Diabetic patients have a high prevalence of erectile dysfunction which is mainly caused by disturbance of the microvascular bed [1, 2]. This disturbance can be enhanced by hypertension, hyperlipoproteinemia and smoking, which are also risk factors for macroangiopathy [3, 4]. Therefore diabetics with erectile dysfunction and the presence of other cardiovascular risk factors have a higher likelihood of having coronary artery disease [5, 6]. Symptoms are often absent in those patients despite severe myocardial ischemia.

In earlier investigations it was demonstrated that the adenosine-mediated flow reserve (CFR) of the left anterior descending (LAD) artery is reduced to values in the lower normal range in most diabetic patients, indicating disturbance of microvascular flow dynamics [7]. Reduction of CFR below a cut-off value of 200% is closely correlated with exercise-induced myocardial ischemia by either microvascular dysfunction or significant coronary artery stenoses [8, 9]. Our aim was to evaluate whether sildenafil alters CFR in diabetics with erectile dysfunction.

CFR measurements at baseline and after sildenafil were performed in 21 patients. Minor side effects occurred in 5 patients including headache, flush and nasal congestion. Blood pressure decreased significantly after sildenafil (Δ RR syst. -10 mmHg, Δ RR diast. -8 mmHg, p < 0.002). One patient experienced vasovagal syncope 30 minutes after ingestion of sildenafil which was treated by a rapid volume substitution. CFR measurements were repeated in this patient at a later time and were performed without complications. Baseline CFR values were within the lower normal range, except in 4 patients in whom it exceeded 300%.

At baseline, CFR correlated inversely with the value of individual HbA1c (r = 0.5, p = 0.04). The mean average coronary flow velocities at baseline and after adenosine were higher in obese patients and those with left ventricular hypertrophy (p < 0.001), and correlated with the body mass index (r = 0.52, p = 0.01). Furthermore, the increase of the mean and peak average coronary flow in response to the administration of adenosine correlated with the duration of the diabetes (r = 0.6, p < 0.001).

CFR after sildenafil administration decreased insignificantly in 11/21 patients (Δ CFR -10%, p = 0.3). Accordingly, there was a trend for a smaller average mean flow velocity response to adenosine after sildenafil compared to baseline measurements (Δ average mean flow velocity -0.06 m/s, p = 0.06). The decrease of CFR was more pronounced in obese diabetics (BMI > 25 kg/m²) who had a HbA1c > 7.0 % and left ventricular hypertrophy, while for the other patients CFR tended to increase after sildenafil (Δ CFR -10 % vs 1 %, p = NS). None of the patients had the CFR drop below 200% after administration of sildenafil.

Erectile dysfunction caused by microvascular or neurogenic disturbance can be improved by sildenafil and other phosphodiesterase type 5 inhibitors. Microvascular dysfunction is mostly caused by factors that enhance risk for cardiovascular disease. Not surprisingly, patients with overt cardiovascular disease exhibit a high erectile dysfunction rate [5]. In patients with symptomatic myocardial ischemia, nitrates are commonly prescribed to improve anginal status. The concomitant use of nitrates and sildenafil causes a potentiation of vasodilating effects inherent to both drugs [11, 12]. Systemic hypotension aggravating myocardial ischemia in the presence of significant coronary artery disease after ingestion of both drugs is believed to be the cause for cardiac deaths [11, 13, 14]. Because the concomitant use of these drugs has been prohibited, patients with symptomatic myocardial ischemia can not be treated with sildenafil for erectile dysfunction. Vascular and metabolic effects of sildenafil in the presence of myocardial ischemia and the resulting risk potential is unknown since patients with significant and symptomatic heart disease have been excluded from most clinical trials [13]. Cardiac expenditure during sexual activity varies widely and silent myocardial ischemia does frequently occur during sexual intercourse in patients with chronic ischemic heart disease [15]. Myocardial ischemia enhances ventricular ectopy and thereby can cause sudden death. Ectopy might be enhanced due to the proarrhythmogenic effects which were shown to occur at high dosages of sildenafil by prolongation of cardiac repolarization [16]. Furthermore, sildenafil increases sympathetic activity resulting in elevated plasma norepinephrine levels and sympathetic nerve traffic [17]. With this knowledge, the effects of sildenafil on cardiac microcirculation are of interest, especially in diabetics who develop endothelial dysfunction during the course of the disease and who more frequently have silent ischemic events.

