Hemodynamic consequences of prostaglandin E2 activation of the renin-angiotensin system in heart failure.
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Dinoprostone↗
Biomedical subjects
T B Levine
Publications and source records attributed to T B Levine.
Normalization of sympathetic nervous system function after orthotopic cardiac transplant in man.
Plasma norepinephrine (PNE) levels are significantly elevated in patients with endstage congestive heart failure. To assess whether this abnormality is reversible, 32 patients were studied before and 3 to 9 months after orthotopic cardiac transplantation. PNE decreased after the transplant procedure form 739 +/- 363 to 301 +/- 161 pg/ml (p less than .05). In 13 patients, PNE was measured sequentially during the first 3 months after the transplant procedure. PNE decreased from 590 +/- 293 to 321 +/- 208 pg/ml at 2 weeks and remained stable at 1 month (308 +/- 239 pg/ml), 2 months (307 +/- 196 pg/ml), and 3 months (331 +/- 131 pg/ml), even while arterial hypertension developed. No correlation was found between PNE, systolic, diastolic, or mean arterial pressure and cyclosporine A blood levels. These data demonstrate that normalization of plasma levels of norepinephrine occurs shortly after cardiac transplantation in man. This decrease in PNE is probably independent of immunosuppression therapy. Finally, the development of arterial hypertension in cyclosporine A-treated cardiac transplant patients is not due to activation or persistent activation of the sympathetic nervous system.
Adult↗
Effects of orthotopic heart transplantation on sympathetic control mechanisms in congestive heart failure.
Abnormal sympathetic nervous system activity in severe congestive heart failure (CHF) was studied in 14 patients before and 3 to 6 months after orthotopic heart transplantation. Before transplantation plasma norepinephrine (NE) levels at rest were elevated (909 +/- 429 pg/ml, p less than 0.01 compared with normal, 185 +/- 60 pg/ml). No reflex activation of the sympathetic nervous system was seen with infusion of sodium nitroprusside despite a significant decrease in arterial pressure. The response to orthostatic tilt also was blunted in the patients before transplantation. Exercise capacity was reduced in these patients and plasma NE increased promptly at low exercise loads. After cardiac transplantation plasma NE levels returned to normal (319 +/- 188 pg/ml) and the sympathetic response to the stresses of orthostatic tilt (320 +/- 196 to 419 +/- 197, p less than 0.002) and nitroprusside infusion (255 +/- 94 to 555 +/- 130, p less than 0.001) normalized within 6 months after transplantation. Exercise capacity increased and the increase in plasma NE levels at various exercise loads was reduced for any given workload. Therefore, abnormal adrenergic activity in patients with severe CHF results mostly from the reduction in left ventricular pump function and is reversible if adequate pump function is restored.
Adult↗
Angiotensin converting enzyme inhibitors in congestive heart failure. Overview in comparison of captopril and enalapril.
In this study, the use of enalapril and captopril is compared in the treatment of congestive heart failure. Although both drugs act on the renin-angiotensin system via converting enzyme inhibition, their different chemical structures may dispose them to different pharmacologic and physiologic activity. Both drugs exert a vasodilator effect, with reduction of left and right ventricular filling pressures and aortic impedance. In short-term hemodynamic studies, the onset of action and peak effect are earlier with captopril. Enalapril has a much more gradual onset and longer duration of action. Both drugs have a shallow dose-response curve and both produce comparable hormonal changes: an increase in plasma renin activity and a decrease in aldosterone levels. Captopril also increases prostaglandin production. Long-term efficacy trials have demonstrated symptomatic improvement in patients given captopril and those receiving enalapril who were also receiving digitalis and diuretics. Baseline hemodynamics may not predict long-term improvement. There are few adverse effects for the two drugs, but their incidences differ, suggesting a relationship to chemical structure. Recent studies in congestive heart failure suggest a reduction in mortality with various drug regimens.
Aldosterone↗
Coronary artery spasm in a denervated orthotopic transplanted human heart.
A case of catheter-induced spasm in a 40-year-old male one year after orthotopic cardiac transplantation is presented. The fact that spasm can occur in this setting of total cardiac denervation demonstrates that other factors can play an important part in modifying the status of coronary artery patency.
Adult↗
Dissociation of the responses of the renin-angiotensin system and sympathetic nervous system to a vasodilator stimulus in congestive heart failure.
