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* From the Division of Cardiothoracic Surgery (Drs. Fung, Yim, and Arifi), Department of Surgery, Prince of Wales Hospital, Shatin, Hong Kong, China; Department of Physiology, Faculty of Medicine (Dr. Fiscus), The Chinese University of Hong Kong, Shatin, Hong Kong, China; and Bristol Heart Institute (Dr. Angelini), University of Bristol, Bristol, UK.
Correspondence to: Ahmed A. Arifi, MD, FRCS, Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China; e-mail: arifi64{at}surgery.cuhk.edu.hk
Abstract
Exaggerated vasospasm, platelet activation, and early graft occlusion are significant barriers to successful coronary artery bypass grafting (CABG). Interestingly, vascular smooth muscle and platelets are predominant sources of type-5 phosphodiesterase (PDE5) in the body, and this enzyme is specifically inhibited by PDE5 inhibitors (eg, sildenafil citrate). Together with endogenous nitric oxide, sildenafil can induce pulmonary and coronary vasodilation, precondition the myocardium, reduce platelet activation, and potentially reduce early graft occlusion. Currently, there are no published clinical trials investigating sildenafil in coronary surgery. Recent studies on the potential use of sildenafil strongly support its beneficial effects in a wide range of patients with cardiovascular diseases. Therefore, we sought to review the literature, explore the current hypothesis that the use of sildenafil in coronary surgery patients can be beneficial, and attempt to define its potential place in the setting of CABG.
Key Words: coronary artery bypass grafting • phosphodiesterase • sildenafil
Type-5 phosphodiesterase (PDE5) is an enzyme with a predominant presence in the corpus cavernosum, vascular smooth muscle, and platelets.12 PDE5 inhibitors in conjunction with endogenous nitric oxide (NO) can produce potent relaxation of corpus cavernosal smooth muscle,3 which explains their popularity in the treatment of erectile dysfunction. Sildenafil citrate, vardenafil, and tadalafil are chemical agents that specifically inhibit PDE5. Among them, sildenafil has been the most well studied.
Clinical trials456 have shown significant benefits of sildenafil in patients with pulmonary arterial hypertension. More recently, the endothelium-enhancing effects of sildenafil in preconditioning prior to ischemia/reperfusion in healthy human subjects has been demonstrated.7 Sildenafil has powerful effects in conduits that are useful in coronary artery bypass grafting (CABG), including the saphenous vein, and the coronary, mammary, and radial arteries.891011
CABG has now matured to a point where the all-cause hospital mortality rate in low-risk patients is generally < 1%.12 The highest risk period is that immediately after operation, and the incremental number of risk factors positively correlates with higher mortality rates.1314 The use of auxiliary pharmacologic agents intraoperatively and/or perioperatively may help to modify risks, particularly in an aging patient population with increasing operative risks. Although there are currently no published clinical studies or trials investigating PDE5 inhibitors in this regard, accumulating evidence strongly suggests that they may be potential candidates for these roles: the reduction of vasospasm of the bypass graft, improvement in myocardial perfusion and coronary blood flow, and reduction of untoward events associated with platelet activation during cardiac surgery.
Mechanisms of Vasodilation Related to PDE5
Phosphodiesterases (PDEs) are key enzymes that control cyclic nucleotide levels within cells; to date, at least 11 classes have been described in the literature.15 Type-3A PDE (PDE3A) and PDE5 are the predominant isozymes present in vascular smooth muscle that are important in the regulation of vessel tone by way of altering the intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), respectively.16
PDE3A, also known as cGMP-inhibited PDE, is responsible for hydrolyzing cAMP. The alternative descriptor of cGMP-inhibited PDE has been named as such because elevated levels of cGMP have been found to suppress PDE3A-mediated hydrolysis of cAMP, allowing cAMP to accumulate.16 In vascular smooth muscle, a heightened level of cAMP is associated with activation of protein kinase A, a reduction of intracellular calcium level, and subsequent mechanisms of vasorelaxation caused by a decrease in the formation of calcium-calmodulin myosin light chain kinase complex and altered phosphorylation of myosin light chain.17
PDE5 differs from PDE3A in that cGMP rather than cAMP is the specific substrate hydrolyzed.16 Sildenafil functions by specifically inhibiting PDE5, resulting in the enhanced accumulation of cGMP.1 Certain endogenous factors, such as NO and the natriuretic peptides (eg, atrial natriuretic peptide, brain/B-type natriuretic peptide [BNP] and C-type natriuretic peptide) that activate soluble and particulate guanylyl cyclases, respectively, cause vasodilations via the elevation of intracellular cGMP levels, which activates protein kinase G (PKG), leading to the phosphorylation of various intracellular proteins that lower intracellular calcium levels in vascular smooth-muscle cells.1819 Key substrates known to be phosphorylated by PKG include ion channels (eg, Ca2+-dependent K+ channels), phospholamban (regulating Ca2+-ATPase of the endoplasmic reticulum), and the 1,4,5-inositol trisphosphate receptor and its associated protein IRAG in the endoplasmic reticulum.20 Activation of the cGMP/PKG signaling pathway by NO also inhibits cell cycle progression in cultured vascular smooth-muscle cells.21 Thus, the abnormal proliferation of smooth-muscle cells associated with atherosclerosis or the restenosis following vascular surgery would be inhibited, at least in part, by endogenous NO and the activation of the cGMP/PKG pathway.
