Fig. 7.1
Relation between erectile dysfunction prevalence and type of coronary syndrome (a). Time interval (months) between erectile dysfunction and coronary artery disease symptom onset in chronic coronary syndrome according to the number of vessels involved (b). ACS acute coronary syndrome, CCS chronic coronary syndrome, G1 ACS and 1-VD, G2 ACS and 2-,3-VD, G3 CCS, VD vessel disease, C the control group with normal coronary angiography (With permission from Montorsi et al. The COBRA trial [20])
It is also important to stress that ED severity might impact on the risk of CAD events and extent of CAD [20, 36–40]. In this context, the erectile function domain of the International Index of Erectile Function (IIEF), a validated 15-item self-administered questionnaire used to assess the degree of erectile dysfunction, has been shown to be correlated to the plaque burden calculated according to the Gensini’s score [20, 37, 39].
These mounting pieces of evidence coming from retrospective studies led to an increased attention to the relationship between ED and CAD. This ultimately resulted in the planning and execution of prospective studies that tried to better characterize the role of ED in patients with CVD. Large investigations that included elderly patients as well found a strong association between sexual dysfunction and the subsequent risk of cardiovascular events: individuals complaining of ED had roughly 1.5–2-fold higher risk of experiencing CAD during follow-up compared to their counterparts with satisfactory erectile function [38, 41]. Of note, this held true even when considering patients at increased risk of CAD, such as diabetic individuals [42–45]. On the other hand, conflicting results have been reported by other smaller prospective studies [46, 47]. However, the validity of these observations is undermined by the inclusion of relatively young patients at lower risk of CAD with an inadequate follow-up period.
Recently, two meta-analyses provided additional evidence in favor to the association between ED and the risk of CAD [48, 49]. The most recent one included more than 90,000 patients from 14 studies and showed that, after a mean follow-up of 6.1 years, patients with ED had a risk of cardiovascular events, myocardial infarction, and overall mortality by 44, 62, and 25 %, respectively [48].
7.3 Erectile Dysfunction and Heart Failure
Erectile dysfunction is a highly prevalent condition among patients with HF, where up to 90 % of these individuals complain of decrease in sexual interest or varying degrees of cessation of sexual activity altogether [3, 50, 51]. Although ED and HF might share many risk factors and pathophysiological conditions, this relationship might be more complex than what observed in patients with CAD. Indeed, HF itself might profoundly affect patients’ sexual activity, eventually causing ED [3, 50, 51].
7.3.1 Association Between Erectile Dysfunction and Heart Failure
Endothelial Dysfunction
As previously discussed, endothelial dysfunction is a key factor in the pathogenesis and development of ED [6, 7]. Similarly, it plays a major role in HF progression and impairment of the patient’s general health status. Indeed, HF is a complex syndrome associated with several metabolic alterations, which include impairment of nitric oxide synthase activity and vascular relaxation [3]. This, in turn, leads to the production of free oxygen radical products and ultimately to a decrease in peripheral oxygen supply [52–54].
Cardiac Drugs in HF Patients and ED
The administration of many drugs used in patients with HF is known to be associated with an increased risk of ED. This is mainly related to their multiple metabolic, vascular, and neural activities.
Diuretics are one of the most commonly implicated drugs in the pathogenesis of ED in HF patients. Sexual dysfunction is a well-known side effect in patients treated with thiazide diuretics, such as hydrochlorothiazide, chlorthalidone, and bendroflumethiazide [55]. Despite their beneficial effect in treating hypertension, these agents have been shown to cause endothelial dysfunction, increased oxidative stress, stimulation of the sympathetic nervous system, hyperlipidemia, and insulin resistance [3, 56–58]. As a consequence, ED may ensue in the long term [56]. Similarly, spironolactone, an effective anti-aldosterone agent, has been associated with breast tenderness, gynecomastia, and ED [59].
The administration of beta-blockers is also associated with an impairment of sexual function in patients with HF. First- and second-generation beta-blockers might act both on the central nervous system and peripherally, finally resulting in an increased risk of ED [55, 60]. Particularly, these drugs might induce sexual dysfunction through the inhibition of the sympathetic nervous system, which is involved in the control of erection and ejaculation [55, 61]. On the other hand, it should be emphasized that nebivolol, a novel third-generation beta-1 blocker, appears to be associated with neutral or beneficial effects in hypertensive patients [55, 61, 62].
When considering lipid-lowering medications, results are conflicting regarding the role of these drugs on sexual function [3, 55]. While some authors proposed a protective effect of statins on erectile function [63–65], other studies demonstrated an increased risk of ED in patients using statins and fibrates [3, 55]. Finally, digoxin use has been shown to be associated with an increased risk of experiencing ED [66]. However, the underlying mechanism has not been completely understood yet.
Despite the fact that the abovementioned medications might be associated with an increased risk of ED, other classes of drugs, such as ACE inhibitors, angiotensin II receptor antagonists, and calcium channel antagonists, have been shown to be safe in terms of sexual side effects [55]. Additionally, recent studies suggest that these agents might include improved erectile function in their array of actions [55, 67, 68].
Psychological Factors
The impact of psychological factors on the subsequent risk of sexual dysfunctions in patients with HF should not be underestimated. Indeed, HF patients often suffer from depression, which might result in decreased libido and impaired erectile function [3, 69]. Additionally, these individuals might be afraid of triggering new cardiovascular events during sexual activity [3]. On the other hand, moderate physical exercise is not contraindicated in patients with stable HF, but it is beneficial for their general health status. In this context, accurate individual risk assessment and detailed counseling is mandatory in HF patients interested in sexual activity [70].