The ability of neurohumoral reflex control mechanisms to respond to a vasodilator mediated alteration in hemodynamic status was studied. A sodium nitroprusside infusion was administered to 5 normal subjects and 47 patients with severe congestive heart failure resulting in significant decreases in mean arterial pressure and in systemic vascular resistance. As expected in normals the vasodilator stimulus caused a reflex activation in both the renin-angiotensin system and sympathetic nervous system as measured by increased plasma renin activity and plasma norepinephrine, respectively. In the patients with heart failure, plasma renin activity rose similarly in response to nitroprusside (+63% in heart failure, 100% in normals, P = NS) while plasma norepinephrine remained essentially unchanged (+11% in heart failure, 98% in normals, P less than 0.01). These data demonstrate that the neurohumoral dysfunction seen in patients with heart failure is not uniform. In patients with severe congestive heart failure the renin-angiotensin system apparently is activated by mechanisms other than sympathetic nervous stimulation. This intact reflex humoral response may still function in opposition to the beneficial hemodynamic effects produced by direct vasodilators such as nitroprusside.
Adult↗
Evidence for a direct renal stimulating effect of prostaglandin E2 on renin release in patients with congestive heart failure.
The reduced responsiveness of the renin-angiotensin system to hemodynamic changes in patients with congestive heart failure (CHF) could be due to a defect of the juxtaglomerular apparatus. To test this hypothesis, the responses to viprostol, an analog of prostaglandin E2 (PGE2) that is known to stimulate both the macula densa and the juxtaglomerular cells, and to nitroprusside were compared in patients with CHF. An average fall in mean arterial pressure (MAP) of 6 mm Hg with viprostol was associated with a fivefold increase in plasma renin activity (PRA) from 11.4 +/- 6.4 to 47.9 +/- 31.0 ng/ml/hr; in contrast PRA did not change with nitroprusside, despite a significant decrease in preload and an average decrease in MAP of 16 mm Hg. These data demonstrate that the renin-angiotensin system could be activated by PGE2 in patients with CHF, this activation is not related to the global hemodynamic changes induced by PGE2, and the previously reported unresponsiveness of the renin-angiotensin system in patients with CHF cannot be attributed to a defective response of the juxtaglomerular apparatus.
Adult↗
Persistent hemodynamic effects without long-term clinical benefits in response to oral piroximone (MDL 19,205) in patients with congestive heart failure.
Piroximone (MDL 19,205), a new phosphodiesterase inhibitor with positive inotropic and vasodilating properties, was administered orally to 12 patients with severe congestive heart failure (NYHA class III to IV). After a mean dose of 1.7 +/- 0.4 (SD) mg/kg, cardiac index increased from 2.0 +/- 0.5 to 3.0 +/- 0.6 liters/min/m2 while pulmonary wedge pressure decreased from 23 +/- 6 to 15.6 +/- 7 mm Hg and systemic vascular resistance from 1520 +/- 370 to 1000 +/- 320 dyne-sec-cm-5. Mean arterial pressure was slightly reduced from 80 +/- 13 to 75 +/- 11 mm Hg and forearm blood flow increased by 79% (all p less than .01). Eleven patients were selected for long-term treatment. Two patients received a heart transplant soon after the treatment was started. The remaining nine patients were followed for a mean of 5.6 months (range 2 to 10). Severe congestive heart failure recurred in eight of these nine patients, resulting in the death of three patients within 4 months. The remaining six patients underwent repeat hemodynamic evaluation 2 months after the initiation of the treatment. A short-term hemodynamic response to the drug in this group demonstrated that piroximone retains its circulatory effect during continuous therapy. Nevertheless, three more patients of this group died within 8 months and two required heart transplants. Of the nine patients receiving long-term treatment, only one had sustained subjective improvement and increased exercise capacity. Therefore long-term therapy with piroximone did not appear to benefit patients with severe congestive heart failure. A drug-related deterioration of their clinical status cannot be excluded.
Administration, Oral↗
Role of vasodilators in the treatment of congestive heart failure.
