Endothelial Dysfunction, Erectile Dysfunction, and Coronary Heart Disease: The Pathophysiologic and Clinical Linkage

TREATING ERECTILE DYSFUNCTION Endothelial Dysfunction, Erectile Dysfunction, and Coronary Heart Disease: The Pathophysiologic and Clinical Linkage Richard A. Stein, MD Weill Cornell Medical Center, New York, NY, and Brooklyn Hospital Center, Brooklyn, NY Our rapidly expanding knowledge regarding the biology of the endothelial cell and the pathophysiology of coronary heart disease (CHD) and endothelial dysfunction indicates important common factors and overlapping clinical presentations. We are, in effect, presented with a new paradigm—that of varying vascular manifestations of disease linked to the functioning of endothelial cell lining. This article reviews these areas of advancement and addresses their clinical implications regarding erectile dysfunction and CHD, as well as the role of the phosphodiesterase-5 inhibitor sildenafil. [Rev Urol. 2003;5(suppl 7):S21-S27] © 2003 MedReviews, LLC Key words: Erectile dysfunction • Coronary heart disease • Endothelium • Phosphodiesterase n 1980, Robert Furchgott, PhD, noted that strips of rabbit aorta wall suspended in an isotonic bath dilated when acetylcholine was added to the bath if the layer of endothelial cells was intact, and failed to dilate when the endothelial layer had been abraded off the inside surface.1 He deduced that, when exposed to acetylcholine, the endothelial cell produced a substance he termed “endothelial-derived relaxation factor" (EDRF), which caused the smooth muscle cell layer that surrounds the artery to relax, with subsequent dilatation of the artery. I VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S21 Endothelial Dysfunction, ED, and CHD continued Further Nobel Prize–winning work by Dr Furchgott and others determined that EDRF was in fact nitric oxide (NO) and that the dilatation of the arterial blood vessel was caused by the production of NO, its movement to the smooth muscle cells, and the subsequent production of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells. This “second messenger" alters calcium flux at the smooth muscle cell surface, resulting in relaxation. With this observation, our understanding of the endothelial cell evolved from that of a barrier cell layer separating blood clotting components from tissue factor to that of an organ that produces substances with local and remote effects in response to specific stimuli. Subsequent studies determined that endothelial cells contain angiotensin-converting enzyme and produce angiotensin II and the breakdown products angiotensin III and IV, as well as a host of vasoactive small chemicals called cytokines, which are prothrombotic or antithrombotic, proinflammatory or antiinflammatory, and proatherogenic or antiatherogenic. The endothelial cell is now understood to mediate not only the local vascular tone but also the major facets of the atherosclerotic process that result in coronary artery disease, stroke, and peripheral vascular disease. Recent studies have demonstrated that measurement of endothelial cell function may provide important prognostic information for various clinical states. There are a number of ways to assess endothelial cell function in vivo. A direct method of measuring regional endothelial function in the coronary arteries involves the injection of acetylcholine into the coronary artery, with subsequent injection of a contrast agent to permit angiographic measurement of the change in vessel diameter. The coro- S22 VOL. 5 SUPPL. 7 2003 nary vessel segment with normal endothelium will dilate, in contrast to the constriction that occurs in areas of atherosclerotic disease with dysfunctional endothelium. These effects represent the direct activation of the smooth muscles of the arteries by acetylcholine, which is overridden by the NO-mediated dilation in the setting of normal endothelial function but left unopposed in endothelial dysfunction. Alternatively, measurements of brachial artery diameter (by ultrasonography) or forearm blood flow (by impedance plethysmography) can be taken in the arm; changes steps in the atherogenic process.3 An early step in the process is the movement of low-density lipoprotein (LDL) cholesterol particles across the endothelial cells into the intimal layer of the arterial wall and their “minimal oxidation" by free radicals. The minimally oxidized LDL cholesterol then triggers the endothelial production of cytokines that recruit macrophage and T-lymphocyte white blood cells to the plaque by causing