Severe Chronic Congestive Heart Failure Research Articles

Cardiorenal Effects of an Orally Active Dopamine Prodrug (TA-870) in Patients with Congestive Heart Failure

The effects of TA-870, a newly synthesized orally active dopamine prodrug, on the cardiorenal functions were investigated in 12 patients with severe chronic congestive heart failure. A single oral dose of TA-870 (1,200 mg) improved left ventricular fractional shortening and mean circumferential velocity on M-mode echocardiography (p less than 0.01 for both). Renal plasma flow and glomerular filtration rate improved with TA-870 (p less than 0.01 and p less than 0.05, respectively); urine volume and sodium excretion increased (p less than 0.01 for both). Blood pressure and heart rate did not change during the 4-h experimental period. Mean plasma free dopamine levels peaked 1 h after dosing. These data suggest that the cardiorenal effects of oral TA-870 are comparable with those of continuous intravenous injections of dopamine. Thus, TA-870 appears to be a useful alternative drug to intravenous dopamine.

Direct and indirect assessment of skeletal muscle blood flow in chronic congestive heart failure

In patients with chronic congestive heart failure (CHF), skeletal muscle blood flow can be measured directly by the continuous thermodilution technique and by the xenon133 clearance method. The continuous thermodilution technique requires retrograde catheterization of the femoral vein and, thus, cannot be repeated conveniently in patients during evaluation of pharmacologic interventions. The xenon133 clearance, which requires only an intramuscular injection, allows repeated determination of skeletal muscle blood flow. In patients with severe CHF, a fixed capacity of the skeletal muscle vasculature to dilate appears to limit maximal exercise performance. Moreover, the changes in peak skeletal muscle blood flow noted during long-term administration of captopril, an angiotensin-converting enzyme inhibitor, appears to correlate with the changes in aerobic capacity. In patients with CHF, resting supine deep femoral vein oxygen content can be used as an indirect measurement of resting skeletal muscle blood flow. The absence of a steady state complicates the determination of peak skeletal muscle blood flow reached during graded bicycle or treadmill exercise in patients with chronic CHF. Indirect assessments of skeletal muscle blood flow and metabolism during exercise performed at submaximal work loads are currently developed in patients with chronic CHF.

Dopexamine hydrochloride in chronic congestive heart failure with improved cardiac performance without increased metabolic cost

Dopexamine hydrochloride is a new intravenous, short-acting agent with agonist activity at beta 2-adrenergic and DA1-dopaminergic receptors. The effects of dopexamine hydrochloride infusion on systemic and coronary hemodynamics, myocardial metabolism and the neuroendocrine system were evaluated in 10 patients with chronic severe congestive heart failure at baseline, at rates of 1, 2, 4 and 6 micrograms/kg/min at 15-minute intervals, and after a 1-hour infusion of the "optimal" dose. Right atrial pressure was reduced by 25% (p less than 0.01), pulmonary capillary wedge pressure by 26% (p less than 0.05), systemic vascular resistance by 44% (p less than 0.001) and pulmonary vascular resistance by 34% (p less than 0.01) after the optimal dose. Heart rate increased by 17% (p less than 0.01), rate-pressure product by 17% (p less than 0.01) and stroke volume index by 31% (p less than 0.001). There was no change in mean arterial pressure, myocardial oxygen consumption, coronary sinus blood flow, myocardial oxygen extraction or norepinephrine balance. None of the patients demonstrated net myocardial lactate production. These findings suggest that dopexamine hydrochloride improves systemic hemodynamics and cardiac performance without adversely affecting myocardial energetics or norepinephrine balance. Thus, dopexamine hydrochloride may be a useful agent for the short-term treatment of congestive heart failure.