We have shown that the cAMP-elevating and vasorelaxant effects of adrenomedullin are synergistically enhanced by the natriuretic peptide BNP via a mechanism involving cGMP-mediated inhibition of PDE3A and subsequent enhanced accumulation of cAMP in vascular smooth-muscle cells.22 With inhibition of PDE5, the major source of cGMP degradation in vascular smooth-muscle cells, all of the above-mentioned effects of NO and natriuretic peptides, including the direct vasodilatory effects, the antiproliferative effects, and the synergism with agents that stimulate cAMP biosynthesis (eg, adrenomedullin), are expected to be enhanced. Clinically, in patients with erectile dysfunction and ischemic heart disease, the co-administration of nitrates and sildenafil can produce profound vasodilation and adverse outcome in some patients, potentially leading to severe hypotension and even death. The adverse synergistic hypotensive response induced by nitrates and the PDE5 inhibitors is a combination of exaggerated enhancement of the cGMP-mediated activation of PKG and inhibition of PDE3A consequent to the heightened cGMP elevations in vascular smooth-muscle cells of small resistance-size arteries and arterioles.
Our current knowledge in the use of sildenafil in the cardiovascular surgical setting is limited. Interestingly, a study23 found that oral sildenafil, 0.83 mg/kg, effectively reduced vasospasm in patients 7 days after subarachnoid hemorrhage. As vasospasm can be a vexing problem in the short and long term for CABG as well as for peripheral vascular surgery, especially with arterial grafts,24 the use of PDE5 inhibitors in preventing spasm of grafts by pretreatment of the harvested conduits prior to anastomosis, or by intra/perioperative administration, may be avenues for investigation.
Effects of PDE5 Inhibitors on Platelet Function
Thrombosis and vascular inflammation are an integral response that is perpetuated by activated platelets.2526 The initial adhesion events that precede platelet activation are complex, but worthwhile mentioning is the dynamic interplay between platelets, the endothelium, and subendothelium involving molecules that include the following: P-selectin, for platelet rolling on the endothelium2728; platelet glycoprotein (GP) Ib-IX-V complex and integrins, for stabilization of adhesion to subendothelial von Willebrand factor and fibronectin/collagen/laminin, respectively2930; and GP IIb-IIIa (fibrinogen receptor; a ß3 integrin), for formation of fibrinogen bridges.31 Platelet activation encompasses a series of events following adhesion that include changes in platelets their surface expression of receptors, cytoskeletal organization, and biochemical and metabolic kinetics.32 The adenosine diphosphate (ADP) [P2Y12] receptor has been found to play a central role in this process in recent years.33 Activated platelets adhering to the vessel wall, if not countered by endothelial-derived antiaggregant factors such as NO and prostacyclin, eventually lead to induction of other adhesion molecules (eg, intracellular adhesion molecule-1), the release from platelets of a range of substances including potent vasoconstricting peptides (eg, serotonin), arachidonic acid derivatives (eg, thromboxane A2), cytokines (eg, interleukin-1ß), and other chemoattractants (eg, monocyte chemoattractant protein-1, RANTES [regulated upon activation, normal T-cell expressed and secreted]) that induce further adhesion of platelets, vasospasm, attract leukocytes, and promote vascular inflammation and subsequent remodeling.203435363738
The detailed mechanisms elicited by PDE5 inhibitors in platelets are still poorly understood. However, there is a large amount of data on the NO/cGMP and the cAMP pathways3940 that can help us to better understand the potential roles of PDE5 inhibitors. NO possesses powerful inhibitory effects on platelet aggregation that are attributable to its stimulatory activity on guanylyl cyclase leading to the formation of cGMP. It is widely accepted that the accumulation of cGMP and activation of PKG in platelets result in the inactivation of ADP, and thus dampening of platelet activation and further aggregation.394041 Sildenafil has been found to exert such inhibitory effects on ADP-dependent platelet aggregation via potentiation of an NO donor (S-nitroso-N-acetylpenicillamine) in humans.42 Moreover, nitrovasodilators have been described to synergistically inhibit platelet function induced by prostaglandin E1, a cAMP-elevating agent.43 This synergistic enhancement in the physiologic response is again mediated via cGMP inhibition of PDE3A, leading to cAMP accumulation. It seems that the preponderant expression of PDE3A and PDE5 in vascular smooth-muscle cells and platelets is also paralleled by the existence of the synergistic pathway of cGMP-inhibited cAMP elevation but with two entirely different physiologic responses.
