Diabetes and Obesity, and the Li Ka Shing Institute of Health Sciences, The Hong Kong Foundation for Research and Development in Diabetes, established …
Journal of the American College of Cardiology 2008 by the American College of Cardiology Foundation Published by Elsevier Inc
Vol 51, No 21, 2008 ISSN 0735-1097/08/3400 doi:101016/jjacc200802051
Erectile Dysfunction Predicts Coronary Heart Disease in Type 2 Diabetes
Ronald Ching-Wan Ma, MA, Wing-Yee So, MBCHB, Xilin Yang, PHD, Linda Wai-Ling Yu, MBCHB, Alice Pik-Shan Kong, MBCHB, Gary Tin-Choi Ko, MD, Chun-Chung Chow, MBBS, Clive Stewart Cockram, MD, Juliana Chung-Ngor Chan, MD, Peter Chun-Yip Tong, PHD Hong Kong SAR, China
Objectives Background Methods
We examined the predictive power of erectile dysfunction ED on coronary heart disease CHD events in Chinese men with type 2 diabetes Subjects with diabetes are prone to develop cardiovascular complications Erectile dysfunction is strongly associated with CHD in cross-sectional studies, but prospective data are lacking A consecutive cohort of men with no clinical evidence of cardiovascular disease underwent comprehensive assessments for diabetic complications Erectile dysfunction was defined according to the definition of the National Institutes of Health Consensus Conference 1992 Coronary heart disease events were censored with
centralized territory-wide hospital databases in 2005 Of 2,306 subjects age: 542 127 years; follow-up: 40 [range 17 to 71] years, 267 had ED at baseline The incidence of CHD events was higher in men with ED than those without 197/1,000 person-years, 95 confidence interval [CI] 143 to 252 person-years vs 95/1,000 person-years, 95 CI 74 to 117 person-years Men who developed CHD events were older; had a higher frequency of ED and microvascular complications; had longer duration of diabetes; and had higher blood pressure, total cholesterol, low-density lipoprotein cholesterol, and urinary albumin/creatinine ratio but lower high-density lipoprotein cholesterol and estimated glomerular filtration rate than those without CHD events Erectile dysfunction remained an independent predictor for CHD events hazard ratio 158, 95 CI 108 to 230, p 0018 after adjustment for other covariates along with age, duration of disease, and use of antihypertensive agents and albuminuria In type 2 diabetic men without clinically overt cardiovascular disease, the presence of ED predicts a new onset of CHD events Symptoms of ED should be independently sought to identify high-risk subjects for comprehensive
cardiovascular assessments J Am Coll Cardiol 2008;51:204550 2008 by the American College of Cardiology Foundation
Results
Conclusions
Men with diabetes have a higher prevalence of erectile dysfunction ED compared with the general population In these subjects, the prevalence of ED increases with age and duration and severity of disease 1,2 Studies in different populations have reported frequencies of ED ranging from 20 to 90, depending on choice of assessment methods 3 6
From the Department of Medicine and Therapeutics, Hong Kong Institute of Diabetes and Obesity, and the Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China This study was partially supported by an MSD University Grant and the Hong Kong Foundation for Research and Development in Diabetes, established under the auspices of the Chinese University of Hong Kong The authors had full access to the data and take responsibility for its integrity All authors have read and agree to the article as written Manuscript received October 2, 2007; revised manuscript received January 30, 2008, accepted February 5, 2008
Recent studies suggest close
associations between ED and atherosclerosis, and ED might serve as a clinical marker for coronary, peripheral, or cerebrovascular diseases 712 In cross-sectional studies, strong associations between calculated Framingham coronary risk score and ED have been reported 11,13,14 However, to date, the prognostic value of ED in predicting adverse cardiovascular events such as coronary heart disease CHD has not been confirmed in prospective analyses
See page 2051
In the present study, we examined the impact of ED on the incidence of CHD events in a prospective cohort of Chinese type 2 diabetic men who did not have clinical evidence of cardiovascular diseases at baseline
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Ma et al Erectile Dysfunction and CHD in Diabetes
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Patients and methods Patients with diabetes were referred from general practitioners and general ACR albumin/creatinine medical and specialist hospital ratio clinics to the Prince of Wales ARB angiotensin Hospital Diabetes Centre for comreceptor blocker prehensive assessment of complicaCHD coronary heart tions and risk factors based on disease the European DIABCARE proCI confidence interval tocol 15 Between 1995 and DBP
