiopulmonary responses during exercise in a group of impotent patients [43] in which 41 patients with erectile dysfunction (mean age ± SD; 52.3 ± 8.6 years) underwent a cardiopulmonary exercise test before and after the administration of sildenafil citrate (100 mg). Cardiopulmonary exercise test measurements at rest, at the anaerobic threshold, at peak exercise, and at 1-minute recovery were recorded, including systolic and diastolic blood pressure, the heart rate, oxygen (O2) consumption, carbon dioxide (CO2) production, ventilation, and the respiratory rate. Also calculated were O2 consumption per kg of body weight, the ventilatory equivalent for O2 consumption (ventilation/O2 consumption) and CO2 production (ventilation/CO2 production), the respiratory quotient, metabolic equivalents, oxygen pulse (O2 consumption/heart rate), and the change in O2 consumption/change in heart rate.

The results of the study revealed a statistically significant decrease in systolic and diastolic blood pressure after sildenafil use at all stages tested (p < 0.002 to 0.001). The heart rate mildly increased after sildenafil use at rest and at peak exercise (p = 0.018). The O2 pulse decreased at the anaerobic threshold (p = 0.003), peak exercise (p = 0.001), and recovery (p = 0.047). Results in the various patient groups were:

Based on their findings, the authors concluded that hemodynamic changes after sildenafil administration should be considered minimal in concert with patient health status. Younger patients without signs of systemic arteriosclerosis compensate the vasodilatory effect of sildenafil during exercise, while in older patients with vasculogenic erectile dysfunction, moderate changes may be noted regardless of cardiovascular disease in the medical history.

Effects on Platelets
Initial data suggested that sildenafil has no direct effects on platelet function but modestly potentiates the inhibitory effect of the NO-donor sodium nitroprusside on adenosine diphosphate-induced platelet aggregation ex vivo, consistent with the requirement for an NO drive for sildenafil to produce its pharmacologic effects [21]. Despite this, no adverse bleeding episodes have been reported with the use of sildenafil [21]. However, because the effects of sildenafil have not been evaluated in patients with bleeding disorders or in patients taking nonaspirin antiplatelet agents (e.g., ticlopidine, clopidogrel, or dipyridamole), caution should be exercised when the drug is administered in these clinical settings [44].

Of interest is a 2003 study by Li and colleagues suggesting that sildenafil, a cGMP-enhancing agent, promoted von Willebrand factor or thrombin-induced platelet aggregation [45]. The cGMP-stimulated platelet responses are biphasic, consisting of an initial transient stimulatory response that promotes platelet aggregation and a subsequent inhibitory response that limits the size of thrombi. According to the authors, the results of this study provide a possible mechanism for sildenafil-related cardiac deaths.


   Emerging Therapeutic Indications
Top
 Abstract
 Introduction
 Phosphodiesterase-5 and...
 Cardiovascular Effects of...
 Emerging Therapeutic Indications
References
 
As more and more information becomes available on the physiologic function and interaction of the different PDE isoforms and their tissue distribution, novel therapeutic indications of sildenafil are emerging. This section reviews available evidence on the potential use of sildenafil for treating cardiovascular disorders.

Sildenafil as a Pulmonary Vasodilator
Pulmonary hypertension is a serious, often fatal condition. The clinical hallmarks are progressive breathlessness, exertion limitation, and frequently, an inexorable decline to right ventricular failure and death. Since its initial description more than 100 years ago, pulmonary hypertension has remained a difficult and frustrating condition to diagnose and manage for patients and physicians alike. However, based on bedside clinical observation, clinical trials, and basic biologic research, we are in a time of great enthusiasm and optimism on both scientific and therapeutic fronts [46].

