Relation of Erectile Dysfunction to Subclinical Myocardial Injury

Relation of Erectile Dysfunction to Subclinical Myocardial Injury Torbjørn Omland, MDa,b,*, Anna Randby, PhDa,b, Harald Hrubos-Strøm, PhDc, Helge Røsjø, PhDa,b, and Gunnar Einvik, PhDa,b The circulating concentration of cardiac troponin I (cTnI) is an index of subclinical myocardial injury in several patient populations and in the general population. Erectile dysfunction is associated with greater risk for cardiovascular events, but the association with subclinical myocardial injury is not known. We aimed to test the hypothesis that the presence and severity of erectile dysfunction is associated with greater concentrations of cTnI in the general population. The presence and severity of erectile dysfunction was assessed by administering the International Index of Erectile Function 5 (IIEF-5) questionnaire to 260 men aged 30 to 65 years recruited from a population-based study. Concentrations of cTnI were determined by a high-sensitivity (hs) assay. Hs-cTnI levels were significantly higher in subjects with than in those without erectile dysfunction (median 2.9 vs 1.6 ng/l; p <0.001). Men with erectile dysfunction (i.e., IIEF-5 sum score <22) were also significantly older; had a higher systolic blood pressure, lower estimated glomerular filtration rate, higher augmentation index and N-terminal pro-B-type natriuretic peptide; and had a higher prevalence of hypertension, diabetes mellitus, and previous coronary artery disease than subjects without erectile dysfunction. These covariates were adjusted for in a multivariate linear regression model, yet the IIEF-5 sum score remained significantly negatively associated with the hs-cTnI concentration (standardized b L0.206; p <0.001). In conclusion, the presence and severity of erectile dysfunction is associated with circulating concentrations of hs-cTnI, indicating subclinical myocardial injury independently of cardiovascular risk factors, endothelial dysfunction and heart failure biomarkers. Ó 2016 Elsevier Inc. All rights reserved. (Am J Cardiol 2016;-:-e-) High-sensitivity (hs) troponin assays permit reliable measurement of very low circulating concentrations of cardiac troponin I (cTnI) and T.1 Large population-based studies have shown that hs-cTnI is a marker of subclinical myocardial injury and is associated with the incidence of clinical heart failure and cardiovascular death.2 Erectile dysfunction is defined as the inability to obtain or maintain penile erection leading to inadequate sexual performance. Erectile dysfunction shares many risk factors with atherosclerotic disease and is associated with endothelial dysfunction, commonly considered an early marker of generalized vascular disease.3 Erectile dysfunction has also been found associated with increased risk of coronary events, stroke, peripheral artery disease, and cardiovascular death.4,5 However, whether erectile dysfunction is associated with subclinical myocardial injury in the general population is unknown. Accordingly, we tested the hypothesis that erectile dysfunction, as assessed by the International Index of Erectile Function 5 (IIEF-5) questionnaire,6 is associated with circulating concentrations of hs-cTnI, a Department of Cardiology, Division of Medicine and cDepartment of Otorhinolaryngology, Division of Surgery, Akershus University Hospital, Lørenskog, Norway; and bCenter for Heart Failure Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. Manuscript received June 10, 2016; revised manuscript received and accepted August 23, 2016. See page 4 for disclosure information. *Corresponding author: Tel: (þ47) 40107050; fax: (þ47) 67968860. E-mail address: [email protected] (T. Omland).

0002-9149/16/$ - see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2016.08.070

independent of traditional cardiovascular risk factors and indicators of endothelial function and heart failure. Methods Akershus Sleep Apnea Project was a 2-phased epidemiologic study with a primary aim of investigating risk factors of obstructive sleep apnea.7 The aims of the cardiovascular branch of the study included identification of predictors for early markers of cardiovascular injury and dysfunction in the general population. In the first study phase, a questionnaire concerning demographic factors, cardiovascular disease history, and sleep data was distributed. In the second phase, the participants underwent an overnight examination. In the present report, all 260 men who participated in the clinical phase and who had data on IIEF-5 and hs-cTnI concentrations available were included (Figure 1). Fasting venous blood were obtained in the morning and centrifuged within 1 hour and serum and plasma aspirated and frozen at
20 C for maximum 14 days, before being stored at
80 C at a central biobank pending analysis of serum hs-cTnI with the ARCHITECT STAT High Sensitivity Troponin assay (Abbott Diagnostics, Abbott Park, Illinois). The characteristics and analytical variation of the assay in our laboratory have been reported previously.8 Participants with hs-cTnI concentration below the level of detection (1.2 ng/l), were assigned a concentration of 1.2 ng/l. N-terminal pro-B-type natriuretic peptide (NT-proBNP) was measured by an electrochemiluminescent www.ajconline.org