Cumulative Hemodynamic Response to Short-Term Treatment with Flosequinan (BTS 49465), a New Direct-Acting Vasodilator Drug, in Severe Chronic Congestive Heart Failure

Pharmacologic tolerance develops rapidly to the hemodynamic effects of many vasodilator drugs used in the treatment of congestive heart failure. We evaluated the responses to 3 days of therapy with a new long-acting vasodilator drug, flosequinan (BTS 49465), in 16 patients with severe chronic heart failure. On each of the 3 days, flosequinan (100 or 150 mg orally) produced marked increases in cardiac index and decreases in left ventricular filling pressure, mean right atrial pressure, and systemic vascular resistance (all p less than 0.01) without significant changes in heart rate. Whereas the effects of flosequinan on right and left ventricular filling pressures on the first and third days were similar, cardiac index was higher and systemic vascular resistance was lower after the third dose than after the first dose of the drug, indicating the occurrence of a cumulative vasodilator effect on arterial resistance vessels. Since all hemodynamic changes persisted for longer than 24 h after each dose of the drug, the daily administration of flosequinan also produced a progressive improvement in the hemodynamic state recorded before each dose of the drug. These data indicate that pharmacologic tolerance does not develop to the effects of flosequinan during short-term therapy with the drug in patients with severe chronic heart failure. Instead, further hemodynamic improvement may occur because of a cumulative vasodilator effect that results from the drug's prolonged duration of action.

Hemodynamic, renal and endocrine effects of atrial natriuretic peptide infusion in severe heart failure

The cardiac release and total body and renal clearances and the hemodynamic, renal and endocrine effects of increasing doses of atrial natriuretic peptide were investigated in 12 patients with severe chronic congestive heart failure. Immunoreactive arterial plasma levels of atrial natriuretic peptide were 10-fold higher than normal and there was no correlation between aortic atrial natriuretic peptide and cardiac filling pressures. The heart released atrial natriuretic peptide into the coronary sinus. The kidney, though a major clearance site, accounted for only 33% of the total body clearance. Administration of 0.3 μg/kg per min atrial natriuretic peptide produced significant changes in heart rate (95 ± 4 to 85 ± 4 beats/min) and mean arterial (92 ±8 to 77 ± 9 mm Hg), right atrial (13 ± 3 to 8 ± 2 mm Hg) and mean pulmonary artery occluded (27 ± 3 to 14 ± 3 mm Hg) pressures. Atrial natriuretic peptide increased cardiac index (2.25 ± 0.18 to 2.83 ± 0.3 liters/min per m2) and stroke work index (21 ± 1.5 to 29 ± 3.4 g/m2), whereas systemic vascular resistance (1,424 ± 139 to 1,033 ± 97 dynes-s-cm−5) decreased.Infusion of 0.1 μg/kg per min atrial natriuretic peptide increased urinary flow 128%, fractional excretion of sodium 133% and fractional excretion of potassium 35%. The filtration fraction increased from 29 ± 2 to 31 ± 4%. This represented a disproportionate rise in glomenuar filtration rate over renal plasma Bow. Plasma aldosterone and norepinephrine decreased whereas plasma renin activity remained unchanged. In association with these hemodynamic, excretory and endocrine changes, the urinary excretion of cyclic guanosine monophosphate doubled. Placebo had no effect. These results showed that, despite high circulating levels of atrial natriuretic peptide, administration of this hormone in heart failure is associated with potentially beneficial hemodynamic, renal and endocrine effects.

Pimobendane (UD-CG115 BS) in Chronic Congestive Heart Failure: Short-Term and One-Month Effects of a New Inotropic Vasodilating Agent

We studied the effects of oral administration of pimobendane on hemodynamics, blood gas levels, the renin-angiotensin system, and plasma catecholamines in 11 patients who were affected by severe chronic congestive heart failure. Following the administration of 5 mg, the cardiac index increased from 2.0 +/- 0.2 to 2.5 +/- 0.2 L/min/m2 (p less than 0.01), and the pulmonary wedge pressure decreased from 28 +/- 3 to 17 +/- 4 mm Hg (p less than 0.01). The maximal changes were noted five hours after intake of the drug. In spite of a significant decrease in arterial oxygen pressure (PaO2) (from 81 +/- 4 to 67 +/- 5 mm Hg; p less than 0.05), a significant increase in the oxygen delivery index was seen (from 322 +/- 32 to 436 +/- 38 ml/min/m2; p less than 0.01). The patients who were submitted to long-term treatment (5 mg twice daily) and who were reassessed after at least one month exhibited an improved cardiac index from 1.9 +/- 0.2 to 2.5 +/- 0.1 L/min/m2 (p less than 0.01), as well as a decreased pulmonary wedge pressure from 26 +/- 2 to 14 +/- 4 mm Hg (p less than 0.01). The norepinephrine levels were significantly reduced after one month (from 1,496 +/- 185 to 678 +/- 95 pg/ml; p less than 0.01), whereas the plasma renin activity was not. One patient died suddenly during the one-month follow-up period. With the exception of one case, which was also treated with heparin, a transient cutaneous rash and a drop in the level of blood platelets were observed, pimobendane was well tolerated. This new inotropic and vasodilating drug thus seems to have promise for the treatment of chronic congestive heart failure.

