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Biomedical subjects

J N Cohn

Publications and source records attributed to J N Cohn.

At least 217 records · Page 12Linked to original sources
PubMed1987

Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure: influence of prerandomization variables on the reduction of mortality by treatment with hydralazine and isosorbide dinitrate.

The Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure was designed to determine whether vasodilator drugs could alter the survival of patients with chronic congestive heart failure treated with digoxin and diuretics. Among the 642 patients entered into the study, 273 were randomly assigned to placebo, 186 were randomly assigned to the combination of hydralazine and isosorbide dinitrate, and 183 patients were randomly assigned to prazosin; all patients were followed for periods ranging from 6 months to 5.7 years. Treatment with hydralazine-nitrate produced a 28% reduction in mortality compared with that in patients receiving placebo (95% confidence interval, 3% to 46%), whereas prazosin exerted no apparent beneficial effect. Data were further examined to determine if any baseline variables had an impact on the response to treatment. Mortality in the placebo group was higher in those with coronary artery disease, with a history of antiarrhythmic drug use, and with values lower than the median for ejection fraction and exercise tolerance. A reduction in mortality with hydralazine-isosorbide dinitrate was observed in all of the above pairs of subgroups as well as in those above and below 60 years of age and those with and without a history of hypertension or excess alcohol ingestion. The benefit of hydralazine and isosorbide dinitrate was particularly prominent in younger patients with a lower ejection fraction and those with a history of hypertension and without an alcoholic history.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Beneficial effects of atrioventricular synchrony in dogs with right coronary artery embolization, and complete heart block.

Complete heart block complicating right ventricular infarction frequently is accompanied by shock. Hemodynamic responses to different pacing modes were studied in six anesthetized, closed chest dogs following right coronary artery embolization with mercury and heart block induced by repetitive trans-septal DC shock. Hemodynamics were recorded at control, following right coronary artery embolization, during atrioventricular sequential pacing (DVI) and ventricular pacing (VVI). With respect to the hemodynamics recorded during VVI and DVI pacing; (1) The mean arterial pressure increased by 29.4% during DVI pacing (92.1 +/- 31.3 mm Hg vs 73.4 +/- 28.9 mm Hg p less than 0.005). This increase was primarily due to an augmentation in systolic arterial pressure. (2) The left ventricular end diastolic pressure increased by 35.8% during DVI pacing (16.3 +/- 5.3 mm Hg vs 12.0 +/- 4.3 mm Hg p less than 0.01). (3) Cardiac output improved by 33.8% during DVI pacing (2.34 +/- 0.75 L/min vs 1.76 +/- 0.59 L/min, p less than 0.0005). This was a consistent improvement in cardiac output with a narrow range of 27.1% to 39.0%. (4) There were no significant changes in right atrial, pulmonary, pulmonary capillary wedge pressures or in systemic vascular resistance. In dogs with right coronary artery occlusion and complete heart block DVI pacing is clearly superior to VVI pacing. This is probably because the atrial contribution to ventricular filling, in this model, is critically important to maintain an adequate cardiac output.

Animals↗
PubMed1987

Hemodynamic and regional blood flow response to piroximone (MDL 19,205) in dogs with congestive heart failure: a comparison with dobutamine.

This study compares the effects of piroximone (MDL 19,205), a new inotropic agent, with dobutamine in dogs with congestive heart failure. With dobutamine, (15 micrograms/kg/min) left ventricular (LV) dp/dt increased from 2220 +/- 215 (mean +/- S.E.M.) to 2815 +/- 280 mm Hg/sec and cardiac index increased from 2.9 +/- 0.2 to 3.7 +/- 0.4 liters/min/m2, whereas LV filling pressure was essentially unchanged (18.7 +/- 2.6-16.3 +/- 2.4 mm Hg). The hemodynamic effects of piroximone (50 micrograms/kg/min) were more pronounced. LV dp/dt increased from 2615 +/- 260 to 3760 +/- 410 mm Hg/sec and cardiac index from 3.0 +/- 0.1 to 4.4 +/- 0.6 liters/min/m2, whereas LV filling pressure decreased from 15.6 +/- 2.4 to 6.4 +/- 1.8 mm Hg (all P less than .05). Systemic vascular resistance index decreased from 2730 +/- 225 to 1905 +/- 256 dynes sec cm-5 m-2. Regional blood flow to the myocardium increased 48% with dobutamine and 24% with piroximone, whereas skeletal muscle flow increased 59% with dobutamine and 36% with piroximone. Renal blood flow remained unchanged with either drug. We conclude that piroximone is an inotropic agent with vasodilator properties that has an interesting hemodynamic profile somewhat similar to that of dobutamine but with the advantage of being orally active; therefore piroximone could be useful in the treatment of heart failure.

Animals↗
PubMed1987

Safety of graded symptom-limited exercise testing in patients with congestive heart failure.

