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Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction
Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction Abhiram Prasad, MBBS, MD, MRCP,a Stuart T. Higano, MD, FACC,a Jassim Al Suwaidi, MB, ChB,a David R. Holmes, Jr, MD, FACC,a Verghese Mathew, MD, FACC,a Geralyn Pumper, RN,a Ryan J. Lennon, MS,b and Amir Lerman, MD, FACCa Rochester, Minn
Background
Coronary endothelial dysfunction may potentially lead to myocardial ischemia and to the progression of heart failure. Though endothelial dysfunction is associated with advanced heart failure in humans, relatively little is known regarding their temporal relationship. Thus, the current study was designed to test the hypothesis that coronary endothelial dysfunction is present in patients with asymptomatic left ventricular dysfunction.
Methods and Results Three hundred patients without symptoms of heart failure, with normal or mildly diseased coronary arteries at angiography underwent coronary vascular reactivity evaluation using intracoronary adenosine, acetylcholine (ACH) and nitroglycerin. Patients were divided into 2 groups based on the left ventricular ejection fraction (EF): patients with asymptomatic left ventricular dysfunction (ALVD), EF ⬍45% (n ⫽ 11); and patients with EF ⱖ45% (n ⫽ 289, controls). Except for a lower high-density lipoprotein level in patients with ALVD, there were no significant differences between the groups in regards to conventional cardiovascular risk factors. There was no difference in the change (mean ⫾ SE) in epicardial diameter in response to ACH (⫺21.7% ⫾ 7.2% vs ⫺13.8% ⫾ 1.5%, P ⫽ .3). The change in coronary blood flow in response to ACH was significantly attenuated in the patients with ALVD when compared to the controls (⫺18.5% ⫾ 14.9% vs 74.0% ⫾ 7.2%, P ⬍ .013). By multivariate analysis, EF was an independent predictor of coronary microvascular dilation with ACH (P ⬍ .001). Conclusion The current study demonstrates that coronary microvascular endothelial dysfunction is present in ALVD. Thus, coronary endothelial dysfunction may be an early event in the pathophysiology of heart failure. (Am Heart J 2003; 146:549 –54.) Despite significant advances in the prevention and treatment of cardiovascular disease in the past 2 decades, the incidence and prevalence of chronic heart failure have been increasing. Heart failure affects approximately 5 million individuals in the United States, but it remains a poorly understood and inadequately treated condition.1,2 The coronary endothelium plays an important role in the physiological regulation of myocardial structure and function, as well as the control of blood flow.3 From the Division of Cardiovascular Diseases and Department of Internal Medicine, and Section of Biostatistics, Center for Coronary Physiology and Imaging, Mayo Clinic and Mayo Foundation, Rochester, Minn. Supported by NIH Grant R01 HL-63911, American Heart Association, Miami Heart Research Institute, the Bruce and Ruth Rappaport Vascular Biology Program, and the Mayo Foundation. Submitted October 14, 2002; accepted March 10, 2003. Reprint requests: Amir Lerman, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected] © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/S0002-8703(03)00364-8
Coronary endothelial dysfunction is associated with myocardial perfusion abnormalities4,5 that may contribute to the development of myocardial ischemia, impairment in contractility, and, potentially, the progression of congestive heart failure. Although, previous studies have demonstrated that advanced left ventricular dysfunction is associated with coronary endothelial dysfunction,6 – 8 there is a lack of information on coronary endothelial function in patients with asymptomatic left ventricular dysfunction without significant coronary artery disease. Thus, the current study was designed to test the hypothesis that coronary endothelial function is impaired in patients with asymptomatic left ventricular systolic dysfunction.
Methods Study population Three hundred patients who had been referred for cardiac catheterization to evaluate for chest pain or an abnormal stress test were enrolled in the study. The decision to refer patients for endothelial function studies was made at the dis-
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550 Prasad et al
Figure 1
Percent change of coronary blood flow in response to ACH (left) and acoronary flow reserve in response to adenosine (right) in the study groups.
cretion of the referring cardiologists. None of the patients had a history of heart failure based on New York Heart Association (NYHA) definition. Coronary endothelial function studies were performed only in patients with normal or minimal coronary artery disease in order to reliably assess microvascular function. Patients were included in this study if they had the following: (1) angiographically smooth arteries or mild irregularities (⬍30% lumen diameter stenosis by visual assessment in any major epicardial vessel), and (2) the proximal coronary arteries were ⬎2.0 mm in diameter. Patients with a history or symptoms of heart failure, variant angina, documented previous myocardial infarction, acute coronary syndromes, previous coronary artery bypass surgery or coronary intervention were excluded from this study. Long-acting nitrates, angiotensin-converting enzyme inhibitors, and calcium-channel blocking agents were withheld for 36 to 48 hours before the study to allow for the assessment of coronary physiology in the baseline state. The study was approved by the Mayo Clinic Institutional Review Board and informed consent was obtained.
