Search

For transplant wait-list patients with end-stage congestive heart failure, reversibility of pulmonary hypertension tested with acute administration of vasodilators is a prerequisite to listing for transplantation. We have shown that the magnitude of the initial pulmonary vasodilatory response to nitroprusside predicts neither the extent of the long-term hemodynamic response nor the subsequent need for transplantation versus clinical improvement and removal from transplant consideration.

Background: The pathophysiology of mental stress-induced myocardial ischemia, which occurs at lower heart rates than during physical stress, is not well understood., Methods and Results: The Psychophysiological Investigations of Myocardial Ischemia Study (PIMI) evaluated the physiological and neuroendocrine functioning in unmedicated patients with stable coronary artery disease and exercise-induced ischemia. Hemodynamic and neurohormonal responses to bicycle exercise, public speaking, and the Stroop test were measured by radionuclide ventriculography, ECG, and blood pressure and catecholamine monitoring. With mental stress, there were increases in heart rate, systolic blood pressure, cardiac output, and systemic vascular resistance that were correlated with increases in plasma epinephrine. During exercise, systemic vascular resistance fell, and there was no relationship between the hemodynamic changes and epinephrine levels. The fall in ejection fraction was greater with mental stress than exercise. During mental stress, the changes in ejection fraction were inversely correlated with the changes in systemic vascular resistance. Evidence for myocardial ischemia was present in 92% of patients during bicycle exercise and in 58% of patients during mental stress. Greater increases in plasma epinephrine and norepinephrine occurred with ischemia during exercise, and greater increases in systemic vascular resistance occurred with ischemia during mental stress., Conclusions: Mental stress-induced myocardial ischemia is associated with a significant increase in systemic vascular resistance and a relatively minor increase in heart rate and rate-pressure product compared with ischemia induced by exercise. These hemodynamic responses to mental stress can be mediated by the adrenal secretion of epinephrine. The pathophysiological mechanism involved are important in the understanding of the etiology of myocardial ischemia and perhaps in the selection of appropriate anti-ischemic therapy.

The relationship between the incidence, frequency and complexity of spontaneous ventricular arrhythmias and the extent of haemodynamic compromise and sympathoadrenergic hyperactivity was evaluated in a canine model of chronic heart failure produced by multiple sequential intracoronary microembolizations. Ambulatory ECG Holter monitoring recorded during chronic heart failure in 18 dogs revealed spontaneous ventricular arrhythmias ranging from single ventricular premature beats (VPBs) to non-sustained episodes of ventricular tachycardia (VT). Single VPBs were present in 94% of dogs, couplets in 67%, triplets in 28% and spontaneous episodes of non-sustained VT in 33%. Dogs with > 28 VPBs.h-1 (n = 9) had a markedly higher plasma norepinephrine (PNE) concentration (1001 +/- 185 vs 561 +/- 31 pg.ml-1) (P < 0.03), and a higher pulmonary artery wedge pressure (PAWP) (18 +/- 2 vs 12 +/- 1 mmHg) (P < 0.03) than dogs with < or = 28 VPBs.h-1 (n = 9). Dogs that developed spontaneous episodes of VT also had significantly higher PNE levels (1119 +/- 247 pg.ml-1) compared to dogs that did not develop VT (612 +/- 64 pg.ml-1) (P < 0.02). Programmed ventricular stimulation performed in seven of 18 dogs resulted in the development of sustained monomorphic VT in three and ventricular fibrillation in three dogs each (43%, 43%). Dogs with inducible sustained monomorphic VT had a significantly higher number of ambient arrhythmias and higher PAWP compared to dogs that did not develop sustained VT. The observed complexity, frequency and incidence of spontaneous and inducible ventricular arrhythmias in this canine model are similar to those described in patients with chronic heart failure.