Pulmonary arterial hypertension is characterized by a progressive increase in pulmonary arterial pressure (mean pressure > 25 mm Hg at rest or 30 mm Hg during exercise) in association with variable degrees of pulmonary vascular remodeling, vasoconstriction, and in situ thrombosis [47]. No underlying cause can be found for some pulmonary hypertension, and secondary forms of pulmonary hypertension are related to collagen vascular disease, congenital systemic-to-pulmonary shunts, human immunodeficiency virus (HIV) infection, portopulmonary hypertension, and drugs [48]. Evidence is emerging that sildenafil is an effective agent for treating pulmonary arterial hypertension (Table 3).


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  		Table 3. Clinical Studies on the Use of Sildenafil in Pulmonary Hypertension

 
In children with congenital heart disease, increased pulmonary vascular resistance in many forms of pulmonary hypertension is associated with pulmonary endothelial dysfunction. Pulmonary endothelial dysfunction is defined as failure of the pulmonary endothelium to produce adequate amounts of endogenous NO [49], and this is amplified by cardiopulmonary bypass surgery in the postoperative child [50]. Inhaled NO has become an important therapeutic modality in these patients.

Inhaled NO has some disadvantages, however. Some patients fail to respond to NO inhalation [51]. Alternatively, responders to long-term NO therapy may develop severe, life-threatening, rebound pulmonary hypertension on withdrawal of NO [52]. Sildenafil has been shown to be equal or superior to a usual therapeutic dose of inhaled NO in reducing the elevated pulmonary vascular resistance in children with congenital heart disease, both during routine cardiac catheterization and after open-heart surgery [53, 54].

A study that investigated the effect of oral sildenafil in patients with severe primary or secondary pulmonary hypertension who were evaluated for potential heart–lung transplantation reported a reduction of pulmonary vascular resistance that was similar in extent to that observed after inhaled NO [55]. In addition, sildenafil slightly increased the cardiac index and decreased pulmonary capillary wedge pressures. The combination of inhaled NO and sildenafil seemed to be effective in a synergistic manner [55, 56].

Another recent study reported additive effects of inhaled iloprost with 25 mg oral sildenafil in lowering pulmonary artery pressure, without major adverse events, in a series of patients with primary pulmonary hypertension [57]. A comparison of inhaled NO in combination with either intravenous epoprostenol or with oral sildenafil in patients with pulmonary hypertension that was due to fibrotic lung disease revealed a marked reduction of pulmonary arterial pressure by both treatments; however, a decreased ratio of pulmonary-to-systemic vascular resistance was only measured in patients who received NO and sildenafil [58]. Of importance is that the ventilation/perfusion mismatch—and subsequently the right-to-left shunt—deteriorated with epoprostenol and NO, but the ventilation–perfusion mismatch was unaltered with a sildenafil and NO combination, which was accompanied by an even slight reduction of right-to-left shunting [58]. In patients with congestive heart failure and erectile dysfunction, a recently published double-blind, placebo-controlled study showed that sildenafil was not only well tolerated and effective for erectile dysfunction but it also improved exercise capacity [59].

In addition to the classic primary pulmonary hypertension and pulmonary hypertension that results from cardiac disease, some benefit might also exist in pulmonary hypertension of relatively rare etiology [34, 60–71], or postoperative pulmonary hypertension, and difficult weaning problems in mechanical respiration [72–75]. The weaning of inhaled NO, which is often followed by a rebound phenomenon, might especially be an indication for sildenafil [73, 75].

We still await the results of the first 3-month international multicenter, randomized, double-blind, placebo-controlled study on sildenafil in pulmonary hypertension (expected results, March 2004) [76]. We do not yet know if 3 months of sildenafil is effective, and we have no information on long-term effects, survival, and safety. Finally, specific issues, such as tolerance (requiring dose increase with long-term exposure) and rebound effects after withdrawal of the drug remain also to be properly evaluated. Despite these words of caution, sildenafil is conceptually attractive for the treatment of pulmonary hypertension, and this novel strategy provides tremendous hope for patients who suffer from this devastating disease [46].