Assessment of autonomic regulation in chronic congestive heart failure by heart rate spectral analysis

Neurohumoral modulation of cardiovascular function is an important component of the hemodynamic alterations in patients with chronic congestive heart failure (CHF). Analysis of heart rate (HR) variability is a noninvasive means of investigating the autonomic control of the heart. The variability of HR and respiratory signals, both derived from ambulatory electrocardiographic recordings, were analyzed with power spectral analysis to evaluate autonomic control in 25 patients with chronic stable CHF (class III or IV) and 21 normal control subjects. In the patients with CHF, HR spectral power was markedly reduced (p < 0.0001) at all frequencies examined (0.01 to 1.0 Hz, period 1 to 100 seconds) and virtually absent at frequencies >0.04 Hz. Heart rate fluctuations at very low frequencies (0.01 to 0.04 Hz) less effectively differentiated CHF patients from control subjects, due to discrete (about 65 seconds, 0.015 Hz) oscillation in HR, which was associated with a similar pattern in respiratory activity in many of the patients with CHF. These findings demonstrate a marked derangement of HR modulation in patients with severe CHF. The frequency characteristics of HR fluctuations in these patients are consistent with abnormal baroreflex responsiveness to physiologic stimuli, and suggest that there is diminished vagal, but relatively preserved sympathetic, modulation of HR.

Atrial natriuretic peptide in congestive heart failure: Postural changes and reset with chronic captopril therapy

The response of atrial natriuretic peptide (ANP) to standing and the acute and chronic administration of the vasodilator, captopril, were examined in 15 patients with chronic congestive heart failure. In the supine position, ANP was increased (361 ± 202 pg/ml); however, only a loose correlation existed between atrial pressures and ANP (right atrial vs ANP, r = 0.03, p = N.S., and pulmonary capillary wedge pressures vs ANP, r = 0.4, p = N.S.). Standing and acute captopril therapy decreased atrial pressures and ANP but did not significantly improve the correlation between atrial pressures and ANP. With chronic captopril therapy, atrial pressures remained decreased; however, ANP had returned to control values (370 ± 254 pg/ml vs 361 ± 202 pg/ml) and failed to decrease with standing (370 ± 259 pg/ml lying vs 351 ± 194 pg/ml standing). These changes in ANP (with chronic captopril therapy) persisted even once the hemodynamic effects of captopril had dissipated (3 hours post dose). This study indicates that in patients with severe chronic congestive heart failure (1) only a poor correlation exists between ANP and atrial pressures and (2) with chronic captopril therapy ANP increases to higher levels for a given atrial pressure and fails to decrease with standing despite a decrease in atrial pressures.

High-Dose Furosemide in the Treatment of Refractory Congestive Heart Failure

Thirty-five patients with severe chronic congestive heart failure that was refractory to conventional therapy were given high dosages of furosemide (250 to 4000 mg/d) because of significantly reduced renal function (mean endogenous creatinine clearance, 0.53 mL/s/1.73 m2 [32 mL/min/1.73 m2]). Natriuresis, weight reduction (mean, 11 kg), and relief of symptoms were achieved in all patients. The mean survival after the start of the high-dose furosemide therapy was 11.3 months (range, 0.5 to 36 months) (n = 35). When this therapy eventually failed, long-term intermittent hemofiltration was performed in eight selected cases, further prolonging survival (mean, 3.0 months). High-dose furosemide therapy and hemofiltration improved the quality of life and prolonged survival. The use of diuretics in congestive heart failure should therefore include treatment with high-dose furosemide, which is effective and can be given over a long period without serious side effects.

