The FRS is a very useful tool to estimate the 10-year cardiac event risk in patients and is supported by the 2010 ACCF/AHA guideline [6] for assessment of cardiovascular risk in asymptomatic adults (ACCF/AHA class I, LOE B) by incorporating age, sex, total cholesterol, high-density lipoprotein (HDL), and use of antihypertensive medications to stratify CVD risk [32]. However, there is little data in patients less than 40 years old suggesting that FRS does not appropriately assess risk in younger patients, especially those with ED. It also lacks family history, fasting glucose level, serum creatinine, urinary albumin to creatinine ratio, and potentially, testosterone level that should be considered to estimate cardiovascular risk in men with ED. The Consensus continues to recommend the FRS as a useful starting tool to estimate subclinical atherosclerosis in men with ED [3]. However, it cautions the use of the FRS alone in men with ED aged 30–60 years without further investigation to other CVD risk factors [3]. ED should alert the physician to increased CVD risk.

The Consensus recommends risk assessments to all men who present with ED regardless of other symptoms [3]. A man with organic ED is considered at increased CVD risk until further workup suggests otherwise. ED can help to identify increased CVD risk in patients both with and without CVD symptoms or event history. The Panel recommends the risk assessments outlined in Table 22.2 [3], consistent with the 2010 ACCF/AHA guidelines [6], to identify men who may need further CVD workup. Therefore, a complete, noninvasive workup, managed by the primary care physician or cardiologist, is recommended, with invasive workup if necessary [33–36]. However, initial evaluation with more specialized tests may be warranted if symptoms suggest increased CVD risk [3].

Given the significant evidence that ED is predictive of future CVD, the Panel recommends that lifestyle modifications will not only improve cardiovascular health but also improve erectile function as shown in Table 22.3 [3, 38].

Several of the recommendations are aimed at preventing progression and even helping to reverse atherosclerotic and other CVD [3]. DM is associated with a twofold increase in CVD [45] and is a CAD equivalent. A recent study of 4,883 men and women 65 years and older followed for 10 years suggested that 90 % of new cases of DM were preventable if patients were in the low-risk group five lifestyle factors shown in Table 22.4 [46].

Waist circumference and waist to hip ratio are better predictors of cardiovascular outcomes than BMI [47, 48]. This is thought to be due to the secretion of excess free fatty acid, inflammatory cytokines, and reduced secretion of adiponectin from abdominal fat [49]. Chronic kidney disease also conveys significant cardiovascular morbidity and mortality. eGFR <60 ml/min and urinary albumin to creatinine ratios greater than 10 mg/g are associated with increased cardiovascular mortality independent of other traditional risk factors [50, 51].

Testosterone measurement has recently become controversial in men without symptoms of low testosterone. Testosterone plays important functions centrally and peripherally in erectile function in animal models [52–55]. This data has been consistent with clinical data. A single-center study of 1,050 men with new evaluation for sexual dysfunction found that 36 % had hypogonadism [56]. A meta-analysis of 7,000 men with ED in nine studies reported serum testosterone levels <300 ng/dL in 12 %. Hypogonadism is a potential cause of ED [57, 58], and testosterone replacement therapy (TRT) has been shown to improve response [58]. Recently, several large epidemiologic studies have associated low testosterone levels with increased all-cause and cardiovascular mortality shown in Table 22.5 [59–67]. However, caution should be advised, as there is no defined lower limit of normal TT.

Additionally, a 2010 meta-analysis of cohort studies in middle-aged men showed no association between endogenous TT levels and CVD risk in middle-aged men [68]. A more recent meta-analysis of 49 cross-sectional studies showed increased CVD in low TT levels and high estradiol levels [69]. However, a separate meta-analysis of 19 studies showed that low TT does not correlate with CVD in healthy men <70 years [68]. The same study, did however, show that low testosterone predicts increased risk for CVD and mortality in elderly men [68]. Nonetheless, the authors cautioned that low TT may be a marker of poor health, rather than testosterone being protective of CVD. This idea is consistent with studies that androgen deficiency is associated with insulin resistance, DM II, metabolic syndrome, and increased deposition of visceral fat [70–73]. The TIMES2 (Testosterone Replacement in Hypogonadal Men With Either Metabolic Syndrome or Type 2 DM) study, a randomized, placebo-controlled study of 6–12 months of transdermal TRT vs. placebo in hypogonadal men with DM II, resulted in improved insulin resistance and glycemic control (ACCF/AHA class Ib) [74]. Additionally, a meta-analysis of five other randomized controlled trials with mean follow-up of 58 weeks showed TRT to be associated with a significant reduction in glucose homeostasis model assessment of insulin resistance index, triglycerides, and WC and an increase in HDL levels [75]. Nonetheless, randomized controlled trials for TRT risks and benefits are needed to establish CVD risk and mortality.

