Effect of sildena l on arterial stiffness and wave re ection

Effect of sildena l on arterial stiffness and wave re ection Charalambos Vlachopoulos, Kozo Hirata and Michael F O Rourke Abstract: While sildena l (Viagra ) is widely prescribed for erectile dysfunction, its effect on arterial function is not established. The elastic properties of the aorta, as well as the magnitude and timing of wave re ection, are important factors for ef cient performance of the cardiovascular system and have been identi ed as prognosticators of cardiovascular risk. A total of 24 subjects with coronary artery disease, of whom 14 were hypertensives, aged 69 8 years, were studied in a randomized, placebo-controlled, double-blind, cross-over design. Measurements lasted for 3 h after the sildena l intake (50 mg, p.o.) or placebo. Aortic elastic properties were evaluated with carotid-femoral pulse wave velocity; wave re ection was evaluated with augmentation index and augmented pressure of the aortic pressure waveform. Pulse wave velocity decreased signi cantly (by 0.65 m=s, p ˆ 0.005), denoting a decrease in aortic stiffness. Augmentation index and augmented pressure decreased signi cantly (by 4.47% absolute and by 4.01 mmhg; p < 0.001 and p ˆ 0.001, respectively), denoting a decreased effect of wave re ection from the periphery. Aortic pulse pressure decreased signi cantly (by 6.74 mmhg, p < 0.05). An active effect of the drug on aortic wall appears to contribute to the decrease in pulse wave velocity, although other mechanisms such as a decrease of blood pressure and autonomic re exes could also have contributed. The effect of sildena l lasted throughout the study (3 h), being evident 30 min after drug intake. In conclusion, this study shows, for the rst time, that sildena l has a favorable effect on aortic stiffness and wave re ection in patients with coronary artery disease. This nding may have important implications for cardiovascular performance and exercise capacity during intercourse. Key words: aorta; arterial stiffness; arteries; coronary disease; sildena l Introduction Erectile dysfunction affects up to 30% of men aged 40 70 years. 1 Sildena l is a highly selective inhibitor of phosphodiesterase type 5, the predominant isoenzyme responsible for the breakdown of cgm P in the corpora cavernosa. By inhibiting cgmp degradation, sildena l allows for improved erectile function and successful sexual intercourse in most men with erectile dysfunction. 2 Erectile dysfunction is particularly common in patients with cardiovascular disease and shares a number of risk factors, including hypertension, older age, diabetes mellitus, hypercholesterolemia and smoking. 1 However, postmarketing data showed temporal association of cardiovascular events with the use of the drug, raising concerns about its safety. Stiffness of the aorta, as well as the magnitude and timing of wave re ection, are important factors for the performance of the cardiovascular system 3 6 and they 7 9 have been identi ed, together with their pathophysiological manifestations (i.e. increased systolic pressure, 10,11 increased pulse pressure 11 15 and reduced diastolic pressure 11,14 ), as prognosticators of cardiovascular risk. Medical Professorial Unit, St Vincent s Hospital and Clinic, University of N ew South Wales, Sydney, Australia Address for correspondence: Charalambos Vlachopoulos, Kerassoundos 17, Athens 11528, G reece. Tel: 30 6972 272727; Fax: 30 210 7473374; E-mail: cvlachop@otenet.gr Arnold 2003 Furthermore, reduction of wave re ection has been associated with improved exercise capacity. 16 Since phosphodiesterase type 5 is widely present throughout the systemic vasculature, 17 we hypothesized that the drug could have a favorable effect on arterial function. In the present study, we investigated the effect of sildena l on arterial stiffness and wave re ection in patients with coronary artery disease. Methods Subjects We studied 24 men (age 69 8 years) with coronary artery disease. In 19 patients, coronary artery disease was de ned angiographically ( ve had single-vessel, 10 had doublevessel, and four had triple-vessel disease). In the remainder, coronary artery disease was de ned clinically and by non-invasive stress testing. F ourteen patients were hypertensive, 15 had hypercholesterolemia, two had diabetes mellitus (one insulin-dependent), and one was a current smoker. The study protocol was approved by the St Vincent s H ospital R esearch Ethics Committee and all subjects gave written informed consent. Study design The study was carried out using a randomized, placebocontrolled, double-blind, cross-over design. Each subject was studied in the morning on 2 days separated with a non- xed interval (mean 16 days) after an overnight fast. One day the subjects received sildena l (Viagra, P zer) 10.1191=1358863x03vm509ra