7.3.2 Sexual Activity in Patients with ED and HF
Sexual intercourse requires a modest exertion. It is equivalent to walking 1 mile on the flat in 20 min or briskly climbing two flights of stairs in 10 s. Sexual intercourse averages 2–3 metabolic equivalents (METs) in the pre-orgasm phase and 3–4 METs in the orgasm phase [3]. Consequently, sexual activity leads to a modest increase in myocardial oxygen demand with a peak lasting only for a short time period.
In 2012, the Third Princeton Consensus Conference developed a novel algorithm for the management of patients with ED [70]. The objective of this tool was to estimate the risk associated with sexual activity in patients with ED and known CVD (Fig. 7.2). These recommendations are based on the most widely used clinical classification of HF, which is the New York Heart Association (NYHA) classification.
Fig. 7.2
Management of a patient with CVD (a) or without known CVD (b) (With permission from Vlachopoulos et al. [51]). *Low-risk patients include those with complete revascularization (e.g., via coronary artery bypass grafting, stenting, or angioplasty), patients with asymptomatic controlled hypertension, those with mild valvular disease, and patients with left ventricular dysfunction/heart failure (NYHA classes I and II) who achieved five metabolic equivalents of the task (METS) without ischemia on recent exercise testing. **Indeterminate risk patients include diabetics, those with mild or moderate stable angina pectoris, past myocardial infarction (2–8 weeks) without intervention awaiting exercise electrocardiography, congestive heart failure (NYHA class III), and noncardiac sequelae of atherosclerotic disease (e.g., peripheral artery disease and a history of stroke or transient ischemic attack); this patient with ED may require assessment for additional vascular disease using carotid intima-media thickness or ankle-brachial index and subsequent reclassification to low or high risk. ***High-risk patients include those with unstable or refractory angina pectoris, uncontrolled hypertension, congestive heart failure (NYHA class IV), recent myocardial infarction without intervention (2 weeks), high-risk arrhythmia (exercise-induced ventricular tachycardia, implanted internal cardioverter defibrillator with frequent shocks, and poorly controlled atrial fibrillation), obstructive hypertrophic cardiomyopathy with severe symptoms, and moderate to severe valve disease, particularly aortic stenosis. ‡Where appropriate CVD cardiovascular disease, FRS Framingham risk score, PDE5i phosphodiesterase type 5 inhibitors, RF risk factor, Tth testosterone therapy; NYHA New York Heart Association
Low-Risk Patients
In patients included in the low-risk group (i.e., NYHA I and II or individuals who achieved 5 METs without ischemia on exercise testing should be included in this category), sexual activity does not represent a significant cardiac risk [70]. These patients can safely perform sexual activity without further testing or evaluation. Additionally, they might benefit from the administration of pharmacological treatments for ED, such as phosphodiesterase type-5 inhibitors [6].
High-Risk Patients
Intermediate-Risk Patients
The intermediate-risk group includes patients with NYHA III. These men should receive exercise stress test in order to be reassigned to low- or high-risk groups [6, 70]. Of note, completing 4 min of the Bruce treadmill protocol (equivalent to 5–6 METs) without symptoms identifies the safety of sexual activity in patients in the intermediate-risk group [70].
7.3.3 Use of Phosphodiesterase Type-5 Inhibitors in Patients with HF
Phosphodiesterase type-5 inhibitors represent a safe treatment for ED in patients with CVD. Additionally, (PDE-5) the well-known pathophysiological association between ED and CVD led to the hypothesis that patients with CVD and HF might benefit from the administration of PDE-5 inhibitors not only in terms of improved erectile function but also to improve HF [52]. Studies have evaluated the effect of PDE-5 inhibitors on HF both at short- and long-term follow-up. For example, the acute administration of sildenafil decreased heart rate during exercise, leading to a reduction of oxygen demand and risk of ischemia [71]. This drug significantly decreases resting mean pulmonary artery pressure and pulmonary and systemic vascular resistance and increases cardiac index [72–75].
Regarding the chronic effects, PDE-5 inhibitors’ administration in HF patients has shown that these drugs may lead to NO-mediated vasodilatation, improved exercise capacity, reduced pulmonary hypertension, and improved ventilatory performance [76–79]. The beneficial effects of PDE-5 inhibitors might be attributed to increased production of cAMP which, in turn, activates protein kinase A, leading ultimately to an increase in intracellular calcium concentration and improvement of myocardial contractility [80]. Moreover, other mechanisms that decrease fibrosis, apoptosis, and hypertrophy, and prevent cardiovascular remodeling may also be responsible [78, 79].
In patients with preserved ejection fraction, results are neutral. Administration of sildenafil for 24 weeks, compared with placebo, did not result in significant improvement in exercise capacity or clinical status [81].
Importantly, when considering the use of PDE-5 inhibitors in HF patients, some clinically relevant issues warrant discussion. Indeed, the concomitant use of nitrates represents one of the main contraindications for the administration of these agents. A time interval of at least 24 h is recommended between the administration of nitrates and PDE-5 inhibitors (24 for sildenafil and vardenafil and 36 for tadalafil) [82].
Finally, it should be noted that other substances, such as L-arginine or capsaicin, might be beneficial in terms of improved erectile and cardiac function in HF patients since they act through an improvement of endothelial function [83–85]. However, clinical evidence regarding the efficacy of these agents is still poor and further well-designed prospective studies are needed.
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