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Blood biomarkers, such as the lipid profile, are widely used in both clinical and research settings to assess atherosclerotic risk. In addition to dyslipidaemia, elevated markers and mediators of inflammation (e.g., C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-ϭɴ

(IL-ϭɴͿ͕ ĂŶĚ ƚƵŵŽƵƌ ŶĞĐƌŽƐŝƐ ĨĂĐƚŽƌ-ɲ ;dE&-ɲͿͿ ĂŶĚ ĞŶĚŽƚŚĞůŝĂů-prothrombotic compounds (e.g., endothelin-1 (ET-1); intracellular adhesion molecule-1 (iCAM-1); vascular adhesion molecule-1 (vCAM-1)); monocyte chemo-attractant protein-1 (MCP-1); fibrinogen and homocysteine (Hcys)) are indicative of a pro-atherogenic state. Although inflammation is an innate protective immunovascular response to insult, chronic inflammation is implicated in the initiation and progression of atherosclerosis [409]. It is both a response to a vascular insult and

an insult itself: inflammation leads to vascular injury, endothelial dysfunction and an altered prothrombotic state which further promotes inflammation and prepares the way for atherosclerotic lesion formation. In particular, CRP has well-established pro-inflammatory and pro-atherogenic properties [410]. In vitro studies have shown CRP inhibits eNO production, reduces its bioavailability and activity, stimulates release of ET-1 and IL-6, upregulates the expression of adhesion molecules, stimulates MCP-1 and monocyte migration, facilitates endothelial cell apoptosis and inhibits endothelial growth factor-stimulated angiogenesis [411, 412]. An elevated CRP level indicates systemic inflammation of the vascular wall and is a significant independent predictor of CV events [413, 414]. It has been shown to be a stronger predictor of CV events than LDL-c [415]. Elevated levels of these markers and mediators may precede both atherosclerosis and vasculogenic ED.

Studies have consistently reported significantly higher inflammatory markers/mediators [406, 416-420] and/or raised endothelial-prothrombotic compounds [416, 417, 421] in men with ED, even in the absence of other CVD risk factors, suggesting they play an important role in the pathogenesis of ED. In 2006, Vlachapoulos et al [417] conducted an observational study of 141 consecutive patients with or without ED and CAD (38 CAD/ED, 25 CAD/no ED, 46 no CAD/no ED, 32 with no CAD/no ED, mean age=58.8 years). Vasculogenic ED was measured using PDS and defined as a peak systolic velocity (PSV) <35 cm/s and/or an end-diastolic velocity (EDV) >5 cm/s. CAD was either documented or determined using coronary angiography and excluded using exercise stress test and stress echocardiography. They investigated the association between ED and inflammation, endothelial dysfunction and an altered prothrombotic state. Overall, ED patients had significantly increased levels of all inflammatory (CRP, IL-6, IL-ϭɴ͕dE&-

ɲͿ ĂŶĚ ĞŶĚŽƚŚĞůŝĂů-prothrombotic (von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (tPA), fibrinogen) markers/mediators. These substances all showed significant correlations with IIEF-5 scores (rs=-0.22 to -0.48, all

ƉчϬ͘ϬϭͿ͘ /ŶƚĞƌĞƐƚŝŶŐůLJ͕ ƚŚĞĞĨĨĞĐƚ ŽĨ ŽŶƚŚĞƐĞŵĂƌŬĞƌƐ;ǁŝƚŚ ƚŚĞ ĞdžĐĞƉƚŝon of IL-6) did not depend on the presence of CAD, supporting earlier studies that inflammation is a key element to ED and may be indicative of subclinical CAD. All of these markers/mediators were also independent predictors of ED in multivariate models adjusting for age, SBP, TC, FPG and BMI (OR 1.1–2.6, all p<0.05); however, the accuracy of inflammatory substances in predicting ED was generally poor (AUC 0.66-0.69, all p<0.01) with slightly better performance from endothelial-prothrombotic substances (AUC 0.63–0.79, all p<0.01). Inflammation may be a marker but not a risk factor for ED; however, further work is needed in this area.

In a 2007 retrospective cross-sectional study of a cohort of health professionals (n=988, age range=46-81 years, 1995-2000), Eaton et al [421] found poor to very poor erectile function was present in 27.5% of the men in 1995 and 39.6% in 2000. At the univariate level, ED was significantly correlated with many atherosclerotic biomarkers (e.g., TG, HDL, TG:HDL-c, TC:HDL- c, CRP, IL-6, TNF receptor 1, iCAM-1, vCAM-1, Factor VII, fibrinogen, all p<0.05) but not non- HDL-c, Lp(a) or Hcys (all p>0.05). After multivariate adjustment, ED was associated in a graded fashion with elevated levels of some atherosclerotic biomarkers of dyslipidemia (TG: OR=1.8, p=0.007; and TC:HDL-c: OR=2.1, p=0.02), endothelial function (iCAM: OR=2.0, p=0.06) and thrombosis (Factor VII: OR=2.9, p=0.03) but not inflammation. This study supported the need for further prospective cohort studies into the association between ED and endothelial function. Ideally such studies would include longitudinal measurement of risk factors, biochemical markers and imaging biomarkers such as carotid IMT, brachial FMD or PWV measurement.

Over the past 5 years, inflammation and endothelial dysfunction have also been linked to ED presence and severity in T2DM patients without symptomatic CHD [418]. Arana Rosainz Mde et al [418] conducted a cross-sectional study of T2DM patients (n=190, 150 ED, 40 no ED). They reported higher inflammatory cytokines (raised TNF-ɲ͕ůŽǁĞƌĞĚ/>-10 and elevated TNF-ɲ͗/>- 10) and endothelial dysfunction (raised E-selectin) markers in T2DM patients with ED (IIEF-5 score) compared to those without ED. In contrast to earlier studies [416, 421], there was no significant difference in the endothelial activation marker iCAM-1. The severity of ED increased with increasing TNF-ɲ ĂŶĚ -selectin levels and multivariate analysis (adjusted for age, diabetes duration, insulin medication, hypertension, IR, glycaemic control and MetS) showed that TNF-ɲ͗/>-10 and E-selectin levels were independent predictors of ED. In a 2013 case- control study (192 ED cases, 33 controls, age range=<40 years), Yao et al [419] found that younger men with ED had significantly higher SBP, HOMA-IR, CRP and IMT and significantly lower FMD values compared with controls. HOMA-IR (AUC 0.759, p<0.001) and FMD (AUC 0.933, p<0.001) were significant predictors of ED in men <40 years of age with ED of unknown etiology. Overall, the evidence suggests that inflammation, endothelial dysfunction and thrombosis are involved the pathogenesis of ED.

Chronic inflammation is implicated in the pathogenesis of cardiometabolic disease and may be the link between these conditions and ED [422]. It is clear that atherosclerosis, arterial stiffness and endothelial dysfunction are more common and severe in men with vasculogenic ED and that these defects occur even in men with no signs of clinical CVD. ED is now accepted as an early marker of endothelial dysfunction, atherosclerosis and CVD.