Study protocol Diagnostic coronary angiography was performed using a 6F Judkins catheter and a standard femoral percutaneous approach. Two thousand five hundred units of intravenous heparin were administered at the beginning of the procedure. Nonionic contrast was used for all patients. Nitroglycerin (NTG) was not given before the diagnostic procedure. Coronary vascular reactivity responses to acetylcholine (ACH) and adenosine were studied according to a previously reported protocol.5,9 After control coronary angiograms had been obtained, a 0.014-inch Doppler guidewire (Endosonics, Santa Anna, Calif)5,9,10 was introduced within a 2.2F coronary infusion catheter into the left anterior descending coronary artery. After stable baseline flow velocities were obtained, endothelium-independent coronary flow reserve was measured using a bolus of intracoronary adenosine (18-42
g). After recovery to baseline, endothelium-dependent responses were assessed using selective intracoronary infusions of ACH at 1 mL/min at concentrations of 0.182, 1.82, and 18.2 g/mL (10⫺6, 10⫺5 and 10⫺4 mol/liter) for 3 minute duration each. At the end of each infusion, the following data were obtained: electrocardiogram, Doppler velocities and coronary angiography, heart rate and blood pressure. Finally, 200 to 300 g of intracoronary NTG bolus was given, and all measurements were repeated. Left ventricular ejection fraction was measured by contrast ventriculography at the time of the cardiac catheterization or by echocardiography within 3 days before the procedure by an independent investigator who was unaware of the results of the coronary hemodynamic data. The patients in this study were divided into 2 groups according to whether their EF was ⬍45% (ALVD group [asymptomatic left ventricular dysfunction], n ⫽ 11) or ⱖ45% (control group, n ⫽ 289).
Quantitative coronary angiography Artery diameter was analyzed from cine films with a modification of the technique previously described.5,9 An end-diastolic still frame at each infusion (baseline, ACH and NTG) was selected from the angiographic sequence. Epicardial diameter was measured 5 mm distal to the tip of the Doppler wire. The measurements were made by experienced observers who were unaware of the results of the coronary vascular reactivity data and EF.
Assessment of coronary blood flow Doppler flow velocity spectra were analyzed on-line to determine time-averaged peak velocity. Volumetric coronary blood flow (CBF) was determined from the following relation: CBF ⫽ cross-sectional area ⫻ average peak velocity ⫻ 0.5. Coronary flow reserve was calculated as the ratio of hyperemic to basal average peak velocity after adenosine administration.
Statistical analysis Continuous variables are summarized as mean ⫾ standard error, unless otherwise indicated. Discrete variables are presented as frequencies and percentages of available data. Differences between groups were tested using 1-way analysis of variance and Pearson’s 2 test, as appropriate. Differences in blood pressure at different time points are tested using a paired t test. A continuous relation between EF and percent change of CBF to NTG was evaluated using Pearson’s correlation coefficient. Multiple linear regression models for percent change of CBF to ACH and coronary flow reserve were used to assess the independent association between EF and these end points. The covariates in these models were age, glucose, high-density lipoprotein (HDL), triglycerides, history of smoking, and hypertension.
Results Patient characteristics There were no significant differences among the study groups with regard to age, sex, body mass index, and conventional risk factors for atherosclerosis except for a lower HDL level in the ALVD group (P ⫽
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Table I. Baseline patient characteristics Characteristics Age (y), mean (range) Male (%) Hypertension, (%) Diabetes (%) Family history (%) Ever smoked (%) Postmenopause (% of women) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Fasting glucose (mg/dL) Body mass index (mean ⫾ SD) Coronary data Blood flow (mL/min) Epicardial diameter (mm)
Table II. Severe coronary endothelial dysfunction and EF EF <0.45
EF >0.45
5 (45) 6 (55)
79 (27) 210 (73)
ALVD (n ⴝ 11)
Controls (n ⴝ 289)
53.2 (24–72) 4 (36) 2 (18) 0 (0) 5 (46) 4 (36) 6 (86) 194 ⫾ 20 149 ⫾ 29 36 ⫾ 4 128 ⫾ 15 103 ⫾ 5 27.5 ⫾ 5.7
50.5 (17–80) 112 (39) 99 (34) 18 (6) 153 (55) 101 (35) 121 (68) 208 ⫾ 3 157 ⫾ 5 52 ⫾ 1* 126 ⫾ 2 98 ⫾ 2 28.6 ⫾ 6.4
tween EF and the percent increase in CBF with NTG (r ⫽ 0.02, P ⫽ .8). Mean coronary flow reserve, as measured with adenosine, was slightly diminished in the ALVD group (2.35 ⫾ 0.2 vs 2.98 ⫾ 0.04, P ⫽ .007) (Figure 1). By multivariate analysis, EF was not an independent predictor of CFR (P ⫽ .25).
50.1 ⫾ 9.2 2.1 ⫾ 0.2
50.0 ⫾ 1.8 2.2 ⫾ 0.04
Discussion
Data presented are mean ⫾ SE unless otherwise indicated. *P ⬍ .05.
.035) (Table I). Mean ⫾ SD of EF in the heart failure group was 35% ⫾ 8% compared to 65% ⫾ 9% in the controls. Of the 11 patients with ALVD, 5 had angiographically normal coronary arteries.
EF and endothelium-dependent responses with ACH There was a significant difference between the groups in mean arterial pressure (95 ⫾ 5 vs 105 ⫾ 1 mm Hg, P ⫽ .04). Baseline coronary blood flow and diameter did not differ between the 2 groups (Table I). Mean arterial blood pressure did not change during ACH infusion (ALVD group difference: ⫺1.2 ⫾ 1.3, P ⫽ .4; control group difference: ⫺0.4 ⫾ 0.4, P ⫽ .4). ACH-mediated increase in CBF was significantly attenuated in the patients with ALVD compared to controls (⫺18.5% ⫾ 14.9% vs 74.0% ⫾ 7.2%, P ⬍ .013) (Figure 1). There was no difference in the change in epicardial diameter in response to ACH (⫺21.7% ⫾ 7.2% vs ⫺13.8% ⫾ 1.5%, P ⫽ .3). By multivariate analysis, EF was an independent predictor of the percent increase in CBF with ACH (P ⬍ .001). Severe coronary endothelial dysfunction, as defined by microvascular constriction, was more prevalent in patients with ALVD, though this did not reach statistical significance (Table II).