In a canine model of mechanically and pharmacologically induced cyclic coronary artery thrombosis after thrombolysis, a specific PDE5 inhibitor zaprinast when co-administered with inhalational NO was found to halt further platelet-mediated coronary artery occlusion.44 Inhalational NO instead of systemic NO donors was chosen to deliver a somewhat more localized pharmacologic action to the cardiopulmonary circuit, obviating systemic hypotension. Although zaprinast alone did not prevent further coronary thrombosis after thrombolysis, it must be borne in mind that the coronary artery segment under study in vivo was constricted instrumentally (> 90% stenosis) and traumatized by external compression to produce thrombosis on thrombin addition. Thus, endothelial dysfunction is presumed to be prominent with little or no endogenous NO release. However, in CABG surgery, an entirely different set of conditions exists, and careful handling of the vascular graft, including the no-touch technique,45 should prevent de-endothelialization and allow endogenous NO and cGMP-elevating factors to be potentiated by PDE5 inhibition. It remains to be seen whether PDE5 inhibitors alone can produce antiaggregatory effects when examined under conditions of CABG, particularly in a manner that would have a bearing on surgical outcome.
Much of our current understanding of sildenafil administered to patients with coronary artery disease requiring intervention comes from a randomized, double-blind, placebo-controlled trial46 of 24 patients undergoing cardiac catheterization evaluation of chest pain. A single dose of oral sildenafil, 100 mg, was shown to dilate epicardial coronary arteries, improve endothelial function, and inhibit platelet activation. Platelet activation was detected to be reduced by flow cytometric analysis of the platelet surface antigens PAC-1 and CD62.
PDE5 Inhibitors in Ischemia/Reperfusion, Preconditioning, and Cardiac Remodeling
Early concerns about detrimental coronary flow changes induced by sildenafil have not been substantiated by experiments on various animal models of coronary artery stenosis/myocardial ischemia.474849 Furthermore, sildenafil has been demonstrated to reduce myocardial infarct size.50 In a study of patients with severe coronary artery disease (> 70% stenosis), Herrmann and colleagues51 found that coronary blood flow, flow reserve, and vascular resistance were not changed by an oral dose of sildenafil, 100 mg, as measured by intracoronary Doppler ultrasound. The authors of that study did not find a significant difference in the way sildenafil increased coronary flow reserve between stenosed and nonstenosed arteries in the presence of intracoronary adenosine. In another study46 of human patients with ischemic heart disease, sildenafil conferred moderate anti-ischemic effects by alleviating myocardial ischemia intermediate between isosorbide dinitrate and placebo, and that coronary endothelial function in the constricting segments (20 to 40% stenosis) was improved following administration of sildenafil.
