Published online before print April 14, 2005, doi: 10.1161/01.ATV.0000166516.52477.81
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© 2005 American Heart Association, Inc.
Vascular Biology |
Systemic Endothelial Dysfunction as an Early Predictor of Adverse Outcome in Heart Failure
From Universitäres Herzzentrum, Medizinische Klinik III, Hamburg, Germany.
Correspondence to Dr Thomas Heitzer, Universitäres Herzzentrum, Medizinische Klinik III, Martinistr. 52, 20246 Hamburg, Germany. E-mail heitzer{at}uke.uni-hamburg.de
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Abstract |
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Objective— Endothelial dysfunction is an early event in the natural progression of heart failure. Increased oxidative stress has been linked to impaired endothelial function and both may play a prognostic role.
Methods and Results— Endothelium-dependent and endothelium-independent vasodilatation were determined in 289 patients with mild left ventricular dysfunction by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. Vascular effects of the coadministration of the antioxidant vitamin C at pharmacological doses (24 mg/min) were assessed. Occurrence of death, heart transplantation, and readmission with worsening heart failure were recorded as clinical outcome parameters during a follow-up period of 4.8 years. Patients experiencing adverse events (n=79) had lower vasodilator responses to acetylcholine (P<0.001) and to sodium nitroprusside (P=0.03) compared with patients without events. However, beneficial effects of vitamin C did not differ between both groups. Cox proportional hazards model demonstrated that age (P=0.001), renal function (P=0.001), and blunted acetylcholine-induced vasodilatation (P=0.007) remained independent predictors of adverse outcome.
Conclusions— Impaired peripheral endothelial function independently predicts long-term adverse outcome in patients with early-stage heart failure. The findings suggest that assessment of peripheral endothelial function may represent an additional mean for risk stratification and therapy management in these patients.
Endothelium-dependent and endothelium-independent vasodilatation was assessed in 289 patients with mild heart failure by measuring forearm blood flow with and without vitamin C administered at pharmacological doses using venous occlusion plethysmography. During follow-up, patients experiencing adverse events had lower vasodilator responses to acetylcholine and sodium nitroprusside, but similar beneficial effects of vitamin C.
Key Words: endothelium • free radicals • heart failure • nitric oxide • prognosis
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Introduction |
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Heart failure is associated with a range of adaptive neural and humoral responses occurring early in the evolution of the syndrome, recognizing chronic heart failure as a systemic rather than only a cardiac disorder involving hemodynamic, neurohumoral, and peripheral vascular derangements.1,2 Enhanced peripheral vasoconstriction in response to exercise and impaired vasodilatation after stimulation with agonists are key features of endothelial dysfunction in congestive heart failure (CHF). Several studies have shown that endothelial dysfunction is an early event in the clinical spectrum of this entity.3–6 This allows speculation that altered endothelial signaling may be a primary pathophysiological process that significantly contributes to the progression of left ventricular dysfunction by causing increased afterload and central effects such as myocardial ischemia. Conversely, endothelial dysfunction could be a secondary event in response to alterations in peripheral hemodynamics and may therefore represent a marker rather than a functionally important factor. Interestingly, very recent observations found that depressed coronary and peripheral vasoreactivity is associated with increased risk for adverse events in patients with more severe left ventricular (LV) dysfunction.7–9 However, it is not known whether measures of peripheral endothelial function have prognostic importance in early CHF.
The underlying mechanisms of endothelial dysfunction in heart failure are likely to be multifactorial and may involve reduced bioavailability of nitric oxide (NO) because of reduced activity/expression of endothelial nitric oxide synthase (eNOS) and/or increased inactivation of NO by superoxide anions. Recent clinical and experimental studies provide indirect evidence that in CHF, increased production of oxygen-derived free radicals may contribute to endothelial dysfunction and may be involved in the progression of heart failure.10–13
Therefore, we prospectively investigated whether systemic endothelial dysfunction and vascular oxidative stress, as assessed by the response to the antioxidant vitamin C, have prognostic impact on adverse long-term outcome in patients with mild heart failure.
