http://orcid.org/0000-0002-1331-5365
Abstract
Introduction: The presence of concomitant erectile dysfunction (ED) with heart failure (HF) is not surprising, because endothelial dysfunction is pathophysiologic signature of both ED and HF. ED significantly and adversely affects quality of life in patients with HF. It was demonstrated that ivabradine treatment can improve endothelial function and ED in experimental models. In this study, we aimed to determine the effect of ivabradine treatment on ED in patients with HF via International Index of Erectile Function (IIEF-5) questionaire.
Material and methods: Consequently, 29 patients, between 18 and 70 years of age, male with chronic HF known for at least 1 year, New York Heart Association functional class I–II, left ventricule ejection fraction less than 40%, in sinus rhythm with a resting HR of at least 70 beats per minute (b.p.m.), who were intended to be treated with ivabradine according to the decision of their physicians were evaluated to determine ED. We used the Turkish version of the IIEF-5 questionnaire to evaluate ED on the last 6-month period. Twenty-four of 29 patients who scored ≤21 were considered to have ED and included to the study. IIEF-5 scores for each question and domains were calculated for all responders at baseline and at 6-month follow-up visit in order to determine any effect of ivabradine treatment on ED in patients with HF.
Results: According to the data of survey, Cronbach's alpha coeffient for all of the patients who were included into the study were 0.84 and detected highly reliable. IEFF-5 questionnaire scores increased significantly (p = .003) after the ivabradine treatment, on the contrary, significant decrease in HR was revealed as expected. HR is decreased steadily after ivabradine treatment and mean decrease in HR was 11.5 ± 9.4 in this study population. Likewise, negative correlation was demonstrated between decrease in HR (p < .001) and increase in IEFF-5 scores (p = .003).
Conclusion: Although lack of patients with HF have been evaluated in this study population, initial results seem promising that ivabradine has favorable effects on ED. These findings were postulated to be dependent exclusively on HR reduction. As a sequel, cardiologist should avoid neglecting ED to improve medical compliance as well as quality of life in patients with heart failure. This pilot study provide some data for further randomized controlled studies.
Introduction
Erectile dysfunction (ED), defined as the persistent inability to attain and maintain a penile erection sufficient enough to permit satisfactory sexual performance [Citation1]. Penile erection is a vascular process with involvement of the penile endothelium and smooth muscle tissue [Citation2].
Heart failure (HF) is a prevalent condition that shares several risk factors with ED such as atherosclerosis and endothelial dysfunction and frequently occurs concomitantly. Besides, HF by itself can cause ED, which leads to experience a general dissatisfaction related to their sexual function [Citation3]. ED significantly and adversely affects quality of life in patients with HF. Additionally, various factors including depression, neurohormonal changes, an imbalance of circulating vasomodulators, reduced cardiac capacity and potential adverse effects of HF medical therapy can contribute to ED in patients with HF [Citation3,Citation4].
The presence of concomitant ED with HF is not surprising, because endothelial dysfunction is pathophysiologic signature of both ED and HF. Furthermore, recent data also revealed heart rate (HR) as an independent risk factor for ED [Citation5]. Ivabradine, a selective inhibitor of the If channel for the treatment of HF, reduces resting and exercise heart rates without affecting cardiac contractility or blood pressure [Citation6]. Custodis et al. recently demonstrated that ivabradine treatment can improve endothelial function in a hypercholesterol mouse model [Citation7].
In this study, we aimed to determine the effect of ivabradine treatment on ED in patients with HF via International Index of Erectile Function (IIEF-5) questionaire including 5 questions to evaluate erectile function quality on the last 6-month period [Citation8].
Materials and methods
Consequentive 29 patients, between 18 and 70 years of age, male with chronic HF known for at least one year, New York Heart Association (NYHA) functional class I–II, left ventricule ejection fraction (LVEF) less than 40% as measured by transthoracic echocardiography, in sinus rhythm with a resting HR of at least 70 beats per minute (b.p.m.), who were intended to be treated with ivabradine according to the decision of their physicians were evaluated to determine ED.
