MRCP Senthil ; Kirubakaran
email: senthilk1uk@yahoo.co.uk

MRCP Andrew Ladwiniec

Aruna Arujuna

Matthew Ginks

Mark Mcphail

MSc Julian Bostock

Gerald Carr-White

Christopher Rinaldi

St

Thomas

Mrcp Mathew

Ginks Mrcp

M B Bs

PhD, CA Rinaldi MD Gerry Carr-White

Male sex and COPD predict a poor clinical response in patients undergoing cardiac resynchronization therapy

Keywords:

wide QRS complex [1][2][3][4][5][6][7][8][9]. CRT improves heart failure symptoms, quality of life, exercise capacity. Based on the current evidence, the American Heart 60 Association/American College of Cardiology/ Heart Rhythm Society and European Society of Cardiology consider CRT a class I indication in patients with drug refractory class III or IV heart failure, with a left ventricular ejection fraction of ≤35% and a wide QRS complex [10,11]. However, approximately 30% of patients selected for CRT based on these criteria do not have a beneficial 65 response. This may be due to several potential causes including appropriate patient selection (evidence of dyssynchrony), the site of the left ventricular placement and whether post implant optimization is performed.

Echocardiographic measures have been used to try to improve patient selection, implantation and optimization, but have been disappointing. In order to enhance 70 patient selection, the PROSPECT study evaluated several echocardiographic measures of mechanical dyssynchrony to predict response to CRT using the assumption that correction of dyssynchrony underlies the major mechanism of CRT [12]. From this study, it appeared that these echocardiographic markers had only modest accuracy to predict response to CRT. 75 Patients with heart failure represent a heterogeneous group with variability in aetiology and the presence of comorbidities such as atrial fibrillation and COPD. Response to CRT is therefore likely due to a combination of these factors rather than dyssynchrony alone. We therefore aimed to investigate and identify predictive factors of non-response to CRT in a group of 80 patients referred for CRT at our institution, which represents a real world experience of patients undergoing CRT worldwide.

Methods

Inclusion criteria 85

All consecutive patients who underwent CRT implantation between

Collection of outcome measures

Using a dedicated CRT database and analysis of medical records the multiple variables were collected for each patient at baseline: age, sex, aetiology 95 of heart failure, drug treatment, presence of comorbidities (COPD, diabetes and hypertension), atrial fibrillation (AF), NHYA class and the presence of ventricular dyssynchrony using the surface ECG and echocardiography [13]. This was defined as a QRS duration of ≥ 150ms in at least two derivations of an ECG. In patients with a QRS duration of 120ms to 149ms either direct referral for a 100 biventricular pacemaker was made, or echocardiographic assessment of mechanical dyssynchrony was performed; this was left to the discretion of the referring physician. In those undergoing echocardiographic assessment of mechanical dyssynchrony 2 out of the following 3 criteria were required: i) aortic pre-ejection delay >140ms, defined as the interval between the onset of 105 the QRS complex and the onset of aortic flow using pulsed wave Doppler ii) interventricular mechanical delay >40ms, defined as the time difference between the onset of pulmonary ejection and aortic ejection using pulsed wave Doppler iii) delayed activation of the posterolateral left ventricular wall, defined as the maximal posterolateral wall inward movement, using M-mode or tissue Doppler 110 echo, occurring later than the start of left ventricular filling, using the transmitral Doppler signal [14]. Following implant, selected patients underwent echocardiographic optimization, which included optimization of AV delays, and RV and LV delay. These patients were selected according to the referring

Clinical indicators of responders vs. non responders

The median follow up was 293 days with a maximum of 1474 days. 90 160 (58.9%) patients had a favourable clinical response to CRT. This was predominantly by converting the patients from NYHA class III heart failure to class II (Figure 1). Baseline characteristics of responders and non-responders to CRT were similar in terms of concurrent drug treatment, age and the presence of 165 defibrillator functionality. There was a trend towards better response rates in patients with non-ischaemic heart failure compared to ischaemic heart failure (ischaemia 50% vs. non-ischaemic 62%) although this did not reach statistical significance. (p=0.131) (Table 2). Females were more likely to respond to CRT (P=0.012), whereas patients with COPD were not (p=0.008). 170

Comparison between potential predictors of response to CRT between the two groups demonstrated that the presence of permanent atrial fibrillation predicted a lack of response to CRT (p=0.017) (Table 3). The percentage of biventricular pacing and the site of LV lead placement were not significantly different between the two groups. The pre-implant QRS width was similar in 175 non-responders and responders to CRT 152ms (CI 131-181ms) and 150ms (CI 122-176ms) respectively.

Predictors of Non response to CRT

Atrial fibrillation 180

To evaluate patients with atrial fibrillation pre-implant, further analysis was performed in those with paroxysmal AF compared to permanent AF. Analysis of patients in sinus rhythm compared to those with paroxysmal AF (PAF) and persistent AF revealed no significant difference in terms of age, preimplant NYHA class, ejection fraction and median QRS width (Table 4). 185

Univariate logistic regression suggests that the presence of persistent AF to be negatively predictive of a symptomatic response to CRT (odds ratio: 0.408, 95% CI: 0.196-0.849, p=0.016), however multivariable logistic regression did not

Deleted: cardiomyopathy

Deleted: cardiomyopathy

Deleted: There was a significant difference between symptomatic response rates in the presence and absence of persistent AF (p=0.017) but not paroxysmal AF (p=0.564). Median best proportion of time pacing both ventricles measured at pacing check 190 was 88.3% for symptomatic responders and 98% for symptomatic nonresponders in patients with persistent AF. AV node ablation was performed in 3 patients with persistent AF, of whom none responded symptomatically.

Deleted: demonstrated

Pre-implant echocardiographic assessment of mechanical dyssynchrony 195

Of the 164 patients selected for CRT in the study, 95 patients had a preimplant echocardiographic dyssynchrony study. Table 5 shows the characteristics and response rates for patients with and without pre-implant assessment of mechanical dyssynchrony. Both groups had similar baseline QRS widths and pre-implant LV ejection fractions. There was no significant difference 200 in symptomatic response rates between the two groups using the χ 2 test (p=0.877) or using univariate logistic regression (OR: 0.903, 95% CI: 0.478-1.704, p=0.752), implying that there is no difference in response rates following CRT whether a pre-implant echocardiographic dyssynchrony assessment is performed or not. 205

Of the 95 patients who had a pre-implant dyssynchrony study, 54 (56.8%) had a positive response rate and 41 (43.2%) a negative response rate to CRT. However of the patients who had a pre-implant dyssynchrony study, 62% had a positive study as defined above. Of those who had a positive dyssynchrony study, 67% had a positive response rate to CRT, compared to 54% positive response in 210 those who had a negative study (p=0.09). There was no difference in baseline ejection fraction. Patients with significant COPD were defined as those with a diagnosis of 215 underlying airways disease on the basis of respiratory assessment including lung function testing for which they were receiving concomitant treatment (typically a steroid inhaler and/or bronchodilator). On this basis 22 patients had coexisting COPD of which only 6 patients (28%) responded to CRT (p=0.008).