diastolic blood 2005, 3,640 men were assessed pressure Patients with type 1 diabetes ED erectile dysfunction n 174 defined as acute preeGFR estimated sentation with diabetic ketoaciglomerular filtration rate dosis, heavy ketonuria 3 , or IIEF International Index continuous requirement of insuof Erectile Function lin within 1 year of diagnosis PAD peripheral arterial were excluded from this analysis disease Patients with clinically evident SBP systolic blood cardiovascular diseases, including pressure CHD, stroke, or peripheral arterial disease PAD, at baseline were not included n 548 Information on ED by questionnaire was not available in 612 patients Hence, 2,306 patients were included in the final analysis Informed consent was obtained from all patients at the time of assessment to allow use of data for research purpose The study was approved by the Chinese University of Hong Kong Clinical Research Ethics Committee Details of clinical assessments and laboratory assays were described previously 16 Presence of CHD-related events was defined as a past history of myocardial infarction, hospital admissions with heart failure, revascularization, or chest pain with abnormal
electrocardiogram or stress test Presence of stroke was defined as admission with typical neurological symptoms with or without recovery and confirmed on imaging Peripheral arterial disease was defined as absent pedal pulses confirmed by ankle-brachial ratio 09 on Doppler ultrasound examination or a history of previous revascularization procedures None of the patients in this consecutive cohort had a history of stroke, CHD, or PAD For all study participants, the use of antihypertensive medications, lipid-lowering agents, and angiotensinconverting enzyme inhibitors ACEIs/angiotensin receptor blockers ARBs at baseline was also recorded Antihypertensive medications included all classes of drugs that are indicated for hypertension, other than ACEI/ARB The use of lipid-lowering drugs included statins and fibrates Patients were asked directly whether they suffered from ED according to the definition of the National Institutes of Health NIH Consensus Conference 1992 17 Erectile dysfunction was defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance The response to the question was either Yes
ACEI angiotensinconverting enzyme
inhibitor
Abbreviations and Acronyms
Methods
or No All patients had at least 2 urinary collections: a sterile, random spot urine sample was used to measure albumin/creatinine ratio ACR followed by a timed collection 4- or 24-h for measurement of urinary albumin excretion rate The definition of albuminuria was based on the mean value of ACR from both the timed and spot urinary samples Normoalbuminuria was defined as a mean ACR 35 mg/mmol, microalbuminuria, 35 to 25 mg/ mmol, and macroalbuminuria, 25 mg/mmol 18 Sensory neuropathy was defined as 2 of 3 abnormal signs or symptoms: numbness in lower limbs or reduced sensation with either monofilament or graduated tuning fork Estimated glomerular filtration rate eGFR; expressed in ml/ min/173 m2 was calculated with the abbreviated Modification of Diet in Renal Disease MDRD formula further adjusted for the Chinese ethnicity 19:
GFR 186 SCR 0011 1154 age 0742 if female
0203
1233 if Chinese
where SCR is serum creatinine expressed as mol/l and 1233 is the adjusting coefficient for Chinese Chronic kidney disease CKD was defined by eGFR 60 ml/min/ 173 m2 20 Clinical outcomes Hong Kong has a heavily subsidized health care system, and 95 of
inpatient and chronic care are provided by public hospitals managed by the Hospital Authority All clinical end points including hospital admissions and mortality were censored on July 30, 2005 with databases from the Hospital Authority Central Computer System, which records admissions to all public hospitals These databases, including the Hong Kong Death Registry, were matched by a unique identification number, the Hong Kong Identity Card number, which is compulsory for all residents in Hong Kong and used by all government departments and major organizations With the International Classification of Diseases-9th Revision code, hard CHD events were defined as: 1 acute myocardial infarction code 410 or death due to coronary cause code 410, 411 to 414, 428; or 2 other nonfatal CHD code 411 to 414, procedure codes 36 and 0066 Statistical analysis The analysis was performed with the Statistical Package for Social Sciences version 115, SPSS Inc, Chicago, Illinois package Triglyceride and ACR were logarithmically transformed, owing to skewed distributions All data are expressed as mean SD or median [interquartile range], as appropriate The Student t test or analysis of variance was used