EF and endothelium-independent responses with NTG and adenosine There was no difference between the ALVD and control subjects with respect to the increase in CBF (23.1% ⫾ 13.5% vs 49.8% ⫾ 6.3%, P ⫽ .5), and epicardial diameter (9.3% ⫾ 5.6% vs 11.5% ⫾ 1.5%, P ⫽ .8) with NTG. Furthermore, there was no correlation be-
Change in CBF with ACH ⱕ0% (Coronary constriction) (%) ⬎0% (Coronary dilation) (%)
The current study demonstrates for the first time that coronary microvascular endothelial function is impaired in patients with asymptomatic (NYHA class I) left ventricular dysfunction. Furthermore, this study supports the hypothesis that coronary endothelial dysfunction may contribute to the progression of heart failure.
Coronary endothelial dysfunction in asymptomatic heart failure ACH is an endothelium-dependent vasodilator, and decreased ACH-mediated vasodilation is a marker for endothelial dysfunction. In the present study, patients with ALVD had significantly attenuated increase in CBF in response to intracoronary ACH compared to controls, and severe coronary endothelial dysfunction was more prevalent in patients with low EF. By multivariate analysis, left ventricular function was a predictor of the magnitude of microvascular endothelial dysfunction, independent of conventional risk factors for endothelial injury. The present study suggests that coronary endothelial dysfunction may precede the onset of symptoms in heart failure. This novel observation extends the findings of previous studies in symptomatic patients demonstrating the presence of coronary6,7 and peripheral endothelial dysfunction.11,12 Patients with reduced EF also had a mild reduction in coronary flow reserve in response to adenosine compared to the controls, suggesting that there may also be a mild impairment of smooth muscle vasodilator capacity that was apparent under conditions of maximal blood flow. By multivariate analysis, EF was not an independent predictor of endothelial independent coronary flow reserve and there was no difference between the 2 groups of patients with regards to epicardial vasomotion in response to ACH and NTG, suggesting that in patients with asymptomatic heart failure, the abnormality is localized to the coronary microcirculation.
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Thus, the current study extends similar observations in patients with symptomatic heart failure.6 – 8 A temporal relationship between coronary endothelial dysfunction and the onset and progression of heart failure is supported by previous animal studies. In-vitro studies using a rat infarct model of cardiac failure suggest that endothelial dysfunction is both an early and progressive time dependent phenomenon.13 Knecht et al have reported in-vivo, that ACH-mediated coronary microvascular dilation is impaired at 1 week, before the onset of abnormal hemodynamics of heart failure or a reduction in coronary flow reserve, in a canine model of ischemic cardiomyopathy.14 The authors concluded that coronary endothelial dysfunction may precede the onset of heart failure. Furthermore, studies in the cardiomyopathic Syrian hamsters suggest that myocardial necrosis occurs secondary to coronary vasoconstriction, and that this is potentially preventable.15,16 These findings are consistent with a recent human study that reported the presence of impaired forearm microvascular endothelium-dependent dilation with relative preservation of endothelium-independent vasodilation in patients with mild heart failure (NYHA class I and II). Moreover, severe heart failure (NYHA class III and IV) was accompanied with significant impairment of endothelium-independent vasodilation,17 advancing the concept that the progression of heart failure is associated with progressive deterioration of vasodilation. The observation that endothelial dysfunction is an early event in the clinical spectrum of heart failure allows speculation that injury to the endothelium may be a primary pathophysiological process that significantly contributes to the progression of left ventricular dysfunction.2 Previous studies in humans have demonstrated that impaired coronary microvascular endothelium-dependent vasomotion is associated with myocardial perfusion defects, suggesting that such patients may potentially suffer from spontaneous silent episodes of myocardial ischemia.4,5 Augmentation of CBF in response to an increase in myocardial oxygen demand during physiological stress is endothelium-dependent and is significantly impaired in patients with endothelial dysfunction.18 Reversal of endothelial dysfunction in humans is associated with an improvement in myocardial perfusion.19 Furthermore, impaired coronary microvascular vasodilator function in patients with angiographically normal epicardial arteries has been associated with abnormalities in regional and global left ventricular systolic function during exercise.20 Thus, it may be speculated that coronary endothelial dysfunction may lead to repetitive episodes of myocardial ischemia, myocardial necrosis and deterioration of heart failure. Indeed, many patients with nonischemic dilated cardiomyopathy have thallium scan defects that are consistent with ischemia, a finding
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that confers adverse prognosis.21 This is consistent with the finding that depressed myocardial blood flow reserve is an independent predictor of progressive left ventricular dysfunction and adverse events,22 and our recent observation that the presence of coronary endothelial dysfunction is a predictor of subsequent myocardial events, including the development of heart failure.9 Alternatively, due to their proximity, impaired endothelial function may directly influence myocardial structure and function. Altered release of paracrine factors such as nitric oxide (NO), endothelin and angiotensin have been implicated in potentiating myocardial hypertrophy, interstitial fibrosis, and abnormal gene expression.3,23 Furthermore, the proinflammatory and procoagulant effects of endothelial dysfunction may accelerate atherogenesis.
