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Left Ventricular Diastolic Function and Endothelial Function in Patients With Erectile Dysfunction
Left Ventricular Diastolic Function and Endothelial Function in Patients With Erectile Dysfunction Nevzat Uslu, MD, Mehmet Eren, MD, Sevket Gorgulu, MD*, Ahmet T. Alper, MD, Ahmet L. Orhan, MD, Aydin Yildirim, MD, Zekeriya Nurkalem, MD, and Huseyin Aksu, MD The aim of this study was to assess left ventricular diastolic function and forearm endothelial function in patients with erectile dysfunction (ED) without overt cardiovascular disease. Forearm endothelial function and diastolic Doppler parameters, including tissue Doppler imaging, were studied in 32 men with ED and 27 age-matched, healthy, male control subjects. Left ventricular diastolic function in patients with ED and the relation between endothelium-dependent vasodilation and the Doppler parameters of left ventricular diastolic function, including tissue Doppler imaging, were assessed. Endotheliumdependent vasodilation (4.1 ⴞ 3.3% vs 9.7 ⴞ 4.2%, p <0.001) as well as the mitral inflow E velocity (0.66 ⴞ 0.17 vs 0.80 ⴞ 0.16 m/s, p ⴝ 0.01), the E/A ratio (the ratio of mitral inflow E velocity to mitral inflow A velocity; 0.91 ⴞ 0.3% vs 1.22 ⴞ 0.26%, p <0.001), and the E/Em ratio (the ratio of mitral A-wave velocity to early diastolic velocity in the annulus derived by tissue Doppler imaging; 7.4 ⴞ 2.7% vs 6.6 ⴞ 1.6%, p ⴝ 0.03) were smaller in the ED group than in the control group. Deceleration time (228.6 ⴞ 61.6 vs 192.9 ⴞ 44.6 ms, p ⴝ 0.03) and isovolumetric relaxation time (112.8 ⴞ 18 vs 94 ⴞ 15.9 ms, p <0.001) were also prolonged in the ED group compared with the control group. The mitral E-wave velocity (r ⴝ 0.40, p ⴝ 0.022), the E/A ratio (r ⴝ 0.40, p ⴝ 0.027), and the E/Em ratio (r ⴝ ⴚ0.52, p ⴝ 0.003) were related to endothelium-dependent vasodilation by univariate analysis. Only the E/Em ratio was correlated with endothelium-dependent vasodilation by multivariate analysis. In conclusion, this study indicates that endothelial function and left ventricular diastolic function are impaired in patients with ED without overt cardiovascular disease. © 2006 Elsevier Inc. All rights reserved. (Am J Cardiol 2006;97:1785–1788) It is well known that myocardial contraction itself is influenced by nitric oxide from coronary microvascular endothelium, and nitric oxide increases diastolic compliance and slightly shortens the duration of contraction, with little or no effect on systolic function.1 The nitric oxide– cyclic guanosine3=5=-monophosphate system is also important in the pathophysiology of erectile dysfunction (ED).2– 4 This system also plays a crucial role in maintaining the function of vascular endothelium.5 Taking all this into account, we hypothesized that there may be generalized dysfunction in the nitric oxide system. If this is the case, there should also be impairment in endothelial function and left ventricular diastolic function. To ascertain the influence of possible generalized nitric oxide system dysfunction, we studied patients with ED without atherosclerosis or its main risk factors to minimize the effects of risk factors that may act with different mechanisms on ED, endothelial function, and left ventricular diastolic function. •••
Thirty-two outpatients with ED (mean age 54.6 ⫾ 9.8 years; consistent inability to achieve or sustain a sufficiently rigid
Siyami Ersek Thoracic and Cardiovascular Surgery Center, Cardiology Department, Istanbul, Turkey. Manuscript received September 20, 2005; revised manuscript received and accepted January 4, 2006. * Corresponding author: Tel: 00-90-216-3499120; fax: 00-90-2165504433. E-mail address: [email protected] (S. Gorgulu). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.01.041
