CLINICAL STUDIES
Effect of intensive therapy for heart failure on the vasodilator response to exercise
Wendy Johnson, MDa,
Caroline Lucas, MDa,
Lynne W. Stevenson, MD, FACCa and
Mark A. Creager, MD, FACCa
a Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
Manuscript received June 1, 1998;
revised manuscript received October 14, 1998,
accepted November 20, 1998.
Reprint requests and correspondence: Dr. Mark A. Creager, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115
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Abstract
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OBJECTIVES
The purpose of the study was to evaluate the lower extremity vascular responsiveness to metabolic stimuli in patients with heart failure and to determine whether these responses improve acutely after intensive medical therapy.
BACKGROUND
Metabolic regulation of vascular tone is an important determinant of blood flow, and may be abnormal in heart failure.
METHODS
The leg blood flow responses were measured in 11 patients with nonedematous class III–IV heart failure before and after inpatient medical therapy and in 10 normal subjects. Venous occlusion plethysmography was used to measure peak blood flow and total hyperemia in the calf after arterial occlusion and also after isotonic ankle exercise. Measurements were repeated following short-term inpatient treatment with vasodilators and diuretics administered to decrease right atrial pressure (18 ± 2 to 7 ± 1 mm Hg), pulmonary wedge pressure (32 ± 3 to 15 ± 2 mm Hg), and systemic vascular resistance (1581 ± 200 to 938 ± 63 dynes·s·cm–5, all p < 0.02).
RESULTS
Leg blood flow at rest, after exercise, and during reactive hyperemia was less in heart failure patients than in control subjects. Resting leg blood flow did not increase significantly after medical therapy, but peak flow after the high level of exercise increased by 59% (p = 0.009). Total hyperemic volume in the recovery period increased by 73% (p = 0.03). Similarly, the peak leg blood flow response to ischemia increased by 88% (p = 0.04), whereas hyperemic volume rose by 98% (p = 0.1).
CONCLUSIONS
The calf blood flow responses to metabolic stimuli are blunted in patients with severe heart failure, and improve rapidly with intensive medical therapy.
In clinical heart failure, hemodynamic alterations lead to an inadequate supply of nutrient blood flow to metabolically active tissues and contribute to exercise intolerance (1,2). Inability to increase blood flow to accommodate metabolic requirements may be attributed, in part, to impaired vascular reactivity in these patients. Many studies have found that peripheral vasodilation in heart failure patients is impaired in response to a variety of pharmacologic stimuli including nitric oxide donors, substance P, phentolamine, and muscarinic agonists (3–9). Moreover, regional blood flow responses to specific metabolic stimuli, such as exercise and ischemia, are abnormal both in experimental models of heart failure and in patients with heart failure (1,2,9–17). Heart transplantation, physical training, and diuresis alone have not been found to normalize blood flow responses to metabolic stimuli in this population (18–21). Whether intensive medical treatment with vasodilators and diuretics titrated to normalize resting hemodynamics can achieve this physiologic objective is not known.
Accordingly, the purpose of this study was to evaluate vascular responsiveness to exercise in patients with severe heart failure, and to determine whether these responses improve after short-term medical therapy. Leg exercise is a common source of symptoms during daily activities in the heart-failure population; therefore, we purposefully investigated vascular function in the lower extremity. Calf vasoreactivity was studied before and after intensive, inpatient medical therapy designed to rapidly improve cardiac hemodynamics.
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Methods
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Study population.
Participants in the study included 11 patients with heart failure, eight men and three women, aged 49 ± 3 years (mean ± SE). All were admitted to the hospital for intensive medical therapy. Each patient had symptoms of heart failure for more than 6 months. Nine patients were New York Heart Association (NYHA) class IV, and two patients were NYHA class III. The average left ventricular ejection fraction was 21 ± 1%, determined by echocardiography. Two subjects had no detectable mitral regurgitation, two patients had mild mitral regurgitation, four had mild to moderate regurgitation, and three had moderate regurgitation as estimated by the color flow Doppler technique (22). In the six patients able to perform an exercise test, the average peak oxygen consumption was 9.3 ml/min/kg. The etiology of left ventricular dysfunction was coronary artery disease in five patients, valvular disease in one patient, and idiopathic cardiomyopathy in five patients. Four heart-failure subjects had diabetes mellitus. These were treated with insulin and maintained stable glucose levels less than 200 mg/dl. Two of the three female heart-failure patients were postmenopausal; they were not taking hormone replacement therapy. Exclusion criteria included detectable peripheral edema, malignant ventricular arrhythmias, angina, electrocardiographic (ECG) evidence of myocardial ischemia during exercise, hypertension, hypercholesterolemia, poorly controlled diabetes mellitus, drug or tobacco use within a year of the study, and use of nonsteroidal anti-inflammatory agents. Study participants also included ten healthy, nonsmoking subjects, five men and five women, mean age 52 ± 2 years (p = 0.41 vs. heart-failure subjects) who were recruited from the local community via newspaper advertisements. All of these subjects had a normal medical history and physical examination. Three of five female control subjects were postmenopausal; they were not taking hormone replacement therapy. All participants gave written, informed, voluntary consent. The study was approved by the Human Research Committee of Brigham and Women’s Hospital.
