Vasodilation In Congestive Heart Failure Research Articles

Rebuttal from Dr. Andreassen

Rebuttal from Dr. Andreassen

ANGIOTENSIN‐CONVERTING ENZYME INHIBITORS AND PNEUMONIA IN ELDERLY PATIENTS WITH INTRACEREBRAL HEMORRHAGE

To the Editor: Angiotensin-converting enzyme (ACE) inhibitors have been shown to have beneficial effects, such as antihypertension, vasodilation in congestive heart failure, and renoprotection.1 It is also reported that ACE inhibitors improve silent aspiration2 and prevent pneumonia in elderly patients with cerebral infarction.3–6 However, little is known about whether ACE inhibitors have a beneficial role in reducing the risk of pneumonia in elderly patients with hemorrhagic brain injury. Therefore, the effects of ACE inhibitors on the incidence of pneumonia in the elderly patients with intracerebral hemorrhage were investigated. Eighty-three patients (40 men, 43 women, mean age±standard error=68±2) hospitalized for intracerebral hemorrhage were enrolled and prospectively followed for 2 years. The criteria for diagnosis of pneumonia, as well as the patients' inclusion and exclusion criteria, were described previously.7 The eligible patients were those who suffered from intracerebral hemorrhage but were not bedridden. Incidence of pneumonia was analyzed in two groups: patients who received ACE inhibitors and patients who did not receive any antihypertensive drugs. Twenty-two hypertensive patients (9 men, 13 women; mean age 72±2) received ACE inhibitors after admission. The control group consisted of 61 patients (31 men, 30 women; mean age 66±2) without hypertension. For the main analysis, the log-rank procedure and Cox proportional hazards model were used to calculate confidence intervals. The cumulative incidence curves were generated using the Kaplan-Meier method for endpoints in the ACE inhibitor and control groups. Significance was set at P<.05. There were no significant differences in age, sex, or stroke severity between the two groups. During the follow-up, new pneumonia was diagnosis in two (9.1%) of 22 patients in the ACE inhibitor group and 13 (21.3%) of 61 patients in the control group. The patients in the ACE inhibitor group had a lower risk of pneumonia than those in the control group (hazard ratio=0.19 (95% confidence interval=0.04–0.86, P=.03). These findings suggest that ACE inhibitors have a beneficial role in reducing the risk of pneumonia in elderly patients with intracerebral hemorrhage as well as in elderly patients with cerebral infarction. Therefore, ACE inhibitors may be useful for preventing aspiration pneumonia in elderly stroke patients. Financial Disclosure(s): Drs. Jun Harada and Kiyohisa Sekizawa do not have a financial relationship with any commercial entity that may have an interest in the subject of this manuscript. Author Contributions: Jun Harada: study design, acquisition of subject, data analysis, preparation of manuscript. Kiyohisa Sekizawa: study concept, interpretation of data, preparation of manuscript. Sponsor's Role: None.

Increased extravascular forces limit endothelium-dependent and -independent coronary vasodilation in congestive heart failure.

The increase in coronary blood flow (CBF) in response to endothelium-dependent vasodilators is reduced in congestive heart failure (CHF) suggesting endothelial dysfunction. However, increases in extravascular compressive forces secondary to elevated left ventricular diastolic pressure (LVEDP) in CHF might contribute to this abnormality. We measured CBF responses to intracoronary doses of the endothelium-dependent vasodilators acetylcholine (ACH) and bradykinin (BK) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in the same eight dogs before (control) and after CHF was produced by 23+/-3 days of rapid ventricular pacing. In five of the dogs with CHF the zero-flow pressure (P(zf)), which reflects extravascular compressive forces in the maximally vasodilated coronary circulation (adenosine) was measured and found to strongly correlate with LVEDP (r=0.91). Coronary vascular resistance (CVR) at each concentration of vasodilator before and after the development of CHF was corrected for estimated coronary back pressure: CVR=(P(Ao)-LVEDP)/CBF, where P(Ao) is mean aortic pressure. CHF resulted in a significant decrease in CBF and increase in heart rate and LVEDP compared to control (P<0.05). The CBF responses to ACH, BK and SNP were all significantly reduced in the failing hearts (P<0.01). However, after correction for the elevated LVEDP in CHF, the response of CVR to the endothelium-dependent vasodilators was not different from normal. These findings suggest that endothelium mediated vasodilation is preserved in CHF, but that increased extravascular compressive forces act to limit the increase in CBF.