erection for sexual intercourse) for ⬎1 year and 27 healthy volunteers (mean age 51.8 ⫾ 7.1 years) as a control group from the hospital’s staff were enrolled in this study. The diagnosis of ED was based on the International Index of Erectile Function-5 questionnaire and penile Doppler study.6,7 None of the patients or controls had clinical evidence of coronary artery disease, diabetes mellitus, hypertension, malignancy, renal failure, congestive heart failure, systemic inflammatory disease, or arrhythmias. None of the subjects was taking medications, alcohol, or vitamin supplements. All subjects gave informed consent before participation. The study protocol was approved by the local ethics committee. All patients and control subjects underwent clinical and electrocardiographic examination. The following risk factors for atherosclerosis were assessed at the first evaluation: fasting glucose, total cholesterol, triglycerides, high- and low-density lipoproteinases, smoking status, and family history of coronary artery disease. Renal and hepatic function tests were also done. A maximal exercise test was performed on all subjects according to Bruce’s protocol, and subjects with negative exercise test results were enrolled in the study. All subjects were asked to complete the international Index of Erectile Function-5 questionnaire to ascertain erectile performance. Transthoracic echocardiography was performed by 1 of the investigators, who had no information on the patients’ clinical data, using a Vivid Seven (GE Vingmed Ultrasound www.AJConline.org
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The American Journal of Cardiology (www.AJConline.org) Table 1 Comparison of the baseline characteristics of 32 patients with erectile dysfunction and 27 control subjects Variable Age (yrs) Body surface area (m2) Heart rate (beats/min) Smokers Plasma glucose level (mg/dl) Total cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglycerides (mg/dl) International Index of Erectile Function ⫽ 5 score
ED Group (n ⫽ 32)
Controls (n ⫽ 27)
54.6 ⫾ 9.8 1.87 ⫾ 0.8 72 ⫾ 10 2 (6.%) 98 ⫾ 15 196 ⫾ 32 43 ⫾ 12 118 ⫾ 26 173 ⫾ 64 9.2 ⫾ 3.2*
51.8 ⫾ 7.1 1.88 ⫾ 0.7 70 ⫾ 9 2 (6%) 96.4 ⫾ 10.1 195 ⫾ 19 39 ⫾ 9 124 ⫾ 25 189 ⫾ 83 21 ⫾ 2.7*
* p ⬍0.001. Figure 1. There was a significant correlation between endothelium-dependent dilation and the mitral E/Em ratio in patients with ED.
Table 2 Echocardiographic parameters of the study subjects Variable
AS, Horten, Norway) with a 2.5-MHz phased-array transducer. Measurements of left ventricular diameter were made on M-mode traces recorded from the parasternal long-axis view according to established standards.8 Transmitral velocities were recorded from the apical window, with a 1- to 3-mm sample volume placed between the tips of the mitral leaflets during diastole. From the transmitral flow tracing, the following variables were measured: peak velocity of early diastolic filling (E), late filling with atrial contraction (A), and the deceleration time of the E wave. The isovolumetric relaxation time was recorded from the apical 4-chamber view by simultaneous recording of the aortic and mitral flows. The pulse-wave spectral mode was used for tissue Doppler imaging. From the apical 4-chamber view, a 5-mm sample volume was placed at the lateral corner of the mitral annulus. Early and late diastolic velocities and systolic velocities were calculated. An average value was obtained from the recordings of 3 to 5 consecutive cardiac cycles with simultaneous electrocardiography. Each subject was studied in the morning having abstained from caffeine and tobacco as well as food for 8 hours before the study. Endothelium-dependent dilation (flow-mediated dilation [FMD]) and non– endothelial-dependent dilation of the brachial artery were assessed noninvasively using a high-resolution ultrasound system (GE Vingmed Ultrasound AS) with a 10-MHz linear-array vascular transducer, as previously described.9,10 End-diastolic frames (coincident with the electrocardiographic R wave) from 3 consecutive cardiac cycles of the baseline, reactive hyperemia, and post-nitrate images were digitized and analyzed by 1 observer, blinded to the protocol, as previously described.10 Pulse-wave Doppler measurements were also done at baseline, hyperemic, and postnitrate measurements. Volume flow was calculated by multiplying the time-averaged velocity of the Doppler flow signal by the heart rate and the vessel cross-sectional area
Ejection fraction (%) Mitral E velocity Mitral A velocity E/A ratio Deceleration time (ms) Isovolumic relaxation time (ms) TDI E velocity TDI A velocity TDI S velocity Mitral E velocity/TDI E velocity (E/Em) ratio
Patients With ED (n ⫽ 32)
Controls (n ⫽ 27)
p Value
65.5 ⫾ 9.6 0.66 ⫾ 0.17 0.75 ⫾ 0.13 0.91 ⫾ 0.3 228.6 ⫾ 61.6 112.8 ⫾ 18
64.4 ⫾ 8.4 0.80 ⫾ 0.16 0.66 ⫾ 0.10 1.22 ⫾ 0.26 192.9 ⫾ 44.6 94 ⫾ 15.9
NS 0.01 0.03 ⬍0.001 0.03 ⬍0.001
8.9 ⫾ 2.8 11.2 ⫾ 3.9 8.9 ⫾ 3.1 7.4 ⫾ 2.7
12.3 ⫾ 2.6 10.2 ⫾ 2.2 8.2 ⫾ 1.6 6.6 ⫾ 1.6
0.001 NS NS 0.03
TDI ⫽ tissue Doppler imaging.