Multivariate logistic regression showed that males and patients with 220 COPD were the only negative independent predictors of response to CRT with an overall p=0.0002 and overall accuracy of 64% (percentage of cases correctly identified) (Table 6). There was a trend towards the presence of permanent atrial fibrillation to be associated with a poor clinical response.

225

Discussion

Our results demonstrate that male sex, COPD and chronic atrial fibrillation are predictors of poor response to CRT in our patient cohort. There was a trend towards better response in patients with echocardiographic evidence of interventricular or intraventricular dyssynchrony but this did not 230 reach statistical significance.

Importantly we have shown that patients with COPD responded poorly to CRT. Although this has not been previously reported, it is likely that differentiating breathlessness due to lung disease and left ventricular impairment can be difficult and when faced with a very symptomatic patient 235 refractory to heart failure treatment, it was reasonable to implant a CRT device.

In addition the poor response in this group might be related to limited up titration of medication and in fact of the 22 patients with COPD, 15 (68%) were and measurements of maximal oxygen consumption using cardiopulmonary exercise testing might be more appropriate in order to ascertain the aetiology of the patient's symptoms before embarking on CRT implantation.

Previous studies have shown improved response rates to CRT in females.

Lilli et al [16] showed greater reductions in LV volumes in women compared to 245 men (76% in women vs. 59% in men, p<0.05) and significant reductions in LV end systolic volumes (LVESV) of ≥10% compatible with LV reverse remodeling at 12 months follow up after controlling for confounding factors such as aetiology. Similar findings were shown in a subgroup analysis of the PROSPECT trial, with ≥30% reduction in LVESV in 53.6% of women compared to 31.2% of 250 men (p=0.0005), suggesting a true gender specific effect [17]. Previous studies have shown different degrees of physiological and pathological remodeling associated with end stage ischaemic heart failure [18], hypertension [START_REF] Carroll | Sex-associated differences in left ventricular function in aortic stenosis of the elderly[END_REF] and aortic stenosis [20] in males and females. In addition, in failing human hearts a higher myocyte death (necrosis or apoptosis) has been clearly demonstrated in 255 men than in women [21]. Based on these observations it is possible that females have a more favourable substrate for reverse remodeling during CRT.

Measures of mechanical dyssynchrony using echocardiography have revealed conflicting results. Initial single centre studies reported a strong association between measures of dyssynchrony and outcomes following CRT 260 [22][23][24][25]. The recently published multicentre PROSPECT trial only demonstrated modest sensitivity and specificity of measures of dyssynchrony to predict CRT response. This in part was thought to be related to a variety of measures of Deleted: [16] Deleted: [18] Deleted: [17] Deleted: [START_REF] Carroll | Sex-associated differences in left ventricular function in aortic stenosis of the elderly[END_REF] Deleted: [20] Deleted: 12 dyssynchrony used to select patients for CRT. Further analysis did show a correlation between these parameters and extent of LV reverse remodeling at 265 6month follow up [17]. In addition, "super-responders" (defined as an LVESV reduction of ≥30% at follow up) had more extensive dyssynchrony suggesting that echocardiographic measures of dyssynchrony might predict LV reverse remodeling. In our current study there was a trend in better response to CRT in patients with significant dyssynchrony defined by the previously described 270 criteria, however our study was under-powered to detect significant differences between these two groups. More promising data is emerging with regards to 3D echocardiographic assessment of dyssynchrony [26] and speckle tracking echocardiography [27], which might prove better predictors of response to CRT.

There was a trend in poor response to biventricular pacing in patients 275 with persistent atrial fibrillation. Although this might have been related to more rapid ventricular rates and therefore a lower percentage of biventricular pacing (sinus rhythm 97±24%, PAF 98±31%, chronic AF 90±39%, p=0.01), it appeared that the permanent AF responders were paced 88% of the time and the nonresponders 98%. Previous studies have postulated that patients with AF can 280 have fusion and pseudofusion beats resulting from interaction between intrinsically conducted and paced beats, which could result in ineffective pacing despite the apparent delivery of CRT. Therefore it is possible that the recorded proportion of the time spent pacing both ventricles might be an overestimate. [28] This can be overcome by performing an AV node ablation. A 285 study by Gasparini et al [29] showed that patients with AF only showed an increase in ejection fraction, reverse remodeling, improved exercise tolerance and reduced mortality if they underwent AV node ablation. Similar findings were Deleted: . Deleted: [25] Deleted: [26] Deleted: The presence of atrial fibrillation, in particular chronic permanent AF, predicted a poor response t Deleted: o CRT Deleted: [27] Deleted: [ [30], who demonstrated comparable outcomes with CRT in patients in sinus rhythm and AF with AV node ablation. This suggests the 290 importance of ensuring close to 100% biventricular pacing although loss of atrioventricular synchrony might also play a role in poor response to CRT in this patient group.

Currently it is recommended that the LV lead should be positioned at the LV free wall, which corresponds to the myocardium drained by the lateral or 295 posterolateral cardiac veins. 87% of our patients had LV lead implanted within these veins. There appeared to be no significant difference between responders and non responders with regards to lead positioning. This is in agreement with a subanalysis of the COMPANION study which showed that LV lead placement was not predictive of response to CRT therapy [31]. However, implantation of the LV 300 lead adjacent to an area of transmural scar is predictive of poor response to CRT [32].

Approximately two-thirds of our patients had ischaemic heart failure.

Response rates appeared to be no different between the ischaemic and non 305 ischaemic group. The aetiology of heart failure has been shown previously to be predictive of clinical response to CRT. Initial work by Marsal et al [33] and more recent evidence from CARE-HF [START_REF] Konstam | Ventricular remodeling in heart failure: a credible surrogate endpoint[END_REF] and PROSECT [17] have shown improved clinical outcome and larger decreases in LVESV in patients with non-ischaemic heart failure compared to ischaemic patients. However the CARE-HF 310 demonstrated similar reductions in mortality in both groups [7]. In our study there was a trend in better response to CRT in patients with non-ischaemic heart Deleted: [30] Deleted: [31] Deleted: cardiomyopathy Deleted: p Deleted: In contrast to our study, Deleted: t

Deleted: cardiomyopathy

Deleted: [32] Deleted: [33] Deleted: [16] Deleted: cardiomyopathy We have demonstrated that in a large cohort of patients undergoing CRT, 315 that a number of factors can influence response. Current guidelines only use LV ejection fraction, NYHA class and QRS width to select patients for these devices.