We used the Turkish version of the IIEF-5 questionnaire to evaluate ED on the last 6 month period, which had been translated into Turkish and had been modified according to validation tests [Citation8]. Patients responses to the five questions range from 1 (worst) to 5 (best), and the maximum score for the erectile function domain is 25. The severity of ED graded as no ED, mild, mild to moderate, moderate and severe according to IEFF-5 scores (scores respectively; 22–25, 17–21, 12–16, 8–11, 5–7). Twenty-four of 29 patients who scored ≤21 were considered to have ED and included to the study. IIEF-5 scores for each question and domains were calculated for all responders at baseline and at 6-month follow-up visit in order to determine any effect of ivabradine treatment on ED in patients with HF.
Baseline demographic data and medications, such as B-blocker, angiotensin-converting enzyme inhibitor (ACE) or angiotensin receptor blockers (ARB), spironolactone, loop diuretics and nitrates, were documented before initiation ivabradine and at 6 month of ivabradine treatment. Ivabradine started 5 mg b.i.d and titrated up to 7.5 mg b.i.d. after one month if the patients were tolerant. In addition, hemoglobin levels, serum potassium, sodium, creatinine levels, mean HR were measured before and after 6 month of ivabradine treatment.
Two of 24 patients were excluded from analyses because of loss to follow up and totally 22 patients were analyzed. The study protocol was approved by the institutional ethics committee, and all patients gave written informed consent before enrollment.
Statistical analyses
The statistical analysis was performed using the Statistical Package for Social Sciences software 20.0 (IBM SPSS 20, SPSS Inc, Chicago, IL). The variables were expressed as mean ± SD and median (25–75%). The variables were tested for normal distribution by normality test of Shapiro–Wilk. Independent sample t-test, paired-sample t-test, two-way analysis of variance (ANOVA) and two-way repeated-measures ANOVA were used for the analysis of normally distributed variables. Mann–Whitney U-test was used for the analysis of non-normally distributed variables. Categorical data were presented as frequencies and percentages and were analyzed by Pearson’s chi-square, continuity correction chi-square and marginal homogeneity test. p values less than .05 were considered as statistically significant.
Results
According to baseline IIEF-5 scores, 83% (n:24) of 29 patients with HF were considered to have ED and 22 patients between 40 and 68 years old (mean age 60.7 ± 6.02) with HF analyzed in this study (loss to follow up, n:2).
Ischemia was revealed as the predominant underlying cause of HF in study population (90,9%, n = 20). The most common comorbit disease was hypertension (72.7%, n = 16) and the latter hyperlipidemia (40.9% n = 9). Patients with diabetes mellitus (DM) was 36.4% (n = 8) and 31.8 (n = 7) were smokers and BMI (kg/m2) was calculated as 27.6 ± 6.6 kg/m2. The proportion of prescribed medicine in our patients was 81.8% (n = 18) loop diuretic, 77.3% (n = 17) ACEs/ARBs, 63,6% (n = 14) B-blocker, 63,6% (n = 14) spironolactone and 27.3% (n = 6) nitrate. There was no statistically significant difference between baseline and 6-month follow-up visit according to medications.
LVEF measured by transtorasic echocardiography and the measurements revealed that mean LVEF at baseline was 25.5 ± 6.0 and after 6 month was 26.8 ± 4.8. No significant difference was shown with comparison of LVEF measurements between baseline and 6 months follow-up (p = .082). Mean values of systolic blood pressure (SBP) at baseline was 116.4 ± 19 and at 6 months was 119.9 ± 15.6; also mean values of diastolic blood pressure (DBP) at baseline was 70.0 ± 12.2 and at 6 months was 73.4 ± 10.9. Systolic and diastolic blood pressure measurements were consonant at baseline and 6 months later (respectively, p = .273, p = .057). The demographic and laboratuary findings were similar before and after 6 months of ivabradine treatment ().
Table 1. Changes in laboratuary findings, IEFF-5 scores, heart rate (HR), ejection fractions (EF) and blood pressures between baseline and 6 month after the ivabradine treatment.