( r2). Endothelium-dependent FMD was calculated as the percentage change in brachial artery diameter 1 minute after reactive hyperemia compared with baseline. Likely non– endothelium-dependent vasodilation was calculated as the percentage change in brachial artery diameter 3 minutes after sublingual nitroglycerin compared with baseline. Reactive hyperemia was calculated as the maximum flow during the first minute after cuff deflation divided by the corresponding flow at rest. Statistical analysis was performed using SPSS version 10 (SPSS, Inc., Chicago, Illinois). To compare responses between the groups, independent-sample Student’s t tests were used. Correlations between left ventricular diastolic parameters and endothelium-dependent vasodilation were analyzed first by simple Pearson’s logistic regression analysis and then by multivariate analysis. Statistical significance was taken as p ⬍0.05. The data in Figure 1 and Tables 1 to 3 are presented as means ⫾ SEM. The demographic, clinical, and biochemical characteristics of the patients with ED and the control subjects are listed in Table 1. The echocardiographic parameters of the subjects stud-
Miscellaneous/Diastolic and Endothelial Function in ED Table 3 Correlations among patient characteristics, including echocardiographic parameters and flow-mediated and non-endothelial-dependent dilation Variable
FMD (r)
Non-EndothelialDependent Dilation (r)
Age (yrs) Heart rate (beats/min) Smokers Fasting glucose level Total cholesterol (mg/dl) Triglyceride (mg/dl) Ejection fraction (%) Body surface area (m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mitral E velocity (cm/s) E/A ratio Deceleration time (ms) Isovolumic relaxation time (ms) TDI E velocity (E/Em) ratio
⫺0.08 0.11 ⫺0.18 0.04 0.34 0.04 0.04 ⫺0.31 ⫺0.02 ⫺0.17 0.40* 0.40* 0.24 ⫺0.06 ⫺0.52*
⫺0.07 0.13 0.19 0.13 ⫺0.28 ⫺0.22 0.19 ⫺0.23 ⫺0.12 ⫺0.08 0.28 0.33 ⫺0.02 ⫺0.25 ⫺0.01
* p ⬍0.05. Abbreviation as in Table 1.
ied are given in Table 2. Mitral inflow E velocity (0.66 ⫾ 0.17 vs 0.80 ⫾ 0.16 m/s, p ⫽ 0.01) and the E/A ratio (0.91 ⫾ 0.3% vs 1.22 ⫾ 0.26%, p ⬍0.001) were smaller in the ED group than in the control group. Pulsewave tissue Doppler imaging E velocity (8.9 ⫾ 2.8 vs 12.3 ⫾ 2.6 cm/s, p ⫽ 0.001) and the E/Em ratio (7.4 ⫾ 2.7% vs 6.6 ⫾ 1.6%, p ⫽ 0.03) were smaller in the ED group than in the control group. Baseline brachial artery diameters were not different between patients with ED and controls (3.87 ⫾ 0.4 vs 3.74 ⫾ 0.4, p ⫽ NS). FMD was significantly decreased in the ED group compared with the control group (4.1 ⫾ 3.3% vs 9.7 ⫾ 4.2%, p ⬍0.001), indicating impaired vascular response to reactive hyperemia in patients with ED. Non– endothelial-dependent dilation was insignificant between the 2 study groups (13.2 ⫾ 4.0% vs 15.7 ⫾ 5.4%, p ⫽ 0.55). Increase in blood flow as a response to hyperemia was reduced in patients with ED compared with controls (147 ⫾ 116% vs 296 ⫾ 168%, p ⬍0.001). On univariate analysis, in patients with ED, endotheliumdependent vasodilation was significantly correlated with E velocity (r ⫽ 0.40, p ⫽ 0.022), the E/A ratio (r ⫽ 0.40, p ⫽ 0.027), and the E/Em ratio (r ⫽ ⫺0.52, p ⫽ 0.003) (Table 3). After controlling for age, heart rate, systolic blood pressure, diastolic blood pressure, smoking status, total cholesterol, triglycerides, body surface area, and the ejection fraction, FMD was still correlated with the mitral E/Em ratio (r ⫽ ⫺0.52, p ⫽ 0.003; Figure 1). •••
The results of this study indicate that endothelial function and left ventricular diastolic function are impaired in patients with ED without overt cardiovascular disease. In addition, the E/Em ratio, which is a reliable parameter in assessing diastolic function, was found to be the most