244 C Vlachopoulos et al and the other, placebo. After baseline measurements, the patients took either 50 mg of sildena l or placebo, and all measurements were repeated at 30, 60, 120, 150 and 180 min after drug intake. Cardiovascular medications were discontinued for 24 h before the study. Background medications included ACE inhibitors (14 patients), -blockers (nine patients), calcium channel blockers (six patients), diuretics (six patients) organic nitrates (one patient), angiotensin receptor blockers (one patient), statins (12 patients) and other hypolipidemic agents (two patients). Evaluation of aortic elastic properties The pulse travels at a higher velocity in a stiff aorta and vice versa. Pulse wave velocity (PWV) is a well-established index of arterial stiffness and a prognosticator of cardiovascular risk. 7,18 22 Carotid femoral PWV was calculated from measurements of pulse transit time and the distance travelled between two recording sites (PWV ˆ distance [meters]=transit time [seconds]), using a validated non-invasive device (Complior, Dupont Medical), which allows on-line pulse wave recording and automatic calculation of PWV. 20 Measurement of wave re ection indices We used a validated, commercially available system (SphygmoCor ; AtCor Medical, Sydney, Australia) 23,24 which employs the principle of applanation tonometry 3,22,25 28 and appropriate acquisition and analysis software for non-invasive recording and analysis of the arterial pulse. The technique has been described in detail previously. 3,22 27 From radial pulse recordings, the central (aortic) arterial pressure was derived with the use of a generalized transfer function which has been shown to give an accurate estimate of the central arterial pressure waveform and its characteristics, 3,23,26,29,30 and by assuming that the mean pressure in the aorta is the same as the mean pressure in the radial artery since there is practically no change in mean pressure along the arterial tree. 3,30 Waveforms of radial pressure were calibrated according to sphygmomanometric systolic and diastolic pressure measured in the brachial artery since there is practically no pressure pulse ampli cation between the brachial and the radial artery. 3 The augmentation index (AIx) and augmented pressure (AP) of the central waveform were measured as indices of wave re ection. 3,22,24,26 29 The pressure waveform recorded at any site of the arterial tree is the sum of the forward traveling waveform generated by pump ejection, and the backward traveling the echo of the incident wave re ected at peripheral sites. The merging point of the incident and the re ected wave can be identi ed on the pressure waveform as an in ection point. 3 AP is the pressure added to the incident wave by the returning re ected one and represents the pressure boost with which the left ventricle must cope and which is caused by wave re ection. The AIx was de ned as the AP divided by pulse pressure and expressed as a percentage. Larger values of AIx indicate increased wave re ection from the periphery and=or earlier return of the re ected wave as a result of increased PWV (due to increased arterial stiffness), and vice versa. Statistical analysis Data are expressed as the mean SEM. Probability values ( p) were derived from two-sided tests, while values less than 0.05 were considered statistically signi cant. Characteristics and resting cardiovascular parameters were compared between the sildena l and placebo sessions using the paired t-test (after controlling for the assumption of normality). Repeated-measures analysis of variance (averaged F) was used to detect statistically signi cant changes in variables within each session separately and between the sildena l and the placebo session (ˆ two drugs [sildena l vs placebo] seven periods [baseline, 30, 60, 90, 120, 150, and 180 min post-drug]). To take into account the potential effect of mean pressure on PWV changes we adjusted for this covariate by using repeatedmeasures analysis of variance-covariance. Calculations were performed with SPSS software, version 10.0 (Chicago, IL, USA) and SAS software (SAS Institute Inc., Cary, NC, USA). Results There were no differences in baseline characteristics between the two sessions (Table 1). Table 1 Baseline characteristics of the study sessions. Sildena l Placebo p-value Heart rate (beats =min) 58.4 1.5 59.6 1.5 NS Ejection duration (ms) 348.5 3.5 344.1 4.0 NS Peripheral SP (mmhg) 141.6 3.3 141.9 3.3 NS Peripheral DP (mmhg) 76.3 2.0 76.8 2.1 NS Peripheral PP (mmhg) 65.3 3.3 65.1 3.2 NS Central SP (mmhg) 132.0 3.2 131.6 3.4 NS Central DP (mmhg) 77.7 2.0 78.3 2.1 NS Central PP (mmhg) 54.2 3.0 53.3 3.0 NS Mean pressure a (mmhg) 99.7 2.0 100.1 2.3 NS Augmentation index (% ) 26.1 1.3 24.9 1.4 NS Augmented pressure (mmhg) 14.9 1.3 14.2 1.4 NS Pulse wave velocity (m=s) 10.3 0.4 10.1 0.4 NS Data are mean SEM. a Mean pressure is considered to be equal in peripheral and central arteries (see text for details). DP, diastolic pressure; PP, pulse pressure; SP, systolic pressure.