for between-group comparisons for continuous variables, and the chi-square test was used for categorical variables Logistic regression analysis was performed to identify factors associated with ED Cox proportional hazards regression analysis was used to estimate the hazard ratio with 95 confidence interval CI for CHD events Univariate analysis was performed with variables including ED; age; duration of diabetes; smoking history; use of antihypertensive, ACEI/ARB, or lipid-lowering
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Ma et al Erectile Dysfunction and CHD in Diabetes Presence of Erectile Dysfunction Chinese Men With Type 2 Diabetes Stratified by Clinical and Metabolic Characteristics of 2,306 the Table 1
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medications; glycosylated hemoglobin HbA1c; fasting plasma glucose; baseline status of retinopathy, sensory neuropathy, and ACR; eGFR; body mass index; waist circumference; systolic blood pressure SBP and diastolic blood pressure DBP; low-density lipoprotein cholesterol; high-density lipoprotein cholesterol; and triglycerides Factors associated with CHD p 01 on univariate analysis were included in the multivariate analysis A forward stepwise algorithm p 010 for
entry, and p 005 for stay was used A p value 005 2-tailed was considered to be significant Results In this cohort of 2,306 subjects mean age 542 127 years with a median follow-up period of 40 years interquartile range 17 to 71, 616 267 had ED according to the NIH definition There was no difference in clinical and biochemical parameters between the 612 in whom information on ED was not available and the remainder data not shown Men with ED were older and had a longer duration of diabetes and higher SBP, high-density lipoprotein cholesterol, serum creatinine, and ACR but lower eGFR and body mass index than those without ED They also had higher rates of retinopathy, sensory neuropathy, albuminuria, and chronic kidney disease and were more frequently using antihypertensive medications or lipid-lowering agents or taking ACEIs/ARBs Table 1 After adjusting for other confounding factors on logistic regression modeling, ED at baseline was associated with age odds ratio [95 CI] 103 [102 to 104], p 0001, body mass index 096 [093 to 099], p 0007, retinopathy 191 [152 to 239], p 0001, sensory neuropathy 165 [132 to 207], p 0001, use of antihypertensive medications 135 [107 to 171], p 0013, and
use of ACEI/ARB 150 [116 to 193], p 0002 Although there was no clinical evidence of cardiovascular disease at baseline, new CHD events occurred in 123 53 subjects during the 4-year observational period, giving an annualized incidence of 120/1,000 person-years 95 CI 990 to 141 In men with ED, the incidence was 197/ 1,000 person-years 95 CI 143 to 252 compared with 95 95 CI 74 to 117 in those without ED Men who developed new CHD events were older and had a longer duration of diabetes, higher SBP and DBP, total cholesterol, low-density lipoprotein cholesterol, and urinary ACR but lower high-density lipoprotein cholesterol and eGFR These subjects also had higher frequencies of retinopathy, albuminuria, use of antihypertensive medications, and ED at baseline Table 2 On univariate Cox regression analysis, age hazard ratio [95 CI] 104 [102 to 105], p 0001, duration of diabetes 106 [104 to 109], p 0001, SBP 102 [101 to 103], p 0001, albuminuria 342 [224 to 523], p 0001, retinopathy at baseline 238 [166 to 341], p 0001, eGFR 099 [098 to 099], p 0001, use of
Clinical and Metabolic Characteristics of 2,306 Chinese Men With Type 2 Diabetes Stratified by the Presence of Erectile
Dysfunction
Erectile Dysfunction No Yes 616 267 590 76 879 136 77 246 79 89 52 13 31 105 65 97 20 11 37 18 35 12 03 09 0001 0001 0399 0001 0450 0001 0094 0080 0645 0007 0254 0252 0001 0001 0001 0020 478 266 256 192 198 432 324 244 385 367 0001 0001 0001 681 210 109 57 245 156 102 539 251 210 117 388 297 141 0001 0001 0001 001 p Value
n Age yrs Duration of diabetes yrs Waist cm SBP mm Hg DBP mm Hg Body mass index kg/m2 HbA1c Fasting plasma glucose mmol/l Total cholesterol mmol/l HDL-cholesterol mmol/l LDL-cholesterol mmol/l Triglycerides mmol/l, n IQR Serum creatinine mol/l, n IQR Urine albumin/creatinine ratio mg/mmol, n IQR eGFR ml/min/173 m2 Smoking Never-smoker Ex-smoker Current smoker Retinopathy Sensory neuropathy Albuminuria Normoalbuminuria Microalbuminuria Macroalbuminuria Chronic kidney disease Use of antihypertensive medications Use of ACEI/ARB Use of lipid-lowering agents
1,690 733 524 53 883 132 78 252 77 86 52 12 32 130 59 97 18 11 39 19 33 12 03 10