Mechanisms for endothelial dysfunction The endothelium regulates vascular tone by releasing endothelial derived vasodilator factors such as NO and vasoconstrictors such as endothelin. Heart failure is associated with diminished NO activity.8,24,25 Conversely, plasma endothelin concentrations are elevated in patients with heart failure,26 and correlate with the severity of the disease. Thus, the underlying mechanism for the impairment in coronary microvascular vasomotion in early heart failure may result from imbalance between endothelial vasodilator and vasoconstrictor factors as a consequence of endothelial injury. Increased oxidative stress is an important cause for endothelial injury in diseases such as hypercholesterolemia, diabetes mellitus, hypertension, and atherosclerosis, where endothelial dysfunction contributes directly to the pathophysiology.27 Recent human studies have confirmed that heart failure is also accompanied by increased oxidative stress and that this is present in patients with asymptomatic heart failure and increases with disease severity.28,29 Increased free radical generation may be secondary to activation of cytokines such as tumor necrosis factor, and the renin-angiotensin system.29,30 Thus, increased oxidative stress may also promote endothelial dysfunction in heart failure. Further indirect support for the vascular hypothesis is provided by the observation that angiotensin-converting enzyme inhibitors, which are effective in treating heart failure, also reverse coronary endothelial dysfunction,31,32 decrease oxidative stress,33 and reduce ischemia.34 Similarly, HMG-CoA reductase inhibitors that reverse endothelial dysfunction also appear to decrease the onset of heart failure; in the 4S trial, simvastatin decreased the rate of development of heart failure symptoms after myocardial infarction.35 In the CARE trial, pravastatin therapy decreased cardiac events in the subset of patients with reduced systolic function.36 More recently, endothelin receptor antago-
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nists have been shown to reverse endothelial dysfunction and have beneficial effects in patients with heart failure.37 These preliminary observations raise the possibility that novel therapies that reverse endothelial dysfunction may be effective in reducing morbidity and mortality associated with heart failure. Indeed, recent studies indicate that physical training, vitamin C, and L-arginine therapies reverse endothelial dysfunction in heart failure.38 – 40
Limitations This is a cross-sectional study and its findings warrant confirmation through a prospective study. Second, although all traditional risk factors for endothelial dysfunction have been analyzed, other nontraditional risk factors and genetic predisposition have not been evaluated. Third, because this study was conducted in patients undergoing coronary angiography because of chest pain or abnormal stress test, selection bias cannot be ruled out. Finally, we did not assess the relationship between diastolic function and CBF responses.
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8.
9.
10.
11.
12.
13.
14.
15.
Conclusions Our study demonstrates that microvascular coronary endothelial dysfunction is present in asymptomatic (NYHA class I) left ventricular dysfunction, and provides circumstantial evidence to support the hypothesis that endothelial injury may be an important element in the pathophysiology of early heart failure. Thus, therapeutic interventions targeting the neurohormonal activation may reverse endothelial dysfunction and slow the progression of left ventricular dysfunction.
16.
References
20.
1. Ghali JK, Cooper R, Ford E. Trends in hospitalization rates for heart failure in the United States, 1973-1986: evidence for increasing population prevalence. Arch Intern Med 1990;150:769 – 73. 2. Gheorghiade M, Bonow RO. Chronic heart failure in the United States: a manifestation of coronary artery disease. Circulation 1998;97:282–9. 3. Shah AM. Paracrine modulation of heart cell function by endothelial cells. Cardiovasc Res 1996;31:847– 67. 4. Zeiher AM, Krause T, Scha ¨ chinger V, et al. Impaired endotheliumdependent vasodilation of coronary resistance vessels is associated with exercise-induced myocardial ischemia. Circulation 1995;91: 2345–52. 5. Hasdai D, Gibbons RJ, Holmes DR Jr, et al. Coronary endothelial dysfunction in humans is assoacited with myocardial perfusion defects. Circulation 1997;197:2601–10. 6. Treasure CB, Vita JA, Cox DA, et al. Endothelium-dependent dilation of the coronary microvasculature is impaired in dilated cardiomyopathy. Circulation 1990;81:772–9. 7. Holdright DR, Clarke D, Fox K, et al. The effects of intracoronary substance P and acetylcholine on coronary blood flow in patients
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with idiopathic dilated cardiomyopathy. Eur Heart J 1994;15: 1537– 44. Drexler H, Hayoz D, Munzel T, et al. Endothelial function in chronic congestive heart failure. Am J Cardiol 1992;69:1596 – 601. Al Suwaidi J, Hamasaki S, Higano ST, et al. Long-term follow-up of patients with mildly diseased coronary arteries and endothelial dysfunction. Circulation 2000;101:948 –54. Doucette JW, Corl PD, Payne HM, et al. Validation of a Doppler guidewire for intravascular measurement of coronary artery flow velocity. Circulation 1992;85:1899 –911. Kubo SH, Rector TS, Bank AJ, et al. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation 1991;84:1589 –96. Katz SD, Biasucci L, Sabba C, et al. Impaired endothelium-mediated vasodilation in the peripheral vasculature of patients with congestive heart failure. J Am Coll Cardiol 1992;19:918 –25. Teerlink JR, Clozel M, Fischli W, et al. Temporal evolution of endothelial dysfunction in a rat model of chronic heart failure. J Am Coll Cardiol 1993;22:615–20. Knecht M, Burkhoff D, Yi GH, et al. Coronary endothelial dysfunction precedes heart failure and reduction of coronary reserve in awake dogs. J Mol Cell Cardiol 1997;29:217–27. Factor SM, Cho SH, Scheuer J, et al. Prevention of hereditary cardiomyopathy in the Syrian hamster with chronic verapamil therapy. J Am Coll Cardiol 1988;12:1599 – 604. Factor SM, Minase T, Cho S, et al. Microvascular spasm in the cardiomyopathic Syrian hamster: a preventable cause of focal myocardial necrosis. Circulation 1982;66:342–54. Bank AJ, Lee PC, Kubo SH. Endothelial dysfunction in patients with heart failure: relationship to disease severity. J Card Fail 2000;6: 29 –36. Quyyumi AA, Dakak N, Andrews NP, et al. Contribution of nitric oxide to metabolic coronary vasodilation in the human heart. Circulation 1995;92:320 – 6. Campisi R, Czernin J, Schoder H, et al. L-Arginine normalizes coronary vasomotion in long-term smokers. Circulation 1999;99: 491–7. Epstein SE, Cannon RO, Bonow RO. Exercise testing in patients with microvascular angina. Circulation 1991;83(3 Suppl):III73– 6. Doi YL, Chikamori T, Tukata J, et al. Prognostic value of thallium201 perfusion defects in idiopathic dilated cardiomyopathy. Am J Cardiol 1991;67:188 –93. Neglia D, Michelassi C, Trivieri MG, et al. Prognostic role of myocardial blood flow impairment in idiopathic left ventricular dysfunction. Circulation 2002;105:186 –93. MacCarthy PA, Grocott-Mason R, Prendergast BD, et al. Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ET(A) receptor antagonist. Circulation 2000;101:142–7. Habib F, Dutka D, Crossman D, et al. Enhanced basal nitric oxide production in heart failure: another failed counter-regulatory vasodilator mechanism? Lancet 1994;344:371–3. Wang J, Seyedi N, Xu XB, et al. Defective endothelium-mediated control of coronary circulation in conscious dogs after heart failure. Am J Physiol 1994;266:H670 – 80. Wei CM, Lerman A, Rodeheffer RJ, et al. Endothelin in human congestive heart failure. Circulation 1994;89:1580 – 6. Witztum JL. The oxidation hypothesis of atherosclerosis. Lancet 1994;344:793–5.
