Cardiovascular Effects of Phosphodiesterase Type 5 Inhibitors

Phosphodiesterase type 5 (PDE5) inhibitors are widely used as first-line therapy for erectile dysfunction (ED). Their efficacy and safety combined with an increasing understanding of cyclic guanosine monophosphate (cGMP)-regulated mechanisms have triggered a number of attempts to determine their effects on the cardiovascular system and their potential benefits in cardiovascular conditions. To review and discuss recent findings regarding the cardiovascular effects of PDE5 inhibitors and to highlight current and future clinical applications beyond ED. Results of preclinical and clinical studies evaluating the cardiovascular effects of PDE5 inhibitors are analyzed and critically put into perspective. Extensive PubMed literature search reviewing relevant data on effects and mechanisms of PDE5 inhibitors on the cardiovascular system. In recent years, extensive but very heterogeneous preclinical and clinical evidence has been reported. PDE5 inhibition has proven collateral benefits for a multitude of risk factors or diseases associated with or accompanying ED. However, these agents appear to have the potential of expanding their indications. To date, PDE5 inhibition has been shown to be effective for the treatment of idiopathic pulmonary artery hypertension, and sildenafil is approved for this indication. Importantly, accumulating data show that the therapeutic potential extends to the myocardium, the coronary and peripheral arteries, subliclinical inflammation, oxidative stress, thrombosis, neurological recovery, and pathways of fibrosis. Thus, the spectrum of patients who may benefit has expanded to include, for instance, patients with heart failure or coronary artery disease. PDE5 inhibitors are an exciting class of drugs with pleiotropic effects. Current or future PDE5 inhibitors are a conceptually attractive therapeutic strategy with potential clinical applications in a variety of cardiovascular conditions. Vlachopoulos C, Ioakeimidis N, Rokkas K, and Stefanadis C. Cardiovascular effects of phosphodiesterase type 5 inhibitors. J Sex Med 2009;6:658-674

Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: Common links

Objective: Erectile dysfunction (ED) may be the early clinical manifestation of a generalized vascular disease and carries an independent risk for cardiovascular events. Low-grade subclinical inflammation affects endothelial function and is involved in all stages of the atherosclerotic process. This review identifies potential pathophysiologic links among low-grade inflammation, ED, metabolic syndrome, and coronary artery disease (CAD) and presents the clinical implications in terms of ED diagnosis, assessment of patient risk, and therapy. Methods: A comprehensive evaluation was performed for available published data in full-length papers that were identified in MedLine up to July 2007. Results: Studies support an association between metabolic syndrome, ED, and increased inflammatory state. Increased circulating levels of inflammatory and endothelial-prothrombotic compounds are related to the presence and severity of ED. Specific inflammatory biomarkers and their combination appear to have the potential to aid ED diagnosis or exclusion. ED and CAD may confer a similar unfavorable impact on the inflammatory and prothrombotic state, whereas ED adds an incremental activation on top of CAD; these findings have important implications for cardiovascular risk. Lifestyle and risk factor modification, as well as pharmacologic therapy, are associated with anti-inflammatory effects. Conclusions: Low-grade systemic inflammation could be an important element of the association between metabolic syndrome, ED, and CAD. Its individualized assessment may be a valuable tool for ED diagnosis, risk assessment, and rationalized therapeutic approach especially in patients with ED who have metabolic syndrome and carry an intermediate risk for future cardiovascular events. (c) 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved

Interactions between erectile dysfunction, cardiovascular disease and cardiovascular drugs

Sexual health has a fundamental role in overall health and well-being, and a healthy and dynamic sex life can make an important contribution to a good quality of life. Sexual dysfunction, and especially erectile dysfunction (ED) in men, is highly prevalent in patients with cardiovascular disease (CVD). CVD and ED have shared risk factors and pathophysiological links, such as endothelial dysfunction, inflammation and low plasma testosterone levels. ED has been shown to be an independent and early harbinger of future CVD events, providing an important window to initiate preventive measures. Therefore, screening and diagnosing ED is essential for the primary and secondary prevention of CVD because the assessment of ED offers an easy and low-cost prognostic tool that is an alternative to other investigational cardiovascular biomarkers. Moreover, ED is a major contributing factor to the discontinuation of, or poor adherence to, cardiovascular therapy. Cardiovascular drugs have divergent effects on erectile function, with diuretics and beta-blockers having the worst profiles, and renin-angiotensin-aldosterone system inhibitors and nebivolol having the best profiles. Pharmacological treatment of ED has an equivocal effect on the risk of CVD, suggesting a complex interaction between ED and drugs for CVD. In this Review, we discuss how sexual function could be incorporated into the patient history taken by physicians treating individuals with CVD, not merely as part of the diagnostic work-up but as a means to pursue tangible and essential benefits in quality of life and cardiovascular outcomes. Cardiovascular disease (CVD) and erectile dysfunction (ED) have shared risk factors and mechanisms. Moreover, ED is an independent predictor of CVD events and is an adverse effect of some cardiovascular drugs. This Review discusses how sexual function should be considered when treating patients with CVD to improve quality of life and cardiovascular outcomes

Arterial function and intima-media thickness in hypertensive patients with erectile dysfunction