Appreciation of the important role played by peripheral vasoconstriction in the pathophysiology of congestive heart failure (CHF) has led to the widespread use of vasodilators as treatment. Short-term studies show that, regardless of the vasodilator used, the arterial and venous dilatation produced invariably results in improvement in the hemodynamic status of patients. This short-term response, however, does not automatically translate to long-term clinical improvement. The reasons for this are not well understood but such factors as differing mechanisms of action, development of tolerance and unique patterns of regional redistribution of blood flow may all play a modifying role in differentiating one vasodilator from another. Nevertheless, a number of controlled trials have demonstrated sustained symptomatic and functional improvement when vasodilators such as the converting enzyme inhibitors or nitrates are given to patients with CHF.
Captopril↗
A cooperative multicenter study of captopril in congestive heart failure: hemodynamic effects and long-term response.
The acute hemodynamic effects, long-term clinical efficacy, and safety of the oral angiotensin-converting enzyme inhibitor, captopril, were assessed in a multicenter cooperative study of 124 patients with heart failure resistant to digitalis and diuretics. The cardiac status of most patients was deteriorating prior to the study. Favorable acute hemodynamic effects consistently occurred with captopril. Maximal mean percentage increases in cardiac index, stroke index, and stroke work index were, respectively, 35%, 44%, and 34%. Systemic and pulmonary vascular resistances were each decreased by approximately 40%, as were the filling pressures of the right and left heart. Infusion of nitroprusside in some of the same patients to an end point of a pulmonary capillary wedge pressure of 12 to 18 mm Hg (equivalent to that after captopril) revealed no significant difference in the effect of either drug on the other hemodynamic parameters. Recatheterization after 8 weeks of captopril therapy revealed sustained hemodynamic changes. Significant and sustained improvements in clinical status were observed in most patients as measured by changes in New York Heart Association (NYHA) functional classification and exercise tolerance times. Seventy-nine percent of patients for whom there were adequate NYHA class data improved. Twenty percent remained unchanged and 1% deteriorated. Those patients who had both pretreatment and post-treatment exercise stress testing exhibited a highly significant mean increase in exercise tolerance times of 34% (317 +/- 32 seconds pretreatment to 425 +/- 34 seconds, final measurement). There was no evidence of tachyphylaxis over an 18-month period.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis.
Hemodynamic and neurohumoral responses to acute diuretic therapy were measured in 15 patients with severe chronic heart failure given intravenous furosemide, 1.3 +/- 0.6 (SD) mg/kg body weight. Left ventricular pump function deteriorated by 20 minutes, as indicated by a fall in stroke volume index (27 +/- 8 to 24 +/- 7 mL/min X m2 body surface area, p less than 0.01) and an increase in left ventricular filling pressure (28 +/- 7 to 33 +/- 9 mm Hg, p less than 0.01). Increases occurred in heart rate (87 +/- 13 to 91 +/- 16 beats/min, p less than 0.01), mean arterial pressure (90 +/- 15 to 96 +/- 15 mm Hg, p less than 0.01), systemic vascular resistance (1454 +/- 394 to 1676 +/- 415 dynes X s X cm-5, p less than 0.01), plasma renin activity (9.9 +/- 8.5 to 17.8 +/- 16 ng/mL X h, p less than 0.05), plasma norepinephrine level (667 +/- 390 to 839 +/- 368 pg/mL, p less than 0.01), and plasma arginine vasopressin level (6.2 +/- 1.3 to 8.3 +/- 2.0 pg/mL, p less than 0.01). During the next 3.5 hours the patients had diuresis (2085 +/- 1035 mL) and the expected fall in filling pressure (28 +/- 7 to 22 +/- 10 mm Hg, p less than 0.01). Neurohumoral indicators also returned toward the control levels. Intravenous furosemide, in patients with severe chronic heart failure, is associated with acute pump dysfunction temporally related to activation of the neurohumoral axis.
Adult↗
Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.
Hemodynamics, plasma norepinephrine, and plasma renin activity were measured at supine rest in 106 patients (83 men and 23 women) with moderate to severe congestive heart failure. During follow-up lasting 1 to 62 months, 60 patients died (57 per cent); 47 per cent of the deaths were sudden, and 45 per cent were related to progressive heart failure. Statistically unrelated to the risk of mortality were cause of disease (60 patients had coronary disease, and 46 had cardiomyopathy), age (mean, 54.8 years), cardiac index (mean, 2.11 liters per minute per square meter of body-surface area), pulmonary wedge pressure (mean, 24.5 mm Hg), and mean arterial pressure (mean, 83.2 mm Hg). A multivariate analysis of the five significant univariate prognosticators--heart rate (mean, 84.4 beats per minute), plasma renin activity (mean, 15.4 ng per milliliter per hour), plasma norepinephrine (mean, 700 pg per milliliter), serum sodium (mean, 135.7 mmol per liter), and stroke-work index (mean, 21.0 g-meters per square meter)--found only plasma norepinephrine to be independently (P = 0.002) related to the subsequent risk of mortality. Norepinephrine was also higher in patients who died from progressive heart failure than in those who died suddenly. These data suggest that a single resting venous blood sample showing the plasma norepinephrine concentration provides a better guide to prognosis than other commonly measured indexes of cardiac performance.