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closely related parameter to endothelial function in multivariate analysis. Because our study showed endothelial dysfunction in patients with ED (p ⬍0.001), a more generalized vascular disease may play a major role in patients with ED without atherosclerosis or its risk factors. In other words, generalized nitric oxide system dysfunction may be the main reason for ED and cause endothelial dysfunction by affecting vascular remodeling.11,12 In accordance with our results, Kaiser et al13 demonstrated that patients with ED and no significant cardiac risk factors or other clinical cardiovascular disease had peripheral vascular abnormalities in the nitric oxide– cyclic guanosine monophosphate pathway, as measured by brachial artery FMD. However, they concluded that the defect in the nitric oxide– cyclic guanosine monophosphate vasodilator pathway must involve the smooth muscle, because vasodilation to the direct smooth muscle dilator nitroglycerin was impaired in the brachial arteries of patients with ED. In contrast to Kaiser et al’s13 results, we found brachial artery vasodilation impairment only to shear stress stimulus, and the nitroglycerin response was not different from that in controls (13.2 ⫾ 4.0% vs 15.7 ⫾ 5.4%, p ⫽ 0.55). We suggest, therefore, that endothelial function, rather than smooth muscle function, is adversely affected in patients with ED. Left ventricular diastolic dysfunction found in our patients with ED may also be the result of generalized nitric oxide dysfunction, which decreases diastolic compliance and slightly prolongs the duration of contraction, with little or no effect on systolic function.1 There is a cyclic release of nitric oxide in the heart that is most marked subendocardially and that peaks at the time of relaxation and filling. These brief bursts of nitric oxide release provide a beat-tobeat modulation of relaxation and stiffness.14 Another possible mechanism is that endothelial dysfunction may have an adverse influence on diastolic function.15 The relation between the E/Em ratio and endothelial function presented in our study supports this notion. Because it has been shown that aortic stiffness is closely related to diastolic function parameters,16,17 increased aortic stiffness as a result of endothelial dysfunction18 or generalized nitric-oxide-system dysfunction19 may explain the rationale of diastolic dysfunction in our patients with ED. 1. Paulus WJ, Vantrimpton PJ, Shah AM. Paracrine coronary endothelial control of left ventricular function in humans. Circulation 1995;92: 2119 –2126. 2. Azadzoi KM, Saenz de Tejada I. Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1991;146:238 –240. 3. Azadzoi KM, Goldstein I. Erectile dysfunction due to atherosclerotic vascular disease: the development of an animal model. J Urol 1992; 147:1675–1681. 4. Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989;320:1025–1030.
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5. Hansson GK, Nilsson J. Pathogenesis of atherosclerosis. In: Crawford MH, Dimarco JP, Paulus WJ, eds. Cardiology. St. Louis, MO: Mosby, 2004:5. 6. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319 –326. 7. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49: 822– 830. 8. Sahn D, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantification in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–1083. 9. Calermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivian ID, Lloyd JK, Deanfield JE. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–1115. 10. Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. The effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 2000;36: 758 –765. 11. Baig MK, Mahon N, McKenna WJ, Caforio AL, Bonow RO, Francis GS, Gheorghiade M. The pathophysiology of advanced heart failure. Am Heart J 1998;135:216 –230.