The cardioprotective effects of sildenafil are attributed to activation of inducible NO synthase, protein kinase C, and mitochondrial adenosine triphosphate-sensitive potassium (KATP) channels.5253 KATP channels are key players in modulating coronary circulation and in myocardial (ischemic or pharmacologic) preconditioning,5455565758 and these channels can be activated in response to cGMP/PKG stimulation induced by NO or BNP.5960 Ischemic preconditioning is a phenomenon in which a tissue (myocardium) previously exposed to short periods of ischemia subsequently becomes more resistant and tolerant to the genuine insult.61 The ability to elicit preconditioning by a pharmacologic agent has previously been demonstrated by a limited number of drugs: certain KATP channel openers (eg, nicorandil, pinacidil, diazepoxide).575862
In a randomized, double-blind, placebo-controlled crossover study7 of healthy human subjects, a single dose of oral sildenafil, 50 mg, administered 2 h before pressure cuff-induced ischemia to the radial artery was shown to afford effects of preconditioning (ie, endothelium-dependent, flow-mediated dilatation) by acting via the opening of KATP channels. Those beneficial effects were found to be markedly blunted in the presence of glibenclamide, a KATP channel blocker. This has important implications for myocardial protection before and during cardiac surgery because postoperative cardiac recovery is often delayed due to myocardial ischemia, and in some instances of prolonged aortic cross-clamping or cardiopulmonary bypass with low oxygen tension, myocardial stunning,63 or even severe contracture leading to a condition known as "stone heart"64 can result. The prospect of PDE5 inhibitors as a new class of agents that can produce pharmacologic preconditioning is promising,5865 and should be investigated and exploited fully.
In cardiac remodeling, Takimoto and colleagues66 demonstrated the impact of chronically administered sildenafil on reversing myocardial hypertrophy in mice with pressure-loaded hearts induced artificially by transverse aortic constriction (aortic banding). The long-term effects of sildenafil mediated through stimulation of cGMP/PKG-166 and its down-regulation of intracellular calcium levels via L-type calcium channels, the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, other effector proteins, and downstream fetal gene transcription pathways67 are responsible for the reversal of cardiac hypertrophy and remodeling; tadalafil also has similar in vitro stimulatory activity on PKG-1.66 The findings are remarkable, and it remains to be seen whether these putative benefits can be reproduced in human patients.
Ventricular remodeling after myocardial infarction is a progressive process undertaken by the remaining viable myocardium that aims to attain a favorable geometry so as to maintain adequate cardiac output.6869 This compensatory process begins to fail particularly when the hyperfunctioning myocardium becomes ischemic.70 It is unknown whether PDE5 inhibitors could alleviate ischemic cardiomyopathy, and whether this type of eccentric remodeling, as opposed to the concentric remodeling associated with pressure overload induced by aortic banding discussed above, can be favorably modulated. It would also be important to study the effects of sildenafil in patients with ischemic mitral regurgitation, a group with invariably higher operative risk, postoperative morbidity, complications, and prolonged hospital stay.71 Put together, the uses of PDE5 inhibitors in myocardial protection in coronary surgery can be envisaged as follows: (1) preoperatively, to achieve pharmacologic preconditioning against ischemia caused by aortic cross-clamping and cardiopulmonary bypass under suboptimal oxygen tension; (2) intraoperatively, as a constituent of the reperfusate used in controlled surgical reperfusion of an infarct zone (performed via a side branch of the vascular graft while completing a proximal anastomosis72), with the aim to achieve early recovery of regional contractility and to reduce reperfusion-related complications (eg, arrhythmias7374); and (3) postoperatively, as maintenance therapy to improve coronary flow and myocardial perfusion.
Pulmonary Hypertension and Cardiopulmonary Bypass
In addition to its responsiveness in the corpus cavernosum and coronary artery, PDE5 inhibitors also act selectively in the pulmonary vasculature, and patients with elevated pulmonary pressures appear to benefit significantly from its action even when administered orally. Published data have come primarily from the study of sildenafil.
A randomized double-blind trial75 found that sildenafil was protective against acute hypoxia (11% inspired oxygen) in healthy human volunteers, almost completely reversing the raised pulmonary artery pressure. In a study4 of five consecutive patients with pulmonary hypertension, oral sildenafil (50 mg q8h) decreased pulmonary capillary wedge pressures, increased cardiac index, improved functional capacity, and led to a reduction of right ventricular mass measured by MRI. Systolic and diastolic pressures were found to be unchanged in these patients. In another similar study,6 oral sildenafil, 50 mg tid, for 3 months significantly reduced pulmonary artery pressure and pulmonary vascular resistance, increased cardiac output and exercise tolerance (measured by using the 6-min walk test), and improved quality of life. A larger, double-blind, placebo-controlled crossover trial5 of 22 patients confirmed similar benefits: significant improvement in exercise tolerance (+ 44% measured by treadmill exercise time), improved cardiac index, and reduced pulmonary artery systolic pressure. Patient symptoms were reported to be improved in the above studies.