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28. Mallat Z, Philip I, Lebret M, et al. Elevated levels of 8-iso-prostaglandin F2alpha in pericardial fluid of patients with heart failure: a potential role for in vivo oxidant stress in ventricular dilatation and progression to heart failure. Circulation 1998;97:1536 –9. 29. Keith M, Geranmayegan A, Sole MJ, et al. Increased oxidative stress in patients with congestive heart failure. J Am Coll Cardiol 1998;31:1352– 6. 30. Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 2000;101:594 –7. 31. Mancini GBJ, Henry GC, Macaya C, et al. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 1996;94:258 – 65. 32. Prasad A, Narayanan S, Husain S, et al. Insertion-deletion polymorphism of the ACE gene modulates reversibility of endothelial dysfunction with ACE inhibition. Circulation 2000;102:35– 41. 33. Hornig B, Landmesser U, Kohler C, et al. Comparative effect of ace inhibition and angiotensin ii type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 2001;103:799–805.
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34. Prasad A, Mincemoyer R, Quyyumi AA. Anti-ischemic effects of angiotensin- converting enzyme inhibition in hypertension. J Am Coll Cardiol 2001;38:1116 –22. 35. Kjekshus J, Pedersen TR, Olsson AG, et al. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997;3:249 –54. 36. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–9. 37. Berger R, Stanek B, Hu¨lsmann M, et al. Effects of endothelin a receptor blockade on endothelial function in patients with chronic heart failure. Circulation 2001;103:981– 6. 38. Hornig B, Maier V, Drexler H. Physical training improves endothelial function in patients with chronic heart failure. Circulation 1996;93:210 – 4. 39. Hornig B, Arakawa N, Kohler C, et al. Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure. Circulation 1998;97:363– 8. 40. Rector TS, Bank AJ, Mullen KA, et al. Randomized double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure. Circulation 1996;93:2135– 41.
Background
Coronary endothelial dysfunction may potentially lead to myocardial ischemia and to the progression of heart failure. Though endothelial dysfunction is associated with advanced heart failure in humans, relatively little is known regarding their temporal relationship. Thus, the current study was designed to test the hypothesis that coronary endothelial dysfunction is present in patients with asymptomatic left ventricular dysfunction.
Methods and Results Three hundred patients without symptoms of heart failure, with normal or mildly diseased coronary arteries at angiography underwent coronary vascular reactivity evaluation using intracoronary adenosine, acetylcholine (ACH) and nitroglycerin. Patients were divided into 2 groups based on the left ventricular ejection fraction (EF): patients with asymptomatic left ventricular dysfunction (ALVD), EF ⬍45% (n ⫽ 11); and patients with EF ⱖ45% (n ⫽ 289, controls). Except for a lower high-density lipoprotein level in patients with ALVD, there were no significant differences between the groups in regards to conventional cardiovascular risk factors. There was no difference in the change (mean ⫾ SE) in epicardial diameter in response to ACH (⫺21.7% ⫾ 7.2% vs ⫺13.8% ⫾ 1.5%, P ⫽ .3). The change in coronary blood flow in response to ACH was significantly attenuated in the patients with ALVD when compared to the controls (⫺18.5% ⫾ 14.9% vs 74.0% ⫾ 7.2%, P ⬍ .013). By multivariate analysis, EF was an independent predictor of coronary microvascular dilation with ACH (P ⬍ .001). Conclusion The current study demonstrates that coronary microvascular endothelial dysfunction is present in ALVD. Thus, coronary endothelial dysfunction may be an early event in the pathophysiology of heart failure. (Am Heart J 2003; 146:549 –54.) Despite significant advances in the prevention and treatment of cardiovascular disease in the past 2 decades, the incidence and prevalence of chronic heart failure have been increasing. Heart failure affects approximately 5 million individuals in the United States, but it remains a poorly understood and inadequately treated condition.1,2 The coronary endothelium plays an important role in the physiological regulation of myocardial structure and function, as well as the control of blood flow.3 From the Division of Cardiovascular Diseases and Department of Internal Medicine, and Section of Biostatistics, Center for Coronary Physiology and Imaging, Mayo Clinic and Mayo Foundation, Rochester, Minn. Supported by NIH Grant R01 HL-63911, American Heart Association, Miami Heart Research Institute, the Bruce and Ruth Rappaport Vascular Biology Program, and the Mayo Foundation. Submitted October 14, 2002; accepted March 10, 2003. Reprint requests: Amir Lerman, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected] © 2003, Mosby, Inc. All rights reserved. 0002-8703/2003/$30.00 ⫹ 0 doi:10.1016/S0002-8703(03)00364-8
Coronary endothelial dysfunction is associated with myocardial perfusion abnormalities4,5 that may contribute to the development of myocardial ischemia, impairment in contractility, and, potentially, the progression of congestive heart failure. Although, previous studies have demonstrated that advanced left ventricular dysfunction is associated with coronary endothelial dysfunction,6 – 8 there is a lack of information on coronary endothelial function in patients with asymptomatic left ventricular dysfunction without significant coronary artery disease. Thus, the current study was designed to test the hypothesis that coronary endothelial function is impaired in patients with asymptomatic left ventricular systolic dysfunction.