Experimental protocol.
Each participant was studied in the postabsorptive state in a quiet, 22°C temperature-controlled room with minimal auditory and visual stimulation. Calf blood flow was measured by venous occlusion mercury-in-silastic strain gauge plethysmography (Hokanson EC4, DE Hokanson, Bellevue, Washington). The calf was positioned 15 cm above the level of the right atrium. Venous occlusion was attained by rapid inflation of a sphygmomanometric cuff on the thigh. The cuff was inflated suddenly to the lowest pressure necessary to obtain the maximum rate of increase in calf circumference; this pressure was determined at the beginning of each study. Average venous occlusion pressure was 35 ± 5 mm Hg. Calf blood flow was derived from the rate of change in calf circumference during venous occlusion, and is expressed in ml/min/100 ml tissue. Foot blood flow was excluded by inflation of an ankle cuff to 50 mm Hg above systolic pressure during all measurements. Blood pressure was measured every 3 min, and heart rate and ECG were continuously monitored. All calf blood flow measurements were recorded on a Gould physiologic recorder (Gould, Cleveland, Ohio).
The baseline calf blood flow determination consisted of at least five measurements made at 15-s intervals while the subject was resting. Baseline measurements were repeated until stability was assured. Each subject then performed ankle flexion exercise for 2 min through a 60° range of motion at two rates, 30 and 60 cycles/min, monitored by a metronome. Calf blood flow measurements commenced immediately following cessation of each exercise period and continued every five s for two min, then every 15 s for an additional two min. Ten minutes after these measurements, blood flow measurements were made at rest to assure that flow had returned to the baseline. The exercise protocol was then repeated. Measurements derived from these two periods of exercise were subsequently averaged for each exercise rate. After restoration of basal calf blood flow, ischemia-induced reactive hyperemia was measured following release of a sphygmomanometric cuff, which had been inflated on the lower thigh to suprasystolic pressures for five min. Calf blood flow was measured immediately following cuff deflation, then every five s for two min, and then every 15 s for another 2 min.
Medical therapy.
In the normal subjects, calf blood flow measurements were made on one occasion. In the heart-failure patients, calf vascular function was studied before and after intensive medical therapy. Within 24 h of the first vascular study, a Swan-Ganz catheter was inserted into an internal jugular or subclavian vein, using the modified Seldinger technique, under sterile conditions and local anaesthetic (1% lidocaine). Baseline measurements were made to document systemic blood pressure, right atrial pressure, pulmonary capillary wedge pressure, pulmonary artery pressure, cardiac output, systemic vascular resistance, and pulmonary vascular resistance. A combination of nitroprusside and diuretics was used to attain the following predetermined, hemodynamic objectives: right atrial pressure  7 mm Hg, pulmonary capillary wedge pressure 15 mm Hg, and systemic vascular resistance between 1000 and 1200 dynes·s·cm–5, while maintaining a systolic blood pressure  80 mm Hg (23). One subject was monitored with central venous pressures only.
Once these goals were achieved, nitroprusside was weaned and oral vasodilators were added in doses to maintain the hemodynamic objectives. Initially, captopril was given at a dose of 6.25 mg orally every eight h and titrated upwards to 75 mg every eight h as indicated to maintain the optimal hemodynamics defined above. Oral isosorbide dinitrate was then added at a dose of 10 mg every eight h and titrated to achieve the hemodynamic goals during which time the intravenous medication was decreased or discontinued. Hydralazine was then initiated, if necessary, and titrated to optimize the hemodynamic measurements. The dosing regimens established at the end of therapy closely approximated the patients’ regimens at discharge from the hospital. The mean doses of captopril before and after tailored therapy were 111.6 ± 19.9 mg/day and 137.5 ± 15.8 mg/day, respectively (p = 0.36), and the mean doses of isosorbide dinitrate before and after therapy were 32.7 ± 13.1 mg/day and 49.1 ± 10.9 mg/day, respectively (p = 0.03). Two subjects were started on hydralazine during treatment. Table 1 shows the mean hemodynamic values and patient weights before and after medical therapy. Within 24 h of attaining these hemodynamic goals on an oral regimen, patients returned to the vascular laboratory for repeat vascular studies. All cardiac and vasoactive medications were held for four h prior to the study. The average number of days between studies was 7.8 ± 3.4.