Peak III phosphodiesterase (PDE) inhibitors have combined positive inotropic and vasodilator effects. We studied 10 patients with chronic heart failure during and after infusion of intravenous (i.v.) ICI 153,110, an investigational peak III PDE inhibitor. Maximum hemodynamic response for the group occurred after cessation of infusion at a lower plasma drug concentration. At maximum hemodynamic response, cardiac index (CI) increased (2.4 +/- 0.5 vs. 3.2 +/- 0.37 L/min/m2, p less than 0.05) with a decrease in mean arterial pressure (MAP 91 +/- 5 vs. 80 +/- 3 mm Hg, p less than 0.05), pulmonary capillary wedge pressure (PCWP 25 +/- 2 vs. 17 +/- 3.1 mm Hg, p less than 0.01), systemic vascular resistance (SVR 1,422 +/- 106 vs. 983 +/- 97 dynes.s.cm-5, p less than 0.05) and pulmonary vascular resistance (PVR 227 +/- 39 vs. 16 +/- 31 dynes.s.cm-5, p less than 0.05). During the infusion, plasma renin activity (PRA) decreased from 6.34 +/- 2.53 to 3.6 +/- 3 ng/ml/h (NS). The five patients with high baseline PRA had a significant decrease (11.2 +/- 2.5 vs. 5.4 +/- 1.67 ng/ml/h, p less than 0.01) that preceded changes in CI and SVR by 1-2 h. These data suggest that reduction in PRA may have contributed to the hemodynamic effects of this peak III PDE inhibitor.

Acute and chronic hemodynamic effects at rest and during exercise of a new dihydropyridine calcium antagonist, nicardipine hydrochloride, were studied in 10 patients with chronic heart failure. Acute intravenous administration of nicardipine resulted in a significant decrease in arterial blood pressure, systemic vascular resistance, and pulmonary capillary wedge pressure. There was a significant increase in cardiac index, stroke volume index, and the left ventricular stroke work index. Cardiac index measured at peak exercise increased significantly when compared with the cardiac index obtained at peak exercise before the infusion. After 9 days of continuous therapy with nicardipine, 30 mg three times a day, a significant decrease in arterial blood pressure and systemic vascular resistance and a significant increase in the cardiac index, stroke volume index, and left ventricular stroke work index at rest were observed in response to a single oral dose of 30 mg nicardipine. Data at peak exercise were also obtained before and 2 hours after the oral administration of nicardipine. With this comparison there was a significant increase in cardiac index, stroke work index, and exercise duration. It is concluded that in this group of patients with severe chronic heart failure, nicardipine enhanced myocardial performance during rest and exercise and this enhancement is sustained after 9 days of oral therapy.

CI-930, a new type III phosphodiesterase inhibitor, was evaluated for treatment of refractory congestive heart failure. The hemodynamic, pharmacokinetic and clinical response to the drug was determined in 10 patients. At the peak plasma concentration after intravenous CI-930, cardiac index increased from 2.0 to 2.7 liters/min/m2 (p less than 0.002), pulmonary artery wedge pressure decreased from 26 to 17 mm Hg (p less than 0.001) and systemic vascular resistance decreased from 1,999 to 1,471 dynes cm-5 (p less than 0.05). Heart rate and blood pressure did not change significantly. Similar changes were observed with oral CI-930. Peak CI-930 plasma concentration occurred 1.2 +/- 0.8 hours after oral administration. Beneficial hemodynamic effects were sustained 12 to 18 hours after the oral dose. The sustained hemodynamic effects observed after oral administration appear to be related to an active metabolite of CI-930 that has prolonged duration of action and slow washout. The drug was well tolerated and has potential for treatment of congestive heart failure.

Hemodynamic response after intravenous and oral administration of a new phosphodiesterase inhibitor, CI-914, was studied in 13 patients with severe congestive heart failure. Comparable significant increases in cardiac index of 26% (p less than 0.01) and 19% (p less than 0.02) after intravenous and oral administration were observed. Systemic vascular resistance, right atrial and pulmonary artery wedge pressure decreased significantly after intravenous drug administration. Although similar changes occurred after oral administration, they were not statistically significant. Peak CI-914 plasma concentration occurred 2.3 +/- 2.2 hours after oral drug administration and exhibited measurable hemodynamic effects for up to 10 to 12 hours. Seven of the 13 patients received long-term oral CI-914 for as long as 12 weeks and exhibited an improvement in New York Heart Association functional class and exercise capacity. Five patients died with progressive heart failure, 1 patient died suddenly and 1 died of sepsis. The drug was well tolerated and appears to have potential as a cardiotonic agent.