The American College of Physicians recommends only testing for testosterone levels in men with ED when accompanied by the presence of other symptoms (decreased libido, decreased spontaneous erection) or other physical exam findings (testicular mass or muscle atrophy) [76]. Conversely, the Consensus recommends CVD risk and testosterone levels be measured in all men diagnosed with organic ED [3], especially for those who have failed PDE5 inhibitor therapy [6], consistent with British Society for Sexual Medicine [77], International Society for Sexual Medicine [78], Endocrine Society [79], and a combined proposal from the International Society of Andrology, International Society for the Study of the Aging Male, European Association of Urology European Academy of Andrology, and the American Society of Andrology [80] as outlined in Fig. 22.1 [81].

High sensitivity C reactive protein (hsCRP) is an independent predictor of coronary events after adjustment of traditional risk factors [6, 82–84] (i.e., age, total cholesterol, HDL, smoking, BMI, DM, hypertension, exercise level, and family history of CAD). Consequently, the Centers for Disease Control and Prevention and AHA recommended measurement of the hsCRP in addition to global risk prediction, especially those with intermediate risk [85]. The hsCRP level was also shown to improve the predictive value of the FRS in high-risk patients for CAD [86]. Similar evidence was also noted in a meta-analysis of 54 long-term prospective studies without history of vascular disease where high CRP was associated with increased risk of CAD, cerebrovascular disease, vascular mortality, and nonvascular mortality [87]. Additionally, there is evidence that hsCRP correctly reclassifies patients from intermediate-risk CVD to low or high risk [88].

Serum uric acid levels in asymptomatic patients are not specifically addressed in the 2010 ACCF/AHA guidelines [6]; however, the Consensus recommends serum uric acid measurement due to recent evidence that increased levels are predictive of increased cardiovascular risk [89].

A recent analysis from the Atherosclerosis Risk in Communities Study found that the addition of glycated hemoglobin to prediction models with traditional risk factors improved CAD risk prediction in nondiabetic patients with no previous history of CVD [90]. A meta-analysis of 26 cohort studies showed that microalbuminuria was associated with a 50 % increased risk of CAD. Macroalbuminuria more than doubled CAD risk [91]. However, overall there is inconsistency regarding adding glycated hemoglobin and urinary albumin to traditional risk factors in reassessing CVD risk.

Lipoprotein-associated phospholipase A2 levels were shown to be independent predictors of CVD in healthy adults after adjustment for hsCRP and standard risk factors [92–95]. Measurement of lipoprotein-associated phospholipase A2 is consistent with the 2010 ACCF/AHA guidelines for intermediate-risk adults [6].

EST may prove particularly beneficial to evaluate silent CAD risk in patients with ED and DM. In patients with DM II, 33.8 % of men with silent CAD had ED, while only 4.7 % of men had ED without silent CAD [10]. Chemical stress testing (with dipyrimadole or adenosine with nuclear imaging) is appropriate for patients who cannot undergo EST due to disabling condition [3]. If the baseline EKG makes EST unequivocal, the Panel recommends referral to a cardiologist [3].

The 2010 ACCF/AHA guidelines state that it is reasonable to perform CIMT, CACS, and ABI during CVD assessment of intermediate-risk patients [6]. This was further supported by the Society for Heart Attack Prevention and Eradication task force that stated all asymptomatic men 45–75 years and women 55–75 years who do not have very-low-risk characteristics or a documented history of CVD be evaluated with CACS or CIMT for subclinical CAD [96]. Analysis from the Atherosclerosis Risk in Communities Study, CIMT, and plaque detection with ultrasound added to traditional risk factors improved CAD detection [97]. The Multi-Ethnic Study of Atherosclerosis showed that CACS has better predictive value of CVD than CIMT [98]. A meta-analysis of 16 population-based cohort studies showed that ABI ≤0.90 was associated with twice the 10-year overall mortality, cardiovascular mortality, and cardiovascular events than each FRS category [99]. Recent meta-analysis of 17 longitudinal studies with 7.7-year average follow-up found that patients with high aortic PWV were also at higher risk for overall mortality, cardiovascular mortality, and cardiovascular events [100].

Although endothelial dysfunction has yet to be thoroughly studied in men with ED, endothelial dysfunction was found to be an independent predictor of cardiac death, MI, revascularization, or cardiac hospitalization in symptomatic outpatients over 7-year follow-up [101]. Additionally, brachial artery endothelial function assessed by flow-mediated dilation [102, 103] or in the forearm microvasculature assessed by Doppler flow [104] predicted poor cardiovascular outcome independent of the FRS.