Statistical analysis.
Data are expressed as mean ± SE. Both the peak flow rates after exercise and during ischemia-induced reactive hyperemia, and the total volume repaid in the 4 min following exercise or ischemia (an integration of the flow rate vs. time curve), were analyzed. Comparisons of group means for baseline demographics and limb blood flow measurements between the control and heart-failure groups were made by an unpaired, two-tailed Student t test with a Bonferroni correction for multiple comparisons. Pretreatment and posttreatment central and limb hemodynamic measurements were compared using a paired, two-tailed Student t test with a Bonferroni correction for multiple comparisons. Statistical significance was accepted at the p 0.05 level. The reported p-values are those calculated with the Bonferroni correction.
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Results
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Comparative findings between control and heart-failure subjects.
Prior to intensive medical therapy, resting calf blood flow was significantly lower in the patients with heart failure than in the healthy control subjects (1.0 ± 0.1 vs. 1.6 ± 0.1 ml/min/100 ml, p = 0.004) (Fig. 1). Decompensated heart-failure subjects also showed significantly lower peak calf blood flow responses to exercise at both rates (30 cycles/min: 6.5 ± 1.1 vs. 12.8 ± 1.5 ml/min/100 ml, p = 0.006; 60 cycles/min: 6.8 ± 1.0 vs. 14.0 ± 1.6 ml/min/100 ml, p = 0.0016) (Fig. 1). In the 4 min following exercise, total hyperemic volume was less in the heart-failure patients than in control subjects (30 cycles/min: 5.9 ± 0.7 vs. 9.3 ± 1.8 ml/100 ml, p = 0.04. 60 cycles/min: 7.1 ± 1.1 vs. 11.9 ± 1.1 ml/100 ml, p = 0.011) (Fig. 2). Peak flow following the ischemic stimulus was significantly lower in heart-failure subjects (9.0 ± 1.4 vs. 17.5 ± 3.3 ml/min/100 ml, p = 0.05) (Fig. 3). Mean total hyperemic volume after ischemia was lower in heart-failure patients, but these data did not reach statistical significance (5.2 ± 0.6 vs. 7.9 ± 1.5 ml/100 ml, p = 0.22) (Fig. 3).
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Figure 1 Calf blood flow at rest and peak flow after 2 min of isotonic exercise at 30 cycles/min (Ex30) and 60 cycles/min (Ex60) in control subjects and heart-failure patients before (Pre-rx) and after (Post-rx) medical therapy. *p 0.05 compared to Pre-rx.
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Figure 2 Calf hyperemic volume in the 4 min following isotonic exercise at 30 cycles/min (Ex30) and 60 cycles/min (Ex60) in control subjects and heart-failure patients before (Pre-rx) and after (Post-rx) medical therapy. *p 0.05 compared to Pre-rx.
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Figure 3 Peak calf blood flow (left) after five min of arterial occlusion in control subjects (Control), decompensated heart-failure patients (Pre-rx), and the same patients after intensive medical therapy (Post-rx). Total hyperemic volume (right) is shown in the four min following arterial occlusion in the same subject groups. *p 0.05 compared to Pre-rx.
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Effect of treatment on response to exercise.
Baseline blood flow did not increase significantly after intensive medical therapy (pretreatment 1.0 ± 0.1 vs. posttreatment 1.2 ± 0.1 ml/min/100 ml, p = 0.20) (Fig. 1). The peak calf blood flow response to exercise, however, improved after treatment (30 cycles/min: 6.5 ± 1.1 to 9.6 ± 1.6 ml/min/100 ml, p = 0.09; 60 cycles/min: 6.8 ± 1.0 to 10.8 ± 1.4 ml/min/100 ml, p = 0.01) (Fig. 1). Total hyperemic volume in the four min following exercise also increased after treatment (30 cycles/min: 5.9 ± 0.7 to 9.8 ± 1.9 ml/100 ml, p = 0.09; 60 cycles/min: 7.1 ± 1.0 to 12.3 ± 2.1 ml/100 ml, p = 0.04) (Fig. 2). After adjustment for multiple comparisons, the response to exercise at the higher level, 60 cycles/min, was statistically significant. Posttreatment total hyperemic response was comparable to that of the healthy control subjects.