135 095210 132 091193 87 76100 14 0661 894 254 92 81110 27 07180 791 250
ACEI angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker; DBP diastolic blood pressure; eGFR estimated glomerular
filtration rate; HbA1c glycosylated hemoglobin; HDL high-density lipoprotein; IQR interquartile range; LDL low-density lipoprotein; SBP systolic blood pressure
lipid-lowering agents 177 [101 to 311], p 0047, use of antihypertensive medications 234 [162 to 337], p 0001, use of ACEI/ARB 215 [140 to 330], p 0001, and ED 223 [155 to 320], p 0001 were associated with new CHD events In addition, DBP 101 [100 to 103], p 009 had borderline statistical significance These factors were entered in a forward stepwise model for multivariate analysis to identify independent predictors Erectile dysfunction remained an independent predictor of CHD events hazard ratio 158 [95 CI 108 to 230], p 0018, after adjusting for other confounding factors Other independent factors were age, duration of diabetes, use of antihypertensive medications, and baseline status of macroalbuminuria Table 3 The Kaplan-Meier curves for CHD events in subjects stratified by ED separated early and continued to diverge over time p 0001 Fig 1
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Ma et al Erectile Dysfunction and CHD in Diabetes
JACC Vol 51, No 21, 2008 May 27, 2008:204550 Multivariate With Type of CHD Events Chinese Men New Onset 2 Diabetes Within 2,306
Predictors ofAnalysis Table 3 Predictors of New Onset of CHD Events in 2,306 Chinese Men With Type 2 Diabetes With Multivariate Analysis
Hazard Ratio Yes 123 53 p Value Age Duration of diabetes 0001 0001 0320 0001 0004 0701 0457 0208 0002 0033 0001 0592 0005 0001 0003 0127
Other covariates not selected in the final model included SBP, DBP, retinopathy at baseline, eGFR, use of lipid-lowering agents, and use of ACEI/ARBs Abbreviations as in Tables 1 and 2
Presence of New Onset 2 CHD Events Chinese Men With Type of Diabetes Stratified by Clinical and Metabolic Characteristics of 2,306 the Table 2 Clinical and Metabolic Characteristics of 2,306 Chinese Men With Type 2 Diabetes Stratified by the Presence of New Onset of CHD Events
CHD Events No n Age yrs Duration of diabetes yrs Waist cm SBP mm Hg DBP mm Hg Body mass index kg/m HbA1c Fasting plasma glucose mmol/l Total cholesterol mmol/l HDL-cholesterol mmol/l LDL-cholesterol mmol/l Triglycerides mmol/l, n IQR Serum creatinine mol/l, n IQR Urine albumin/creatinine ratio mg/mmol, n IQR eGFR ml/min/173 m2 Smoking Nonsmoker Ex-smoker Current smoker Retinopathy Erectile dysfunction Albuminuria Normoalbuminuria Microalbuminuria
Macroalbuminuria Chronic kidney disease Use of antihypertensive medications Use of ACEI/ARB Use of lipid-lowering agents
CHD
2
95 Confidence Intervals 100104 100106
p Value 0026 0025
102 103
2,184 947 530 58 881 133 77 250 78 87 52 124 32 128 61 98 19 11 39 19 34 12 034 10
585 84 890 139 80 251 79 91 55 117 35
110 64 73 19 10 32 17 35 13 030 10
Albuminuria Normoalbuminuria Microalbuminuria Macroalbuminuria Use of antihypertensive medications Erectile dysfunction 100 128 216 158 158 081203 137341 106235 108230 030 0001 0025 0018
134 093205 142 101209 88 77102 15 0677 1073 316 93 80112 44 11481 985 328
470 281 249 233 260
385 295 320 402 393 0001 0001 0001
653 220 127 71 277 809 112
466 237 297 107 393 762 115 0144 001 024 088
ported that 70 of patients with type 2 diabetes had ED The association between ED and CHD might be due to their many common risk factors The prevalence of ED was higher among subjects with diabetes and silent CHD angiographically proven than those with diabetes alone In a cross-sectional study, the presence of ED was associated with a 148-fold increased risk of CHD and was the most efficient predictor among other conventional cardiovascular
risk factors 8 In another cross-sectional survey, 58 of type 2 diabetic men with angiographic evidence of CHD had symptoms of ED before the development of symptoms of angina 23 These findings strongly support the notion that ED might be a surrogate marker for future CHD, although prospective data are lacking Approximately 25 of middle-age men are estimated, with the Framingham Risk Engine, to develop CHD within 12 years 12 In the present study with a median follow-up period of 44 years, Chinese type 2 diabetic men with ED
coronary heart disease; other abbreviations as in Table 1
Discussion In this cohort of Chinese men with type 2 diabetes and no clinical evidence of cardiovascular disease, 26 reported symptoms of ED Erectile dysfunction was associated with age, disease duration, and presence of other microvascular complications More importantly, men with ED had a 16-fold increased risk of developing CHD events than those without, after adjustment for age, duration of diabetes, and other cardiovascular risk factors Previous studies have documented that patients with diabetes are more likely to suffer from ED In type 1 diabetes, symptoms of ED preceded typical symptoms of CHD by