Age Factors↗
Hemodynamic and regional blood flow response to captopril in congestive heart failure.
In 19 patients with moderate to severe congestive heart failure the over-all hemodynamic response to captopril was compared with its effect on regional blood flow. Ninety minutes after administering a single dose of captopril (25 to 150 mg), right atrial pressure decreased from 6.1 +/- 6.1 to 3.2 +/- 5.1 mm Hg (p less than 0.001), pulmonary artery pressure from 33.1 +/- 8.3 to 26.5 +/- 9.1 mm Hg (p less than 0.001), pulmonary capillary wedge pressure from 22.4 +/- 6.2 to 15.2 +/- 7.4 mm Hg to (p less than 0.001), mean arterial pressure from 77.2 +/- 8.0 to 66.5 +/- 13.7 mm Hg (p less than 0.001), and systemic vascular resistance from 1,630 +/- 503 to 1,233 +/- 443 dyne-s-cm-5 (p less than 0.001), and cardiac index increased from 2.0 +/- 0.6 to 2.4 +/- 0.7 l/minute/m2 (p less than 0.001). Despite the significant increase in cardiac index there was no increase in either hepatic blood flow (203 +/- 212 to 142 +/- 101 units, N.S.) or forearm blood flow (2.2 +/- 0.9 to 2.2 +/- 1.0 ml/100 g per minute, N.S.) after captopril. Similarly, the global reduction in systemic vascular resistance was not accompanied by a reduction in either hepatic vascular resistance (0.93 +/- 0.90 to 0.83 +/- 0.69 units, N.S.) or forearm vascular resistance (41.3 +/- 18.4 to 34.9 +/- 12.4 mm Hg/ml/100 g per minute, N.S.). The over-all improvement in hemodynamics that is seen when captopril is given to patients with severe heart failure does not apply uniformally to all vascular beds. The heterogeneous response reflects the variable vasoconstrictor part played by the renin-angiotensin system in regulating flow to individual regional circulations.
Adult↗
Hemodynamic effects of a new inotropic agent, piroximone (MDL 19205), in patients with chronic heart failure.
The hemodynamic and neurohumoral effects of cummulative intravenous doses of piroximone (MDL 19205), a noncatecholamine, nonglycoside, imidazole derivative with positive inotropic and vasodilating properties, were studied in eight patients with severe congestive heart failure. A dose of 1.25 mg/kg in seven patients and 1.75 mg/kg in one patient increased cardiac index by 75% from 1.96 to 3.41 liters/min per m2 and decreased systemic vascular resistance (-41%), right atrial (-66%) and pulmonary wedge pressure (-35%) (all p less than 0.005). Mean arterial pressure was slightly reduced from 78 to 71 mm Hg (p less than 0.05) and forearm blood flow increased by 42%. Plasma norepinephrine decreased from 830 to 542 pg/ml (p less than 0.05) and plasma renin activity tended to increase. In four patients, dobutamine (15 micrograms/kg per min) produced a comparable increase in cardiac index (+100%), but less decrease in pulmonary wedge pressure (-21 versus -41%, p less than 0.05 versus piroximone) and, unlike piroximone, significantly increased heart rate (+22%, p less than 0.05 versus piroximone) and heart rate-blood pressure product (+30%, p less than 0.01 versus piroximone). In four other patients, a single intravenous dose of piroximone (1 mg/kg) resulted in a 35% increase in the first derivative of left ventricular pressure (dP/dt) from 796 to 1,068 mm Hg/s (p less than 0.01). Thus, piroximone is a potent inotropic agent with an acute hemodynamic profile that may be more favorable than that of dobutamine. Because the drug is orally absorbed, clinical trials of chronic efficacy are indicated.
