Vasodilation In Heart Failure Research Articles

Effects of Vasodilation in Heart Failure With Preserved or Reduced Ejection Fraction: Implications of Distinct Pathophysiologies on Response to Therapy

The purpose of this study was to compare hemodynamic responses to vasodilator therapy in patients with heart failure (HF) and preserved ejection fraction (HFpEF) versus HF and reduced ejection fraction (HFrEF). There is no proven therapy for HFpEF. In the absence of data, medicines with established benefit in HFrEF such as vasodilators are frequently prescribed for HFpEF. We compared baseline hemodynamics and acute responses to vasodilation with intravenous sodium nitroprusside in patients with HFrEF (n = 174) and HFpEF (n = 83), determined invasively by cardiac catheterization. Baseline blood pressure, stroke volume, and cardiac output were greater in HFpEF than HFrEF, while pulmonary artery mean and pulmonary wedge pressures were similar. Left ventricular filling pressures were reduced to a similar extent in each group with nitroprusside, but the drop in systemic arterial pressure was 2.6-fold greater in HFpEF (p < 0.0001), and improvements in stroke volume and cardiac output were each ∼60% lower in HFpEF compared to HFrEF (p < 0.0001). Despite similarly elevated filling pressures, HFpEF patients were fourfold more likely than HFrEF to experience a reduction in stroke volume with nitroprusside (p < 0.0001), suggesting greater vulnerability to preload reduction. Pulmonary artery systolic pressure dropped more in HFpEF than in HFrEF despite similar reduction in pulmonary mean pressure and resistance, suggesting higher right ventricular systolic elastance in HFpEF. As compared to patients with HFrEF, patients with HFpEF experience greater blood pressure reduction, less enhancement in cardiac output, and greater likelihood of stroke volume drop with vasodilators. These findings emphasize fundamental differences in the 2 HF phenotypes and suggest that more pathophysiologically targeted therapies are needed for HFpEF.

Impaired endothelium-mediated vasodilation in heart failure: Clinical evidence and the potential for therapy

Numerous studies in the last decade have clearly shown an attenuated endothelium-dependent vasodilation in patients with chronic heart failure. This abnormality has been demonstrated in the peripheral, pulmonary, and coronary circulation in patients with both ischemic and nonischemic cardiomyopathy; its magnitude correlates with the severity of symptoms. Endothelial dysfunction in patients with cardiomyopathy and a relatively new onset of symptoms suggests that change in endothelial function occurs early in the course of the disease. In contrast to other circulatory beds, renal circulation has shown significant vasodilatory response to endothelial stimulation. The development of endothelial dysfunction may not be homogenous, and its magnitude may differ among circulatory systems. Although the clinical implications of the attenuated endothelium-dependent vasodilation in heart failure are not clear, this condition may lead to decreased organ perfusion, impaired exercise tolerance, and progression of disease. Many therapeutic interventions have resulted in improvement of endothelial function in patients with heart failure. Some of these interventions have also proven effective in enhancing exercise capacity, symptoms, and survival in patients with heart failure. This association suggests a therapeutic role for improvement of endothelial function in patients with chronic heart failure.

Even low-dose aspirin inhibits arachidonic acid-induced vasodilation in heart failure.

There is some evidence that aspirin may be harmful to patients with congestive heart failure treated with angiotensin-converting enzyme (ACE) inhibitors, but there has never been any direct examination of the vascular effects of aspirin in these patients. We sought to determine whether there is an arachidonic acid-dependent vasodilator pathway in resistance arteries in humans, whether it is affected by congestive heart failure, and whether it is inhibited by low-dose aspirin. A locally active dose of arachidonic acid was infused into the nondominant brachial artery while forearm blood flow was measured by venous occlusion plethysmography in 10 healthy subjects in a control group and 15 patients with congestive heart failure treated with ACE inhibitor. Patients with congestive heart failure were studied after administration of 0 mg, 75 mg, and 300 mg aspirin for 14 days. Arachidonic acid produced progressive and incremental vasodilation (up to 64%). There was no significant difference between patients and healthy control subjects studied after administration of 0 mg aspirin. In patients, however, administration of 75 mg and 300 mg aspirin inhibited mean vasodilation by 55% and 59%, respectively. There is an arachidonic acid-dependent vasodilator pathway in humans. This pathway is not significantly affected by congestive heart failure. It is significantly inhibited by even low-dose aspirin therapy. These results imply that even the very lowest dose of aspirin in common use for cardioprotection has potentially detrimental vasoconstrictor effects.

Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure.

The extent to which abnormal endothelium-dependent vasodilator mechanisms contribute to abnormal resting vasoconstriction and blunted reflex vasodilation seen in heart failure is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vascular tone that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. Thirteen advanced heart-failure patients (New York Heart Association III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine (20 microg/min), or L-arginine (10 mg/min) was infused into the brachial artery, and forearm blood flow was measured by venous plethysmography at rest and during mental stress. At rest, acetylcholine decreased forearm vascular resistance in normal subjects, but this response was blunted in heart failure. During mental stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm vascular resistance was not greater than during saline control in heart failure [saline control vs. acetylcholine (7 +/- 3 vs. 6 +/- 3, P = NS) or vs. L-arginine (9 +/- 2 units, P = NS)]. The increase in forearm blood flow was not greater than during saline control in heart failure [saline control vs. acetylcholine (1. 2 +/- 0.3 vs. 1.3 +/- 0.3, P = NS), or vs. L-arginine (1.2 +/- 0.2 ml x min(-1) x 100 ml(-1), P = NS)]. Furthermore, during mental stress with nitroprusside, the decrease in forearm vascular resistance was not greater than during saline control [saline control vs. nitroprusside (7 +/- 3 vs. 5 +/- 4 ml x min(-1) x 100 g(-1), P = NS)], and the increase in forearm blood flow was not greater than during saline control [saline control vs. nitroprusside (1.2 +/- 0.3 vs. 1.3 +/- 0.5 ml x min(-1) x 100 g(-1), P = NS)]. Because the endothelial-independent agent nitroprusside was unable to restore resting and reflex vasodilation to normal in heart failure, we conclude that impaired endothelium-mediated vasodilation with acetylholine-nitric oxide cannot be the principal cause of the attenuated resting- or reflex-mediated vasodilation in heart failure.

Prostaglandin production contributes to exercise-induced vasodilation in heart failure

Endothelial release of prostaglandins may contribute to exercise-induced skeletal muscle arteriolar vasodilation in patients with heart failure. To test this hypothesis, we examined the effect of indomethacin on leg circulation and metabolism in eight chronic heart failure patients, aged 55 +/- 4 yr. Central hemodynamics and leg blood flow, determined by thermodilution, and leg metabolic parameters were measured during maximum treadmill exercise before and 2 h after oral administration of indomethacin (75 mg). Leg release of 6-ketoprostaglandin F1alpha was also measured. During control exercise, leg blood flow increased from 0.34 +/- 0.03 to 1. 99 +/- 0.19 l/min (P < 0.001), leg O2 consumption from 13.6 +/- 1.8 to 164.5 +/- 16.2 ml/min (P < 0.001), and leg prostanoid release from 54.1 +/- 8.5 to 267.4 +/- 35.8 pg/min (P < 0.001). Indomethacin suppressed release of prostaglandin F1alpha (P < 0.001) throughout exercise and decreased leg blood flow during exercise (P < 0.05). This was associated with a corresponding decrease in leg O2 consumption (P < 0.05) and a higher level of femoral venous lactate at peak exercise (P < 0.01). These data suggest that release of vasodilatory prostaglandins contributes to skeletal muscle arteriolar vasodilation in patients with heart failure.

Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure.

Endothelium-dependent vasodilation in response to acetylcholine (ACh) and ischemic vasodilation during reactive hyperemia are attenuated in the forearm of patients with heart failure (HF). It has been shown that L-arginine augments endothelium-dependent vasodilation in healthy subjects. Thus, the aim of the present study was to determine if L-arginine improves endothelium-dependent and ischemic vasodilation in the forearm in HF. Forearm blood flow was measured by a strain-gauge plethysmograph in 20 patients with HF and in 24 age-matched control subjects (C). Resting forearm vascular resistance (FVR) was significantly higher in HF than in C (37 +/- 4 versus 22 +/- 2 U, P < .01). Intra-arterial infusions of ACh or sodium nitroprusside (SNP) at graded doses progressively decreased FVR in HF as well as in C. The magnitude of ACh-induced vasodilation was attenuated in HF (P < .01), whereas SNP-induced vasodilation was similar between the two groups. The minimal FVR during reactive hyperemia after 10 minutes of arterial occlusion was significantly higher in HF (n = 12) than in C (n = 12) (3.2 +/- 0.4 versus 2.1 +/- 0.1 U, P < .05). L-Arginine significantly augmented maximal vasodilation evoked with ACh and decreased minimal FVR during reactive hyperemia in HF (P < .01) but not in C. L-Arginine did not affect SNP-induced vasodilation in HF or C. Our results suggest that defective endothelial function may contribute to impaired ischemic vasodilator capacity in HF.