We have shown that in addition to these measures it is important to consider comorbidities in particular COPD when considering patients for CRT.

320

Limitations of the study

This study is limited by the retrospective design. In addition our definition of response to CRT was confined as an improvement in NYHA class and lack of hospitalization with heart failure. It is unclear whether an improvement in clinical status translates into improved mortality. Other studies 325 have adopted more objective measures including echocardiographic evidence of LV reverse remodeling which correlates well with survival in heart failure trials of medical interventions [START_REF] Wilinski | Different response rates to cardiac resynchronization therapy (CRT) according to the applied definition[END_REF], which was not analysed in this study. In addition we have defined non responders as no change in symptom class, however this may represent a positive outcome as disease progression might be reduced 330 compared with the natural history without CRT. As a result, CRT response rates are dependent on the definition of 'response' [36].

Conclusion

This study showed that gender (males) and the coexisting COPD were 335 predictors of poor response to CRT. This highlights the importance of

3

 3 What is already known about this topicApproximately a third of patients fulfilling the criteria for cardiac resynchronization therapy derive little or no benefit following implantation. Introduction 55 Cardiac resynchronization therapy (CRT) is an established treatment for heart failure patients with left ventricular systolic function and prognosis in patients with moderate or severe heart failure, reduced left ventricular function and a

Formatted

  January 2004 and November 2007 at St Thomas' Hospital were retrospectively analysed. Standard criteria for implantation of a CRT system were used: Class III or IV NYHA (New York Heart Association) class heart failure refractory to drug ventricular ejection fraction ≤35% and evidence of ventricular 90 dyssynchrony using the surface ECG or echocardiography.

  significance (odds ratio: 0.482, 95% CI 0.215-1.081, p=0.077).

10

 10 Chronic obstructive pulmonary disease (COPD)

  a β blocker due to poor tolerance. Therefore, more objective measures of the severity of lung disease such as a formal lung function testing 240

  this study was under-powered to detect significant differences between these two groups.

16 Table 1 :

 161 characteristics, in particular the presence of comorbidities that might affect the response to CRT. Baseline characteristics (n=164), IHD-ischaemic heart disease, CABGcoronary artery bypass grafting, COPD -chronic obstructive pulmonary disease, NYHA -New York Heart Association, ICD -internal cardiac defibrillator, LBBBleft bundle branch block, RBBB -right bundle branch block, IVCDintraventricular conduction delay. 365 Age(mean yrs±SD) 67±13 Men/Women (

Figure 1 :

 1 Figure 1 : Distribution of NHYA Heart failure class at baseline and following CRT (%).

Figure

  Figure

  Figure 1

Table 2 :

 2 Comparison of baseline characteristics for responders and non 370 responders to cardiac resynchronization therapy.

		International Journal of Clinical Practice	Page 16 of 28
				Deleted: Cardiomyopathy
	%)		78/22	Deleted:
	Ischaemic Heart Failure (%)		64	Deleted: cardiomyopathy
	Non ischaemic Heart Failure (%)	36
	Comorbidities (n)
	IHD		105
	CABG		46
	COPD		22
	Hypertension		70
	Valvular heart disease	37
	Diabetes		36
	Symptoms at baseline	(%)
	NYHA Class I		0.6
	NYHA Class II		11
	NHYA Class III		73
	NYHA Class IV		15
	Sinus Rhythm / AF (%)		54/46
	Preexisting pacemaker		17
	Preexisting ICD		5
	QRS duration
	Mean (ms)		156
	120-149 (%)		49
	>150 (%)		51
	Resting ECG (%)
	LBBB		88
	RBBB		4
	IVCD		8
	Ejection Fraction (%)
	<20%		16
	20-30%		40
	30-40%		44
	LV lead implantation site (%)
	Posterolateral or lateral vein	87
	Middle cardiac vein		4
	Anterior		9
		International Journal of Clinical Practice

Table 3 :

 3 Comparison of potential predictors of response to CRT the non responders and responders.

		International Journal of Clinical Practice	Page 18 of 28
	Variable	Non-	Responders	P value
		Responders
	Ischaemic (Y:N)	52:22	53:37	0.131
	AF (Y:N)	36:38	35:54	0.124
	Pers/permAF (Y:N)	24:36	14:54	0.017
	PAF(Y:N)	15:61	22:67	0.564
	Median QRS width	152(131-181)	150(122-176)	0.527
	(ms)
	QRS 120ms-149ms	3:25	6:31	0.525
	(Y:N)
	QRS > 150ms (Y:N)	15:13	19:18	0.859
	Dyssynchrony echo	45:26	54:35	0.726
	(Y:N)
	LBBB (Y:N)	41:12	54:12	0.542
	Optimised (Y:N)	34:42	29:62	0.121
	Median Bivent	99(96-100)	99(98-100)	0.197
	paced (%)
	LV lead	57:8	73:10	0.961
	Posterior/lateral
	(Y:N)
	Median	48(27-84)	48(23-61)	0.450
	Interventricular
	delay (ms)
	Median maximum	57(29-83)	48(32-70)	0.494
	Intraventricular
	delay (ms)
	380
		International Journal of Clinical Practice

Table 4 :

 4 Characteristics for patients with atrial fibrillation (paroxysmal and chronic) and sinus rhythm.

			Sinus rhythm	Paroxysmal	Persistent AF
				AF
	Median age (years)	68 (24-85)	68 (41-83)	74 (45-87)
	Mean pre-implant NYHA	2.99	3.0	3.15
	class
	Median	pre-implant	25% (11-45)	25.5%(13-58) 30% (10-58)
	ejection fraction
	Median QRS duration (ms) 149.5(104-214) 142(107-189) 152(116-224)

Table 5 :

 5 Characteristics and response rates for patients with and without pre-

	385	implant assessment of mechanical dyssynchrony
			Pre-implant	No pre-implant
			dyssynchrony echo	dyssynchrony echo
		Median age (years)	67 (24-85)	72.5 (31-87)
		Mean pre-implant NYHA class 3.07	2.88
		Median pre-implant ejection	25% (10-48)	30% (15-58)
		fraction
		Median QRS duration (ms)	148 (100-250)	150 (100-234)
		Response rate	55/102 (54%)	35/62 (56%)
	390
	395

Table 6 :

 6 Multivariable logistic regression for predictors of clinical response deemed significant at univariate analysis. Only sex (male) and COPD are negatively associated with clinical response, overall p = 0.0002, and overall accuracy (percentage of cases correctly classified) is 64%. Having a large AF 400 burden is almost statistically significant for having a poorer clinical response.