Comparison of effects of ascorbic acid on endothelium-dependent vasodilation in patients with chronic congestive heart failure secondary to idiopathic dilated cardiomyopathy versus patients with effort angina pectoris secondary to coronary artery disease

Impaired endothelium-dependent vasodilation has been reported to play an important role in the pathogenesis of cardiovascular diseases such as coronary artery disease (CAD) and congestive heart failure (CHF). However, the precise mechanism of endothelial dysfunction has not been elucidated in these conditions. To evaluate the role of oxidative stress in endothelial dysfunction, the effect of antioxidant ascorbic acid on brachial flow-mediated, endothelium-dependent vasodilation during reactive hyperemia and nitroglycerin-induced endothelium-independent vasodilation was examined with high resolution ultrasound in 12 patients with CHF caused by idiopathic dilated cardiomyopathy without established coronary atherosclerosis and in 10 patients with CAD. Flow-mediated vasodilation in CHF (4.4 ± 0.5%) and CAD (4.0 ± 0.8%) was significantly (p <0.05) attenuated compared with that in 10 control subjects (9.6 ± 0.9%). However, nitroglycerin-induced vasodilation was similar in 3 groups (13.7 ± 1.3% in control, 13.9 ± 1.1% in CHF, 12.7 ± 1.4% in CAD). Ascorbic acid could significantly improve flow-mediated vasodilation only in patients with CAD (9.1 ± 0.9%) but not with CHF (5.6 ± 0.6%), and had no influence on nitroglycerin-induced vasodilation (13.6 ± 1.1% in CHF, 14.0 ± 1.3% in CAD). These results suggest that, in brachial circulation, augmented oxidative stress mainly leads to endothelial dysfunction in CAD but not in CHF caused by idiopathic dilated cardiomyopathy.

Impaired nitric oxide-mediated renal vasodilation in rats with experimental heart failure: role of angiotensin II.

Congestive heart failure (CHF) is associated with a decrease in renal perfusion. Because endothelium-derived NO is important in the regulation of renal blood flow (RBF), we tested the hypothesis that an impairment in the NO system may contribute to the decrease in RBF in rats with experimental CHF. Studies were performed in rats with experimental high-output CHF induced by aortocaval (AV) fistula and sham-operated controls. In controls, incremental doses of acetylcholine (ACh, 1 to 100 microg x kg(-1) x min(-1)) increased RBF and caused a dose-related decrease in renal vascular resistance (RVR). However, the increase in RBF and decrease in RVR were markedly attenuated in rats with CHF. Likewise, the effects of ACh on urinary sodium and cGMP excretion were also diminished in CHF rats, as was the renal vasodilatory effect of the NO donor S-nitroso-N-acetylpenicillamine (SNAP). These attenuated responses to endothelium-dependent and -independent renal vasodilators in CHF rats occurred despite a normal baseline and stimulated NO2+NO3 excretion and normal expression of renal endothelial NO synthase (eNOS), as determined by eNOS mRNA levels and immunoreactive protein. Infusion of the NO precursor L-arginine did not affect baseline RBF or the response to ACh in rats with CHF. However, administration of the nonpeptide angiotensin II receptor antagonist A81988 before ACh completely restored the renal vasodilatory response to ACh in CHF rats. This study demonstrates that despite a significant attenuation in the NO-related renal vasodilatory responses, the integrity of the renal NO system is preserved in rats with chronic AV fistula. This impairment in NO-mediated renal vasodilation in experimental CHF appears to be related to increased activity of the renin-angiotensin system and may contribute further to the decrease in renal perfusion seen in CHF.