Methods Study population Three hundred patients who had been referred for cardiac catheterization to evaluate for chest pain or an abnormal stress test were enrolled in the study. The decision to refer patients for endothelial function studies was made at the dis-
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550 Prasad et al
Figure 1
Percent change of coronary blood flow in response to ACH (left) and acoronary flow reserve in response to adenosine (right) in the study groups.
cretion of the referring cardiologists. None of the patients had a history of heart failure based on New York Heart Association (NYHA) definition. Coronary endothelial function studies were performed only in patients with normal or minimal coronary artery disease in order to reliably assess microvascular function. Patients were included in this study if they had the following: (1) angiographically smooth arteries or mild irregularities (⬍30% lumen diameter stenosis by visual assessment in any major epicardial vessel), and (2) the proximal coronary arteries were ⬎2.0 mm in diameter. Patients with a history or symptoms of heart failure, variant angina, documented previous myocardial infarction, acute coronary syndromes, previous coronary artery bypass surgery or coronary intervention were excluded from this study. Long-acting nitrates, angiotensin-converting enzyme inhibitors, and calcium-channel blocking agents were withheld for 36 to 48 hours before the study to allow for the assessment of coronary physiology in the baseline state. The study was approved by the Mayo Clinic Institutional Review Board and informed consent was obtained.
Study protocol Diagnostic coronary angiography was performed using a 6F Judkins catheter and a standard femoral percutaneous approach. Two thousand five hundred units of intravenous heparin were administered at the beginning of the procedure. Nonionic contrast was used for all patients. Nitroglycerin (NTG) was not given before the diagnostic procedure. Coronary vascular reactivity responses to acetylcholine (ACH) and adenosine were studied according to a previously reported protocol.5,9 After control coronary angiograms had been obtained, a 0.014-inch Doppler guidewire (Endosonics, Santa Anna, Calif)5,9,10 was introduced within a 2.2F coronary infusion catheter into the left anterior descending coronary artery. After stable baseline flow velocities were obtained, endothelium-independent coronary flow reserve was measured using a bolus of intracoronary adenosine (18-42
g). After recovery to baseline, endothelium-dependent responses were assessed using selective intracoronary infusions of ACH at 1 mL/min at concentrations of 0.182, 1.82, and 18.2 g/mL (10⫺6, 10⫺5 and 10⫺4 mol/liter) for 3 minute duration each. At the end of each infusion, the following data were obtained: electrocardiogram, Doppler velocities and coronary angiography, heart rate and blood pressure. Finally, 200 to 300 g of intracoronary NTG bolus was given, and all measurements were repeated. Left ventricular ejection fraction was measured by contrast ventriculography at the time of the cardiac catheterization or by echocardiography within 3 days before the procedure by an independent investigator who was unaware of the results of the coronary hemodynamic data. The patients in this study were divided into 2 groups according to whether their EF was ⬍45% (ALVD group [asymptomatic left ventricular dysfunction], n ⫽ 11) or ⱖ45% (control group, n ⫽ 289).
Quantitative coronary angiography Artery diameter was analyzed from cine films with a modification of the technique previously described.5,9 An end-diastolic still frame at each infusion (baseline, ACH and NTG) was selected from the angiographic sequence. Epicardial diameter was measured 5 mm distal to the tip of the Doppler wire. The measurements were made by experienced observers who were unaware of the results of the coronary vascular reactivity data and EF.
Assessment of coronary blood flow Doppler flow velocity spectra were analyzed on-line to determine time-averaged peak velocity. Volumetric coronary blood flow (CBF) was determined from the following relation: CBF ⫽ cross-sectional area ⫻ average peak velocity ⫻ 0.5. Coronary flow reserve was calculated as the ratio of hyperemic to basal average peak velocity after adenosine administration.
Statistical analysis Continuous variables are summarized as mean ⫾ standard error, unless otherwise indicated. Discrete variables are presented as frequencies and percentages of available data. Differences between groups were tested using 1-way analysis of variance and Pearson’s 2 test, as appropriate. Differences in blood pressure at different time points are tested using a paired t test. A continuous relation between EF and percent change of CBF to NTG was evaluated using Pearson’s correlation coefficient. Multiple linear regression models for percent change of CBF to ACH and coronary flow reserve were used to assess the independent association between EF and these end points. The covariates in these models were age, glucose, high-density lipoprotein (HDL), triglycerides, history of smoking, and hypertension.