them to adhere to the surface of the endothelial cell layer and facilitate their movement across the endothelial cell to the intimal layer of the arterial wall. In the next step, the Measurement of endothelial cell function may provide important prognostic information for various clinical states. induced with endothelial stimulators of NO release (acetylcholine, bradykinin, or increased shear stress on the surface of the endothelium resulting from the increase in blood flow that follows the release of an occlusive blood pressure cuff) are then analyzed. An increase in vascular diameter in the range of 10% is considered normal, whereas the diameter ranges from unchanged to slightly increased when there is endothelial dysfunction. It is now possible in research laboratories to measure blood levels of E-selectin and vascular cell adhesion molecule, proatherogenic cytokines produced by the endothelial cell that is acting in a prothrombotic, proatherogenic, and vasoconstrictive mode. These cytokines play an important role in the flux of macrophage white blood cells into the atherogenic plaque.2 The Current Model of Atherogenesis Studies over the last decade have identified a number of significant REVIEWS IN UROLOGY fully oxidized LDL cholesterol, which is no longer recognized by LDL cholesterol receptors on cell surfaces, is treated as a foreign body and ingested by the macrophage without limit to produce a foam cell (so called because under the microscope it looks most like a glass of just-poured beer as seen from directly above). The bubbles of the “foam" are oxidized LDL cholesterol particles. The foam cells not only move cholesterol to the center of the plaque but also produce an enzyme called a metalloproteinase, which is able to break apart the intertwined strands of collagen in the nearby cap of the plaque, thinning the cap and increasing its likelihood of fracturing. Pathology studies have noted that fractured plaques are characterized by an increased number of foam cells (macrophage white blood cells filled with oxidized LDL cholesterol), a large core of cholesterol ester, fewer smooth muscle cells, and a thin cap of collagen and endothelial cells over the plaque.4 Endothelial Dysfunction, ED, and CHD Once plaque fracture has occurred and tissue factor is exposed to the blood clotting factors, the activated platelets, linked by von Willebrand factor and fibrinogen, form the thrombus at the site of the fracture. This thrombus can grow quickly to totally occlude the vessel (an acute myocardial infarction [MI]) or can undergo a sequence of growth, partial occlusion, and being washed away with the blood flow (the pathophysiology of unstable angina pectoris). The endothelial cell, through its production of plasminogen activator and plasminogen activator inhibitor, as well as its production of NO and the resulting effect on platelet activation, is also an important regulator of this process. The role of the endothelial cell in the development of plaque and in determining the plaque’s growth and vulnerability (likelihood of fracture) is the focus of intense interest. As noted above, the mediation of the process by endothelial-derived cytokines and by chemical agents produced by the macrophages and T lymphocytes that have been recruited to the plaque by endothelial cytokines supports a critical “executive" role of the endothelium. Studies that measure atherosclerosis and, especially, coronary artery atherosclerosis are of great clinical importance in the treatment or prevention of coronary heart disease (CHD). They have specific bearing on the evaluation of the patient with erectile dysfunction (ED), given the data regarding common risk factors, clinical association, and common underlying etiology. Coronary angiography has long been considered the gold standard for diagnosis of coronary atherosclerosis, for prediction of a patient’s CHD event risk, and as the basis for intervention via surgery or medical therapy. Exercise stress testing that demonstrates significant ischemia by elec- trocardiogram (EKG) changes or, via nuclear imaging, a failure of a segment of the myocardium to take up a normal amount of isotope is highly predictive of a greater than 70% narrowing of a coronary artery. Exercise testing with echo imaging to detect exercise-induced wall motion abnormalities also can detect significant occluding plaque in the coronary artery. These tests are used as screen- beam computed tomography can, in a very short imaging time, detect calcium deposits in the coronary arteries. These deposits will nearly