388 months on average 21 Although impotence–a manifestation of ED–is common in type 2 diabetes, most studies were retrospective or cross-sectional in nature In a cross-sectional survey of type 2 diabetic patients, 34 reported problems of ED 22 Giuliano et al 1, with the International Index of Erectile Function IIEF-5 score, re-
Figure 1
Cumulative HR of CHD Events Stratified by ED in 2,306 Chinese Men With Type 2 Diabetes
Other covariates included age, duration of diabetes, systolic blood pressure, use of antihypertensive agents, low-density lipoprotein cholesterol, estimated glomerular filtration rate, retinopathy, and albuminuric status at baseline CHD coronary heart disease; ED erectile dysfunction; HR hazard ratio
JACC Vol 51, No 21, 2008 May 27, 2008:204550
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had an annualized CHD event rate of 20/1,000 personyears This represents a 16-fold increased risk compared with those without ED Compared with Caucasians, Chinese subjects are known to have lower risk of CHD 24 However, in this analysis, Chinese men with diabetes and ED had a CHD event rate comparable to the Caucasian general population 25 Importantly, the risk
association between ED and new CHD events remained significant after adjustment for other confounding factors Besides, none of these men had pre-existing cardiovascular diseases, thus strongly supporting that ED is an early marker of CHD in patients with diabetes Recently, a guideline on identification of cardiovascular diseases in patients with diabetes was published 26 Our results argue that documentation of ED should be included in the assessment of cardiovascular risk Age, disease duration, and use of antihypertensive medications are important risk factors for CHD, in agreement with other reports 6,2729 In addition, macroalbuminuria and ED conferred a 2- and 16-fold increased risk of CHD, respectively, independently of these risk factors There are strong data showing that endothelial dysfunction is an important antecedent event in the development of CHD and atherosclerosis 30,31 There is consensus that albuminuria might be a marker of endothelial dysfunction 32 Although we did not measure endothelial dysfunction in these subjects, we have previously reported that Chinese type 2 diabetic patients with macroalbuminuria and renal dysfunction had reduced forearm flow-mediated
dilation with Doppler ultrasound scan 33 Taken together, it is conceivable that the penile microcirculation might be affected early by metabolic and hemodynamic factors such as hyperglycemia, dyslipidemia, blood pressure, oxidative stress, and glycation end products These might result in vascular dysfunction giving rise to ED characterized by delay in time to maximal erection, reduced rigidity, and decreased ability to sustain an erection In these subjects, similar pathological processes might be expected in other parts of the circulation Impaired endotheliumdependent and -independent vasodilation are present in diabetic patients with ED and precede the onset of overt CHD 34,35 A potential limitation of the current study is the use of NIH criteria during interview to define ED Sexuality is a cultural taboo in China These factors might contribute to the relatively low frequency of ED as compared with other studies 1,2,36 In more recent studies, information on ED was collected by using the IIEF or IIEF-5 questionnaires, which include more objective items, rather than using a single question as in the NIH criteria Nevertheless, the latter was regarded as the standard for assessment
when the current study was initiated in 1995 Besides, other studies have indicated a reasonable correlation between subjective assessment by NIH criteria and more detailed assessment based on the IIEF-5 1,37 Although this relatively low
percentage of subjects with ED is less likely to give rise to type 1 error, it is possible that subjects with more severe symptoms of ED were more likely to respond positively and thus bias the results toward a positive association Nevertheless, in this prospective analysis, we have collected conventional risk factors and complications at baseline, and ED remained a significant risk factor after controlling for these confounding factors There are other limitations to this study Selection bias might be present when patients are recruited from a single center However, in Hong Kong, most patients with chronic diseases such as diabetes are managed in a public hospital where care is heavily subsidized Although variability with single laboratory measurements might introduce errors, our results also demonstrate the benefit of asking a single question on ED and documenting clinical and biochemical measurement on a single occasion to identify subjects at