According to the data of survey, Cronbach's alfa coeffient for all of the patients who were included into the study were 0.84 and detected highly reliable. IEFF-5 questionnaire scores increased significantly (baseline = 13.5 ± 3.6, 6 month = 15.1 ± 3.9; p = .003) after the ivabradine treatment, on the contrary, significant decrease in HR (baseline = 87.6 ± 11.0, 6 month = 76.2 ± 7.9; p < .001) was revealed as expected (). HR is decreased steadily after ivabradine treatment and mean decrease in HR was 11.5 ± 9.4 in this study population. Likewise, negative correlation was demonstrated between decrease in HR (p < .001) and increase in IEFF-5 scores (p = .003). On the other hand, no significant change in ED severity grades (p = .096) was revealed after the ivabradine treatment when compared with baseline (). Statistically significant increase in IEFF-5 scores was demonstrated by subgroup analyses according to concomitant disease (HT, HPL and smokers) and treatment (ACE/ARB, B blocker, loop diuretics, spironolactone, ans nitrates), except DM. Although significant HR reduction (p = .031) was demonstrated, increase in IEFF-5 scores was not statistically significant (p = .47) after 6 month of ivabradine treatment in patients concomitant with DM and HF ().
Figure 1. Changes between baseline and 6 month after the ivabradine treatment according to IEFF-5 scores and heart rate.
Table 2. Changes in IEFF score grades between baseline an 6 month after the ivabradine treatment.
Table 3. IEFF-5 score and HR changes according to concomitant diseases and treatments.
Discussion
IIEF-5 scores increased significantly after 6 month of ivabradine treatment in patients with HF (baseline = 13.5 ± 3.64, 6 month = 15.1 ± 3.91; p = .003). Severity of ED among IEFF-5 scores grading did not change after 6 months of ivabradine treatment when compared with baseline (p = .096). According to the data of survey, Cronbach's alpha coefficient for all of the patients who were included into the study were 0.84 and detected highly reliable. Although this was the first study for assessment the effects of ivabradine on ED, this pilot study included a limited number of patients with HF. Furthermore, significant increase in IEFF-5 scores were revealed. So the results of the ivabradine treatment in patient with HF for improving ED is promising. In order to our results which provide the proof of concept, a randomized controlled study is urgently needed.
Endothelial dysfunction appears to be affecting not only the coronary but also almost all peripheral circulation [Citation9,Citation10]. The smaller penile artery has a greater endothelial surface and erection requires a large degree of vasodilation to occur when compared with arteries in other organs [Citation11]. Thus, the penis is likely to be another end-organ affected by endothelial dysfunction and atherosclerosis in men [Citation4,Citation12]. However, endothelial dysfunction plays a role in ED in nonischemic cardiomyopathy without atherosclerosis [Citation3]. Moreover, it was clearly demonstrated via the IIEF scores of 1549 patients that ED is a potent predictor of all-cause death and the composite of cardiovascular death, myocardial infarction, stroke and heart failure in men with cardiovascular disease [Citation13].
HR and blood pressure is an independent risk factor for both endothelial dysfunction and atherosclerosis. Furthermore, HR is more predictive for the development of erectile dysfunction than blood pressure [Citation14]. Increase in HR is contributing to ED due to the strong association between endothelial and erectile functions [Citation12]. Thus, decrease in HR is suggested to prevent cardiovascular outcomes [Citation6], endothelial dysfunction and probably ED [Citation12]. The experiments support the potential of heart rate reduction as an intervention to improve endothelial function and to attenuate progression of atherosclerosis [Citation7].
Custodis et al. demonstrated that HR reduction by ivabradine leads to inhibition of vascular oxidative stress, endothelial dysfunction and atherosclerotic lesion formation in ApoE deficient mouse model regardless of blood pressure and plasma cholesterol levels [Citation7]. Similarly, Baumhakel et al. revealed that ivabradine restores endothelial function of the corpus cavernosum in hypercholesterolemic ApoE-deficient mice by HR reduction [Citation12]. In these experimental models, HR reduction with ivabradine has been demonstrated to protect from atherosclerosis and restores erectile function in both primary and secondary prevention [Citation7,Citation12,Citation15].
Furthermore, treatment with ivabradine reduced HR by about 14% in experimental model of Baumhakel et al [Citation12]. After 1 month of ivabradine treatment, an uncorrected heart rate reduction was 15 bpm and 13 bpm in SHIfT and INTENSIfY trials, respectively [Citation6,Citation16]. In our study, HR reduction was 11.5 ± 9.4 similarly. According to both these experimental models’ and our results suggest that selective heart rate reduction with ivabradine could be effective in the prevention and also in the improvement of ED in patients with HF. We postulated that the favorable effects by ivabradine on ED were only dependent on HR reduction. It is grateful that ivabradine has no influence on myocardial contractility and relaxation which enables to study the HR reduction solely.