The safety and end points of graded symptom-limited bicycle exercise were assessed in 607 patients before they were randomized to vasodilator or placebo in the Veterans Administration Cooperative Study-Vasodilator Heart Failure Trial. Their mean age was 58 years and left ventricular ejection fraction averaged 30%. The peak exercise responses were as follows: oxygen consumption, 14.5 +/- 3.9 ml/kg/min; heart rate, 132 +/- 24 beats/min; systolic blood pressure, 154 +/- 29 mm Hg. No major complications occurred with the baseline tests. The initial baseline test was stopped in only 10 patients (1.6%) for arrhythmias and in one patient for hypotension. Ventricular tachycardia assessed by ambulatory electrocardiographic monitoring during the second exercise test (before exercise, during exercise, and 4 hr after the test) revealed a prevalence of 5.7% during exercise and 28.8% during the rest of the monitoring period. This study has demonstrated that stable male patients with congestive heart failure can safely exercise on a bicycle ergometer to their peak effort in a well-supervised setting. In addition, we have demonstrated that ambulatory electrocardiographic monitoring is a better method than exercise testing to evaluate presence and extent of ventricular arrhythmias in patients with congestive heart failure.

Adolescent↗
PubMed1986

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↗
PubMed1986

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↗
PubMed1986

Calcium antagonists and left ventricular function: effects of nitrendipine in congestive heart failure.

Calcium antagonists can affect the arterial vasculature, the venous capacitance vessels and the myocardium. The net effect of these agents on left ventricular (LV) performance depends on the interaction of effects on these 3 vascular components, and the state of LV function at the time that the drugs are administered. A calcium antagonist with profound arterial vasodilator effect might favorably influence LV performance even if it had negative inotropic properties. To demonstrate the direct effect of nitrendipine, a 1,4 dihydropyridine, on LV performance, the acute hemodynamic response to oral nitrendipine was studied in 8 patients with congestive heart failure. Administration of 10 to 20 mg of nitrendipine reduced preload, caused a decrease in both pulmonary wedge pressure and systemic vascular resistance, produced a modest decrease in blood pressure and an increase in stroke volume. In addition, plasma norepinephrine levels were significantly decreased. Plasma renin activity also tended to decrease. These data confirm that the drug can favorably alter performance of the failing left ventricle and further suggest that the vasodilator effect is not accompanied by reflex neurohumoral stimulation.

Adrenergic beta-Antagonists↗
PubMed1986

Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.

To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.

Clinical Trials as Topic↗
PubMed1986

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↗
PubMed1986

ZK 36-374, a stable analog of prostacyclin, prevents acute hypoxic pulmonary hypertension in the dog.

Vasodilator therapy in pulmonary hypertension is limited by the lack of an agent selective for the pulmonary circulation. The effects of intravenous prostacyclin and two stable prostaglandin analogs, ZK 36-374 and CL 115,347, were assessed on the preconstricted pulmonary vasculature of the anesthetized dog. During hypoxic vasoconstriction ZK 36-374 (0.4 micrograms/kg per min) markedly reduced pulmonary artery pressure (26 +/- 3 to 13 +/- 1 mm Hg) (p less than 0.05) and pulmonary vascular resistance (6.2 +/- 1.1 to 2.8 +/- 0.2 mm Hg/liter per min) (p less than 0.01). There was no significant effect on cardiac output, aortic pressure or arterial blood gases. Pulmonary vasoconstriction induced by prostaglandin F2 alpha was similarly affected by ZK 36-374, and in this instance the aortic pressure was also reduced (158 +/- 11 to 129 +/- 11 mm Hg) (p less than 0.01). ZK 36-374 (0.2 micrograms/kg per min) was more effective in lowering hypoxic pulmonary vascular resistance (from 6.5 +/- 0.6 to 3.0 +/- 0.3 mm Hg/liter per min) than was prostacyclin (0.75 micrograms/kg per min) (from 6.3 +/- 0.6 to 4.2 +/- 0.4 mm Hg/liter per min) (p less than 0.05) and resulted in a smaller fall in aortic pressure (p less than 0.05). CL 115,347 (1.0 micrograms/kg per min) had no effect on the pulmonary vasculature during normoxia or when preconstricted by prostaglandin F2 alpha or hypoxia, but reduced aortic pressure and total systemic resistance (p less than 0.05). It appears to be a selective systemic vasodilator with no pulmonary vascular activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Hemodynamic effects of infused arginine vasopressin in congestive heart failure.