Acute Hemodynamic Improvement by Thermal Vasodilation in Congestive Heart Failure

A warm-water bath (WWB) or sauna bath (SB) has generally been considered inappropriate for patients with severe congestive heart failure (CHF). However, a comprehensive investigation of the hemodynamic effects of thermal vasodilation in CHF has not been previously undertaken. To investigate the acute hemodynamic effects of thermal vasodilation in CHF, we studied 34 patients with chronic CHF (mean age, 58 +/- 14 years). Clinical stages were New York Heart Association functional class II in 2, III in 19, and IV in 13 patients. Mean ejection fraction was 25 +/- 9%. After a Swan-Ganz catheter was inserted via the right jugular vein, the patient had a WWB for 10 minutes at 41 degrees C or an SB for 15 minutes at 60 degrees C. Blood pressure, ECG, echo-Doppler, expiration gas, and intracardiac pressures were recorded before, during, and 30 minutes after each bath. Oxygen consumption increased mildly, pulmonary arterial blood temperature increased by 1.2 degrees C, and heart rate increased by 20 to 25 beats per minute on average at the end of WWB or SB. Systolic blood pressure showed no significant change. Diastolic blood pressure decreased significantly during SB (P < .01). Cardiac and stroke indexes increased and systemic vascular resistances decreased significantly during and after WWB and SB (P < .01). Mean pulmonary artery, mean pulmonary capillary wedge, and mean right atrial pressures increased significantly during WWB (P < .05) but decreased significantly during SB (P < .05). These pressures decreased significantly from the control level after each bath (P < .01). Mitral regurgitation associated with CHF decreased during and 30 minutes after each bath. Cardiac dimensions decreased and left ventricular ejection fraction increased significantly after WWB and SB. In an additional study, plasma norepinephrine increased significantly during SB in healthy control subjects and in patients with CHF and returned to control levels by 30 minutes after SB. Hemodynamics improve after WWB or SB in patients with chronic CHF. This is attributable to the reduction in cardiac preload and afterload. Thus, thermal vasodilation can be applied with little risk if appropriately performed and may provide a new nonpharmacological therapy for CHF.

Decreased skeletal muscle vasodilation in patients with congestive heart failure.

In congestive heart failure (CHF), excessive vasoconstriction is present, which is due to overactive vasoconstrictor mechanisms although vasodilator mechanisms may be impaired. In the present study, we examined vasodilation in CHF by measuring forearm blood flow with a strain gauge plethysmograph. Patients with CHF had higher forearm vascular resistance than normal control subjects. Patients with CHF had decreased forearm vasodilation in response to intra-arterial infusions of atrial natriuretic peptide (ANP) and acetylcholine, but not in response to sodium nitroprusside or nitroglycerin. Oral captopril did not alter the degree of forearm vasodilation during handgrip exercise. These results suggest that endothelium-dependent and ANP-induced forearm vasodilation is impaired in patients with CHF but the decreased vasodilation is not due to impaired vascular smooth muscle responsiveness to a vasodilator. The renin-angiotensin system does not seem to play a major role in the maintenance of vascular resistance during exercise in CHF.

Effects of therml vasodilation in congestive heart failure

Effects of therml vasodilation in congestive heart failure

The rationale for combined use of diuretics, digitalis, and vasodilators in congestive heart failure

The rationale for combined use of diuretics, digitalis, and vasodilators in congestive heart failure

Vasodilators in Chronic Congestive Heart Failure-Reply

In Reply. — We strongly disagree the place of vasodilators, including angiotensin converting enzyme inhibitors, in the treatment of heart failure is ambivalent and uncertain. Individual trials as well as combined data from multiple trials have shown that (1) use of most vasodilator agents improves functional status, (2) combined therapy with nitrates and hydralazine probably decreases mortality, and (3) treatment with angiotensin converting enzyme inhibitors both improves functional status and decreases mortality. We agree that this study was a metaanalysis and that it was based on a careful systematic review of reports regarding vasodilators in congestive heart failure that were identified from a computer search, bibliographies, national experts, and drug manufacturers.

Effects of vasodilators on the coronary circulation in congestive heart failure

Pressure or volume overload of the myocardium increases the wall stress, particularly of the subendocardium, and leads to hypertrophy. Even though cardiac hypertrophy is viewed as a beneficial compensatory process that normalizes wall stress, the increased muscle mass carries with it the need of increased blood supply. Overall flow per unit mass is similar at rest in hypertrophic and normal hearts but a reduction of flow to the subendocardium and an increase in minimal coronary vascular resistance have been described. Thus, the potential exists for a vasodilator-induced steal mechanism shunting blood away from potentially ischemic areas. Angiotensin-converting enzyme inhibitors reduced myocardial oxygen consumption and coronary blood flow in parallel manner in some studies, indicating preserved coronary autoregulation, but there is also some evidence of a coronary vasodilator effect. Calcium antagonists reduce coronary vascular resistance and improve the myocardial demand-supply ratio, but the clinical usefulness of the newer compounds with supposedly little or no negative inotropic effects remains to be established. Hydralazine improved the myocardial oxygen demand-supply ratio in patients with dilated cardiomyopathy, but metabolic function may deteriorate more often after hydralazine than after angiotensin-converting enzyme inhibitors in patients with coronary heart disease. Similar observations have been made using alpha-adrenergic blockers. Although progress has been made in the understanding of the coronary circulation and the influence of vasodilators in congestive heart failure, many questions await clarification using refined or new methodology.