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Methods |
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Patient Population
Between February 1998 and November 2000, 289 consecutive patients who had been referred for invasive evaluation of effort dyspnea or echocardiographic finding of systolic dysfunction were studied prospectively. The cardinal inclusion criterion was mild LV systolic dysfunction, defined as an ejection fraction <50% and not <35%. LV ejection fraction was determined by LV angiography. This method was used, because it is well-known that an echocardiographic determination of LV ejection fraction can only be obtained in 70% to 85% of patients. Patients showed no reduction in their functional capacity (class I according to New York Heart Association classification), and there was mild or moderate limitation of exercise capacity, as determined by cardio-pulmonary exercise testing by the use of a standard protocol with upright bicycling. Patients were in a chronic, stable condition, and assessment of LV function was performed within 3 months before inclusion into the study. Each subject was screened by a complete history, physical examination, and laboratory analysis. Exclusion criteria included significant valvular heart disease, active myocarditis, known congenital heart disease, recent acute coronary syndrome (within 6 months), pending revascularization, uncontrolled hypertension, and/or significant endocrine, hepatic, renal or inflammatory disease. The glomerular filtration rate (GFRC) was calculated for each participant from serum creatinine concentrations using the Modification of Diet in Renal Disease (MDRD) equation.14 Vasoactive medications, including calcium channel blockers, angiotensin-converting enzyme inhibitors, and long-acting nitrates, were withheld for
24 hours before the study. All female subjects were postmenopausal. Only 5 women were receiving hormone replacement therapy. Risk factors were assessed at the time of endothelial function test. No caffeine or smoking was allowed before the study. The study was approved by the local ethics committee and informed consent was obtained from all participants.
Study Protocol
All studies were performed after a 12-hour overnight fast with the subjects lying supine in a quiet, temperature-controlled room (22°C to 24°C). With the use of sterile conditions and 2% lidocaine, a 20-gauge polyethylene catheter was inserted into the brachial artery of the nondominant arm for measurement of blood pressure and infusion of drugs. Forearm blood flow was measured by venous occlusion plethysmography with calibrated mercury-in-silastic strain gauges as previously described.15 During forearm blood flow measurement circulation to the hand was excluded by a wrist cuff, inflated 40 mm Hg above systolic blood pressure. At the beginning of each study protocol, normal saline (0.9% sodium chloride) was infused intra-arterially at a rate of 0.4 mL/min. Endothelium-dependent vasodilation was assessed by infusing acetylcholine (ACh) in increasing concentrations of 7.5, 15, and 30 µg/min (ACh 1 to 3) into the brachial artery. Sodium nitroprusside (SNP) was infused to assess endothelium-independent vasodilation (1, 3, and 10 µg/min). The sequence of ACh and SNP infusion was randomized. The dose–response curve to ACh and SNP was repeated during coinfusion of vitamin C at 24 mg/min. This dose of vitamin C was chosen to provide a final plasma concentration of 
10 mmol/L.15–17 A recent study has demonstrated that acute intra-arterial administration of vitamin C at this concentration increases local vitamin C concentration in the forearm >100-fold to 3 mmol/L.17 Given the rapid reaction rate between NO and superoxide anion (1.9x1010M–1–s), acute administration of such a high dose of vitamin C is believed to protect NO from premature deactivation by superoxide, thereby improving NO-mediated vasodilation.18–19 Vitamin C was started 10 minutes before ACh and continued throughout. Finally, the dose–response curve to SNP was repeated during coinfusion of ascorbic acid. A 30-minute washout was allowed between each dose–response curve.
Laboratory Analyses
Venous blood samples were drawn from each study participant before endothelial function tests. Serum samples were frozen immediately and kept at –70°C until used for analysis. Highly sensitive C-reactive protein levels were measured with ultrasensitive test (CRP Latex HS; Roche). N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured with an electrochemiluminescence sandwich immunoassay (Roche) on an Elecsys System 2010 and all measurements were performed in duplicate. The detection limit reported by the manufacturer is 5 pg/mL.