Arterial stiffness, wave re ection and sildena l 245 Heart rate increased in the sildena l session (maximum at 90 min, by 2.5 beats per min, p < 0.05), whereas there was no change in the placebo session and no drug interaction. Ejection duration remained unchanged during the study both in the sildena l and placebo sessions and there was no signi cant drug interaction as regards this variable. Both radial and aortic systolic pressures decreased in the sildena l session ( p < 0.001 for both), whereas they increased in the placebo session ( p < 0.001 for both). There was a signi cant drug interaction for radial ( p < 0.001) and aortic ( p < 0.001) systolic pressure (F igures 1 and 2). Similarly, both radial and aortic diastolic pressures decreased in the sildena l session ( p ˆ 0.001 for both), whereas they increased in the placebo session ( p < 0.001 for both). For both radial and aortic diastolic pressure there was a signi cant drug interaction ( p < 0.001 for both; F igures 1 and 2). R adial pulse pressure decreased ( p < 0.05) in the sildena l session and increased ( p < 0.001) in the placebo session; there was no signi cant drug interaction (Figure 1). Aortic pulse pressure decreased ( p < 0.01) in the sildena l session and increased ( p < 0.001) in the placebo session; the drug interaction was signi cant ( p < 0.05; Figure 2). PWV decreased ( p < 0.05) in the sildena l session and increased ( p < 0.001) in the placebo session. The change in PWV was evident at 30 min and persisted throughout the 3 h of the study. There was signi cant drug interaction as regards PWV ( p ˆ 0.005; Figure 3). The interaction remained signi cant ( p < 0.05) after adjusting for the effect of mean pressure, indicating that an active effect of the drug on aortic wall contributed in aortic stiffness changes. AIx decreased ( p < 0.05) in the sildena l session and increased ( p < 0.01) in the placebo session; the drug interaction was signi cant ( p < 0.001; Figure 3). The Figure 1 Radial systolic, diastolic and pulse pressures in the sildena l and placebo sessions during the study (mean and standard error of measurement); p-values refer to the drug interaction between the two sessions. Figure 2 Aortic systolic, diastolic and pulse pressures in the sildena l and placebo sessions during the study (mean and standard error of measurement); p-values refer to the drug interaction between the two sessions.