The hemodynamic effects of exogenously administered arginine vasopressin were assessed in 11 patients with chronic congestive heart failure. Infusion rates of 0.1 to 0.8 pmol/kg per min increased plasma arginine vasopressin from 6.5 +/- 2.7 (SD) pg/ml at control to 63 +/- 39 pg/ml at the highest infusion rate. There were progressive decreases in cardiac output and stroke volume, with increases in systemic vascular resistance and pulmonary capillary wedge pressure, but only minimal changes in heart rate and blood pressure. Changes in cardiac output, stroke volume and systemic resistance were evident from the first infusion rate, which increased plasma arginine vasopressin from 6.5 +/- 2.7 to 9.9 +/- 4.6 pg/ml. A paired analysis of baseline hemodynamic data with those measured during infusions producing an arginine vasopressin level averaging 15 +/- 2.6 pg/ml yielded the following changes: cardiac output decreased from 4.6 +/- 1.2 to 4.2 +/- 0.96 liters/min (p less than 0.01), stroke volume decreased from 60 +/- 19 to 54 +/- 16 ml (p less than 0.005) and systemic vascular resistance increased from 1,329 +/- 396 to 1,443 +/- 395 dynes X s X cm-5 (p = 0.01). Thus, small increases in circulating arginine vasopressin cause modest but significant adverse circulatory effects in patients with congestive heart failure. A fall in cardiac output, probably as a result of increased afterload, is seen at levels of arginine vasopressin within the basal range found in congestive heart failure. These data demonstrate that circulating arginine vasopressin in physiologic concentrations is capable of influencing hemodynamics in patients with congestive heart failure and suggest that therapy for this condition directed at inhibition of the vascular effect of arginine vasopressin may be potentially useful.

Adult↗
PubMed1986

Transdermal nitroglycerin as a step 3 antihypertensive drug.

The antihypertensive effect of transdermal nitroglycerin was tested in 11 men with hypertension (mean age 60 years) whose diastolic blood pressure exceeded 90 mm Hg while receiving a diuretic and a beta-adrenergic blocker. In a double-blind, randomized crossover trial the subjects received weekly increments of placebo or nitroglycerin (5, 10, 20, and 30 cm2) for 4 weeks each. The final dose of nitroglycerin was 22.5 cm2 (mean). During week 4 of nitroglycerin dosing, sitting and standing systolic blood pressures were reduced (P less than 0.05). Diastolic blood pressures and heart rates did not change during the study. In the five subjects with systolic hypertension (greater than or equal to 150 mm Hg), the mean reduction in systolic blood pressure was 24 mm Hg (P less than 0.01). Further studies are needed to determine if transdermal nitroglycerin has a role in the treatment of systolic hypertension.

Administration, Topical↗
PubMed1986

Nervous system control mechanisms in heart failure.

Alterations in the peripheral circulation by influencing aortic impedance and venous capacitance have a remarkable effect on cardiac performance in patients with left ventricular dysfunction. Systemic vasoconstriction in heart failure is influenced by activation of the sympathetic nervous system (increased plasma norepinephrine), the renin-angiotensin system (increased PRA) and the antidiuretic hormone system (increased arginine vasopressin). The level of plasma norepinephrine is related weakly to the severity of resting left ventricular dysfunction and strongly to the subsequent risk of mortality. Attenuation of reflex responsiveness to low pressure mechanoreceptors (orthostatic tilt) and to carotid and aortic baroreceptors (nitroprusside infusion) occurs in heart failure and the degree of abnormality also may be related to mortality. Vasodilation with consequent improvement in left ventricular function may be accomplished by non-specific dilators (nitroprusside, nitrates, hydralazine, nitrendipine) or by specific interference with neurohumoral mechanisms (sympathetic blockade, converting enzyme blockade, AVP blockade). Plasma norepinephrine may be reduced by central or presynaptic mechanisms (guanabenz, bromocriptine, captopril). The hemodynamic effect of this anti-sympathetic effect appears to be related to the relative influence on cardiac vs. peripheral sympathetic tone and/or concomitant effects of the drugs. Long-term trials are needed to determine whether chronic inhibition of the sympathetic nervous system will have a salutary effect on the hemodynamics, symptomatology and prognosis of cardiac failure.

Catecholamines↗
PubMed1986

Vasodilator therapy of dilated cardiomyopathy.

Vasoconstriction increases impedance to ventricular ejection and impairs the performance of the dilated myopathic heart. Vasodilator drug therapy by reducing vascular resistance, increasing vascular compliance and increasing vascular capacitance improves cardiac function and relieves the signs and symptoms of congestive heart failure. Earlier intervention in an attempt to alter the natural history of cardiomyopathy should be studied.

Blood Pressure↗
PubMed1986

The autonomic nervous system in congestive heart failure.

Congestive heart failure is a complex clinical syndrome characterized by striking abnormalities of the autonomic nervous system. The mechanisms and biological importance of these disturbances are not clearly defined. Nonetheless, it is possible that autonomic disturbances play an important role in the pathophysiology and prognosis of heart failure, and therefore drugs that alter autonomic function may provide additional therapeutic options in the management of this syndrome.

Adrenergic beta-Antagonists↗
PubMed1986

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↗