Delayed reversal of impaired vasodilation in congestive heart failure after heart transplantation

The effects of changes in central cardiovascular function on peripheral vasodilation were investigated. Strain gauge plethysmography was used to measure the maximal blood flow response following release of forearm arterial occlusion and the peak reactive hyperemic blood flow response (ml/min · 100 ml) before and twice after orthotopic heart transplantation in 10 subjects with severe congestive heart failure. The 2 posttransplantation studies were done before hospital discharge (mean 18 days after transplantation) and again after discharge (mean 114 days after transplantation). Transplantation led to a significant but delayed increase in maximal vasodilation (reactive hyperemic blood flow: pretransplant 21 ± 3; predischarge 25 ± 2; postdischarge 43 ± 5) and a concurrent significant reduction in minimal forearm resistance. Although the improvement in peripheral vasodilator function may be linked to improvement in cardiac function, this linkage is not direct, nor is it immediate. If the normalization of maximal metabolic blood flow is related to resumption of normal physical activity post-discharge, then much of the basic abnormality in vasodilator capacity in congestive heart failure may be related to physical deconditioning.

Enhanced metabolic vasodilation secondary to diuretic therapy in decompensated congestive heart failure secondary to coronary artery disease

Since sodium and water retention have been implicated as major factors limiting maximal metabolic vasodilation in congestive heart failure (CHF), the effect of rigorous diuresis on maximal vasodilatory capacity was studied systematically in 9 subjects hospitalized with decompensated CHF. Peak reactive hyperemic blood flow, measured by straingauge plethysmography, was used as an index of maximal vasodilatory capacity. After 24 hours of diuresis and a 2.2-kg weight loss, maximal flow increased from 19.9 to 26.1 ml/min · 100 ml (p < 0.05). Despite a further 1.4-kg weight loss between 24 and 48 hours, maximal blood flow increased no more (26.1 to 25.8 ml/min · 100 ml). Since blood pressure did not change significantly, minimal forearm resistance and maximal conductance showed similar improvements. It is unlikely that vasoconstrictor hormone changes could account for this effect since a marked decrease in plasma norepinephrine occurred in only 2 of 8 subjects and plasma renin activity decreased in only 1 subject. As a group there was no significant change in norepinephrine level, which remained substantially above normal (1,525 to 1,148 pg/ml), or in plasma renin activity (12.3 to 18.9 ng/ml/hour). Because the improvement in vasodilator capacity reached a plateau by 24 hours despite continued diuresis, and because peak reactive hyperemic blood flow was still 32% below normal, it is suggested that a second mechanism besides sodium and water retention is responsible for a significant portion of the impaired peripheral vasodilation in CHF.

Hemodynamic effects of nifedipine in congestive heart failure

Nifedipine, a potent coronary vasodilator, was administered in a single sublingual dose of 20 mg to eight patients with mild to moderate congestive heart failure. Nifedipine produced a slight increase in heart rate (mean ± standard error of the mean 73.3 ± 3.2 versus 80.9 ± 2.1 beats/min, p <0.025) and an increase in cardiac index (from a control value of 3.51 ± 0.22 to 4.06 ± 0.31 liters/ min per m 2, p <0.01). Arterial blood pressure decreased from 112.9 ± 6.2 67.7 ± 4.2 ( mean 84.9 ± 4.0) to 100.8 ± 4.4 56.4 ± 11.0 ( mean 76.1 ± 4.3) mm Hg (p <0.01) and total systemic vascular resistance also decreased from a control value of 15.6 ± 1.0 to 12.4 ± 0.8 units (p <0.01) after administration of nifedipine. These data suggest that nifedipine may be useful for vasodilation in congestive heart failure.