				Page 20 of 28
	Variable	Odds ratio	95% CI OR	p-value
	Age	0.979	0.952-1.005	0.117
	Sex (male)	0.273	0.111-0.671	0.005
	COPD	0.225	0.075-0.671	0.007
	Pers/permAF	0.482	0.215-1.081	0.077
	Echo	0.903	0.478-1.704	0.752
	dyssynchrony
	pre-implant
	assessment
	405
	410

International Journal of Clinical PracticeInternational Journal of Clinical Practice


MD Magnus Baumhäkel
email: magnus@baumhaekel.de

MS Nils Schlimmer

MS Mario Kratz

Geoffrey Hackett

MD Graham Jackson

MD Michael Böhm

MD Geoffrey Hacket

Cardiovascular Risk, Drugs and Erectile Function -A Systematic Analysis

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What´s known?

Erectile dysfunction is known to be related to endothelial dysfunction and therefore, cardiovascular risk factors and diseases are closely associated. Those cardiovascular risk patients have to be treated with cardiovascular drugs according to evidence based guidelines.

These drugs were often accused to impair erectile function as a major adverse effect, likely to influence treatment adherence of patients.

What´s new?

Only thiazide diuretics and beta-blockers except nebivolol may adversely influence erectile function. ACE-inhibitors, angiotensin-receptor-blockers, and calcium-channel-blockers are reported to have no relevant or even a positive effect on erectile function. Knowledge about these effects of drug-treatments on erectile function and about the major role of the endothelium in penile function might improve patients' adherence to evidence based treatment of cardiovascular diseases.

Introduction

Erectile dysfunction is defined as the inability to attain or maintain a penile erection sufficient for satisfactory sexual performance [START_REF] Hacket | Impotence. NIH Consensus Development Panel on Impotence[END_REF]. Prevalence of erectile dysfunction in the Western industrialized countries amounts to 20-30% in the general male population and probably higher, about 75% in cardiovascular high-risk [START_REF] Hackett | The burden and extent of comorbid conditions in patients with erectile dysfunction[END_REF]. This imposes an enormous economical and psychological impact on affected individuals and society [START_REF] Braun | Epidemiology of erectile dysfunction: results of the 'Cologne Male Survey[END_REF][START_REF] Feldman | Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study[END_REF][START_REF] Solomon | Erectile dysfunction: the need to be evaluated, the right to be treated[END_REF][START_REF] Jackson | Cardiovascular aspects of sexual medicine[END_REF].

Physiology of erectile function is dependent on a balanced vascular, neurologic, hormonal, and psychological system. Sexual stimuli are processed within the central nervous system and relayed to the spinal cord by neural signals. Neural impulses initiate blood flow to the pelvic vascular bed via the non-adrenergic/non-cholinergic nerves by a consecutive release of nitric oxide [START_REF] Krane | Impotence[END_REF]. Initiation and maintenance of penile erection is primarily dependent on the function of the vascular system within an appropriate hormonal milieu. Initial blood flow into the corpora cavernosa and the corpus spongiosum starts an erection. Pressure within the intracavernosal spaces increases to prevent penile venous outflow, allowing a firm erection.

High levels of nitric oxide in the corpora cavernosa maximize blood flow and penile engorgement [START_REF] Burnett | Nitric oxide: a physiologic mediator of penile erection[END_REF]. Appropriate testosterone levels have been demonstrated to be necessary for maintenance of intrapenile nitric oxide synthase levels [START_REF] Mills | Androgen maintenance of erectile function in the rat penis[END_REF].

Previously, psychological factors have been suggested to be the major cause of erectile dysfunction, but in the last two decades, it has been recognized that endothelial dysfunction and subsequent cardiovascular diseases account for erectile problems more often than not [START_REF] Kloner | Erectile dysfunction and atherosclerosis[END_REF][START_REF] Thompson | Erectile dysfunction and subsequent cardiovascular disease[END_REF]. The Massachusetts Male Aging Study as well as the Cologne Male Survey demonstrated a correlation between age and incidence of erectile dysfunction with an increase in erectile dysfunction in patients with cardiovascular risk factors or diseases [START_REF] Braun | Epidemiology of erectile dysfunction: results of the 'Cologne Male Survey[END_REF][START_REF] Feldman | Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study[END_REF]. The prevalence of erectile dysfunction amounts to 75% in cardiovascular high-risk patients reinforcing the Erectile dysfunction, as a symptom of impairment of the endothelial monolayer of the corpus cavernosum and the penile arteries is recognised to become clinically relevant prior to cardiovascular events due to the extensive network (surface area) of endothelium in the penis [START_REF] Baumhakel | Erectile dysfunction correlates with left ventricular function and precedes cardiovascular events in cardiovascular high-risk patients[END_REF]. Erectile dysfunction therefore represents an early sign and symptom of generalized endothelial dysfunction and atherosclerosis, providing a means for the early detection of highrisk individuals with the opportunity to prevent cardiovascular events [START_REF] Jackson | Erectile dysfunction: a marker of silent coronary artery disease[END_REF].

Within the last four decades the medical press and the lay media have reported on an association of impaired erectile function with drugs used for treatment of cardiovascular diseases and hypertension in particular. The publicity surrounding these reports has caused concerns among patients, thereby potentially impairing adherence to important cardiovascular medical regimens. Results from small trials suggested that the treatment of hypertension with ACE-inhibitors, AT1-antagonists, beta-blockers, diuretics or calcium-channel blockers rather than hypertension itself could be associated with vascular and organ damage, contributing to erectile dysfunction [START_REF] Modebe | Erectile failure among medical clinic patients[END_REF]. This manuscript presents and evaluates data from clinical trials, but also preclinical studies and possible mechanisms of action of drugs commonly used for the treatment of cardiovascular diseases regarding adverse or beneficial effects on erectile function. Cochrane Clinical Trials Registry. The following terms were used for research: "erectile dysfunction or impotence" in combination with "ACE-inhibitors", "angiotensin", "betablockers", "calcium antagonist", and "diuretics".