Echocardiographic study for predicting the prognosis in patients with chronic congestive heart failure.

Echocardiograms(ECHOs)of 43 patients with severe chronic congestive heart failure (CHF)were analyaed in order to correlate the prognosis of these patients with cardiac dimensions, left ventricular mass (LVM), and LV function. Of these 43 patients, 29 survived with 14patients having died three days to mine months following the ECHO study. ECHO parameters indicating the status of contractility were better among survivors. The individual parameters in the survivors and nonsurvivors were: shortening fraction of the LV(△FS), 16±7%vs 11±5%(p＜0.025);the E point-septal separation(EPSS), 22±6mm vs 27±9mm (p＜0.025);LV end-diastolic dimension (LVEDD), 62±9 mm vs 68±9 mm (p＜0.025). ECHO indices of wall thickness were greater in the survivors compared to the nonsurvivors, including posterior wall thickness in diastole (LVPWt)and ratio of posterior wall thickness to radius of the LV in diastole (RWT).Neither LV mass nor septal wall thickness (IVSt)differed significantly between the survivors and the nonsurvivors.Furthermore, long-term survival seems to be predicted by LVEDD or △FS, but not by other ECHO parameters including LVESD, IVST,RWT, LVPWt, LVM and EPSS. Thus, echocardiography may be useful in predicting the survival of patients with chronic CHF.

Potential mechanisms of improved left ventricular function with enoximone in severe congestive heart failure

Enoximone, a phosphodiesterase inhibitor, is a potent inotropic vasodilator agent that causes a marked improvement in systemic hemodynamics in patients with severe chronic congestive heart failure. Cardiac index, stroke volume index and stroke work index increase, and there is a significant decrease in pulmonary capillary wedge pressure. Left ventricular dP dt increases, despite a decrease in arterial pressure and systemic vascular resistance and without any significant change in heart rate, indicating a positive inotropic effect. A marked decrease in systemic vascular resistance indicates that decreased left ventricular outflow resistance resulting from peripheral vasodilation also contributes to improvement in left ventricular function. In some patients, left ventricular end-diastolic volume increases despite a marked decrease In pulmonary capillary wedge pressure, suggesting an improvement in apparent left ventricular compliance, which may also be contributory to improved left ventricular function.

Hemodynamic factors limiting the response to transdermal nitroglycerin in severe chronic congestive heart failure

Hemodynamic factors limiting the response to transdermal nitroglycerin in severe chronic congestive heart failure

Use of invasive ergometric exercise to assess the hemodynamic response to nicardipine

The calcium antagonists are potent vasodilators. This physiologic property suggests that these agents have a potential role in the treatment of patients with hypertension and congestive heart failure. Although the clinical response to calcium antagonism in hypertension is promising, the response in patients with congestive heart failure is less than hoped for; this is due to the fact that this class of agents may induce a hemodynamically important degree of negative inotropic effect. To test the hemodynamic response to nicardipine, a second-generation dihydropyridine, the hemodynamic response to maximal ergometric exercise was evaluated in a group of patients with moderate to severe chronic congestive heart failure. One week of nicardipine therapy was associated with a significant reversal of vasoconstriction at rest and during peak exercise with a secondary increase of cardiac index, and a decrease in pulmonary wedge pressure. The reversal of vasoconstriction was associated with a decrease in mean arterial pressure, with no change in the heart rate. There was no change in oxygen consumption or carbon dioxide production; however, there was a decrease in arteriovenous oxygen difference, consistent with a reduction of oxygen extraction. This short-term study identified the potent vasodilator properties of nicardipine in patients with chronic congestive heart failure; a hemodynamically significant negative inotropic effect could not be identified. Although the use of calcium antagonists for the treatment of congestive heart failure may have a limited role, this study nonetheless suggests that nicardipine may have a favorable vasodilator effect without an overt negative inotropic effect. This would be of considerable advantage in the treatment of hypertension, when compared with β-adrenergic blocking agents.