Results Patient characteristics There were no significant differences among the study groups with regard to age, sex, body mass index, and conventional risk factors for atherosclerosis except for a lower HDL level in the ALVD group (P ⫽
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Table I. Baseline patient characteristics Characteristics Age (y), mean (range) Male (%) Hypertension, (%) Diabetes (%) Family history (%) Ever smoked (%) Postmenopause (% of women) Total cholesterol (mg/dL) Triglycerides (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Fasting glucose (mg/dL) Body mass index (mean ⫾ SD) Coronary data Blood flow (mL/min) Epicardial diameter (mm)
Table II. Severe coronary endothelial dysfunction and EF EF <0.45
EF >0.45
5 (45) 6 (55)
79 (27) 210 (73)
ALVD (n ⴝ 11)
Controls (n ⴝ 289)
53.2 (24–72) 4 (36) 2 (18) 0 (0) 5 (46) 4 (36) 6 (86) 194 ⫾ 20 149 ⫾ 29 36 ⫾ 4 128 ⫾ 15 103 ⫾ 5 27.5 ⫾ 5.7
50.5 (17–80) 112 (39) 99 (34) 18 (6) 153 (55) 101 (35) 121 (68) 208 ⫾ 3 157 ⫾ 5 52 ⫾ 1* 126 ⫾ 2 98 ⫾ 2 28.6 ⫾ 6.4
tween EF and the percent increase in CBF with NTG (r ⫽ 0.02, P ⫽ .8). Mean coronary flow reserve, as measured with adenosine, was slightly diminished in the ALVD group (2.35 ⫾ 0.2 vs 2.98 ⫾ 0.04, P ⫽ .007) (Figure 1). By multivariate analysis, EF was not an independent predictor of CFR (P ⫽ .25).
50.1 ⫾ 9.2 2.1 ⫾ 0.2
50.0 ⫾ 1.8 2.2 ⫾ 0.04
Discussion
Data presented are mean ⫾ SE unless otherwise indicated. *P ⬍ .05.
.035) (Table I). Mean ⫾ SD of EF in the heart failure group was 35% ⫾ 8% compared to 65% ⫾ 9% in the controls. Of the 11 patients with ALVD, 5 had angiographically normal coronary arteries.
EF and endothelium-dependent responses with ACH There was a significant difference between the groups in mean arterial pressure (95 ⫾ 5 vs 105 ⫾ 1 mm Hg, P ⫽ .04). Baseline coronary blood flow and diameter did not differ between the 2 groups (Table I). Mean arterial blood pressure did not change during ACH infusion (ALVD group difference: ⫺1.2 ⫾ 1.3, P ⫽ .4; control group difference: ⫺0.4 ⫾ 0.4, P ⫽ .4). ACH-mediated increase in CBF was significantly attenuated in the patients with ALVD compared to controls (⫺18.5% ⫾ 14.9% vs 74.0% ⫾ 7.2%, P ⬍ .013) (Figure 1). There was no difference in the change in epicardial diameter in response to ACH (⫺21.7% ⫾ 7.2% vs ⫺13.8% ⫾ 1.5%, P ⫽ .3). By multivariate analysis, EF was an independent predictor of the percent increase in CBF with ACH (P ⬍ .001). Severe coronary endothelial dysfunction, as defined by microvascular constriction, was more prevalent in patients with ALVD, though this did not reach statistical significance (Table II).
EF and endothelium-independent responses with NTG and adenosine There was no difference between the ALVD and control subjects with respect to the increase in CBF (23.1% ⫾ 13.5% vs 49.8% ⫾ 6.3%, P ⫽ .5), and epicardial diameter (9.3% ⫾ 5.6% vs 11.5% ⫾ 1.5%, P ⫽ .8) with NTG. Furthermore, there was no correlation be-
Change in CBF with ACH ⱕ0% (Coronary constriction) (%) ⬎0% (Coronary dilation) (%)
The current study demonstrates for the first time that coronary microvascular endothelial function is impaired in patients with asymptomatic (NYHA class I) left ventricular dysfunction. Furthermore, this study supports the hypothesis that coronary endothelial dysfunction may contribute to the progression of heart failure.
Coronary endothelial dysfunction in asymptomatic heart failure ACH is an endothelium-dependent vasodilator, and decreased ACH-mediated vasodilation is a marker for endothelial dysfunction. In the present study, patients with ALVD had significantly attenuated increase in CBF in response to intracoronary ACH compared to controls, and severe coronary endothelial dysfunction was more prevalent in patients with low EF. By multivariate analysis, left ventricular function was a predictor of the magnitude of microvascular endothelial dysfunction, independent of conventional risk factors for endothelial injury. The present study suggests that coronary endothelial dysfunction may precede the onset of symptoms in heart failure. This novel observation extends the findings of previous studies in symptomatic patients demonstrating the presence of coronary6,7 and peripheral endothelial dysfunction.11,12 Patients with reduced EF also had a mild reduction in coronary flow reserve in response to adenosine compared to the controls, suggesting that there may also be a mild impairment of smooth muscle vasodilator capacity that was apparent under conditions of maximal blood flow. By multivariate analysis, EF was not an independent predictor of endothelial independent coronary flow reserve and there was no difference between the 2 groups of patients with regards to epicardial vasomotion in response to ACH and NTG, suggesting that in patients with asymptomatic heart failure, the abnormality is localized to the coronary microcirculation.