Long-Term Follow-Up
All patients were followed-up prospectively after vascular function test every 6 months in a heart failure clinic or by telephone contact. To achieve a minimum follow-up duration of 3 years, vital status was determined for all enrolled subjects as of May 2004. During long-term follow-up, these adverse events were assessed as primary end points: (1) death from cardiac causes defined as sudden cardiac death or death resulting from progressive pump failure; (2) development or progression of heart failure that required hospitalization for an intravenous treatment of heart failure within the first 3 days after admission; or (3) heart transplantation. For patients experiencing >1 adverse event, only the first event was considered in the analysis. All information regarding potential adverse events was validated by review of source data, including hospital record forms, death certificates, and other available original documents. Additional vascular events such as stroke, nonfatal myocardial infarction, or need for coronary revascularization procedures were also assessed but not included into the outcome analysis. Medical therapy, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, and lipid-lowering drugs was documented.
Statistical Analysis
Data of baseline characteristics are expressed as mean ± SD or n (%). Responses to ACh and SNP with and without vitamin C are presented as mean ± SEM and were analyzed by ANOVA for repeated measures, and Scheffe test was applied for multiple comparison testing. Cumulative event rates were estimated by Kaplan–Meier survival curves and compared by the log-rank test. Responses to ACh and SNP were divided into quartiles for survival analysis. Cox proportional hazards regression analysis was performed for analyzing follow-up data; among 16 variables tested (Table 2), only those variables with statistical significance set at P<0.05 at univariate analysis were included in a multivariate cox regression model to determine independent predictors of adverse events (Table 3). Statistical analysis was performed using SPSS software (SPSS for windows, Release 10.0.7).
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Results |
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Patient Characteristics
Of the 289 patients studied, 2 patients were excluded because follow-up could not be obtained. Patients were followed-up for a mean of 58 months (range, 38 to 97 months). At follow-up, we documented 91 events in 79 patients. Forty-one died of cardiac causes (sudden death in 30 and refractory heart failure in 11 patients) and 7 underwent heart transplantation. Thirty-one patients showed development or progression of heart failure, characterized by worsening of NYHA functional class in all (to NYHA class III and IV) and need for hospitalization and intravenous treatment for heart failure. Seventy patients experienced 1 event, 6 patients had 2 events, and 3 patients had 3 events. Death attributable to noncardiac causes occurred in 2 patients, one caused by lung cancer and another patient died of acute cerebral ischemia without evidence for an embolic event. Patient characteristics according to the clinical outcome are given in Table 1. The proportion of patients who received pharmacological agents such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blockers, and statins did not differ significantly among the group with and without events.
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Endothelium-dependent vasodilatation in response to ACh was markedly reduced in patients experiencing adverse events during follow-up compared with those without events (Figure 1A). Endothelium-independent vasodilatation to SNP was slightly but significantly attenuated in patients with adverse events compared with patients free of events (Figure 1B). Coinfusion of vitamin C improved Ach response in patients with and without events. The effect of vitamin C did not differ between both groups (Figure 2A). Vitamin C infusion had no significant effect on endothelium-independent vasodilatation to SNP in patients with and without events (Figure 2B).
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By Kaplan–Meier analysis, event-free survival from adverse events was significantly associated with vasodilator response to ACh. The incidence of adverse events increased with more depressed vasodilator response (Figure 3A). Trends were noted for endothelium-independent response to SNP, but statistical significance was not achieved (Figure 3B). The response to vitamin C was not associated with poor outcome.