Effect of treatment on response to reactive hyperemia.
The peak calf reactive hyperemic response to ischemia increased significantly after treatment (9.0 ± 1.4 to 16.8 ± 2.7 ml/min/100 ml, p = 0.04). The mean total hyperemic volume in the 4 min following cuff deflation was higher after therapy, but this did not reach statistical significance (5.2 ± 0.6 vs. 10.3 ± 2.3 ml/100 ml, p = 0.10) (Fig. 3). Responses following treatment approached normal levels.
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Discussion
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This study demonstrates that 1) lower extremity vascular responsiveness to the metabolic stimuli of submaximal, isotonic exercise and postischemic reactive hyperemia is reduced in patients with decompensated heart failure, and that 2) these responses improve after a brief period of intensive medical therapy designed to normalize cardiac filling pressures and systemic vascular resistance. These findings support the rationale for aggressive treatment of patients with heart failure, for favorable peripheral vasomotor responses are likely to result.
In heart failure, exercise intolerance is related closely to prognosis, yet limitation in activity does not correlate with the left ventricular ejection fraction or the resting hemodynamic indices of cardiac function (24). The failure of dobutamine to enhance peak aerobic capacity despite an immediate increase in cardiac output during exercise implicates peripheral factors as important determinants of exercise tolerance in heart failure (25–27). Peripheral vasomotor reactivity may be an important contributor to patients’ exercise capacity (1,2), yet no prior study has investigated the dynamic nature of the abnormality longitudinally, and few studies have examined the regulation of leg blood flow in patients with heart failure.
The finding in this study that heart-failure patients have diminished vasomotor responses to metabolic stimuli supports the observations of several prior studies (1,2,9), but differs from others (10,17,26). These apparently conflicting observations may be due to the differing severity of illness or to the fact that vascular function was measured in the leg versus the arm. Jondeau et al. (1) has shown that, in the calf, but not the forearm, blood flow response to ischemia is related linearly to peak oxygen consumption in patients with NYHA class II–III heart failure. Thus, compared to severely symptomatic individuals, patients with mild heart failure and higher peak oxygen consumption may have near-normal limb vascular reactivity, particularly if the arm is the target of the investigation. In normal healthy subjects, deconditioning has been shown to reduce reactive hyperemic responses to ischemia (28), and may alter muscle metabolism (29). As heart failure progresses, patients typically decrease their lower extremity physical activity, which may lead to a cycle of deconditioning and further inactivity. Therefore, the leg vascular responsiveness may become impaired sooner than the arm during the course of the disease.
In light of these differences in limb vascular reactivity, we chose to investigate the leg in this metabolic study because lower extremity exercise is essential for activities of daily living, and is more often a source of symptoms for heart-failure patients. In this study, 82% of the patients were in NYHA class IV heart failure, and 18% in class III, indicative of the marked severity of heart-failure symptoms in these patients. All subjects had greater than six months’ duration of symptoms. Therefore, the abnormal responses in this patient population are representative of lower extremity vascular function in patients with severe, chronic heart failure.
Rapid improvement in vasoreactivity.
We found that in patients with heart failure, abnormal responses to important metabolic stimuli improved to near normal levels following a short period of intensive pharmacologic therapy. In the present study, we used intensive, hemodynamically guided medical therapy directed at normalization of right atrial pressure, pulmonary capillary wedge pressure, and systemic vascular resistance. The cardiac index also improved with treatment, although not to normal levels. By contrast, the forearm responses to reactive hyperemia initially do not increase after cardiac transplantation despite immediate improvement in cardiac function (20,30). Less intensive therapy with diuretics alone may improve forearm conductance in a subset of patients, but not to normal levels (21). Medical therapy, like that used in this study, has been shown to improve functional status and exercise capacity in patients with severe decompensated heart failure after 6 ± 5 months (31). This clinical improvement may result in part from the enhanced vasodilator response to exercise. Early improvement in vasodilator responses to metabolic stimuli may set the stage for improved exercise capacity with resultant exercise reconditioning and, over time, with associated neurohormonal changes (32). Whether the improved vasoreactivity demonstrated in this study is sustained or merely a short-term effect is not known.