Methods

Data Sources and Searches

Study Selection

Selection of references was performed in three steps (figure 2). Studies were first excluded if they were nonhuman data, letters, reviews, case-reports or manuscripts in a language other than English. Secondly, trials dealing with combined treatment with PDE-5 inhibitors or combination treatment with more than one substance were excluded. Finally, clinical trials, which did not explore the effects of single cardiovascular drugs were excluded, e.g. the Massachusetts Male Aging Study [START_REF] Feldman | Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study[END_REF]. These trials are demonstrated in a separate table, including epidemiological trials with more than 500 patients (table). Additionally, trials evaluating erectile function with a validated questionnaire or direct assessment of penile rigidity were extracted. Both reviewers conducted the complete selection process independently. Effects of cardiovascular drugs on erectile function and possible mechanisms are described in detail in the discussion section.

Results

Systematic analysis of literature revealed eight trials evaluating the effects of beta-blockers, five trials evaluating the effect of treatment with ace-inhibitors or angiotensin-receptorblockers and one trial evaluating the effect of treatment with diuretics on erectile function (table). There was no trial evaluating the effect of calcium-channel-blockers on erectile function. Most of these trials were performed in patients with hypertension. Moreover, five epidemiological trials with more than 500 patients studied the effects of different Results of these trials demonstrate that only thiazide diuretics and beta-blockers, except Nebivolol, may influence erectile function. ACE-inhibitors, angiotensin-receptor-blockers and calcium-channel-blockers are reported to have no relevant or even a positive effect on erectile function.

Discussion

Beta-Blockers

Beta-blockers were frequently suggested to be associated with impairment of sexual desire, libido and especially erectile dysfunction. Several trials from the 1980s in patients with hypertension treated with different beta-blockers revealed conflicting results regarding influence on erectile function, but these data were limited. In most trials, erectile dysfunction was not the primary objective and was assessed by patient-reports, instead of evaluation with a questionnaire or measurement of penile rigidity [START_REF] Rasmussen | Blood pressure, body fluid volumes and glomerular filtration rate during treatment with labetalol in essential hypertension[END_REF][START_REF] Ohman | Enalapril and atenolol in primary hypertension--a comparative study of blood pressure lowering and hormonal effects[END_REF][START_REF]Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Report of Medical Research Council Working Party on Mild to Moderate Hypertension[END_REF][START_REF] Lorimer | Long-term comparison of metoprolol and methyldopa in the treatment of hypertension[END_REF].

In the late 1990s, trials compared the beta-blockers carvedilol and atenolol to the ACEinhibitor lisinopril and the AT1-antagonist losartan (table). Treatment with carvedilol and atenolol decreased the frequency of sexual contacts in men with newly diagnosed hypertension compared to lisinopril or losartan [START_REF] Fogari | Sexual function in hypertensive males treated with lisinopril or atenolol: a cross-over study[END_REF][START_REF] Fogari | Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study[END_REF]. However, these trials were limited to the surrogate of sexual contacts, which is not equivalent to erectile function. Carvedilol is a lipophilic, non-selective adrenergic blocker with multiple cationic channel blocking properties. Various data and underlying mechanisms are difficult to interpret, especially in comparison to different beta-blockers. Furthermore, a meta-analysis of the later beta-blocker trials in the 90s including 35.000 patients indicated a small, but significant increase in the ). This analysis however, concerned sexual behaviour and not specifically erectile dysfunction [START_REF] Ko | Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction[END_REF].

Recent randomized, prospective trials have failed to confirm any negative effects of betablockers on erectile function. In 65 patients with coronary heart disease treatment with metoprolol (95mg) for four months did not influence erectile function, which was assessed with a standardized and validated questionnaire [START_REF] Franzen | Effects of beta-blockers on sexual performance in men with coronary heart disease. A prospective, randomized and double blinded study[END_REF]. Increase of erectile dysfunction in connection with beta-blockers might be biased by psychological effects derived from the awareness of being treated with a certain substance. Patients who were informed about potential adverse effects of beta-blockers on erectile function more frequently reported erectile dysfunction compared to patients without knowledge about the drug used, but nevertheless, this trial evaluated erectile dysfunction without a standardized questionnaire (figure 3) [START_REF] Silvestri | Report of erectile dysfunction after therapy with beta-blockers is related to patient knowledge of side effects and is reversed by placebo[END_REF]. In those patients with impaired erectile function, treatment with sildenafil and placebo was similarly effective showing a psychological impact on the provenance of this adverse effect. These results were confirmed in a recent trial with hypertensive patients treated with metoprolol [START_REF] Cocco | Erectile dysfunction after therapy with metoprolol: the Hawthorne effect[END_REF].

Recent clinical trials reported beneficial effects of nebivolol, a third generation beta-blocker with nitric-oxide-mediated vasodilatory properties [START_REF] Brixius | Nitric oxide, erectile dysfunction and betablocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men[END_REF]. In hypertensive patients treated with atenolol, metoprolol or bisoprolol, switching treatment to nebivolol improved erectile function in 69% of patients [START_REF] Doumas | Beneficial effects of switching from betablockers to nebivolol on the erectile function of hypertensive patients[END_REF]. Another trial demonstrated no effects of nebivolol on erectile function in patients with hypertension, whereas atenolol decreased erectile function [START_REF] Boydak | A Randomised Comparison of the Effects of Nebivolol and Atenolol with and without Chlorthalidone on the Sexual Function of Hypertensive Men[END_REF]. Similar effects were demonstrated in a cross-over trial in hypertensive men treated with metoprolol and nebivolol. Metoprolol decreased sexual function, whereas nebivolol improved sexual activity and erectile dysfunction subscores even though both drugs showed similar [START_REF] Brixius | Nitric oxide, erectile dysfunction and betablocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men[END_REF]. This advantage to erectile function has been supposed to be related to nitric-oxide-release and direct vasodilation by nebivolol [START_REF] Franzen | Effects of beta-blockers on sexual performance in men with coronary heart disease. A prospective, randomized and double blinded study[END_REF]. A recent observational trial confirmed these results. In univariate analysis, treatment with carvedilol was associated with decreased erectile function, whereas nebivolol improved erectile function in multivariate analysis [START_REF] Cordero | Erectile dysfunction in high-risk hypertensive patients treated with beta-blockade agents[END_REF].

Mechanisms

Several reports on varying frequencies of sexual dysfunction depending on structure and lipophilicity of beta-blockers were published, but only a few studies addressed possible mechanisms [START_REF] Rosen | Beta-blocker effects on sexual function in normal males[END_REF]. Direct effects on penile and vascular smooth muscle cells with a decreased perfusion pressure due to unopposed alpha-receptor stimulation were suggested, but not experimentally proven or clinically investigated [START_REF] Shiri | Cardiovascular drug use and the incidence of erectile dysfunction[END_REF]. Decreased levels of testosterone and, in part, of the follicle-stimulating hormone by metoprolol, pindolol, atenolol and propranolol have been suggested to be involved in reduction of sexual function and desire [START_REF] Rosen | Beta-blocker effects on sexual function in normal males[END_REF].