Acute hemodynamic, hormonal and electrolyte effects of ramipril in severe congestive heart failure

The response to ramipril, 10 and 20 mg on consecutive days, in 9 patients with severe (New York Heart Association functional class III or IV) chronic congestive heart failure was measured. Hemodynamic cannulae were placed more than 2 days before ramipril administration to ensure a stable base-line. Dietary sodium (40 mmol daily) and potassium (80 mmol daily) were constant before and during the study, and maintenance doses of digoxin and furosemide (80 to 1,000 mg daily) were continued unchanged. Ramipril induced pronounced, sustained decreases in angiotensin converting enzyme activity, angiotensin II and aldosterone levels, and a reciprocal increase in plasma renin activity. Plasma catecholamines, antidiuretic hormone and cortisol levels were not altered. Urinary sodium and potassium excretion diminished, plasma sodium decreased and plasma potassium increased. Plasma urea and creatinine levels increased. Ramipril treatment resulted in a decrease in systemic arterial pressure that was sustained for 24 hours, a decrease in heart rate and an increase in cardiac index, but little change in pulmonary artery pressure or right atrial pressure. Three patients were drowsy after ramipril administration, and 1 patient had a marked, temporary reduction in urine output. It was concluded that ramipril is a potent, long-acting angiotensin converting-enzyme inhibitor that is likely to be beneficial in patients with severe cardiac failure.

Oscillatory hyperventilation in severe congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy

Thirty-one subjects with chronic congestive heart failure (CHF) were separated into 3 groups according to ventilatory patterns during graded exercise: Group 1-oscillators (n = 6); group 2—intermediate oscillators (n = 14); and group 3—nonoscillators (n = 11). Group 1 patients showed cyclic fluctuations in minute ventilation (change of 30 to 40 liters/min) and arterial P02 (change of 38.0 ± 4.1 mm Hg) and PCO 2 (change of 11 ± 2.8 mm Hg). The nadir in arterial PO 2 occurred at times when wasted ventilatory effort was maximal. The amplitude of ventilatory oscillations in group 1 patients increased in the transition from rest to light exercise and damped with heavy exercise. There was no evidence of alveolar hypoventilatlon at the nadirs of minute ventilation; arterial PCO 2 was always 40 mm Hg or less. Substantial hyperventilation (ventilatory equivalent for C02 twice normal) occurred with maximal minute ventilation in group 1 patients. Oscillatory hyperventilation correlated with severity of CHF. Maximal oxygen uptake was significantly lower in group 1 (11.7 ± 1.1 ml/kg/min) than group 3 (17.9 ± 1.8 mi/kg/min) (p <0.05). Oscillatory hyperventilation during exercise may accompany severe CHF and compounds the inadequate delivery of oxygen by the failing heart.

Converting-Enzyme Inhibition in the Management of Severe Chronic Congestive Heart Failure

Evidence from the experimental and clinical laboratory suggests that the heart failure state is characterized not only by an excessive degree of systemic vasoconstriction but also by an exaggerated neurohormonal response to the decline in cardiac performance. Therapeutic interventions directed only at the first abnormality may serve to exacerbate the second, and thus may fail to produce long-term hemodynamic and clinical benefits. Converting-enzyme inhibitors successfully antagonize both homeostatic malfunctions, and thus are among the few vasodilators that have been shown to produce consistent circulatory and symptomatic improvement in patients with severe chronic heart failure in controlled clinical trials; the responses to treatment with these agents have been superior to those seen during therapy with placebo or other vasodilator drugs. Furthermore, experimental and clinical evidence suggests that converting-enzyme inhibitors exert favorable effects on the survival of patients with severe heart failure; this potential has now been confirmed in a large-scale, multicenter, placebo-controlled trial. Despite its benefits, converting-enzyme inhibition may be accompanied by adverse circulatory and metabolic reactions (symptomatic hypotension, renal insufficiency, and potassium retention), which are predictable consequences of interference with the homeostatic role of angiotensin II in low-output states.

Effects of captopril on cardiorenal hemodynamics in patients with severe chronic congestive heart failure.