Mechanisms of vascular dysfunction.
Several potential mechanisms may explain the abnormal vasomotor response to metabolic stimuli in heart failure. Normal mediators of blood flow following exercise and during reactive hyperemia include nitric oxide (33–38), prostaglandins (39,40), adenosine (41–43), ATP-sensitive potassium channels (3,44,45), and the sympathetic nervous system (46). Abnormalities in one or more of these pathways could lead to the decreased vascular reactivity observed in this study. In fact, Katz et al. (14) found that regional inhibition of nitric oxide synthesis decreased the forearm blood flow response to isometric exercise in normal human controls, but not in heart-failure patients, suggesting that nitric oxide-mediated vasodilation during exercise is impaired in heart failure. The contribution of other mechanisms to decreased vasodilator responsiveness in heart failure is not known.
Mechanisms of improvement in vascular reactivity may include reduced vessel wall edema, decreased influence of counter-regulatory vasoconstrictive substances, and enhanced local vasodilator function. Although none of our patients had clinically demonstrable edema, therapy resulted in an average diuresis of 3.5 ± 0.5 liters, which could have altered vascular wall sodium and water content, improving vasodilator reserve (47–49). In normal subjects, increased sympathetic tone leads to increased forearm vascular resistance during reactive hyperemia, raising the possibility that normalization of sympathetic tone in heart-failure patients during therapy may improve vasodilation to an ischemic stimulus (46).
Alternatively, the observed improvement in vascular responsiveness may be due to increased bioavailability of endothelium-derived nitric oxide and, in some cases, the addition of an exogenous nitric oxide donor, isosorbide dinitrate, to the regimen (34,38). Endothelium-derived nitric oxide may be affected by treatment, particularly with angiotensin-converting enzyme inhibitors. In this study, 64% of patients were taking a higher dose of captopril at the end of the study compared to the dose at the time of the initial vascular measurements. This may have resulted in increased bioavailability of nitric oxide due to decreased bradykinin degradation (50,51) or decreased formation of angiotensin II (52–54). A decrease in angiotensin II, systemically or locally, over the course of therapy could theoretically lead to decreased superoxide-mediated nitric oxide inactivation (52), and, consequently, improved vascular responses to metabolic stimuli.
Conclusions.
This study demonstrates that calf vascular responsiveness to exercise is markedly abnormal in heart-failure patients. Calf vascular reactivity to exercise, as well as postocclusive reactive hyperemia, can be improved rapidly to near normal levels with optimization of cardiac hemodynamics using an aggressive medication regimen. The ability to improve vasomotor responses to metabolic stimuli and thus reverse the cycle of vascular dysfunction and deconditioning in heart-failure patients may be crucial to long-term improvement in exercise capacity and functional status in this population.
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Footnotes
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This research was supported by a National Institutes of Health Program Project Grant in Vascular Biology and Medicine (HL-48743), National Institutes of Health, Bethesda, Maryland, and by a grant from the Fannie E. Rippel Foundation, for heart failure/novel therapies. Dr. Johnson is a recipient of the 1996 ACC/Merck Research Fellowship Award, the American College of Cardiology, Bethesda, Maryland.
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L. W. Stevenson, T. H. Le Jemtel, E. U. Alt, L. W. Stevenson, T. H. Le Jemtel, and E. U. Alt
Hemodynamic Goals Are Relevant
Circulation,
February 21, 2006;
113(7):
1020 - 1033.
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D. W. Wray, P. J. Fadel, M. L. Smith, P. Raven, and M. Sander
Inhibition of {alpha}-adrenergic vasoconstriction in exercising human thigh muscles
J. Physiol.,
March 1, 2004;
555(2):
545 - 563.
[Abstract]
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J. M. Hare, G. C. Nguyen, A. F. Massaro, J. M. Drazen, L. W. Stevenson, W. S. Colucci, J. C. Fang, W. Johnson, M. M. Givertz, and C. Lucas
Exhaled nitric oxide: a marker of pulmonary hemodynamics in heart failure
J. Am. Coll. Cardiol.,
September 18, 2002;
40(6):
1114 - 1119.
[Abstract]
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A. R. Patel, J. T. Kuvin, N. G. Pandian, J. J. Smith, J. E. Udelson, M. E. Mendelsohn, M. A. Konstam, and R. H. Karas
Heart failure etiology affects peripheral vascular endothelial function after cardiac transplantation
J. Am. Coll. Cardiol.,
January 1, 2001;
37(1):
195 - 200.
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Abstract
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