Sildenafil for Endothelial Dysfunction
Another potential indication of sildenafil that might have some clinical impact is related to endothelial dysfunction. The vascular endothelium continues to attract particular interest in relation to cardiovascular disease and its regulation of vascular homeostasis [10]. Endothelial dysfunction is an abnormal endothelial response that leads to a reduction in the bioavailability of NO and impaired vasodilatation, and that plays a major role in the development of arteriosclerosis and acute coronary syndromes [77, 78]. The reduced bioavailable NO may also affect platelet aggregation, vascular wall inflammation, and smooth muscle cell proliferation.

Endothelial dysfunction is associated with many of the risk factors for cardiovascular disease, such as dyslipidemia, hypertension, heart failure, diabetes mellitus, and smoking. Some of the drugs shown to have a benefit on morbidity and mortality in cardiovascular conditions, such as the ACE inhibitors in heart failure and both 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and ACE inhibitors in ischemic heart disease, have additionally been shown to improve endothelial function [10]. Furthermore, evidence is becoming available to suggest that measures of endothelial dysfunction might have value as prognostic factors for cardiovascular event rates [79, 80]. However, whether an improvement in endothelial function contributes to beneficial effects on morbidity and mortality remains to be demonstrated.

There are data to suggest that sildenafil might be of use in reversing endothelial dysfunction. Sildenafil has been demonstrated to improve the vasomotor aspect of endothelial dysfunction in patients with heart failure [81] and patients with type 2 diabetes mellitus [82]. Whether this might reflect an improvement in some of the other abnormal features of endothelial dysfunction, such as platelet aggregation, increased smooth muscle proliferation, and leukocyte adhesion, is unknown. Furthermore, exercise tolerance and the functional class of heart failure has been shown to correlate with the severity of endothelial dysfunction [83]. It is reasonable to speculate that improving endothelial dysfunction might have a beneficial effect on exercise tolerance in patients with heart failure. It has been demonstrated that acute dosing with sildenafil in patients with heart failure was well tolerated and significantly improved exercise capacity as well as erectile dysfunction [59]. Further work in this area is justified.

Dishy and colleagues presented data describing the effect of sildenafil on the NO-mediated vascular response in healthy subjects [16]. The effects of sildenafil (50 mg), isosorbide dinitrate (5 mg), and placebo on flow-mediated dilatation of the brachial artery were studied. Treatment with isosorbide dinitrate increased brachial artery diameter and flow-mediated dilatation significantly. Treatment with sildenafil did not significantly affect baseline brachial artery diameter or flow-mediated dilatation. It was concluded that sildenafil does not potentiate endogenous NO-mediated vascular responses in the forearm conduit or resistance vessels in healthy volunteers.

However, Halcox and colleagues studied the effects of sildenafil on unobstructed coronary arteries in 25 subjects with or without arteriosclerosis [15]. Coronary artery endothelial function was assessed by using infusions of 15 mg/min of intracoronary acetylcholine (endothelium dependent) and 300 mg/min of verapamil (endothelium independent) before and 45 minutes after treatment with oral sildenafil (100 mg). Reductions occurred in pulmonary artery pressure, pulmonary artery wedge pressure, and mean arterial pressure after treatment with sildenafil (–2.3 ± 0.6, –1.8 ± 0.5 and –2.6 ± 1.5 mm Hg, respectively). Heart rate, cardiac output, and systemic and pulmonary vascular resistances were unchanged after treatment with sildenafil. The segments of coronary artery that demonstrated a vasoconstrictor response to acetylcholine (endothelial dysfunction) at BASELINE improved after treatment with sildenafil (–12 ± 3 vs –7% ± 3%; p < 0.005). The vasodilator response in the normal segments was unchanged (+10 ± 1 vs + 9% ± 2%). These findings suggest that sildenafil dilates epicardial coronary arteries and improves endothelial dysfunction in the coronary circulation of patients with arteriosclerosis.