246 C Vlachopoulos et al Figure 3 PWV (pulse wave velocity), Alx (augmentation index) and AP (augmented pressure) in the sildena l and placebo sessions during the study (mean and standard error of measurement); p-values refer to the drug interaction between the two sessions. change in AIx was evident at 30min, reached a nadir at 60 min and persisted throughout the 3 h of the study. AP decreased ( p < 0.005) in the sildena l session and increased ( p < 0.001) in the placebo session; the drug interaction was signi cant ( p ˆ 0.001; Figure 3). In the subgroup of hypertensive patients (n ˆ 14), the ndings regarding all variables were similar to those of the total study population. Discussion To the best of our knowledge, this is the rst study to demonstrate the effect of sildena l on aortic elastic properties and wave re ection in patients with coronary artery disease. Oral sildena l decreased aortic stiffness and led to decreased wave re ection, with effects evident 30min after administration, and lasting for at least 3 h. M any patients with erectile dysfunction, taking sildena- l, have coronary and=or other cardiovascular disease since the two conditions share a number of common risk factors, including hypertension, older age, diabetes mellitus, hypercholesterolemia and smoking. 1 Post-marketing data have shown a temporal association of coronary events with the use of the drug. Although the true association between these events and the effect of the drug is dif cult to de ne, concerns about its use have persisted. In this study, sildena l produced a bene cial effect on arterial function by reducing aortic stiffness, wave re ection and aortic pulse pressure. In older subjects, such as those studied here, aortic stiffness and early wave re ection increase left ventricular load and myocardial oxygen demands and hinder ventricular function. 3,4 Furthermore, they compromise coronary blood ow and predispose to ischemia. 3,5,27 In addition, by increasing pulse pressure, they increase pulsatile stretch of the arteries leading to mechanical fatigue of their elastic components. Thus, through these mechanisms, stiffening of the aorta and enhanced early wave re ection exert a combined adverse effect on the integrity of the heart and the arteries in older humans. Indeed, increased aortic stiffness, 7,8 enhanced wave re ection, 9 increased systolic pressure, 10,11 pulse pressure 11 15 (and especially central pulse pressure 15 ), and reduced diastolic pressure, 11,14 have been identi ed as independent components of cardiovascular risk. Our study was conducted in the resting state and extrapolations for other situations should be interpreted with caution. H owever, the results of the present study may have implications for exercise capacity, which is an important parameter for successful sexual intercourse. It has been demonstrated that reduction of wave re ection is associated with improved exercise capacity in elderly patients, 16 and studies 31 have shown improvement in exercise capacity with use of sildena l. Vascular effects of sildena l in humans include dilation of brachial 32 and epicardial coronary arteries, 33 improvement of coronary blood ow reserve in patients with coronary artery disease 34 and improvement in endothelial function. 32,33,35 Furthermore, similarly to our ndings, sildena l reduces wave re ection in hypertensive patients. 36,37 Reduction in wave re ection and part of the reduction in PWV with sildena l can be attributed to dilation of conduit arteries 3 as seen with nitric oxide donors such as nitrates. 38,39 The mechanisms involved in the effects of sildena l on arterial function can be inferred from its pharmacological action as a vasodilator since PD E5 is present throughout the whole systemic vasculature. 17 An activation of autonomic re exes could also have contributed to the changes observed. The non-signi cant drug interaction on heart rate changes, however, indicates that the contribution of these re exes is probably small. Although specially designed methodology 19 is needed in order to distinguish whether the effect of a drug on aortic stiffness is due to changes of the intrinsic properties of the aortic wall or due to changes in blood pressure, insights on the mechanism of action of sildena l can be inferred from our study. Indeed, the fact that PWV changes remained signi cant after adjusting for changes in mean pressure