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; censored cases), 7.5 to 10 mL/100 mL/min (
; censored cases), 7.5 to 3.5 mL/100 mL/min (
; censored cases), and <3.5 mL/100 mL/min (
; censored cases). Log-rank test P<0.0001. B, Cumulative proportion of patients without adverse events during follow-up (Kaplan–Meier). Survival is shown separately for patients with a maximal SNP-induced vasodilatation >15.2 mL/100 mL/min (On univariate analysis, age, LV ejection fraction, plasma NT-proBNP, GFRc, ACh response, and SNP response were significantly associated with the occurrence of adverse events during follow-up (Table 2). However, in a multivariate Cox analysis including all these variables, only age, GFRc, and ACh response remained independent prognostic markers of adverse events (Table 3). When the outcome was restricted to death or transplantation, response to ACh remained a significant (P=0.04) predictor of outcome.
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Discussion |
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The results of the present study demonstrate that impaired systemic endothelial vasodilator function is an early independent predictor of clinical deterioration and death in patients with mild LV dysfunction. This relation persisted after adjustment for other predictive parameters, such as age, systolic ejection fraction, NT-pro-BNP, and GFRc. Furthermore, the finding of similar beneficial effects of acute vitamin C application in patients with and without future events suggests that vascular oxidative stress may not play a major role in the early progression of heart failure.
Neurohumoral changes occur early in the course of heart failure and are present even in asymptomatic LV dysfunction.1 Although endothelial dysfunction is known to be a critical component in the systemic vasoconstriction and reduced peripheral perfusion of severe heart failure, less attention has been devoted to patients with only mild LV dysfunction. The concept of temporal relationship between peripheral endothelial dysfunction and the onset and progression of heart failure is supported by results of animal6,20 and recent human studies.4–5 These studies have demonstrated that endothelial dysfunction is an early manifestation in the natural progression of LV systolic dysfunction and may even precede the onset of symptoms in heart failure. Consistent with these findings are our data of endothelial dysfunction in patients with mild systolic dysfunction. Endothelium-dependent vasodilatation in response to ACh was markedly depressed, whereas endothelium-independent vasodilatation to SNP was relatively preserved. This is consistent with the notion that heart failure is associated with a selective endothelial dysfunction early in the course of the disease, whereas more generalized impairment of vasodilatory capacity may occur with progressive deterioration of heart failure.
Although endothelial dysfunction has been demonstrated in the coronary and peripheral circulations in patients with mild heart failure, the prognostic implications of these observations are unknown. A recent study in patients with different degrees of left ventricular dysfunction has shown that the degree of myocardial blood flow reduction (in response to dipyridamole and measured by positron emission tomography) is an independent predictor of subsequent cardiac events.7 Another small study in 10 patients with acute-onset dilated cardiomyopathy showed that preservation of coronary endothelial function was associated with a favorable outcome and subsequent improvement in LV function, whereas patients with endothelial dysfunction did not improve.21 Recent studies investigating the peripheral vascular of patients with more severe heart failure showed conflicting results.8–9,22 In one study of 46 patients, peripheral vasodilatory response to the endothelium-dependent vasodilator ACh was not significantly associated with progressive deterioration during follow-up.22 In contrast, 2 other studies in patients with NYHA class II-III CHF found that endothelial dysfunction is an independent prognostic factor for future clinical events.8–9 Our present data extend these observations to the early stage of heart failure, demonstrating that peripheral endothelial vasodilator dysfunction is associated with increased risk for adverse events and may serve as an independent predictor of poor outcome in these patients with NYHA class I. Patients with impaired endothelial function had a significantly higher risk for adverse events, including heart failure progression, need for transplantation, and death. The vasodilatory response to SNP, although slightly reduced in patients with subsequent events, was not significantly associated with outcome. Because impaired SNP response is supposed to be caused by decreased responsiveness of vascular smooth muscle, this finding argues against a nonspecific observation.