12. Chrysant SG. Vascular remodeling: the role of angiotensin-converting enzyme inhibitors. Am Heart J 1998;135:21–30. 13. 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 –184. 14. Paulus WJ. Beneficial effects of nitric oxide on cardiac diastolic function: “the flip side of the coin.” Heart Failure Rev 2000;5:337– 344. 15. Ma LN, Zhao SP, Gao M, Zhou QC, Fan P. Endothelial dysfunction associated with left ventricular diastolic dysfunction in patients with coronary heart disease. Int J Cardiol 2000;72:275–279. 16. Eren M, Gorgulu S, Uslu N, Celik S, Dagdeviren B, Tezel T. Relation between aortic stiffness and left ventricular diastolic function in patients with hypertension, diabetes, or both. Heart 2004;90:37– 43. 17. Gorgulu S, Eren M, Celik S, Dagdeviren B, Uslu N, Suer N, Tezel T. The effects of hormonal therapy on aortic stiffness and left ventricular diastolic function. Acta Cardiol 2003;58:1– 8. 18. Gorgulu S, Uslu N, Eren M, Celik S, Yıldırım A, Dagdeviren B, Tezel T. Aortic stiffness in patients with cardiac syndrome X. Acta Cardiol 2003;58:507–511. 19. Uslu N, Gorgulu S, Alper AT, Eren M, Nurkalem Z, Yildirim A, Ozer O. Erectile dysfunction as a generalized vascular disorder. J Am Soc Echocardiogr 2006;19:341–346.
Thirty-two outpatients with ED (mean age 54.6 ⫾ 9.8 years; consistent inability to achieve or sustain a sufficiently rigid
Siyami Ersek Thoracic and Cardiovascular Surgery Center, Cardiology Department, Istanbul, Turkey. Manuscript received September 20, 2005; revised manuscript received and accepted January 4, 2006. * Corresponding author: Tel: 00-90-216-3499120; fax: 00-90-2165504433. E-mail address: [email protected] (S. Gorgulu). 0002-9149/06/$ – see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.01.041
erection for sexual intercourse) for ⬎1 year and 27 healthy volunteers (mean age 51.8 ⫾ 7.1 years) as a control group from the hospital’s staff were enrolled in this study. The diagnosis of ED was based on the International Index of Erectile Function-5 questionnaire and penile Doppler study.6,7 None of the patients or controls had clinical evidence of coronary artery disease, diabetes mellitus, hypertension, malignancy, renal failure, congestive heart failure, systemic inflammatory disease, or arrhythmias. None of the subjects was taking medications, alcohol, or vitamin supplements. All subjects gave informed consent before participation. The study protocol was approved by the local ethics committee. All patients and control subjects underwent clinical and electrocardiographic examination. The following risk factors for atherosclerosis were assessed at the first evaluation: fasting glucose, total cholesterol, triglycerides, high- and low-density lipoproteinases, smoking status, and family history of coronary artery disease. Renal and hepatic function tests were also done. A maximal exercise test was performed on all subjects according to Bruce’s protocol, and subjects with negative exercise test results were enrolled in the study. All subjects were asked to complete the international Index of Erectile Function-5 questionnaire to ascertain erectile performance. Transthoracic echocardiography was performed by 1 of the investigators, who had no information on the patients’ clinical data, using a Vivid Seven (GE Vingmed Ultrasound www.AJConline.org
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The American Journal of Cardiology (www.AJConline.org) Table 1 Comparison of the baseline characteristics of 32 patients with erectile dysfunction and 27 control subjects Variable Age (yrs) Body surface area (m2) Heart rate (beats/min) Smokers Plasma glucose level (mg/dl) Total cholesterol (mg/dl) High-density lipoprotein (mg/dl) Low-density lipoprotein (mg/dl) Triglycerides (mg/dl) International Index of Erectile Function ⫽ 5 score
ED Group (n ⫽ 32)
Controls (n ⫽ 27)
54.6 ⫾ 9.8 1.87 ⫾ 0.8 72 ⫾ 10 2 (6.%) 98 ⫾ 15 196 ⫾ 32 43 ⫾ 12 118 ⫾ 26 173 ⫾ 64 9.2 ⫾ 3.2*
51.8 ⫾ 7.1 1.88 ⫾ 0.7 70 ⫾ 9 2 (6%) 96.4 ⫾ 10.1 195 ⫾ 19 39 ⫾ 9 124 ⫾ 25 189 ⫾ 83 21 ⫾ 2.7*
* p ⬍0.001. Figure 1. There was a significant correlation between endothelium-dependent dilation and the mitral E/Em ratio in patients with ED.