Arterial stiffness, wave re ection and sildena l 247 indicates that, apart from blood pressure lowering, an active effect of the drug on aortic wall appears to contribute to aortic stiffness changes. N evertheless, the importance and the clinical implications of our ndings are valid irrespective of the mechanism involved. Our study has some limitations. The results might not be directly extendable to patients with other characteristics and further studies are warranted. In addition, augmentation indices vary with heart rate. However, this effect of heart rate on AIx has been quanti ed 40 and since ejection duration remained constant despite an increase in heart rate it can be inferred that, at peak effect, the increase of heart rate by 2.4 beats per minute could have accounted for only 0.97% of the total 4.47% decrease in AIx. Since cardiovascular medications were stopped for 24 h, a small interaction of long-acting drugs with sildena l cannot be excluded. Conclusion Sildena l has a bene cial effect on arterial function in patients with coronary artery disease. The effect is explicable on the basis of vascular phosphodiesterase type 5 inhibition. This nding expands our understanding of the overall cardiovascular pro le of sildena l and may have implications for factors affecting cardiovascular performance and exercise capacity during intercourse. Acknowledgements The authors wish to thank D emosthenes Panagiotakos, PhD for his expert statistical advice. Potential con icts of interest: the study was supported by a grant from P zer; Dr M O Rourke is a Director of AtCor Medical, which manufactures systems for pulse wave analysis. References 1 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54 61. 2 Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildena l in the treatment of erectile dysfunction. N Engl J Med 1998; 338: 1397 404. 3 Nichols WW, O Rourke MF (eds). M cdonald s blood ow in arteries, fourth edition. London: Edward Arnold, 1998: 170 222, 284 315, 347 395, 450 476. 4 Kelly RP, Tunin R, Kass DA. Effect of reduced aortic compliance in cardiac ef ciency and contractile function of in situ canine left ventricle. Circ Res 1992; 71: 490 502. 5 Ohtsuka S, Kakihana M, Watanabe H, Sugishita Y. Chronically decreased aortic distensibility causes deterioration of coronary perfusion during increased left ventricular contraction. J Am Coll Cardiol 1994; 24: 1406 14. 6 Stefanadis C, Vlachopoulos C, Tsiamis E et al. Unfavorable effects of passive smoking on aortic function in men. Ann Intern M ed 1998; 128: 426 34. 7 Blacher J, Asmar R, Djane S, London G, Safar M. Aortic pulse wave velocity as a marker of cardiovascular risk in hypertensive patients. Hypertension 1999; 33: 1111 17. 8 Stefanadis C, Dernellis J, Tsiamis E et al. Aortic stiffness is a risk factor for recurrent acute coronary events in patients with ischaemic heart disease. Eur Heart J 2000; 21: 390 96. 9 London GM, Blacher J, Pannier B, Guerin A, Marchais S, Safar M. Arterial wave re ections and survival in end-stage renal failure. Hypertension 2001; 38: 434 38. 10 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAM A 1991; 265: 3255 64. 11 Vlachopoulos C, O Rourke M. Diastolic pressure, systolic pressure, or pulse pressure? Curr Hypertens Rep 2000; 2: 271 79. 12 Benetos A, Safar M, Rudnichi A et al. Pulse pressure: a predictor of long-term cardiovascular mortality in a French male population. Hypertension 1997; 30: 1410 15. 13 Domanski MJ, Mitchell GF, Norman JE, Exner DV, Pitt B, Pfeffer MA. Independent prognostic information provided by sphygmomanometrically determined pulse pressure and mean arterial pressure in patients with left ventricular dysfunction. J Am Coll Cardiol 1999; 33: 951 58. 14 Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure useful in predicting coronary heart disease? The Framingham Study. Circulation 1999; 100: 354 60. 15 Safar M, Blacher, Pannier B et al. Central pulse pressure and mortality in end-stage renal disease. Hypertension 2002; 39: 735 38. 16 Chen CH, Nakayama M, Talbot M et al. Verapamil acutely reduces ventricular vascular stiffening and improves aerobic exercise performance in elderly individuals. J Am Coll Cardiol 1999; 33: 1602 609. 