always represent coronary artery atherosclerotic plaques, and the size, intensity, and location of the calcium deposits have been significant predictors of coronary artery disease seen on angiography. Such findings in the presence of high calcium scores have been shown Electron beam computed tomography can, in a very short imaging time, detect calcium deposits in the coronary arteries. ing studies to determine the presence and extent of disease and to help in the physician’s decision to refer a patient for coronary artery angiography. Experimental, “almost ready for prime time" imaging of the coronary artery anatomy using computed tomography or magnetic resonance imaging (MRI) will, in many instances, reduce the need for invasive coronary angiography. The recent introduction into clinical use of intravascular ultrasonography permits, for the first time, the direct visualization of the vascular wall and atherosclerotic lesion. This has provided important information concerning a process termed “vascular remodeling," which is the expansion of the arterial wall at the site of the plaque. This is the basis of the finding that early lesions do not, in fact, impinge on the lumen, which explains the presentation of acute MI in an area of an artery with a normal lumen as measured on angiography (now sometimes referred to as lumenography). In addition, recent studies have indicated that both intravascular ultrasonography and MRI have the potential to measure factors that are associated with plaque stability and may, in the future, be able to detect the vulnerable plaques.5,6 Electron in recent studies to be predictive of clinical events.7 Studies have also demonstrated that this same imaging technique can be used to reconstruct images of the coronary arteries that are increasingly correlated with the results derived from angiography.8 Until recently, MI was thought to occur when a large, near–totally occlusive plaque became the site of a thrombus that occluded the small remaining lumen. Then, new data arose from angiographic regression studies in which angiograms from the inception of the study were available for some patients presenting with MI, allowing visualization of the size of the plaque a short time before the MI. In addition to these data, reasonable estimations of plaque size before fracture can often be made from angiograms obtained after thrombolysis for acute MI. These reports noted that these plaques, prefracture, were often (more the half of the time) small, obstructing the artery’s lumen by less than 50%.9 This observation focused attention on biologic issues that determined plaque stability versus vulnerability in contrast to plaque growth and plaque size and has resulted in the functional status of the endothelium being a prime target of treatment. VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S23 Endothelial Dysfunction, ED, and CHD continued Table 1 Phosphodiesterase (PDE) Types and Biologic Roles PDE Family Functional Role PDE-1 Vascular smooth muscle proliferation PDE-2 Olfaction PDE-3 Cardiac contractility, insulin secretion, lipolysis PDE-4 Inflammation, smooth muscle tone, depression PDE-5 Penile erection, smooth muscle tone PDE-6 Vision PDE-7 T-cell activation, skeletal muscle metabolism PDE-8 T-cell activation PDE-9 Unknown PDE-10 Dopamine signaling PDE-11 Spermatogenesis Erectile Dysfunction The finding that a phosphodiesterase (PDE)-5 inhibitor, sildenafil, enhanced erectile function in men with ED occurred as the complex role of the endothelial cells in atherosclerosis was becoming clear. The significant effect of sildenafil focused attention on the physiology of the erectile process and the role of the endothelial cells that line the blood vessels to the penis and the septa of the corpus cavernosum in initiating and sustaining penile erection. Erection was now understood to occur with an orchestrated downregulation of the sympathetic nervous system and upregulation of the parasympathetic nervous system innervation of penile blood vessels. This is associated with the release of NO from vascular and corpus cavernosum endothelial cells.10 The resultant dilation of the arteries supplying blood to the penis engorges the corpus, achieving an intracorpus pressure that is greater than that of the penile venous system. The pressure gradient collapses the veins, trapping blood in the corpus under increased pressure. Developing and sustaining this pres- S24 VOL. 5 SUPPL. 