Table 2 Echocardiographic parameters of the study subjects Variable
AS, Horten, Norway) with a 2.5-MHz phased-array transducer. Measurements of left ventricular diameter were made on M-mode traces recorded from the parasternal long-axis view according to established standards.8 Transmitral velocities were recorded from the apical window, with a 1- to 3-mm sample volume placed between the tips of the mitral leaflets during diastole. From the transmitral flow tracing, the following variables were measured: peak velocity of early diastolic filling (E), late filling with atrial contraction (A), and the deceleration time of the E wave. The isovolumetric relaxation time was recorded from the apical 4-chamber view by simultaneous recording of the aortic and mitral flows. The pulse-wave spectral mode was used for tissue Doppler imaging. From the apical 4-chamber view, a 5-mm sample volume was placed at the lateral corner of the mitral annulus. Early and late diastolic velocities and systolic velocities were calculated. An average value was obtained from the recordings of 3 to 5 consecutive cardiac cycles with simultaneous electrocardiography. Each subject was studied in the morning having abstained from caffeine and tobacco as well as food for 8 hours before the study. Endothelium-dependent dilation (flow-mediated dilation [FMD]) and non– endothelial-dependent dilation of the brachial artery were assessed noninvasively using a high-resolution ultrasound system (GE Vingmed Ultrasound AS) with a 10-MHz linear-array vascular transducer, as previously described.9,10 End-diastolic frames (coincident with the electrocardiographic R wave) from 3 consecutive cardiac cycles of the baseline, reactive hyperemia, and post-nitrate images were digitized and analyzed by 1 observer, blinded to the protocol, as previously described.10 Pulse-wave Doppler measurements were also done at baseline, hyperemic, and postnitrate measurements. Volume flow was calculated by multiplying the time-averaged velocity of the Doppler flow signal by the heart rate and the vessel cross-sectional area
Ejection fraction (%) Mitral E velocity Mitral A velocity E/A ratio Deceleration time (ms) Isovolumic relaxation time (ms) TDI E velocity TDI A velocity TDI S velocity Mitral E velocity/TDI E velocity (E/Em) ratio
Patients With ED (n ⫽ 32)
Controls (n ⫽ 27)
p Value
65.5 ⫾ 9.6 0.66 ⫾ 0.17 0.75 ⫾ 0.13 0.91 ⫾ 0.3 228.6 ⫾ 61.6 112.8 ⫾ 18
64.4 ⫾ 8.4 0.80 ⫾ 0.16 0.66 ⫾ 0.10 1.22 ⫾ 0.26 192.9 ⫾ 44.6 94 ⫾ 15.9
NS 0.01 0.03 ⬍0.001 0.03 ⬍0.001
8.9 ⫾ 2.8 11.2 ⫾ 3.9 8.9 ⫾ 3.1 7.4 ⫾ 2.7
12.3 ⫾ 2.6 10.2 ⫾ 2.2 8.2 ⫾ 1.6 6.6 ⫾ 1.6
0.001 NS NS 0.03
TDI ⫽ tissue Doppler imaging.
( r2). Endothelium-dependent FMD was calculated as the percentage change in brachial artery diameter 1 minute after reactive hyperemia compared with baseline. Likely non– endothelium-dependent vasodilation was calculated as the percentage change in brachial artery diameter 3 minutes after sublingual nitroglycerin compared with baseline. Reactive hyperemia was calculated as the maximum flow during the first minute after cuff deflation divided by the corresponding flow at rest. Statistical analysis was performed using SPSS version 10 (SPSS, Inc., Chicago, Illinois). To compare responses between the groups, independent-sample Student’s t tests were used. Correlations between left ventricular diastolic parameters and endothelium-dependent vasodilation were analyzed first by simple Pearson’s logistic regression analysis and then by multivariate analysis. Statistical significance was taken as p ⬍0.05. The data in Figure 1 and Tables 1 to 3 are presented as means ⫾ SEM. The demographic, clinical, and biochemical characteristics of the patients with ED and the control subjects are listed in Table 1. The echocardiographic parameters of the subjects stud-
Miscellaneous/Diastolic and Endothelial Function in ED Table 3 Correlations among patient characteristics, including echocardiographic parameters and flow-mediated and non-endothelial-dependent dilation Variable
FMD (r)
Non-EndothelialDependent Dilation (r)
Age (yrs) Heart rate (beats/min) Smokers Fasting glucose level Total cholesterol (mg/dl) Triglyceride (mg/dl) Ejection fraction (%) Body surface area (m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Mitral E velocity (cm/s) E/A ratio Deceleration time (ms) Isovolumic relaxation time (ms) TDI E velocity (E/Em) ratio
⫺0.08 0.11 ⫺0.18 0.04 0.34 0.04 0.04 ⫺0.31 ⫺0.02 ⫺0.17 0.40* 0.40* 0.24 ⫺0.06 ⫺0.52*
⫺0.07 0.13 0.19 0.13 ⫺0.28 ⫺0.22 0.19 ⫺0.23 ⫺0.12 ⫺0.08 0.28 0.33 ⫺0.02 ⫺0.25 ⫺0.01
* p ⬍0.05. Abbreviation as in Table 1.