Objective Erectile dysfunction is a predictor of cardiovascular risk with high prevalence in hypertensive men. We investigated whether erectile dysfunction is related to arterial structure and function in hypertensive patients. Methods We evaluated arterial structural and functional characteristics and measured systemic endothelial/inflammatory markers in 52 hypertensive men with vasculogenic erectile dysfunction and in 34 hypertensive men with normal erectile function, matched for age, blood pressure, risk factors and treatment. Results Hypertensive patients with erectile dysfunction had higher common carotid intima-media thickness (0.95 +/- 0.19 vs. 0.83 +/- 0.18 mm, P=0.003) and carotid-femoral pulse-wave velocity (8.89 +/- 1.38 vs. 8.11 +/- 1.10 m/s, P=0.007), lower flow-mediated dilation of the brachial artery ( absolute values of 2.96 +/- 1.64 vs. 4.07 +/- 1.68%, P=0.003) and a higher level of the systemic endothelial dysfunction marker asymmetric dimethylarginine (0.67 +/- 0.13 vs. 0.57 +/- 0.16mmol/l, P=0.003), and the inflammatory markers high-sensitivity C-reactive protein [2.03 ( 1.16-2.89) vs. 1.23 ( 0.67 - 1.90) mg/l, P=0.029] and interleukin-6 (4.13 +/- 2.38 vs. 2.77 +/- 1.92 pg/ml, P=0.011). Multivariable analysis adjusting for age, mean pressure, other risk factors and treatment showed independent associations between erectile dysfunction and parameters of arterial structure and function. In the erectile dysfunction group, there were no significant relationships between the severity of erectile dysfunction (as expressed by the Sexual Health Inventory for Men score) and the above arterial indices and level of circulating markers (all PUNS). Conclusion In hypertensive men, the presence but not the severity of vasculogenic erectile dysfunction is associated with subclinical atherosclerosis, impairment of arterial function and systemic endothelial and inflammatory activation

Amino-Terminal Pro-C-Type Natriuretic Peptide is Associated with the Presence, Severity, and Duration of Vasculogenic Erectile Dysfunction

Background: Endothelial dysfunction is a key event in the pathophysiology of erectile dysfunction (ED) and generalized vascular disease. C-type natriuretic peptide (CNP) is a paracrine molecule that effects endothelial integrity and vascular tone. Objective: To determine the role of CNP in men with vasculogenic ED. Design, setting, and participants: Fifty-two consecutive men (age: 57 +/- 10 yr) with nonpsychogenic and nonhormonal ED for >6 mo and free of cardiovascular disease who were referred to the Cardiovascular Diseases and Sexual Health Unit of our Department for evaluation of ED were compared with 31 subjects with normal erectile function matched for age, body mass index, and traditional risk factors. Measurements: Vasculogenic ED was diagnosed according to comprehensive history, physical examination, Sexual Health Inventory for Men (SHIM-5) scoring, hormonal testing, and penile color-Doppler ultrasound. Amino-terminal proCNP (NT-proCNP) was measured in plasma with enzyme-linked immunosorbent assay (ELISA). Results and limitations: Compared to controls, ED patients had significantly lower NT-proCNP levels (0.21 +/- 0.08 pmol/L in ED patients vs 0.34 +/- 0.07 pmol/L in control subjects; p < 0.001). NT-proCNP levels were associated with erectile performance as expressed by SHIM-5 score (r = 0.57; p < 0.001), even after adjusting for confounders. There was also an inverse linear relationship between ED duration and NT-proCNP levels (p < 0.05). In patients with arteriogenic ED, there was a positive correlation of NT-proCNP levels with peak systolic velocity (PSV) (r = 0.51; p = 0.01). Conclusions: CNP levels are associated with the presence, severity, and duration of ED. These findings provide further insight into the role of CNP in the pathophysiology of ED. (C) 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved

Plasma Total Testosterone and Incident Cardiovascular Events in Hypertensive Patients

BACKGROUND Androgen deficiency confers an independent risk for cardiovascular events and total mortality. Hypertension, a major contributory factor to the development of cardiovascular disease, has also been associated with increased prevalence of low testosterone. We investigated whether low androgen concentration predicts incident major adverse cardiovascular events (MACE) in middle-aged nondiabetic hypertensive patients without clinical atherosclerosis. METHODS MACE in relation to total testosterone (TT) were analyzed with proportional hazards models in 228 male patients (mean age 56 years). RESULTS During a mean follow-up of 44 months, 19 of 228 participants (8.3%) experienced a MACE. Compared to patients who did not experience MACE, hypertensive subjects who developed MACE had lower 7 concentration (3.9 +/- 0.7 ng/ml vs. 4.6 +/- 1.5 ng/ml, P < 0.01) and a higher prevalence of hypogonadism (36% vs. 16%, P < 0.05). Subjects in the lowest 7 tertile (<4.0 ng/ml) had a statistically significant higher risk of MACE compared to those in the highest tertile (>4.9 ng/ml) in multivariate Cox models adjusted for age, systolic blood pressure, and risk factors (all P < 0.05). A 7 plasma level of 5.04 ng/ml was associated with a negative predictive value (ability to “rule out” MACE) of 97.2%. Addition of 7 to standard risk factors model yielded a net reclassification improvement of 38.8% (P < 0.05). CONCLUSIONS Our results show that low plasma testosterone is associated with increased risk for a MACE in hypertensive patients. Low endogenous androgen concentration improves risk prediction when added to standard risk factors and may represent a valuable biomarker of prediction of cardiovascular disease risk in these patients