7 2003 sure gradient is the basis of erectile function. The reduced production of NO by dysfunctional endothelial cells lining the penile arterial system and the corpus have a negative impact on obtaining and sustaining an erection, since perivascular smooth muscle tissue and other cells are often rich in the PDE enzymes that degrade cGMP, limiting the duration of the vasodilatation produced by a given REVIEWS IN UROLOGY quantity of cGMP. This is now understood to be the basis of the majority of cases of ED. There are several types of PDE, with specific organ systems having a greater concentration of a specific type or types (Tables 1 and 2).11 In the penile vascular system and corpus, there is a selective predominance of PDE-5, which exceeds that in other critical organ systems by a significant ratio. Thus, inhibition of PDE-5 produces an enhanced duration and action of cGMP that is of clinical significance in the penile corpus cavernosum only, explaining the clinically selective effect of sildenafil on erectile function. PDE-5 is, however, found in the smooth muscles of the coronary and other systemic arteries and in platelets. This has raised theoretical concerns about the effects of PDE-5 inhibitors on coronary artery flow and platelet function. These concerns have not been substantiated in human studies. Wallis and colleagues11 addressed the distribution of PDE-5 in humans and showed that sildenafil enhanced coronary artery smooth muscle concentrations of cGMP and did not alter platelet function when Table 2 Phosphodiesterase (PDE) Types and Associated Organ Systems PDE Family Tissue Localization (Where Well Characterized) PDE-1 Brain, heart, kidney, liver, skeletal muscle, vascular and visceral smooth muscle PDE-2 Adrenal cortex, brain, corpus cavernosum, heart, kidney, liver, skeletal muscle, visceral smooth muscle PDE-3 Corpus cavernosum, heart, platelets, vascular and visceral smooth muscle, liver, kidney PDE-4 Kidney, lung, mast cells, heart, skeletal muscle, vascular and visceral smooth muscle PDE-5 Corpus cavernosum, platelets, skeletal muscle, vascular and visceral smooth muscle PDE-6 Retina Adapted from Wallis RM et al. Am J Cardiol. 1999;83(5A):3C-12C.11 Endothelial Dysfunction, ED, and CHD tested directly, but it did enhance the anti-aggregatory action of nitroprusside on human platelet-rich plasma. Herrmann and colleagues12 measured coronary artery blood flow with intracoronary Doppler guidewires in 13 persons with 1 or more significantly diseased coronary arteries that this was not noted in an intact animal model or in EKG studies in humans. Sofowra and colleagues15 measured the QT interval in men before and after they received sildenafil, 50 mg; no QT prolongation was demonstrated. Sugiyama and colleagues16 measured action potential ED was associated with increasing age and several atherosclerotic vascular disease risk factors. (greater than 70% occlusion) before and after administration of oral sildenafil, 100 mg. They studied 25 coronary arteries (13 with stenosis and 12 without stenosis). The investigators noted that oral sildenafil produced small decreases in systemic and pulmonary artery pressures (less than 10%), with no effect on pulmonary capillary wedge pressure, heart rate, or cardiac output. Most significant, there was no sildenafilmediated change in coronary blood flow in coronary arteries with or without stenosis. Arruda-Olson and colleagues13 addressed the same issues by looking at exercise wall motion with supine exercise echocardiography before and after sildenafil administration in 105 men with ED who had known or highly probable coronary artery disease. There was no significant increase in ischemia-induced wall motion abnormalities, symptoms, or EKG changes with sildenafil. An additional area of concern was addressed in a study of sildenafil and guinea pig heart cells that demonstrated a relationship of sildenafil to prolongation of the repolarization time of the cardiac action potential.14 This would be reflected on the EKG as a long QT interval and might, therefore, enhance the likelihood of dangerous ventricular arrhythmias. Two subsequent studies showed duration and effective refractory period in a canine model and noted no increases with sildenafil. Clinical Linkage of ED and CHD The epidemiologic relationship of ED and the risk factors for development of CHD were noted in the Massachusetts Male Aging Study.17 This was an observational prospective study of 1709 men, aged 40 to 70 years at the initiation of the study in 1987 to 1989; follow-up occurred from 1995 through 1997. The association of ED and cardiovascular disease was greater than would be expected on the basis of age