ied are given in Table 2. Mitral inflow E velocity (0.66 ⫾ 0.17 vs 0.80 ⫾ 0.16 m/s, p ⫽ 0.01) and the E/A ratio (0.91 ⫾ 0.3% vs 1.22 ⫾ 0.26%, p ⬍0.001) were smaller in the ED group than in the control group. Pulsewave tissue Doppler imaging E velocity (8.9 ⫾ 2.8 vs 12.3 ⫾ 2.6 cm/s, p ⫽ 0.001) and the E/Em ratio (7.4 ⫾ 2.7% vs 6.6 ⫾ 1.6%, p ⫽ 0.03) were smaller in the ED group than in the control group. Baseline brachial artery diameters were not different between patients with ED and controls (3.87 ⫾ 0.4 vs 3.74 ⫾ 0.4, p ⫽ NS). FMD was significantly decreased in the ED group compared with the control group (4.1 ⫾ 3.3% vs 9.7 ⫾ 4.2%, p ⬍0.001), indicating impaired vascular response to reactive hyperemia in patients with ED. Non– endothelial-dependent dilation was insignificant between the 2 study groups (13.2 ⫾ 4.0% vs 15.7 ⫾ 5.4%, p ⫽ 0.55). Increase in blood flow as a response to hyperemia was reduced in patients with ED compared with controls (147 ⫾ 116% vs 296 ⫾ 168%, p ⬍0.001). On univariate analysis, in patients with ED, endotheliumdependent vasodilation was significantly correlated with E velocity (r ⫽ 0.40, p ⫽ 0.022), the E/A ratio (r ⫽ 0.40, p ⫽ 0.027), and the E/Em ratio (r ⫽ ⫺0.52, p ⫽ 0.003) (Table 3). After controlling for age, heart rate, systolic blood pressure, diastolic blood pressure, smoking status, total cholesterol, triglycerides, body surface area, and the ejection fraction, FMD was still correlated with the mitral E/Em ratio (r ⫽ ⫺0.52, p ⫽ 0.003; Figure 1). •••
The results of this study indicate that endothelial function and left ventricular diastolic function are impaired in patients with ED without overt cardiovascular disease. In addition, the E/Em ratio, which is a reliable parameter in assessing diastolic function, was found to be the most
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closely related parameter to endothelial function in multivariate analysis. Because our study showed endothelial dysfunction in patients with ED (p ⬍0.001), a more generalized vascular disease may play a major role in patients with ED without atherosclerosis or its risk factors. In other words, generalized nitric oxide system dysfunction may be the main reason for ED and cause endothelial dysfunction by affecting vascular remodeling.11,12 In accordance with our results, Kaiser et al13 demonstrated that patients with ED and no significant cardiac risk factors or other clinical cardiovascular disease had peripheral vascular abnormalities in the nitric oxide– cyclic guanosine monophosphate pathway, as measured by brachial artery FMD. However, they concluded that the defect in the nitric oxide– cyclic guanosine monophosphate vasodilator pathway must involve the smooth muscle, because vasodilation to the direct smooth muscle dilator nitroglycerin was impaired in the brachial arteries of patients with ED. In contrast to Kaiser et al’s13 results, we found brachial artery vasodilation impairment only to shear stress stimulus, and the nitroglycerin response was not different from that in controls (13.2 ⫾ 4.0% vs 15.7 ⫾ 5.4%, p ⫽ 0.55). We suggest, therefore, that endothelial function, rather than smooth muscle function, is adversely affected in patients with ED. Left ventricular diastolic dysfunction found in our patients with ED may also be the result of generalized nitric oxide dysfunction, which decreases diastolic compliance and slightly prolongs the duration of contraction, with little or no effect on systolic function.1 There is a cyclic release of nitric oxide in the heart that is most marked subendocardially and that peaks at the time of relaxation and filling. These