17 Zusman RM, Morales A, Glasser D, Osterloh I. Overall cardiovascular pro le of sildena l citrate. Am J Cardiol 1998; 83: 35C 44C. 18 Avolio AP, Chen SG, Wang RP, Zhang CL, Li MF, O Rourke MF. Effects of age on changing arterial compliance and left ventricular load in a northern Chinese urban community. Circulation 1983; 68: 50 58. 19 Stefanadis C, Stratos C, Vlachopoulos C et al. Pressure diameter relationship of the human aorta. A new method of determination by the application of a special ultrasonic dimension catheter. Circulation 1995; 92: 2210 19. 20 Asmar R, Benetos A, Topouchian J et al. Assessment of arterial distensibility by automatic pulse wave velocity measurement: validation and clinical application studies. Hypertension 1995; 26: 485 90. 21 Vlachopoulos C, Hirata K, Stefanadis C, Toutouzas P, O Rourke M. Caffeine increases aortic stiffness in hypertensive patients. Am J Hypertens 2003; 16: 63 66. 22 Vlachopoulos C, Hirata K, O Rourke M. Effect of caffeine on aortic elastic properties and wave re ection. J Hypertens 2003; 21: 563 70. 23 Karamanoglu M, O Rourke MF, Avolio AP, Kelly RP. An analysis of the relationship between central aortic and peripheral upper limb pressure waves in man. Eur Heart J 1993; 14: 160 67. 24 Wilkinson IB, Fuchs SA, Jansen IM et al. Reproducibility of pulse wave velocity and augmentation index measured by pulse wave analysis. J Hypertens 1998; 16: 2079 84. 25 Kelly RP, Hayward C, Ganis J, Daley JE, Avolio AP, O Rourke MF. Non-invasive registration of the arterial pressure pulse waveform using high- delity applanation tonometry. J Vasc M ed Biol 1989; 1: 142 49. 26 Chen CH, Nevo E, Fetics B et al. Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Validation of a generalised transfer function. Circulation 1997; 95: 1827 36. 27 Vlachopoulos C, O Rourke M. Genesis of the normal and abnormal pulse. Curr Probl Cardiol 2000; 25: 303 67. 28 Vlachopoulos C, Hirata K, O Rourke M. Pressure-altering agents affect central aortic pressures more than is apparent from upper limb measurements in hypertensive patients: the role of arterial wave re ections. Hypertension 2001; 38: 1456 60. 29 Segers P, Qasem A, De Backer T, Carlier S, Verdonck P, Avolio A. Peripheral oscillatory compliance is associated with aortic augmentation index. Hypertension 2001; 37: 1434 39.

248 C Vlachopoulos et al 30 Pauca A, O Rourke M, Kon N. Prospective evaluation of a method for estimating ascending aortic pressure from the radial artery pressure waveform. Hypertension 2001; 38: 932 37. 31 Bocchi EA, Guimaraes G, Mocelin A, Bacal F, Bellotti G, Ramires JF. Sildena l effects on exercise, neurohumoral activation, and erectile dysfunction in congestive heart failure. A double-blind, plaebo-controlled, randomized study followed by a prospective treatment for erectile dysfunction. Circulation 2002; 106: 1097 103. 32 Desouza C, Parulkar A, Lumpkin D, Akers D, Fonceca V. Acute and prolonged effects of sildena l on brachial artery ow-mediated dilatation in type 2 diabetes. Diabetes Care 2002; 25: 1336 39. 33 Halcox JPJ, Nour KRA, Zalos G et al. The effect of sildena l on human vascular function, platelet activation, and myocardial ischemia. J Am Coll Cardiol 2002; 40: 1232 40. 34 Herrmann HC, Chang G, Klugherz BD, Mahoney PD. Hemodynamic effects of sildena l in men with severe coronary artery disease. N Engl J Med 2000; 342: 1622 26. 35 Katz SD, Balidemaj K, Homma S, Wu H, Wang J, Maybaum S. Acute type 5 phosphodiesterase inhibition with sildena l enhances owmediated vasodilatation in patients with chronic heart failure. J Am Coll Cardiol 2000; 36: 845 51. 36 Mahmud A, Hennesy M, Feely J. Effect of sildena l on blood pressure and arterial wave re ection in treated hypertensive men. J Hum Hypertens 2001; 15: 707 13. 37 Scho eld RS, Edwards DG, Schuler BT et al. Vascular effects of sildena l in hypertensive cardiac transplant patients. Am J Hypertens 2003; 16: 874 77. 38 Kelly RP, Gibbs HH, O Rourke MF et al. Nitroglycerin has more favorable effect on left ventricular afterload than apparent from measurement of pressure in a peripheral artery. Eur Heart J 1990; 11: 138 44. 39 Yaginuma T, Avolio A, O Rourke M et al. Effect of glyceryl trinitrate on peripheral arteries alters left ventricular hydraulic load in man. Cardiovasc Res 1986; 20: 153 60. 40 Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ. The in uence of heart rate on augmentation index and central aortic pressure in humans. J Physiol 2000; 525: 263 70.