and sex alone. ED was associated with increasing age and several atherosclerotic vascular disease risk factors. An elevated LDL cholesterol level or low high-density disease. In a study of 154 men with ED, Walczak and colleagues,18 from the Lahey Clinic, reported that 44% had hypertension, 23% had diabetes, 16% used tobacco, 79% had a body mass index greater than 26 kg/m2, and 74% had an LDL cholesterol level greater than 120 mg/dL. Given these findings, it is not surprising that small clinical studies have noted that coronary artery disease is a powerful indicator of the presence or development of ED. Studies have also found that the greater the extent of the heart disease, the greater the likelihood of ED. Dhabuwala and colleagues19 noted that 42% of their male patients who had MI reported ED. Greenstein and associates20 reported, in a study of 40 men with coronary artery disease, that patients with multivessel coronary artery disease were more likely to experience ED than men with single-vessel disease. Recent studies have focused on the role of “endothelial risk factors." These are risk factors that increase the risk of CHD and/or ED and are associated with endothelial dysfunction. Cigarette smoking and secondhand smoke exposure are associated with transient endothelial dysfunction; elevated LDL cholesterol levels, hypertension, diabetes, poor cardio- Coronary artery disease is a powerful indicator of the presence or development of ED. lipoprotein cholesterol level, diabetes mellitus, hypertension, or smoking at entry into the prospective cohort study were associated with a nearly 4-fold increase in risk of ED development for a single factor and an even greater likelihood of ED if multiple factors were present. Essentially, the risk factors for ED are the same as the risk factors for coronary artery respiratory fitness, and elevated homocysteine levels are all associated with reduced endothelial function that can improve with effective therapy. Given the role of the endothelium in advancing a plaque to a vulnerable state, the potential relationship of ED to severe or unstable coronary artery disease is of interest. There are, as yet, no real data in this regard. VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S25 Endothelial Dysfunction, ED, and CHD continued However, O’Kane and Jackson21 have described 2 subjects who were seen for ED. One subject underwent coronary angiography that revealed 3vessel contrary artery disease and the other had an acute MI 2 months after presenting with ED. Further clinical studies will sustain or reject this interesting hypothesis. An important area of linkage is the triad of ED, CHD, and depression. Goldstein22 reviewed population-based epidemiologic studies in which all 3 variables were measured and concluded that the 3 medical conditions share many of the same risk factors and etiologic association and are best statistically modeled in a 3-way holistic, mutually reinforcing relationship. He noted that patients with sexual dysfunction are likely to have the comorbidities of cardiac vascular disease and depression. Of interest, recent studies have noted that depression is associated with both an enhanced risk of first cardiac presentation and an increased cardiac event rate in patients with known CHD. Increased platelet activation and altered pituitary-adrenal hormonal status have been studied in this regard, as have depression-related failure to adhere to secondary prevention lifestyle modifications (ie, diet, smoking cessation, exercise) and poor compliance with medication. 3. Conclusion Our enhanced knowledge of the role of the endothelium in vascular disease and our appreciation of the importance of endothelial dysfunction in CHD and erectile function have raised important questions concerning the 2 disorders. At the least, they are risk markers for each other. It is possible that ED in a patient with known or unknown coronary artery disease may be a risk marker for the onset of “unstable" coronary disease caused by increased endothelial dysfunction. Data from clinical studies addressing this issue will be of significant clinical importance. Of additional importance is the clinical security afforded by the extensive studies in vitro, in animals, and in humans that demonstrate the selective clinical action and safety of the PDE-5 inhibitor sildenafil. 4. 5. 6. 7. 8. 9. 10. 11. References 1. 2. Furchgott RF, Zawadzki JV. The obligatory role of the endothelial cell in the relaxation of the arterial smooth muscle by acetylcholine. Nature. 