Depression of Leydig cell activity involves beta-2 type receptors [START_REF] Boydak | A Randomised Comparison of the Effects of Nebivolol and Atenolol with and without Chlorthalidone on the Sexual Function of Hypertensive Men[END_REF]. Hence, particularly non-selective beta-blockers such as propranolol were suggested to influence sexual function [START_REF] Anakwe | Beta 2-adrenergic stimulation of androgen production by cultured mouse testicular interstitial cells[END_REF]. Moreover, propranolol was demonstrated to increase latency to initial erection and to inhibit erectile reflexes, which may affect erectile function [START_REF] Shiri | Cardiovascular drug use and the incidence of erectile dysfunction[END_REF]. These effects were dependent on stereo-selectivity of propranolol with (-)-propranolol showing the most pronounced effects and were supposed to be, at least in part, independent of beta-adrenoceptor blockade [START_REF] Smith | The inhibitory effects of propranolol on genital reflexes in male rats[END_REF].

Nebivolol was investigated in an atherosclerotic animal model. Nebivolol, but not metoprolol improved endothelial function of the aorta and the corpus cavernosum with a significant reduction in penile oxidative stress and collagen content [START_REF] Baumhaekel | Nebivolol, but not Metoprolol improves endothelial function of the corpus cavernosum in ApoE-knockout-mice[END_REF]. Nebivolol protected cavernosal tissue against structural changes and increased expression of eNOS, whereas the calciumchannel blocker amlodipine did not [START_REF] Toblli | In vivo and in vitro effects of nebivolol on penile structures in hypertensive rats[END_REF]. As selective beta-blockers might impair erectile Compared to placebo, chlorthalidone was demonstrated to impair erectile function (table) [START_REF] Langford | Effect of weight loss on thiazide produced erectile problems in men[END_REF]. There is a multiplicity of trials with thiazides in combination treatment. These were not considered for analysis, because of the difficulty of interpretation of interaction of combination treatments with ACE-inibitors, AT1-antagonists or calcium-channel blockers.

Results from trials evaluating the influence of multiple drugs on erectile function vary, but even these trials suggest a negative effect of thiazides on erectile function (table). A prospective trial in a general population assessed erectile function with two questions at baseline and after five years in men free from moderate or severe erectile dysfunction at baseline [START_REF] Shiri | Cardiovascular drug use and the incidence of erectile dysfunction[END_REF]. In multivariate analysis, use of diuretics was associated with an increased risk of developing erectile dysfunction (RR=1.3, CI 0.7-2.4). Similar results were obtained in patients with hypertension [START_REF] Doumas | Factors affecting the increased prevalence of erectile dysfunction in Greek hypertensive compared with normotensive subjects[END_REF][START_REF] Derby | Drug therapy and prevalence of erectile dysfunction in the Massachusetts Male Aging Study cohort[END_REF]. The recent ONTARGET/TRANSCEND-erectile dysfunction substudy, a randomized, controlled, blinded trial using multivariate analysis, did not demonstrate a significant association of pre-treatment with diuretics with erectile function in cardiovascular high-risk patients [START_REF] Bohm | Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND)[END_REF]. In summary, thiazide diuretics may have a negative influence on erectile function, but clear data are missing.

There are only insufficient data about the effects of non-thiazide diuretics on erectile function. [START_REF] Derby | Drug therapy and prevalence of erectile dysfunction in the Massachusetts Male Aging Study cohort[END_REF]. Randomized, prospective trials providing data on treatment with aldosterone-antagonists such as spironolactone or eplerenone are lacking.

The Massachusetts Male Aging Study revealed an association of increased prevalence of

Mechanisms

The underlying mechanisms of negative effects of thiazides on erectile function are unknown.

It has been suggested that sodium depletion leads to increased central alpha 2 adrenergic function, which may depress erectile performance [START_REF] Langford | Effect of weight loss on thiazide produced erectile problems in men[END_REF]. However, an influence of thiazides on sex related hormones is not likely, because there was no effect on testosterone, estrodiol or prolactin levels in humans [START_REF] Langford | Effect of weight loss on thiazide produced erectile problems in men[END_REF].

Even though there are no data about aldosterone-antagonists on erectile dysfunction from clinical trials, animal studies revealed information about possible mechanisms. Aldosterone has been demonstrated to enhance norepinephrine-induced contraction of isolated human corpora-cavernosal smooth muscle cells, hence decreasing erectile function [START_REF] Muguruma | Effect of aldosterone on isolated human penile corpus cavernosum tissue[END_REF]. Pretreatment with spironolactone abolished these negative effects completely. On the other hand, spironolactone is supposed to decrease erectile function and sexual desire due to androgen suppression by competing with testosterone and dihydrotestosterone for peripheral androgen binding sites [START_REF] Rastogi | Why do patients with heart failure suffer from erectile dysfunction? A critical review and suggestions on how to approach this problem[END_REF]. Additionally, spironolactone seems to be a weak inhibitor of testosterone synthesis. In summary, use of aldosterone-antagonists could be associated with a negative influence on erectile function, but clinical trials are missing. There are no data about possible mechanism of loop-diuretics on erectile function, but speculation about sodium-depletion may also apply for loop-diuretics.

Calcium-channel blockers

There is no clinical trial evaluating the effect of calcium-channel-blockers on erectile function with adequate assessment of erectile dysfunction. Patients with hypertension or coronary artery disease reported a decrease of erectile function with nifedipine compared to placebo [START_REF] Poole-Wilson | Safety of nifedipine GITS in stable angina: the ACTION trial[END_REF][START_REF] Marley | Safety and efficacy of nifedipine 20 mg tablets in hypertension using electronic data collection in general practice[END_REF]. In contrast, trials evaluating effects of multi-drug treatment did not reveal negative effects of treatment with calcium-channel-blockers on erectile function, except a prospective trial in a general population [START_REF] Bohm | Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND)[END_REF][START_REF] Shiri | Cardiovascular drug use and the incidence of erectile dysfunction[END_REF][START_REF] Doumas | Factors affecting the increased prevalence of erectile dysfunction in Greek hypertensive compared with normotensive subjects[END_REF][START_REF] Derby | Drug therapy and prevalence of erectile dysfunction in the Massachusetts Male Aging Study cohort[END_REF][START_REF] Roth | Prevalence and risk factors for erectile dysfunction in men with diabetes, hypertension, or both diseases: a community survey among 1,412 Israeli men[END_REF]. Although relaxation of vascular and cavernosal smooth muscle cells is crucial in the physiology of erectile function, there is no clinical evidence for beneficial effects of calcium-channel blockers. Calcium-channelantagonists are reported to have no relevant effect on erectile function in men regarding quality of trials demonstrating negative effects on erectile function.