Adult↗
Acute hemodynamic and hormonal response to indoramin in congestive heart failure.
Acute hemodynamic and hormonal responses to a single dose of indoramin, an alpha 1-antagonist, were evaluated in 11 subjects with severe chronic congestive heart failure. A hemodynamic effect began within 1 hr of indoramin and persisted during the 6 hr of hemodynamic monitoring. Decreased right and left ventricular filling pressures were associated with increased stroke index and decreased pulmonary and systemic vascular resistances. Heart rate did not increase despite a fall in systemic arterial pressure. Forearm blood flow, forearm venous capacitance, and plasma norepinephrine levels were unchanged, whereas plasma renin activity rose from 12.7 +/- 17.4 to 16.6 +/- 20.4 ng/ml/hr. The only side effect was drowsiness in five of the 11 subjects. Our data demonstrate the acute effectiveness of indoramin in reducing ventricular preload and systemic vascular resistance in heart failure.
Adult↗
Current concepts in the treatment of congestive heart failure.
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Calcium Channel Blockers↗
Hemodynamic and clinical response to enalapril, a long-acting converting-enzyme inhibitor, in patients with congestive heart failure.
Enalapril, a new oral angiotensin converting-enzyme inhibitor, was administered to nine patients with severe congestive heart failure. Short-term hemodynamic response was noted within 2 hr and persisted for up to 24 hr. At peak effect mean arterial pressure fell from 83.4 +/- 10(SD) to 72.1 +/- 16.2 mm Hg (p less than .01), right atrial pressure from 13.6 +/- 6.0 to 10.4 +/- 7.5 mm Hg (p less than .01), pulmonary arterial pressure from 38.9 +/- 4.8 to 31.9 +/- 4.8 mm Hg (p less than .01), pulmonary capillary wedge pressure from 28.2 +/- 3.5 to 22.1 +/- 5.1 mm Hg (p less than .01), and total pulmonary resistance from 875 +/- 304 to 697 +/- 291 dynes-sec-cm-5 (p less than .05). Cardiac index was not changed, but there was a significant redistribution of regional blood flow with an increase of renal blood flow after enalapril. Plasma renin activity rose significantly from 6.2 to 28.6 ng/ml/hr, whereas plasma norepinephrine did not change after enalapril. Seven patients were treated with enalapril for 4 weeks. Five patients reported symptomatic improvement. Five of six patients tested had an increase in both exercise time (NS) and maximum oxygen consumption (NS). Repeat hemodynamic evaluation in six patients after long-term enalapril therapy showed a persistent effect with significant reductions in right atrial pressure from 13.8 +/- 7.2 to 7.1 +/- 4.7 mm Hg and in mean arterial pressure from 82.5 +/- 10.4 to 76.6 +/- 5.3 mm Hg and a significant increase in cardiac index from 2.1 +/- 0.5 to 2.5 +/- 0.5 l/min/m2 (all p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Hemodynamic effects of nifedipine at rest and during exercise in primary pulmonary hypertension.
The potential short-term pulmonary vasodilator effect of a calcium-channel blocker, nifedipine, was tested in seven patients with primary pulmonary hypertension. Nifedipine (20 mg) produced a significant (p less than 0.01) and persistent decrease in mean pulmonary arterial pressure (58.1 +/- 14.3 to 48.6 +/- 16.3 mm Hg) and pulmonary vascular resistance (1,070 +/- 260 to 695 +/- 266 dynes X sec X cm-5). Cardiac index increased from 2.5 +/- 0.6 to 3.3 +/- 0.8 L/min/m2 (p less than 0.01), and heart rate was unchanged despite a fall in systemic pressure. In three patients tested during exercise on a bicycle, nifedipine resulted in an increase in the duration of exercise in two and a blunting of the exercise-induced increase in pulmonary pressure in all three. Long-term treatment was initiated in five of the seven patients and in two additional patients who did not receive nifedipine in the short-term study; all but one experienced symptomatic improvement. A persistent hemodynamic improvement was observed in three of the four patients restudied after long-term therapy. In conclusion, this study demonstrated the short-term beneficial hemodynamic effects of nifedipine, both at rest and during exercise. A more extensive long-term follow-up is necessary to establish the usefulness of this drug in the treatment of primary pulmonary hypertension.
Adolescent↗