The effects of captopril on cardiorenal function were studied in patients with chronic congestive heart failure. A single oral dose of captopril in 16 patients significantly increased cardiac indices and decreased total systemic vascular resistance. These changes were greater in subjects with higher baseline plasma renin activity (PRA). The increase in PRA and decrease in plasma aldosterone were also greater in this group. During 7 days of captopril therapy, renal plasma flow distinctly increased in 10 patients in whom renal function was followed. The increase in renal blood flow was greater in subjects with higher PRA. Simultaneous infusion of aprotinin in eight of these subjects did not affect the captopril-induced increase in renal plasma flow: these responses were the same in both PRA subgroups. The results suggest that captopril reduces total systemic vascular resistance in patients with chronic congestive heart failure through the inhibition of the renin-angiotensin system and the preferential renal vasodilating effect of captopril seems exclusively to be the sole result of this inhibition, with the kallikrein-kinin system or kinin-mediated prostaglandins not playing a major role.

Hemodynamic effects of BTS 49465, a new long-acting systemic vasodilator drug, in patients with severe congestive heart failure

The hemodynamic effects of BTS 49465, a new oral, direct-acting systemic vasodilator drug, were investigated in 10 patients with severe chronic congestive heart failure. One to 2 hours after the administration of 1.5 mg/kg orally, BTS 49465 produced significant increases in cardiac index, stroke volume index, and stroke work index (26%, 27%, and 23%, respectively, p < 0.01 to 0.001) and marked decresses in left ventricular filling pressure (−12.6 mm Hg, 44%), mean pulmonary artery pressure (−13.2 mm Hg, 31%), and mean right atrial pressure (−7.7 mm Hg, 63%), all p < 0.001, without significant changes in heart rate. These hemodynamic responses were accompanied by notable declines in systemic vascular resistance (−28%, p < 0.001) and pulmonary arteriolar resistance (−24%, p < 0.05). These effects persisted throughout the 24-hour period of observation. The decline in left ventricular filling pressure in our patients ranged in magnitude from 8 to 21 mm Hg, and varied linearly and directly with pretreatment values for left ventricular filling pressure ( r = 0.69). The decrease in systemic vascular resistance ranged in magnitude from 3% to 40% and varied linearly and directly with pretreatment values for systemic vascular resistance ( r = 0.85). These data indicate that BTS 49465, a new oral, direct-acting vasodllator agent, exerts balanced cardiocirculatory effects in patients with severe chronic heart failure, which may be sustained with once-dally oral administration.

Sodium and water excretion abnormalities in congestive heart failure. Determinant factors and clinical implications.

The renal hemodynamic and neurohumoral determinants of sodium and water excretion abnormalities were studied in 66 patients with severe chronic congestive heart failure. Abnormalities were not closely related to any one variable but were the result of the convergence of a number of determinants. The most important determinants for sodium excretion were activation of the renin-angiotensin system and ventricular function; and the most important for water excretion were plasma vasopressin, plasma norepinephrine, and renal and ventricular functions. In a subgroup of patients, neurohumoral overactivation led to severe sodium and water excretion abnormalities and to increased furosemide requirements. A 17-month follow-up of all 66 patients showed a less favorable clinical course for this subgroup even when compared with hemodynamically matched patients.

Effects of Eating on Cardiac Performance in Congestive Heart Failure

We assessed the effects of ingestion of a meal on cardiac performance in patients with chronic severe congestive heart failure. A group of 32 patients underwent right heart catheterization on the day prior to study. Patients then fasted overnight (12 hours). In the morning, baseline hemodynamic measurements were obtained on all patients; then 11 patients (group 1) consumed a liquid meal of 317 kcal, and 21 patients (group 2) received a placebo medication and continued fasting. Hemodynamic measurements were then obtained at intervals over two hours. Significant changes were seen in group 1 only. Cardiac index increased 22 percent, stroke work index increased 14 percent, pulmonary arterial wedge pressure decreased 20 percent, and systemic vascular resistance decreased 22 percent in group 1. This study demonstrates an important effect of ingestion of a meal on cardiac performance in patients with heart failure. To avoid overestimating the beneficial effects of therapy, eating must be carefully controlled when assessing the effects of various therapies in these patients.