Mechanisms

Increase of heart rate after treatment with short acting dihydropyridines might be a reasonable speculation to explain the negative effects of calcium-channel-antagonists on erectile function as it is known to impair endothelial and likely erectile function, but experimental data are lacking [START_REF] Beere | Retarding effect of lowered heart rate on coronary atherosclerosis[END_REF]. In contrast, "in vitro" experiments indicated a reduction of norepinephrine induced contraction of corpora cavernosal smooth muscle cells by nifedipine, diltiazem and verapamil [START_REF] Fovaeus | Effects of some calcium channel blockers on isolated human penile erectile tissues[END_REF]. Further studies confirmed these data and provided information on recovery of impaired neurogenic relaxation of corpora cavernosa in hypertensive rats treated with amlodipine [START_REF] Kerfoot | Characterization of calcium channel blocker induced smooth muscle relaxation using a model of isolated corpus cavernosum[END_REF][START_REF] Ushiyama | Treatment with hypotensive agents affects the impaired relaxation of the penile corpus cavernosum in hypertensive rats[END_REF].

ACE-inhibitors

Data about the influence of ACE-inhibitors on erectile function are limited due to quality of assessment of ED. Currently, there is only one trial evaluating the effects of treatment with an was determined using ultrasound, but there was no significant difference between the ACEinhibitor and placebo. Consistently, there was no influence of treatment with ACE-inhibitors on erectile function in several trials, evaluating the effects of different kinds of cardiovascular drugs (table) [START_REF] Bohm | Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND)[END_REF][START_REF] Shiri | Cardiovascular drug use and the incidence of erectile dysfunction[END_REF][START_REF] Doumas | Factors affecting the increased prevalence of erectile dysfunction in Greek hypertensive compared with normotensive subjects[END_REF][START_REF] Derby | Drug therapy and prevalence of erectile dysfunction in the Massachusetts Male Aging Study cohort[END_REF][START_REF] Roth | Prevalence and risk factors for erectile dysfunction in men with diabetes, hypertension, or both diseases: a community survey among 1,412 Israeli men[END_REF].

Angiotensin-Receptor-Blockers

Comparable to the effects of ACE-inhibitors, the angiotensin receptor blocker valsartan was shown to increase frequency of sexual contacts, compared to the beta-blocker carvedilol [START_REF] Modebe | Erectile failure among medical clinic patients[END_REF].

These preliminary results could be confirmed in 82 patients with hypertension and erectile dysfunction. Treatment with losartan for twelve weeks significantly improved erectile function, satisfaction, and sexual activity significantly [START_REF] Llisterri | Sexual dysfunction in hypertensive patients treated with losartan[END_REF]. Moreover, a recent open-label study in 3502 hypertensive patients, of whom 952 were newly diagnosed, with erectile dysfunction treated with valsartan revealed an improvement of erectile function even in patients, in whom drug treatment had been switched from another class of antihypertensive drugs (figure 4) [START_REF] Dusing | Effect of the angiotensin II antagonist valsartan on sexual function in hypertensive men[END_REF]. Moreover, in patients with the metabolic syndrome, irbesartan improved erectile function in parallel to a decline of blood pressure and independent of concomitant treatment with diuretics [START_REF] Baumhakel | Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome[END_REF]. These results were limited by absence of a control group, but were confirmed in recent trials in patients with hypertension and high cardiovascular risk.

There was no negative effect of treatment with an angiotensin-receptor-blocker on erectile function, except in one trial in a general population [START_REF] Bohm | Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND)[END_REF][START_REF] Shiri | Cardiovascular drug use and the incidence of erectile dysfunction[END_REF][START_REF] Doumas | Factors affecting the increased prevalence of erectile dysfunction in Greek hypertensive compared with normotensive subjects[END_REF][START_REF] Derby | Drug therapy and prevalence of erectile dysfunction in the Massachusetts Male Aging Study cohort[END_REF][START_REF] Roth | Prevalence and risk factors for erectile dysfunction in men with diabetes, hypertension, or both diseases: a community survey among 1,412 Israeli men[END_REF].

Mechanisms

Penile blood flow as well as contractility of cavernosal smooth muscle cells depends on a complex balance between various paracrine regulators including angiotensin II and nitric oxide [START_REF] Navar | Paracrine regulation of the renal microcirculation[END_REF]. Angiotensin II is synthesized in endothelial and smooth muscle cells of penile [START_REF] Kifor | Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum[END_REF][START_REF] Becker | Plasma levels of angiotensin II during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction[END_REF]. Hence, ACE regulates cavernosal smooth muscle tone in a paracrine fashion by local angiotensin II production with tissue concentrations of angiotensin II being one and two orders of magnitude higher compared to the aorta or plasma levels respectively [START_REF] Kifor | Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum[END_REF]. In patients with organic erectile dysfunction, plasma and cavernosal levels of angiotensin II are elevated in the phase of penile detumescence compared to healthy men [START_REF] Becker | Plasma levels of angiotensin II during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction[END_REF]. Consequently, local intracavernosal injection of angiotensin II was demonstrated to spontaneously terminate drug induced erection in anesthetized dogs, while losartan increased intracavernosal pressure in a dose dependent manner resulting in an improvement of erection [START_REF] Kifor | Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum[END_REF]. Moreover, angiotensin II is was demonstrated to upregulate the PDE-V with consecutive detrimental effects on erectile function, which might be abolished by angiotensin-receptorblockers [START_REF] Katz | Potential role of type 5 phosphodiesterase inhibition in the treatment of congestive heart failure[END_REF].