1980;288:373-376. Blankenberg S, Rupprecht HJ, Bickel C, et al. 12. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001;104:1336-1342. Morrow DA, Ridker PM. Inflammation and cardiovascular disease. In: Toprol EJ, ed. Textbook of Cardiovascular Medicine Updates. Cedar Knolls, NJ: Lippincott Williams & Wilkins; 1999:1-12. Lauer M. Inflammation and infection in coronary artery disease. In: Foody JM, ed. Preventive Cardiology. Totowa, NJ: Humana Press; 2001:47-64. Nair A, Kuban BDE, Schoenhagen P, et al. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis. Circulation. 2002;106:2200-2206. Kramer CM. Magnetic resonance imaging to identify the high-risk plaque. Am J Cardiol. 2002;90(10C):15L-17L. Arad Y, Spadaro LA, Goodman K, et al. Predictive value of electron beam computed tomography of the coronary arteries: 19-month follow-up of 1173 asymptomatic subjects. Circulation. 1996;93:1951-1953. Achenbach S, Moshage W, Ropers D, et al. Value of electron-beam computed tomography for the noninvasive detection of high-grade coronaryartery stensoses and occlusions. N Engl J Med. 1998;339:1964-1971. Giles TD. Atherogenesis and coronary artery disease. In: Hypertension Primer. 3rd ed. Dallas: American Heart Association; 2003:193-197. Anderson K, Stief C. Penile erection and cardiac risk: pathophysiologic and pharmacologic mechanism. Am J Cardiol. 2000;86(2A):23F-26F. Wallis RM, Corbin JD, Francis SH, Ellis P. Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. Am J Cardiol. 1999;83(5A):3C-12C. Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med. 2000;343:967-968. Main Points • The link between coronary heart disease (CHD) and erectile dysfunction (ED) lies in the function of endothelial cells, which are now understood to mediate not only vascular dilation but also many facets of atherogenesis. • Atherogenesis begins when low-density lipoprotein (LDL) cholesterol triggers endothelial production of cytokines that recruit macrophages and T lymphocytes to the plaque. • Once a plaque has fractured, the endothelial cell, with its production of nitric oxide (NO), serves as a regulator of the process by which activated platelets form the thrombi that cause acute myocardial infarction and unstable angina pectoris. • The release of NO by penile vascular and corpus cavernosum endothelial cells and the subsequent production of cyclic guanosine monophosphate are now understood to cause the arterial relaxation and dilation necessary for erection; thus, dysfunctional endothelial cells are the culprit behind most cases of ED. • ED and CHD share the same risk factors, many of which can be improved with proper therapy; these “endothelial risk factors" include cigarette smoking and secondhand smoke exposure, elevated LDL cholesterol levels, hypertension, diabetes, poor cardiorespiratory fitness, and elevated homocysteine levels. S26 VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY Endothelial Dysfunction, ED, and CHD 13. Arruda-Olson AM, Mahoney DW, Nehra A, et al. Cardiovascular effects of sildenafil during exercise in men with known or probable coronary artery disease: a randomized crossover trial. JAMA. 2002;287:719-725. 14. Geelen P, Drolet B, Rail J, et al. Sildenafil (Viagra) prolongs cardiac repolarization by blocking the rapid component of the delayed rectifier potassium current. Circulation. 2000; 102:275-277. 15. Sofowra G, Dishy V, Roden D, et al. The effect of sildenafil on QT interval in healthy men [abstract]. Clin Pharmacol Ther. 2001;69(2):P67. 16. 17. 18. 19. Sugiyama A, Satoh Y, Shiina H, et al. Cardiac electrophysiologic and hemodynamic effects of sildenafil, a PDE5 inhibitor, in anesthetized dogs. J Cardiovasc Pharmacol. 2001;38:940-946. Feldman HA, Johannes CB, Derby CA, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts Male Aging Study. Prev Med. 2000;30:328-338. Walczak MK, Lokhandwala N, Hodge MB, Guay AT. Prevalence of cardiovascular risk factors in erectile dysfunction. J Gend Specif Med. 2002;5(6):19-24. Dhabuwala CB, Kumar A, Pierce JM. Myocardial 20. 21. 22. infarction and its influence on male sexual function. Arch Sex Behav. 1986;15:499-504. Greenstein A, Chen J, Miller H, et al. Does severity of ischemic coronary disease correlate with erectile function? Int J Impot Res. 1997;9:123-126. O’Kane PD, Jackson G. Erectile dysfunction: is there a silent obstructive artery disease? Int J Clin Pract. 2001;55:219-220. Goldstein I. The mutually reinforcing triad of depressive symptoms, cardiovascular disease, and erectile dysfunction. Am J Cardiol. 2000;86(2A): 41F-45F. VOL. 5 SUPPL. 7 2003 REVIEWS IN UROLOGY S27