The suggestion that endothelial function has a prognostic role in heart failure is further supported by another study in CHF patients evaluating the effect of the Asp 298 variant of eNOS on event-free survival.23 Demonstrating a significantly poorer outcome in patients with this variant, the authors conclude that deficiencies of NOS activity may alter the rate of heart failure progression and emphasize the importance of NO as a modulator of this clinical syndrome. In addition, recent experimental studies in mice with eNOS deficiency showed increased rates of apoptosis and heart failure during cardiac development.24 The overexpression of the eNOS gene within the vascular endothelium in mice attenuated congestive heart failure and dramatically improved survival.25 In line with these experimental data are our observations in patients with mild systolic dysfunction. Abnormal response to ACh predicted adverse outcomes even after adjustment for other conventional indicators such as age, ejection fraction, renal function, and NT-pro-BNP. Notably, increased plasma levels of NT-pro-BNP were associated with increased risk only in the univariate analysis and lost its significance when adjusted for other indicators. Given the wide range of values of NT-pro-BNP in patients with asymptomatic and mild heart failure, the concept of a single prognostic level might be limited.26 Interestingly, renal insufficiency remained a strong predictor of adverse outcome, supporting recent reports about the prognostic importance of renal function in the early stage of heart failure.27–29
Although endothelial dysfunction in heart failure is likely to be a multifactorial process, 2 major abnormalities have surfaced as important mechanisms, such as increased NO inactivation caused by increased formation of oxygen-derived free radicals or changes in the activity and/or expression of the NOS. Increased vascular production of reactive oxygen species has been found in experimental and clinical studies.10–11,30 Furthermore, several investigations demonstrated that administration of antioxidants improves endothelium-dependent, NO-mediated vasodilatation in heart failure.12–13 In line with this concept of oxidative stress is our finding of beneficial effects of vitamin C infusion on ACh response in patients with mild heart failure. Vitamin C did not alter the response to SNP, indicating a specific effect on the vascular endothelium. Although several mechanisms may underlie the selective effect of vitamin C, these data are consistent with the notion that scavenging of increased oxygen-derived free radicals and thereby improving NO-mediated vasodilatation may account for it in this setting. However, despite the positive effect of vitamin C, endothelium-dependent vasodilatation was still severely depressed in our patients in comparison with healthy controls.15 This finding indicates that other factors beside oxidative stress may contribute importantly to endothelial dysfunction in early CHF. Several studies demonstrated an important role for the downregulation of eNOS in the coronary and peripheral circulations.31–33 Both the activity and expression of the eNOS are regulated by endothelial shear stress. Therefore, reduction in blood flow and the resultant decrease in shear stress may downregulate NOS III expression and endothelial NO production,34 and may represent an early and important mechanism of endothelial dysfunction in patients with asymptomatic or mild heart failure.
Noteworthy, the interesting finding in our study is that the beneficial effects of vitamin C were comparable in patients experiencing future events compared with patients without events and did not predict poor outcome during follow-up. This finding is consistent with the notion that oxidative stress in the vascular wall may contribute to endothelial dysfunction but does not play an important role in early progression or deterioration of heart failure. Although no measures of endogenous antioxidant defense or of oxidant stress in plasma were performed, we think that vascular stress, as indicated by the response to vitamin C, is not a major determinant of outcome in mild systolic dysfunction. Conceivably, the concept of oxidant stress may be of prognostic significance in more advanced stages of the disease because oxidant stress seems to increase with the functional severity of heart failure.10–11 Similarly, we did not find inflammatory parameters such as highly sensitive C-reactive protein to be predictive of subsequent adverse events. Of note, because our study was restricted to the peripheral vasculature, we cannot expand our suggestion to the coronary circulation or the failing myocardium.
In summary, the present study revealed that peripheral endothelial function is a powerful predictor of adverse outcome in patients with mild ventricular dysfunction. This finding suggests that endothelial dysfunction unmasks states of abnormal peripheral circulatory adaptations in the early stage of pump failure, which may be a surrogate marker of heart failure progression. Although future prospective studies with larger patient populations are warranted to confirm these results, the present findings support the rationale to further evaluate peripheral endothelial function for risk stratification in patients with asymptomatic or mild heart failure. Furthermore, therapeutic strategies to enhance endothelial function may be effective in reducing morbidity and mortality of patients with early stage of heart failure.
Received December 25, 2004; accepted March 18, 2005.
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