When comparing sildenafil, vardenafil, and tadalafil, differential pulmonary vasorelaxant effects and arterial oxygenation were observed in a randomized prospective study76 of 60 consecutive patients with New York Heart Association class II-IV pulmonary arterial hypertension. The authors76 noted that significant improvement in arterial oxygenation equivalent to that produced by NO inhalation was only noted with sildenafil, and that the pulmonary to systemic vascular resistance ratio was different among the three.
Although clinical data on the effects of PDE5 inhibitors in the cardiac surgical setting are still lacking, much valuable insight has been gained from studies of inhaled nitric oxide and its cardiopulmonary effects in cardiac surgical patients. Evidence suggests that pulmonary vascular relaxation in response to inhaled NO may be indicative of reversible pulmonary hypertension, a response that is not usually seen in individuals with relatively normal pulmonary vascular resistance at baseline.7778 This reversibility or capacity to be dilated to inhaled NO is seen following on-pump CABG even in patients without significant preexisting pulmonary hypertension,798081 suggesting the presence of postoperative pulmonary endothelial dysfunction.78 Activation of cytokines and the inflammatory responses as a result of cardiopulmonary bypass is thought to be responsible,7782838485 and off-pump CABG was found to produce less pulmonary endothelial dysfunction compared with on-pump CABG.86 It would be important to study PDE5 inhibitors in the context of cardiopulmonary bypass, whether such iatrogenic inflammatory state and pulmonary endothelial dysfunction can be reduced pharmacologically. Also, because of the differing metabolic demands of the heart during on-pump and off-pump CABG, the different cardioplegia solutions being used, and other physicochemical parameters that are being manipulated, thorough investigations into the use of PDE5 inhibitors may yield a useful addition to our armamentarium for the management of patients undergoing CABG.
In adult cardiac patients with postoperative pulmonary hypertension secondary to right ventricular infarction/dysfunction or following mitral valve surgery with the use of cardiopulmonary bypass, sildenafil alone or in combination with inhaled NO effectively lowered pulmonary artery pressure.878889 Sildenafil has also been demonstrated to facilitate weaning of inhaled NO.89 In a study4 comparing the efficacy of inhaled NO and/or sildenafil in 13 consecutive patients with pulmonary hypertension wait-listed for heart-lung transplantation, a single oral dose of sildenafil was found to be as effective and selective as inhaled NO in producing pulmonary vasodilation. The authors4 concluded that sildenafil was superior to inhaled NO because it did not increase pulmonary capillary wedge pressure and decrease cardiac output as did NO, while exerting effective pulmonary vasodilating effects. Sildenafil also appears to confer benefits in hypertensive cardiac transplant recipients. As an adjunct to regular antihypertensive medications, endothelial function, brachial artery reactivity, and central and peripheral arterial BP were reportedly improved, in addition to a reduction in left ventricular afterload and systolic stress.90
Conclusion
Sildenafil is a well-characterized PDE5 inhibitor that appears to be a favorable agent in patients undergoing CABG by virtue of its coronary vasodilating, endothelium-enhancing/preconditioning and platelet inhibitory effects, and its beneficial effects in the myocardium (Fig 1 ) and pulmonary vasculature have been demonstrated amply at the molecular and physiologic levels in animal and human studies. Although its potency is modest compared to other single agents that specifically target platelet adhesion/aggregation or constricted coronary arteries, its modulating antiplatelet effects, NO/cGMP-potentiating, and preconditioning effects on the endothelium may be what are desirable for its adjunctive use in CABG (Fig 2 ). Furthermore, patients administered a powerful antiplatelet agent such as GP IIb-IIIa inhibitor prior to coronary surgery are at high risk of bleeding complications and requirement for transfusion.91
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PDE5 inhibitors have substantial differences in their pharmacologic profiles and actions in the cardiopulmonary circuit76 that warrant further investigation. The beneficial effects of sildenafil on the cardiopulmonary circuit are promising, and its use at the time of CABG should be investigated thoroughly.
Footnotes
Abbreviations: ADP = adenosine diphosphate; BNP = brain/B-type natriuretic peptide; CABG = coronary artery bypass graft surgery; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; GP = glycoprotein; KATP = adenosine triphosphate-sensitive potassium; NO = nitric oxide; PDE = phosphodiesterase; PDE5 = type-5 phosphodiesterase; PDE3A = type-3A phosphodiesterase; PKG = protein kinase G
Received for publication March 20, 2005. Accepted for publication May 16, 2005.
References
IIbß3 (platelet GPIIb-IIIa) dependent homotypic and heterotypic cell-cell interactions. J Clin Invest 1991;8,1128-1134
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