An effect of sildenafil on endothelial function as measured by forearm flow-mediated vasodilatation was confirmed by Katz and colleagues in 48 patients with chronic heart failure (CHF) [81]. Single doses of sildenafil (12.5, 25, or 50 mg) or placebo were studied. At 1 hour after administration of the study drug, the change in flow-mediated vasodilatation after 5 minutes of arterial occlusion in patients who received 25 and 50 mg was significantly more improved than in those who received placebo (4% ± 1.8%, 3.9% ± 1.3%, and 0.6% ± 0.8%, respectively; p < 0.05). The conclusion was that sildenafil improves endothelium-dependent flow-mediated vasodilatation in patients with endothelial dysfunction that is due to CHF.

In summary, it appears that sildenafil improves the vasomotor aspect of endothelial dysfunction in diabetes mellitus and heart failure. These findings warrant further studies to determine whether sildenafil might be beneficial in certain subgroups of patients with endothelial dysfunction. One such subgroup includes patients with vasospastic angina or diffuse coronary microvessel disease, both conditions that have been shown to be accompanied by significant endothelial dysfunction [84].

Sildenafil for Chronic Heart Failure and Myocardial Ischemia
Piccirillo and colleagues performed a study to investigate the effect of sildenafil on cardiac repolarization and sinus autonomic and vascular control in men with mild CHF (New York Heart Association class II) [17]. They hypothesized that changes in these variables could predispose patients to malignant ventricular arrhythmias. They measured QT dispersion, the QT-RR slope, and the index of QT variability (QTVI) and analyzed spectral power of RR and systolic blood pressure variability in 10 men with dilated cardiomyopathy and in 10 control subjects after the administration of a single 50-mg oral dose of sildenafil citrate or placebo at rest (not followed with any attempt at intercourse).

The results of their study demonstrated that, in both groups, oral sildenafil citrate decreased the systolic blood pressure (p < 0.05) and increased the heart rate (p < 0.05). In subjects with CHF, it also increased the QT-RR (p < 0.001) and QTVI (from –0.45 ± 0.07 to –0.27 ± 0.07; p < 0.001), but in controls, it increased the QTVI (from –1.20 ± 0.08 to –0.78 ± 0.014; p < 0.001). In these subjects and controls, oral sildenafil citrate induced a significant reduction in high frequency, expressed in absolute power (subjects with CHF: from 4.04 ± 0.14 to 3.43 ± 0.16 natural logarithm ms2; p < 0.001; controls: from 5.61 ± 0.44 to 4.98 ± 0.32 natural logarithm ms2; p < 0.05) and in normalized units (p < 0.05). In subjects with CHF (but not in controls) it also significantly increased the ratio of low frequency to high frequency (from 1.3 ± 0.12 to 1.89 ± 0.16; p < 0.001) and low frequency expressed in normalized units (p < 0.05). Sildenafil citrate caused no significant changes in the QT interval or dispersion.

These findings led the authors to conclude that in men with CHF, sildenafil citrate reduces vagal modulation and increases sympathetic modulation, probably through its reflex vasodilatory action. The autonomic system changes induced with sildenafil citrate could alter QT dynamics. Both changes could favor the onset of lethal ventricular arrhythmias. Hence, extreme caution must be exercised while prescribing sildenafil in patients with CHF, as these patients are already in a state of "sympathetic overdrive."

In another study, a single oral 50-mg dose of sildenafil citrate was administered to 26 patients who were suffering from chronic Chagas disease and diabetic cardioneuromyopathies, or hypertensive or hypertrophic cardiomyopathies, or both, with or without chronic congestive heart failure [18]. Sildenafil improved the electrocardiogram findings in some patients. It significantly reduced systolic and diastolic arterial blood pressure, and the effect was more pronounced in those with a basal high level. It also significantly improved left ventricular systolic function in those patients with basal reduced function, and significantly modified to the normal pattern the E/A basal altered ratio in those patients with the inverted pattern as well as in those with the restrictive pattern of mitral diastolic influx to the left ventricle during the echo-duplex interrogation (p 0 < 0.0001). Evaluation of right ventricular diastolic function revealed that sildenafil significantly modified to the normal pattern the E/A basal altered ratio in those patients with the inverted pattern as well as in those with the restrictive pattern of tricuspid diastolic influx to the right ventricle during the echo-duplex interrogation (p < 0.0001).