Effects of cardiac transplantation on endothelium-dependent dilation of the peripheral vasculature in congestive heart failure

Patients with congestive heart failure demonstrate attenuated endothelium-dependent vasodilation of the peripheral vasculature, but there are no data regarding the effect of therapies on this abnormality or whether this abnormality is reversible. This study was performed to address the hypothesis that abnormalities in endothelium-dependent vasodilation in heart failure are improved by heart transplantation. Forearm blood flow responses to the intraarterial administration of a dose range of methacholine, an endothelium-dependent vasodilator, and nitroprusside, an endothelium-independent vasodilator, were examined in 2 separate protocols. In protocol 1, forearm blood flow responses to methacholine in 14 heart transplant recipients were 5.02 ± 3.11, 11.55 ± 7.20 and 11.61 ± 10.24 ml/min/100 ml forearm volume. These responses were significantly greater than those in 10 patients with heart failure (2.23 ± 1.22, 4.60 ± 3.43 and 6.70 ± 4.91 ml/min/100 ml forearm volume; p <0.05). In contrast, the responses to nitroprusside were nearly identical in the 2 groups. In protocol 2, six patients were studied before and 4 months (range 1 to 11) after transplantation. Methacholine responses before transplantation were 2.5 ± 1.3, 5.2 ± 1.5 and 7.3 ± 1.5 ml/min/100 ml forearm volume and were significantly improved after transplantation to 5.7 ± 1.2, 12.1 ± 3.0 and 142 ± 2 2 ml/min/100 ml forearm volume (p < 0.05). Peak reactive hyperemia responses increased significantly from 19.0 ± 3.7 to 44.8 ± 6.4 ml/min/100 ml forearm volume (p < 0.01) after transplantation. These data demonstrate that heart transplantation was associated with a significant improvement in the forearm blood flow responses to methacholine. The effect of heart transplantation was consistent when comparing a group of transplant recipients and patients with heart failure and in a separate group of patients studied both before and after transplantation. The improvement in endothelium-dependent vasodilation may occur in the setting of an improvement in overall responsiveness of the peripheral vasculature. These data demonstrate that abnormal endothelium-dependent responses in heart failure are reversible.

The contractile behavior of the heart and its functional coupling to the circulation

The integrated function of the heart and lungs provides for the transfer of O 2 from the atmosphere, for its delivery to the metabolizing tissues, and for the removal of CO 2. When cardiac output is compromised as in heart failure, a series of reflexive and neurohumoral adjustments follow with activation of the adrenergic and renin-angiotensin systems. The resultant vasoconstriction constrains the performance of the failing heart. Accordingly, vasodilators have been used to attenuate this vasoconstriction and to improve cardiac performance in patients with cardiac failure. An understanding of the physiologic consequences of vasodilation, as well as the selection of the most appropriate vasodilator for these patients, requires an understanding of the contractile behavior of the normal and failing heart and of the factors that regulate their performance. Because the myocardium is composed largely of cardiac muscle, muscle force, length, and shortening are used to describe its contractile behavior. Myocardial contractile behavior is a function of: (A) instantaneous shortening load, or the ejection force (afterload), which the muscular wall has to support during its contraction; (b) shortening length; and (c) myocardial contractile state. The failing myocardium characteristically has both a depressed contractile state and an abnormal shortening load. In order to describe the functional coupling of the heart to its arterial and venous circulations, the concept of a mechanical pump having elastic and resistive properties is used. These mechanical properties of the pump determine its ability to generate pressure and flow. Unlike the normal heart, the failing pump with its decreased elastance (i.e., increased volume at normal chamber pressure) is more sensitive to vascular loading, and hence its more favorable response to vasodilators. Finally, the performance of the heart is determined by the coordination and integration of the right and left hearts that result from their anatomical arrangement and the mobile interventricular septum, the pericardium, and the pleural pressure surrounding the heart and lungs. Vasodilators improve the pump function of the failing heart by reducing ventricular interaction and by augmenting chamber distensibility. The consequences of pharmacologic vasodilation in heart failure, then, can best be appreciated by understanding the intrinsic properties of cardiac muscle, the functional coupling of the heart to the arterial and venous circulations, the interplay between ventricles, and the interaction of the heart with its pericardium and with pleural pressure.