Heart failure patients may experience ED for a variety of reasons as similar as the general population. These include underlying atherosclerosis, traumatic injury, neurologic pathology, hormonal deficiencies, medication side effects and psychogenic contributions [Citation3]. A variety of drugs are necessary to manage patients with HF. Only thiazide diuretics and older sz-blockers drugs lead clearly to ED, whereas ACEs and ARBs might have neutral or even positive effects on erectile function [Citation17]. Besides, sexual side effects are not experienced in the majority of patients taking beta-blockers. Studies with both metoprolol and atenolol have demonstrated neutral effects on sexual function. In fact, the vasodilating nebivolol in vitro in Apo knockout mice may even improve erectile function [Citation18]. Statins clearly have beneficial effects on erectile function but a negative effect has been reported in high statin doses, possibly related to a potential reduction in serum testosterone levels [Citation19]. No significant difference was demonstrated between baseline and 6-month follow-up visit according to medications in our results.
High concentrations of glucose have been shown to be associated with endothelial dysfunction. Recent data support the concept that endothelial dysfunction in DM was due to nitric oxide degradation which mediates ED [19]. Diabetic vasculopathy plays a role in pathophysiology of ED, including macrovasculopathy, microvasculopathy and endothelial dysfunction [Citation20]. By various pathophysiological changes, patients with DM leans to suffer from ED. Our results of diabetic patients demonstrated significant HR reduction (p = .031) after 6 month of ivabradine treatment, but no significant increase in IEFF-5 (p = .47) scores revealed in patients concomitant with DM and HF. No significant erectile function improvement in these patients after ivabradine treatment was demonstrated which suppose that HR reduction by ivabradine could not cope with diabetic vasculopathy.
ED is frequently observed in patients with HF with a prevalence between 58% and 85% [Citation4,Citation9,Citation20]. Similarly, 83% of patients suffered from ED according to baseline IIEF-5 scores. Also, severely reduced left ventricular function limits exercise capacity due to reduced cardiac capacity that required for satisfactory sexual intercourse. Jaarsma et al. [Citation20] found sexual function in patients with HF is associated with symptom severity based on history and exercise tolerance, but not LVEF. Also, Apostolo et al. [Citation21] found that sexual function correlates with the symptomatic status (i.e. NYHA functional class and 6-min walk test). ED in the advanced stages of HF is obviously not sensitive to HR due to frailty and aging. So, we included only patients with NYHA functional class I or II in the study. But we did not evaluate 6-min walk test how it affects ED in our patient population.
After all, ED significantly and adversely affect quality of life among HF patients. It was reported in 52% of patients with HF that sexual problems had an impact on their quality of life. [Citation3]. Moreover, improvement of the quality of life (including sexual activity) maybe the major goal rather than improving survival for majority of HF patients. Many patients may become noncompliant with their heart failure medical regimen since they read side-effect profile of medicine on sexual function. Most patients are not receiving adequate counseling about ED in the setting of HF. Addressing the changes related to the disease and providing appropriate counseling for ED is very important particularly in patients with HF. While ED has many causes, it usually involves a physical and emotional aspect. Depression and performance anxiety are associated with increased risk for impotence. Lifestyle and behavior changes including smoking and drinking cessation, following healthy diet, exercising more and relieving anxiety can reduce patient’s struggle with ED. Also exercise training itself can reduce anxiety and depression. On the other hand, exercise training in patients with HF improves exercise capacity, clinical symptoms and quality of life, hence these physical/psychological improvements potentially lead to sexual enhancement [Citation22]. In these individuals, exercise training confers significant clinical benefits not only for cardiac functions but also for erectile functions. This kind of clinical approach rather than medications should be considered in the preliminary. By the end, increased awareness among cardiologists on the sexual function of these patients may improve medical compliance as well as quality of life [Citation9].
Limitations
Lack of patients with HF evaluated in this pilot study. Study can be more durable with 6-min walk test to evaluate exercise capacity. Additionally, objective tools (ie. penile echo color Doppler examination, Laser Doppler Perfusion Imaging, Nailfold Videocapillaroscopy etc.) are neccesary for providing anatomic and physiologic data used to evaluate ED. Further randomized controlled studies recommended with more clear protocol for this issue.