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The American Journal of Cardiology (www.ajconline.org) Table 1 Demographic and clinical characteristics of men with and without erectile dysfunction Variable

Erectile dysfunction

p-value

No (IIEF-5 22) Yes (IIEF-5 <22) (n ¼ 159) (n ¼ 101)

Figure 1. Study flow chart.

immunoassay (Roche Diagnostics, Basel, Switzerland) with a lower detection limit of 5 pg/ml. The presence and severity of erectile dysfunction was assessed by the administration of the IIEF-5 questionnaire.6 The presence or absence of erectile dysfunction was classified according to the IIEF-5 sum scores as <22 versus 22. During the overnight stay, information on medical history, medication, smoking habits, blood pressure measurements, weight, and height was registered. The participants underwent 12-lead electrocardiography, yielding information regarding left ventricular hypertrophy,9 polysomnography, yielding a manually scored (Somnologica 3.2 software; Flaga-Medcare, Buffalo, New York) apneaehypopnea index, and finally a digital peripheral arterial tonometry (EndoPAT 2000; Itamar Medical Ltd., Caesarea, Israel), yielding the augmentation index. These variables were included as covariates based on previous studies linking these to the hs-cTnI concentration and erectile dysfunction.10e12 Characteristics of subjects with and without erectile dysfunction were compared by the Student t test, ManneWhitney U test, or chi-square test, as appropriate. Because of a skewed distribution, hs-cTnI concentrations were transformed by the natural logarithm (ln). The association between erectile dysfunction, as expressed by the IIEF-5 score, and subclinical myocardial injury, as expressed by ln-transformed hs-cTnI concentrations, was assessed by multivariate linear regression analysis, including covariates significantly associated with hs-cTnI in univariate analyses. A p value of <0.05 was considered statistically significant. Statistical Package for the Social Sciences 20.0 (IBM, Chicago, Illinois) was used for all analyses. Akershus Sleep Apnea Project was conducted in accordance with the principles of the Declaration of Helsinki, approved by the Regional Medical Ethics Committee (2011/2421), and all participants provided written informed consent before study commencement. Results Subjects with erectile dysfunction were significantly older; had a higher systolic blood pressure, lower estimated

Age (mean, SD) Current smoker Prior coronary artery disease History of hypertension Diabetes mellitus Estimated creatinine clearance (mL/min [mean, SD]) Systolic blood pressure (mm Hg [mean, SD]) Systolic blood pressure >140 mm Hg Average heart rate (beats/min [mean, SD]) Body mass index (kg/m2 [mean, SD]) Body mass index >30 Total cholesterol (mg/dl [mean, SD]) LDL-cholesterol (mg/dl [mean, SD]) Total-HDL cholesterol ratio (mean, SD) Hypercholesterolemia* Left ventricular hypertrophy AHI (median, 25-75th percentile) AHI > 15 Augmentation index (mean, SD) NT-proBNP (ng/L [median, 25-75th percentile])

4410 41 (26%) 15 (9%)

5410 19 (19%) 26 (26%)

<0.001 0.189 0.001

34 (21%) 13 (8%) 13436

61 (60%) 23 (23%) 12232

<0.001 0.001 0.011

13714

14116

0.045

61 (38%)

49 (49%)

0.106

689

689

0.605

28.8 (4.1)

29.8 (4.6)

0.082

66 (42%) 218 (39)

48 (48%) 208 (45)

0.341 0.076

144 (35)

135 (40)

0.054

5.33.8

4.71.4

0.163

134 (84%) 9 (6%)

68 (68%) 11 (11%)

0.002 0.130

9 (3-22)

12 (3-35)

0.242

60 (38%) 8.4 (16.8)

47 (47%) 15.9 (19.1)

0.172 0.001

48 (23-120)

27 (13-42)

<0.001

AHI ¼ apnea-hypopnea index; HDL ¼ high density lipoprotein; hs-TnI ¼ high-sensitivity troponin I; IIEF ¼ International index of erectile function; LDL ¼ low density lipoprotein; NT-proBNP ¼ N-terminal pro-Btype natriuretic peptide; SD ¼ standard deviation. * Total cholesterol 193 > mg/dL or LDL-cholesterol 116 > mg/dL.