Estimation of the coronary artery flow reserve utilizing adenosine permits detection of clinically relevant restriction of myocardial blood flow during maximum vasodilatation resembling hemodynamic changes during physical exercise [8, 18]. The deterioration of CFR allows identification of severe stenoses of epicardial coronary arteries and microvascular disturbances due to endothelial dysfunction with high sensitivity. Previous investigations in diabetics demonstrated an inverse correlation between the duration and elevation of blood sugar levels and impairment of CFR [19, 20]. Not surprisingly, patients of this study who had suboptimally adjusted long-standing diabetes exhibited a CFR which was uniformly in the lower normal range, indicating the presence of a microcirculatory disturbance. CFR measurements of the LAD in animal studies have demonstrated an increase of the mean flow velocity after sildenafil [21, 11]. In contrast we found a modest reduction of the CFR due to sildenafil in half of the diabetic study patients, but in none of them did CFR decrease below 200 %, which is known to represent a cut-off value to indicate clinically relevant myocardial minor perfusion during exercising [8]. However, this is in accordance with CFR measurements performed in normal coronary arteries in animal models with sildenafil, indicating that cGMP-mediated dilatation of resistance vessels contributes little to the shear stress-induced vasodilatation augmented by adenosine [21, 22]. Thus, sildenafil is unlikely to enhance myocardial ischemia during physical exercise in men with metabolically, severely reduced CFR.

The risk of myocardial ischemia during sexual activity with a familiar partner is low, if the patient can achieve a minimum of 5–6 METS on an exercise test [23]. It was therefore recomended to perform a stress test with ≥ 5 METS in patients at risk of coronary artery disease, which should be completed without symptoms of angina pectoris or myocardial ischemia [13]. A work load of 100 W corresponds to this recommended metabolic equivalent. No evidence of myocardial ischemia at the 100 Watt level was observed in any patient during the stress test. We intended to perform a diagnostic stress test in each patient reaching the age adopted submaximal heart rate; however, most patients were not able to reach their maximal work load, although in 3 a positive result was obtained. Of those, two exhibited CAD in subsequent heart catheterization. Although not having objective signs of a coronary artery disease, invasive diagnostics were performed because of safety reasons in 16 patients reporting atypical chest pain or dyspnea with the presence of 3 or more cardiac risk factors. The surprisingly high number of patients who were demonstrated to have severe coronary artery stenosis or occlusion amounted to about 30% of all study patients. Routine examination would probably not have identified most of these severe CAD cases. Therefore, a critical revision of clinical findings on an individual basis should be made in diabetic patients. Furthermore, we were able to detect severe CAD in 2 patients, including a high grade stenosis of the left main coronary artery in one, by pathologic results of the CFR measurements while clinical assessment was unremarkable.

Recently, several studies investigated hemodynamic effects of sildenafil in the presence of high grade coronary artery stenoses. In an animal investigation sildenafil increased poststenotic blood flow due to lowering peripheral resistance in the presence of a flow limiting stenosis of the LAD [23], whereas in another study it did not [25]. In a human investigation, sildenafil increased CFR values 13 percent above baseline levels in the stenosed arteries and in undiseased reference vessels [26]. Contrary to the former investigation in which 43% were diabetics, CFR generally decreased in our study. The decrease of CFR was mainly seen in the presence of left ventricular hypertrophy, obesity and an inadequately adjusted diabetes, a constellation that is paralleled by severe disturbance of endothelial function. Since CFR results also diverged in the study of Hermann et al. [26], we speculate that more severe microcirculatory dysfunction in diabetics with a high risk profile is responsible for this lowered endothelial responsiveness. However, reduction of the adenosine-mediated increase of the mean flow velocity after sildenafil might be also a result of a more pronounced dilatation of epicardial coronary arteries, since a modest dilatation of coronary arteries induced by sildenafil was found in ex vivo studies [11, 27].

Taking the results of these studies together, it can be stressed that sildenafil does not induce or enhance myocardial ischemia during rest or exercise in the presence of clinically significant coronary macro- or microangiopathy. However, patients with stress-induced myocardial ischemia and erectile dysfunction, who are enabled to resume sexual activity using sildenafil, are at risk of suffering from ischemia-induced cardiac events [14]. Therefore, in diabetics with an elevated cardio-vascular risk profile, intensive judgement of cardiac risk on an individual basis should be performed before administration of sildenafil.