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Thus, the current study extends similar observations in patients with symptomatic heart failure.6 – 8 A temporal relationship between coronary endothelial dysfunction and the onset and progression of heart failure is supported by previous animal studies. In-vitro studies using a rat infarct model of cardiac failure suggest that endothelial dysfunction is both an early and progressive time dependent phenomenon.13 Knecht et al have reported in-vivo, that ACH-mediated coronary microvascular dilation is impaired at 1 week, before the onset of abnormal hemodynamics of heart failure or a reduction in coronary flow reserve, in a canine model of ischemic cardiomyopathy.14 The authors concluded that coronary endothelial dysfunction may precede the onset of heart failure. Furthermore, studies in the cardiomyopathic Syrian hamsters suggest that myocardial necrosis occurs secondary to coronary vasoconstriction, and that this is potentially preventable.15,16 These findings are consistent with a recent human study that reported the presence of impaired forearm microvascular endothelium-dependent dilation with relative preservation of endothelium-independent vasodilation in patients with mild heart failure (NYHA class I and II). Moreover, severe heart failure (NYHA class III and IV) was accompanied with significant impairment of endothelium-independent vasodilation,17 advancing the concept that the progression of heart failure is associated with progressive deterioration of vasodilation. The observation that endothelial dysfunction is an early event in the clinical spectrum of heart failure allows speculation that injury to the endothelium may be a primary pathophysiological process that significantly contributes to the progression of left ventricular dysfunction.2 Previous studies in humans have demonstrated that impaired coronary microvascular endothelium-dependent vasomotion is associated with myocardial perfusion defects, suggesting that such patients may potentially suffer from spontaneous silent episodes of myocardial ischemia.4,5 Augmentation of CBF in response to an increase in myocardial oxygen demand during physiological stress is endothelium-dependent and is significantly impaired in patients with endothelial dysfunction.18 Reversal of endothelial dysfunction in humans is associated with an improvement in myocardial perfusion.19 Furthermore, impaired coronary microvascular vasodilator function in patients with angiographically normal epicardial arteries has been associated with abnormalities in regional and global left ventricular systolic function during exercise.20 Thus, it may be speculated that coronary endothelial dysfunction may lead to repetitive episodes of myocardial ischemia, myocardial necrosis and deterioration of heart failure. Indeed, many patients with nonischemic dilated cardiomyopathy have thallium scan defects that are consistent with ischemia, a finding
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that confers adverse prognosis.21 This is consistent with the finding that depressed myocardial blood flow reserve is an independent predictor of progressive left ventricular dysfunction and adverse events,22 and our recent observation that the presence of coronary endothelial dysfunction is a predictor of subsequent myocardial events, including the development of heart failure.9 Alternatively, due to their proximity, impaired endothelial function may directly influence myocardial structure and function. Altered release of paracrine factors such as nitric oxide (NO), endothelin and angiotensin have been implicated in potentiating myocardial hypertrophy, interstitial fibrosis, and abnormal gene expression.3,23 Furthermore, the proinflammatory and procoagulant effects of endothelial dysfunction may accelerate atherogenesis.
Mechanisms for endothelial dysfunction The endothelium regulates vascular tone by releasing endothelial derived vasodilator factors such as NO and vasoconstrictors such as endothelin. Heart failure is associated with diminished NO activity.8,24,25 Conversely, plasma endothelin concentrations are elevated in patients with heart failure,26 and correlate with the severity of the disease. Thus, the underlying mechanism for the impairment in coronary microvascular vasomotion in early heart failure may result from imbalance between endothelial vasodilator and vasoconstrictor factors as a consequence of endothelial injury. Increased oxidative stress is an important cause for endothelial injury in diseases such as hypercholesterolemia, diabetes mellitus, hypertension, and atherosclerosis, where endothelial dysfunction contributes directly to the pathophysiology.27 Recent human studies have confirmed that heart failure is also accompanied by increased oxidative stress and that this is present in patients with asymptomatic heart failure and increases with disease severity.28,29 Increased free radical generation may be secondary to activation of cytokines such as tumor necrosis factor, and the renin-angiotensin system.29,30 Thus, increased oxidative stress may also promote endothelial dysfunction in heart failure. Further indirect support for the vascular hypothesis is provided by the observation that angiotensin-converting enzyme inhibitors, which are effective in treating heart failure, also reverse coronary endothelial dysfunction,31,32 decrease oxidative stress,33 and reduce ischemia.34 Similarly, HMG-CoA reductase inhibitors that reverse endothelial dysfunction also appear to decrease the onset of heart failure; in the 4S trial, simvastatin decreased the rate of development of heart failure symptoms after myocardial infarction.35 In the CARE trial, pravastatin therapy decreased cardiac events in the subset of patients with reduced systolic function.36 More recently, endothelin receptor antago-
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nists have been shown to reverse endothelial dysfunction and have beneficial effects in patients with heart failure.37 These preliminary observations raise the possibility that novel therapies that reverse endothelial dysfunction may be effective in reducing morbidity and mortality associated with heart failure. Indeed, recent studies indicate that physical training, vitamin C, and L-arginine therapies reverse endothelial dysfunction in heart failure.38 – 40
Limitations This is a cross-sectional study and its findings warrant confirmation through a prospective study. Second, although all traditional risk factors for endothelial dysfunction have been analyzed, other nontraditional risk factors and genetic predisposition have not been evaluated. Third, because this study was conducted in patients undergoing coronary angiography because of chest pain or abnormal stress test, selection bias cannot be ruled out. Finally, we did not assess the relationship between diastolic function and CBF responses.
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Conclusions Our study demonstrates that microvascular coronary endothelial dysfunction is present in asymptomatic (NYHA class I) left ventricular dysfunction, and provides circumstantial evidence to support the hypothesis that endothelial injury may be an important element in the pathophysiology of early heart failure. Thus, therapeutic interventions targeting the neurohormonal activation may reverse endothelial dysfunction and slow the progression of left ventricular dysfunction.
16.
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