glomerular filtration rate, higher augmentation index and NT-proBNP levels; and had higher prevalence of hypertension, diabetes mellitus, and previous coronary artery disease compared to subjects without erectile dysfunction (Table 1). High-sensitivity C-reactive protein was not associated with erectile dysfunction. Detectable levels of hs-cTnI were observed in 196 subjects (75%). The median (twenty-fifth to seventy-fifth percentile) hs-cTnI concentration was 2.0 (1.2 to 3.5) ng/l. Hs-cTnI levels were significantly higher in subjects with than without erectile dysfunction: median 2.9 (1.7 to 5.2) versus 1.6 (1.2 to 2.7) ng/l, p <0.001. When categorizing the severity of erectile dysfunction using the IIEF-5 scale into no versus mild versus moderate-to-severe erectile dysfunction,6 we found a graded association between the

Preventive Cardiology/Erectile Dysfunction and cTnI

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Figure 2. Serum concentration of cardiac troponin I in relation to erectile function (n ¼ 260). *Adjusted for age, previous coronary artery disease, history of hypertension, history of diabetes, current smoking.

Table 2 Univariate associations between cardiac troponin I and demographic and clinical characteristics N IIEF-5 Age, per y Current smoking Prior coronary artery disease History of hypertension Diabetes mellitus Creatinine clearance, per mL/min Systolic blood pressure, per mmHg Average heart rate, per beat/min Body mass index Left ventricular hypertrophy Total cholesterol, per mg/dL LDL-cholesterol, per mg/dL Total-HDL cholesterol ratio Apnea-hypopnea index Augmentation index NT-proBNP, per 10 ng/L

Unstandardized b (95% CI)

p

260 260 257 260

-0.077 0.028 -0.221 0.552

(-0.097, -0.056) (0.021, 0.035) (-0.429, -0.014) (0.321, 0.783)

<0.001 <0.001 0.036 <0.001

260 260 259

0.496 (0.324, 0.668) 0.098 (-0.156, 0.352) -0.005 (-0.007, -0.002)

<0.001 0.447 <0.001

260

0.014 (0.008, 0.019)

<0.001

255

-0.008 (-0.018, 0.022)

0.099

260 258

0.030 (0.010, 0.050) 0.116 (-0.214, 0.446)

0.004 0.489

258

0.000 (-0.002, 0.002)

0.860

254

0.000 (-0.002, 0.003)

0.918

258

0.019 (-0.009, 0.047)

0.187

257 260 260

0.010 (0.006, 0.014) 0.009 (0.005, 0.014) 0.024 (0.017, 0.031)

<0.001 <0.001 <0.001

CI ¼ confidence interval; HDL ¼ high density lipoprotein; IIEF-5 ¼ International Index of Erectile Function-5; LDL ¼ low density lipoprotein; NT-proBNP ¼ N-terminal pro-B-type natriuretic peptide. hs-TnI concentration was logarithmically transformed before linear regression analyses due to a skewed distribution.

2 variables (Figure 2). Age, systolic blood pressure, current smoking, body mass index, estimated glomerular filtration rate, the apneaehypopnea index, augmentation index, NTproBNP, history of coronary artery disease, hypertension, and diabetes mellitus were significantly associated with hscTnI levels in univariate analyses (Table 2) and subsequently entered into the multivariate model. The IIEF-5 sum score remained independently associated with hs-cTnI

concentrations after adjustment (Table 3). The R2 values for the final multivariate models with and without IIEF-5 were 0.381 and 0.350, respectively, indicating a significant (p <0.001) increase in the explained variability by adding IIEF-5 to the model. In a sensitivity analysis excluding the 41 participants with previous coronary artery disease, the multivariate adjusted association between IIEF-5 and hscTnI remained statistically significant (standardized b coefficient
0.257, p <0.001). Discussion The important new information derived from the present study is that the presence and severity of erectile dysfunction provides information concerning subclinical myocardial injury above and beyond that obtained from conventional risk factors and risk markers. After the development of highly sensitive cTn assays that allow accurate determination of circulating concentration in the low ng/l range, it has become evident that low circulating levels of cTn are detectable in the vast majority of the general population, as shown in the present study. One previous study using a less sensitive cTnI assay found detectable cTnI in only 35% of patients with recent onset erectile dysfunction13 and no association between erectile dysfunction severity and cTnI. The discrepancy with the current results may be due to the limited low-range sensitivity of the other assay. The underlying mechanisms for long-term low-level cTn release and how it is linked to greater risk for heart failure and cardiovascular death have not been fully elucidated but may include processes such as increased rate of cardiomyocyte apoptosis and diffuse myocardial fibrosis involved in cardiac remodeling.14 In most erectile dysfunction cases, the cause is considered to be primarily vasculogenic, and erectile dysfunction has been associated with the incidence of atherosclerotic events.4,15 Importantly, in accordance with previous studies,10,11,16 we show evidence of endothelial dysfunction in subjects with erectile dysfunction. Furthermore, we also show that subjects with erectile dysfunction have greater concentrations of NT-proBNP, indicating subclinical heart failure. Our main finding of an independent association