brief bursts of nitric oxide release provide a beat-tobeat modulation of relaxation and stiffness.14 Another possible mechanism is that endothelial dysfunction may have an adverse influence on diastolic function.15 The relation between the E/Em ratio and endothelial function presented in our study supports this notion. Because it has been shown that aortic stiffness is closely related to diastolic function parameters,16,17 increased aortic stiffness as a result of endothelial dysfunction18 or generalized nitric-oxide-system dysfunction19 may explain the rationale of diastolic dysfunction in our patients with ED. 1. Paulus WJ, Vantrimpton PJ, Shah AM. Paracrine coronary endothelial control of left ventricular function in humans. Circulation 1995;92: 2119 –2126. 2. Azadzoi KM, Saenz de Tejada I. Hypercholesterolemia impairs endothelium-dependent relaxation of rabbit corpus cavernosum smooth muscle. J Urol 1991;146:238 –240. 3. Azadzoi KM, Goldstein I. Erectile dysfunction due to atherosclerotic vascular disease: the development of an animal model. J Urol 1992; 147:1675–1681. 4. Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA. Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989;320:1025–1030.
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5. Hansson GK, Nilsson J. Pathogenesis of atherosclerosis. In: Crawford MH, Dimarco JP, Paulus WJ, eds. Cardiology. St. Louis, MO: Mosby, 2004:5. 6. Rosen RC, Cappelleri JC, Smith MD, Lipsky J, Pena BM. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res 1999;11:319 –326. 7. Rosen RC, Riley A, Wagner G, Osterloh IH, Kirkpatrick J, Mishra A. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology 1997;49: 822– 830. 8. Sahn D, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantification in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–1083. 9. Calermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivian ID, Lloyd JK, Deanfield JE. Noninvasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 1992;340:1111–1115. 10. Title LM, Cummings PM, Giddens K, Genest JJ Jr, Nassar BA. The effect of folic acid and antioxidant vitamins on endothelial dysfunction in patients with coronary artery disease. J Am Coll Cardiol 2000;36: 758 –765. 11. Baig MK, Mahon N, McKenna WJ, Caforio AL, Bonow RO, Francis GS, Gheorghiade M. The pathophysiology of advanced heart failure. Am Heart J 1998;135:216 –230.
12. Chrysant SG. Vascular remodeling: the role of angiotensin-converting enzyme inhibitors. Am Heart J 1998;135:21–30. 13. 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 –184. 14. Paulus WJ. Beneficial effects of nitric oxide on cardiac diastolic function: “the flip side of the coin.” Heart Failure Rev 2000;5:337– 344. 15. Ma LN, Zhao SP, Gao M, Zhou QC, Fan P. Endothelial dysfunction associated with left ventricular diastolic dysfunction in patients with coronary heart disease. Int J Cardiol 2000;72:275–279. 16. Eren M, Gorgulu S, Uslu N, Celik S, Dagdeviren B, Tezel T. Relation between aortic stiffness and left ventricular diastolic function in patients with hypertension, diabetes, or both. Heart 2004;90:37– 43. 17. Gorgulu S, Eren M, Celik S, Dagdeviren B, Uslu N, Suer N, Tezel T. The effects of hormonal therapy on aortic stiffness and left ventricular diastolic function. Acta Cardiol 2003;58:1– 8. 18. Gorgulu S, Uslu N, Eren M, Celik S, Yıldırım A, Dagdeviren B, Tezel T. Aortic stiffness in patients with cardiac syndrome X. Acta Cardiol 2003;58:507–511. 19. Uslu N, Gorgulu S, Alper AT, Eren M, Nurkalem Z, Yildirim A, Ozer O. Erectile dysfunction as a generalized vascular disorder. J Am Soc Echocardiogr 2006;19:341–346.