The author concluded that based on these findings, it is feasible to propose the use of sildenafil citrate to treat patients with cardiovascular diseases, with exclusion of severe obstructive coronary artery disease, hypertrophic subaortic stenosis, and patients with funduscopic alterations that may be affected by a significant and acute increase of flow within the ophthalmic arteries. The right ventricular diastolic changes observed with sildenafil may be useful in patients with abnormal right ventricular compliance such as pulmonary stenosis or hypertension.

Of interest is a 2002 study that reported a pronounced infarct size-reducing effect of 0.7 mg/kg sildenafil in an in vivo rabbit model of coronary occlusion [85]. In their study, as this effect could be blocked by 5-hydroxydecanoate, an inhibitor of mitochondrial adenosine triphosphate-sensitive potassium channels, the authors suggest that cardioprotection by sildenafil occurs by activation of these potassium channels, mimicking ischemic preconditioning. Despite its potential benefit in reducing infarct size, it is extremely important to remember that simultaneous intake of sildenafil and nitrates by patients with ischemic heart disease can result in life-threatening hypotension.

Adverse Effects
Most of the studies and anectodal reports of sildenafil use in humans for novel cardiovascular indications either report none or a very low incidence of minor adverse side effects. However, sildenafil can potentially cause serious adverse effects that reflect its pharmacologic activity of PDE-5 inhibition in various tissues and can be broadly classified into four major adverse reactions:

1. Vasodilatory effects that result in headache (16%), flushing (10%), and rhinitis (4%) (the latter presumably as a result of hyperemia of nasal mucosa where PDE-5 is present). Dizziness (2%), hypotension ( < 2%), and postural hypotension ( < 2%) have been reported rarely and occur at a similar rate in sildenafil- and placebo-treated patients [21, 44].

2. Gastrointestinal effects that result in dyspepsia and burning sensation from reflux that is due to the relaxation of lower esophageal sphincter (7%) [8, 44]. Some cases of esophageal ulcers have been reported in patients on sildenafil, and interestingly, sildenafil seems to lower esophageal sphincter tone even in idiopathic achalasia [21, 86].

3. Visual abnormalities that result in blue-green color-tinged vision, increased perception of light, and blurred vision (3%), especially at higher doses [21]. Several case reports describe a temporal association between sildenafil use and nonarteritic anterior ischemic optic neuropathy, which requires further attention [87–90].

4. Musculoskeletal effects that result in myalgias, especially with multiple daily doses. No treatment-related changes in serum creatine kinase levels or electromyogram results have been observed, however [8, 44]. This effect has no obvious pharmacologic explanation.

A Word of Caution
Presently there are few data on effects of long-term sildenafil treatment for these new cardiovascular indications. The available evidence contributes to a building sense of excitement that sildenafil may be an effective treatment in cardiovascular disorders secondary to endothelial dysfunction, especially as sildenafil targets an endogenous deficiency of NO production or activity, a recognized pathobiologic outcome of endothelial dysfunction. However, the safety and dosage of sildenafil for these conditions has still not been established. Moreover, sildenafil therapy in most of the novel cardiovascular indications will require continuous exposure to possibly larger doses, suggesting that adverse effects may be more widespread, especially given that the PDEs are distributed in a variety of tissues.

Because so many novel therapies in the past have not lived up to their initial promise, we should protect our patients (and ourselves) and refrain from empirically administering sildenafil for these emerging indications at present. Several, rigorous, blinded, placebo-controlled, multicenter randomized clinical trials are required to confirm efficacy and establish the safety of long-term sildenafil for these new therapeutic indications.


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