Conclusions
ED in this population is not only due to HF per se, rather than accompanying risk factors. HT, DM, hypercholesterinemia etc. are also associated with ED and these comorbidities are highly prevalent in our study. Even though, initial results seem promising that ivabradine has favorable effects on ED. These findings were postulated to be dependent exclusively on HR reduction. As a sequel, cardiologist should avoid neglecting ED to improve medical compliance as well as quality of life in patients with heart failure. This pilot study provides promising data for further randomized controlled studies.
Disclosure statement
No potential conflict of interest was reported by the authors.
References
- Hatzimouratidis K, Amar E, Eardley I, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. Eur Urol. 2010;57:804–814.
- Vlachopoulos C, Ioakeimidis N, Terentes-Printzios D, et al. The triad: erectile dysfunction–endothelial dysfunction–cardiovascular disease. CPD. 2008;14:3700–3714.
- Schwarz ER, Rastogi S, Kapur V, et al. Erectile dysfunction in heart failure patients. J Am Coll Cardiol. 2006;1948:1111–1119.
- Baraghoush A, Phan A, Willix RD Jr, et al. Erectile dysfunction as a complication of heart failure. Curr Heart Fail Rep. 2010;7:194–201.
- Baumhakel M, Bohm M. Erectile dysfunction correlates with left ventricular function and precedes cardiovascular events in cardiovascular high-risk patients. Int J Clin Pract. 2007;61:361–366.
- Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376:875-885.
- Custodis F, Baumhäkel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E-deficient mice. Circulation. 2008;117:2377–2387.
- Turunç T, Deveci S, Güvel S, et al. The assessment of Turkısh valıdatıon wıth 5 questıon versıon of international index of erectile functıon (IIEF-5). Türk Üroloji Dergisi. 2007;33:45–49.
- Rastogi S, Rodriguez JJ, Kapur V, et al. Why do patients with heart failure suffer from erectile dysfunction? A critical review and suggestions on how to approach this problem. Int J Impot Res. 2005;17 Suppl 1:S25–S36.
- Lue TF. Erectile dysfunction. N Engl J Med. 2000;342:1802–1813.
- Vlachopoulos C, Jackson G, Stefanadis C, et al. Erectile dysfunction in the cardiovascular patient. Eur Heart J. 2013;34:2034–2046.
- Baumhakel M, Custodis F, Schlimmer N, et al. Heart rate reduction with ivabradine improves erectile dysfunction in parallel to decrease in atherosclerotic plaque load in ApoE-knockout mice. Atherosclerosis. 2010;212:55–62.
- Bohm M, Baumhakel M, Teo K, et al. 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. Circulation. 2010;121:1439–1446.
- Kratz MT, Schumacher H, Sliwa K, et al. Heart rate and blood pressure interactions in the development of erectile dysfunction in high-risk cardiovascular patients. Eur J Prev Cardiolog. 2014;21:272–280.
- Drouin A, Gendron ME, Thorin E, et al. Chronic heart rate reduction by ivabradine prevents endothelial dysfunction in dyslipidaemic mice. Br J Pharmacol. 2008;154:749–757.
- Zugck C, Martinka P, Stockl G. Ivabradine treatment in a chronic heart failure patient cohort: symptom reduction and improvement in quality of life in clinical practice. Adv Ther. 201431:961–974.
- Manolis A, Doumas M. Antihypertensive treatment and sexual dysfunction. Curr Hypertens Rep. 2012;14:285–292.
- Baumhäkel M, Schlimmer N, Büyükafşar K, et al. Nebivolol, but not metoprolol, improves endothelial function of the corpus cavernosum in apolipoprotein E-knockout mice [10.1124/jpet.107.135681]. J Pharm Exp Ther. 2008;325:818.
- Solomon H, Samarasinghe YP, Feher MD, et al. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract. 2006;60:141–145.
- Jaarsma T, Dracup K, Walden J, et al. Sexual function in patients with advanced heart failure. Heart Lung. 1996;25:262–270.
- Apostolo A, Vignati C, Brusoni D, et al. Erectile dysfunction in heart failure: correlation with severity, exercise performance, comorbidities, and heart failure treatment. J Sex Med. 2009;6:2795–2805.
- Ades PA, Keteyian SJ, Balady GJ, et al. Cardiac rehabilitation exercise and self care for chronic heart failure. JACC Heart Failure. 2013;241:540–547.