Beneficial effects of angiotensin-receptor-blockers in clinical trials were confirmed in several disease models in rodents. In hypertensive rats, blood pressure related structural changes of penile vessels and the corpus cavernosum were significantly decreased in animals treated with losartan compared to amlodipine [START_REF] Toblli | Different effect of losartan and amlodipine on penile structures in male spontaneously hypertensive rats[END_REF]. Similar effects were demonstrated in hypertensive rats treated with a combination of the PDE-V-inhibitor sildenafil and the angiotensin-receptorblocker losartan. Functional and structural modifications in cavernosal tissue were significantly reduced in animals treated with the combination compared to monotherapy with losartan or even sildenafil [START_REF] Toblli | Functional and morphological improvement in erectile tissue of hypertensive rats by long-term combined therapy with phosphodiesterase type 5 inhibitor and losartan[END_REF]. Moreover, in ApoE-knockout mice, a rodent model for atherosclerosis, treatment with irbesartan improved endothelial function of the aorta as well as the corpus cavernosum to the same extent [START_REF] Baumhaekel | Nebivolol, but not Metoprolol improves endothelial function of the corpus cavernosum in ApoE-knockout-mice[END_REF]. These effects were demonstrated to be independent of blood pressure reduction. Moreover, effects were related to a reduction of oxidative stress in the corpus cavernosum. Angiotensin II increases production of reactive oxygen species via stimulation of the AT1-receptor and consecutively NADPH oxidase with recently shown to balance these negative effects. In isolated human corpora cavernosa, bradykinin increased relaxation of smooth muscle cells in parallel to the increase of intracellular levels of cAMP and cGMP [START_REF] Becker | Possible role of bradykinin and angiotensin II in the regulation of penile erection and detumescence[END_REF]. A head to head trial is missing so far, but data of the recent ONTARGET/TRANSCEND-erectile dysfunction substudy provided information on whether ACE-inhibitors, angiotensin-receptor-blockers, or a combination thereof are able to improve erectile function and whether inhibition of bradykinin-degradation via ACEinhibition will exert any further beneficial effects beyond AT1-antagonism [START_REF] Bohm | Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND)[END_REF]. In 1549 cardiovascular high-risk patients included, there was neither a beneficial effect of the ACEinhibitor ramipril, the angiotensin-receptor blocker telmisartan, nor of the combination of both on erectile function [START_REF] Bohm | Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials[END_REF]. In ACE-intolerant patients in the TRANSCEND-trial, telmisartan was not superior to placebo.

Conclusion

Erectile dysfunction is a major problem, increasing with age, with a prevalence of 20-30% in the general population [START_REF] Braun | Epidemiology of erectile dysfunction: results of the 'Cologne Male Survey[END_REF]. In cardiovascular high-risk patients, prevalence increases to 50-70% with a significant impact of cardiovascular risk factors and diseases on erectile function [START_REF] Bohm | Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND)[END_REF]. Drugs used for treatment of cardiovascular diseases have often been accused of influencing erectile function. Analysis of the literature demonstrates that evidence at best is firm only for thiazide diuretics and beta-blockers having a negative effect whereas nebivolol may have a positive influence on erectile function. ACE-inhibitors, angiotensin-receptor- blockers, and calcium-channel-blockers are reported to have no relevant or, in the case of ARBs, even a positive effect on erectile function respectively. Comparison and valuation of the trials included in this analysis is limited by the different study-designs. Erectile dysfunction was not the primary objective in all trials and evaluation of erectile dysfunction was not standardized. Furthermore, physicians should be aware of the physiological and even psychological impact of cardiovascular events on erectile function. Importantly, patients' concerns about the adverse effects of drugs on erectile function might limit the use of important medications in cardiovascular high-risk patients. Worsening of erectile dysfunction after identifying a patient at risk is more likely to be due to atherosclerosis and cardiovascular risk factors rather than the intake of drugs. We recommend explaining the effects of drugtreatments and the role of atherosclerosis in erectile dysfunction to the patients in order to improve patients' adherence to evidence based treatment of cardiovascular diseases. This analysis clearly demonstrates the importance of a validated evaluation of drug effects on erectile function in future trials on cardiovascular disease. Treatment with valsartan for 6 months decreases prevalence of erectile dysfunction in hypertensive male patients. Pre-specified subgroups were patients with or without previous antihypertensive treatment and patients receiving valsartan as part of a combination therapy.

Erectile dysfunction was assessed using the International Index of Erectile Function (IIEF).

Differences were significant in all groups (p<0.0001).

  in penile function might improve patients' adherence to evidence based treatment of cardiovascular diseases.

  erectile dysfunction with cardiovascular risk factors and diseases[START_REF] Baumhakel | Circulating endothelial progenitor cells correlate with erectile function in patients with coronary heart disease[END_REF][START_REF] Bohm | Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND)[END_REF] with impairment of endothelial function by cardiovascular risk factors such as hypertension being the common pathophysiological link. (figure1)[START_REF] Yavuzgil | Endothelial function in patients with vasculogenic erectile dysfunction[END_REF].

  January 2010. Target databases were MEDLINE, EMBASE and

  erectile function (ace-inhibitors, angiotensin-receptor-blockers, betablockers, diuretics, and calcium-channel-blockers; table).

  developing sexual dysfunction in patients treated with a beta-blocker compared to placebo (5 of 1000 patients, 95% CI 2-8

  contrast, considering the strong correlation and pathophysiological link between endothelial and erectile function, beta-blockers with beneficial effects on nitric oxide synthase and oxidative stress have been suggested to improve erectile function.DiureticsData about the effect of single use of diuretics on erectile function are sparse. A small number of patients and inadequate evaluation of erectile function limits the results of the trials.

  the use of diuretics in univariate analysis, but only non-thiazides such as loop-diuretics and aldosterone-antagonists remained significant after adjustment for co-morbidities (table)

  assessed with a standardized questionaire. Cavernosal blood-flow

  on vascular endothelium[START_REF] Griendling | Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells[END_REF][START_REF] Rajagopalan | Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone[END_REF]. Thus, angiotensin receptor blockade improves endothelial and erectile function via identical mechanisms.Angiotensin receptor blockers improved endothelial and erectile function in several clinical trials, which were in line with experimental studies. While angiotensin II impairs erectile function by contraction of vascular and cavernosal smooth muscle cells, bradykinin was

Figure 1 :

 1 Figure 1: Physiology of penile erection.

Figure 2 :Figure 3 :

 23 Figure 2: Reference selection

Figure 4 :

 4 Figure 4: Treatment with valsartan improves erectile function.

Table : Clinical trials evaluating the association of cardiovascular drugs and erectile function Epidemiological Trials

 :

	Year	Disease	n	Trial design	Measure-	Anal.			Result			Ref
					ment ED	multiv.	ACE-I	ARB	Beta-Blocker	Diuretic	CCB
	2001	General	922	Prospective	Question-	Yes	(+/-)	n.a.	(+/-)	-	(+/-)	(41)
		Popu		Observation	naire					(only non-
		lation								thiazides)
	2003	Diabetes
		/Hyper
		tension