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The American Journal of Cardiology (www.ajconline.org)

Table 3 Standardized beta-coefficients from multivariate linear regression model of determinants of cardiac troponin I (n¼260) Model 1

Sumscore IIEF-5 Age, per year Current smoking Prior coronary artery disease Use of antihypertensive Systolic blood pressure, per mmHg Body mass index, per unit Estimated creatinine clearance, per ml/min Apnea-hypopnea index, per unit Augmentation index, per unit N-terminal pro-B-type natriuretic peptide, per 10 ng/L

Model 2

Model 3

b

p

b

p

b

p

-0.236 0.014 -0.022 0.161 0.017 0.187 0.133 -0.260 0.204

<0.001 0.870 0.696 0.011 0.812 0.001 0.095 0.003 0.001

-0.236 0.028 -0.018 0.161 0.018 0.192 0.132 -0.262 0.203 -0.030

<0.001 0.758 0.752 0.011 0.798 0.001 0.098 0.003 0.001 0.648

-0.209 -0.058 -0.026 0.075 0.006 0.206 0.146 -0.284 0.217 -0.062 0.289

<0.001 0.513 0.630 0.236 0.926 <0.001 0.058 0.001 <0.001 0.322 <0.001

IIEF-5 ¼ International Index of Erectile Function-5; Model 1 ¼ IIEF-5 þ Covariates; Model 2 ¼ Model 1 þ augmentation index; Model 3 ¼ Model 2 þ N-terminal pro-B-type natriuretic peptide.

between erectile dysfunction and hs-cTnI levels seems to provide information on subclinical myocardial injury above and beyond that obtained from conventional risk factors, as well as markers of endothelial dysfunction and heart failure alone. Accordingly, the presence of erectile dysfunction may be considered a bioassay of not only vascular function but also chronic, low-grade myocardial injury. This adds to the value of erectile dysfunction as a possible marker of the need for preventive efforts toward cardiovascular disease.5 Yet, clinicians should, however, be aware that low-level increments of hs-cTnI within the reference range currently cannot assist in such selection of patients. Importantly, the analytical variability of hs-cTnI assay used is relatively high in the low concentration range, making it more difficult to assess whether differences between individual patients are real. The cross-sectional design hinders further speculations of causal pathways. Whether subclinical myocardial damage translates into reduced ventricular function and overt heart failure merits further investigation. Another limitation in the present study is the lack of information regarding the cause of erectile dysfunction, which may differ between vasculogenic and nonvasculogenic causes regarding association with subclinical myocardial damage. Acknowledgment: The authors thank Marit Holmefjord Pedersen, BSc, Clinical Trial Unit, Division of Medicine, Akershus University Hospital, for conducting the hs-TnI analyses and Silje Kjeka Namtvedt, MD, PhD, Institute of Clinical Medicine, University of Oslo, for participating in the collection of the data.

Disclosures Dr. Omland has received speaker and/or consultancy honoraria from Abbott Diagnostics, Roche Diagnostics, and Novartis and research support from Abbott Diagnostics, AstraZeneca, Thermo Fisher Scientific, and Biomedica. Dr. Einvik has received research grants from Astra Zeneca for studies not related to the present study and speaker

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Preventive Cardiology/Erectile Dysfunction and cTnI community-based sample: data from the Akershus Sleep Apnea Project. Sleep 2014;37:1111e1116. 13. Barassi A, Pezzilli R, Morselli-Labate AM, Dozio E, Massaccesi L, Ghilardi F, Damele CA, Colpi GM, d’Eril GV, Corsi Romanelli MM. Evaluation of high sensitive troponin in erectile dysfunction. Dis Markers 2015;2015:548951. 14. Omland T, Rosjo H, Giannitsis E, Agewall S. Troponins in heart failure. Clin Chim Acta 2015;443:78e84.

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