high risk of CHD When the survey was commenced in 1995, comprehensive cardiac assessments were not routinely performed in asymptomatic patients Cardiovascular status was based largely on medical history or typical symptoms in the presence of abnormal electrocardiogram or stress test Thus, it remains possible that patients with silent CHD might have been included in the analysis Another potential limitation is the limited information on the use of concomitant medications, whereby effects from drugs such as beta-blockers or diuretics could not be separated from those due to other antihypertensive agents in terms of the relative contribution to ED in affected subjects Although the use of antihypertensive medications was an independent predictor of new-onset coronary heart disease, impotence remains an independent predictor on Cox regression analysis This finding suggested that the association between ED and new-onset CHD is unlikely to be accounted for by the influence of medications
Conclusions To our knowledge, this is the first prospective analysis of a large cohort of asymptomatic men with type 2 diabetes showing the risk association between ED and new onset of CHD events These
results strongly suggest that ED is a surrogate marker for future CHD Given the preventable nature of CHD, symptoms of ED should be actively sought to identify high-risk subjects for comprehensive cardiovascular and metabolic assessments
Reprint requests and correspondence: Dr Peter C Y Tong, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, The Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, China E-mail: ptong@cuhkeduhk
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JACC Vol 51, No 21, 2008 May 27, 2008:204550 20 K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification Am J Kidney Dis 2002;39: S1266 21 Montorsi F, Briganti A, Salonia A, et al Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease Eur Urol 2003;44:360 4; discussion 364 5 22 De Berardis G, Franciosi M, Belfiglio M, et al Erectile dysfunction and quality of life in type 2 diabetic patients: a serious problem too often overlooked Diabetes Care 2002;25:284 91 23 Solomon H, Man JW, Wierzbicki
AS, Jackson G Relation of erectile dysfunction to angiographic coronary artery disease Am J Cardiol 2003;91:230 1 24 Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes Diabetologia 2001;44 Suppl 2:S14 21 25 Rosamond W, Flegal K, Friday G, et al Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 2007;115:e69 171 26 Ryden L, Standl E, Bartnik M, et al Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology ESC and of the European Association for the Study of Diabetes EASD Eur Heart J 2007;28:88 136 27 Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study J Urol 1994;151:54 61 28 Kaiser FE, Korenman SG Impotence in diabetic men Am J Med 1988;85:14752 29 Sasayama S, Ishii N, Ishikura F, et al Mens Health Study: epidemiology of erectile dysfunction and
cardiovascular disease Circ J 2003; 67:656 9 30 Bonetti PO, Lerman LO, Lerman A Endothelial dysfunction: a marker of atherosclerotic risk Arterioscler Thromb Vasc Biol 2003; 23:168 75 31 Gonzalez MA, Selwyn AP Endothelial function, inflammation, and prognosis in cardiovascular disease Am J Med 2003;115 Suppl 8A:99S106S 32 Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, KofoedEnevoldsen A Albuminuria reflects widespread vascular damage The Steno hypothesis Diabetologia 1989;32:219 26 33 Chan WB, Chan NN, Lai CW, et al Vascular defect beyond the endothelium in type II diabetic patients with overt nephropathy and moderate renal insufficiency Kidney Int 2006;70:711 6 34 Kaiser DR, Billups K, Mason C, Wetterling R, Lundberg JL, Bank AJ Impaired brachial artery endothelium-dependent and -independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease J Am Coll Cardiol 2004;43:179 84 35 Yavuzgil O, Altay B, Zoghi M, Gurgun C, Kayikcioglu M, Kultursay H Endothelial function in patients with vasculogenic erectile dysfunction Int J Cardiol 2005;103:19 26 36 Klein R, Klein BE, Moss SE Ten-year incidence of self-reported erectile dysfunction in
people with long-term type 1 diabetes J Diabetes Complications 2005;19:35 41 37 Derby CA, Araujo AB, Johannes CB, Feldman HA, McKinlay JB Measurement of erectile dysfunction in population-based studies: the use of a single question self-assessment in the Massachusetts Male Aging Study Int J Impot Res 2000;12:197204
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