Cardiac and regional vascular effects of atrial natriuretic peptide in awake dogs with left ventricular dysfunction.
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Animals↗
Biomedical subjects
J N Cohn
Publications and source records attributed to J N Cohn.
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↗
Norepinephrine infusions in congestive heart failure.
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Heart Failure↗
The nuclear stethoscope.
Eighty consecutive patients undergoing radionuclide gamma camera studies for the measurement of ejection fraction were also examined with the nuclear stethoscope. Overall, the correlation coefficient relating these two techniques was acceptable (r = 0.85). However, two groups were identified: patients with symmetrical wall motion had an excellent correlation (r = 0.90) while patients with regional wall motion abnormalities had a poor correlation (r = 0.78). In conclusion, the nuclear stethoscope is a clinically useful device for monitoring left ventricular function in patients with symmetrical wall motion.
Heart Ventricles↗
Nitrates for congestive heart failure.
The use of nitrates in various sublingual, oral, topical and intravenous forms of treatment of patients with congestive heart failure (CHF) is based on their efficacy in dilating capacitance vessels and reducing elevated ventricular diastolic pressure on both the left and right sides of the heart. Their modest arteriolar and arterial dilating effect may also decrease aortic impedance and produce a slight increase in stroke volume despite the reduction in preload. This favorable hemodynamic response requires relatively large doses of the nitrates but these doses are remarkably well tolerated in the majority of patients with CHF. In chronic CHF there has been evidence from small controlled trials of clinical efficacy (increased exercise tolerance and reduction in symptomatology) as well as hemodynamic efficacy. The combination of nitrates with a more potent arteriolar dilator such as hydralazine or minoxidil has produced a more striking acute hemodynamic benefit. Long-term response to such combined therapy is currently the subject of a Veterans Administration cooperative study. The current recommended approach to nitrate therapy in patients with CHF is to use the dosage necessary to normalize ventricular filling pressure. This can be best assessed in the clinic by monitoring jugular venous pressure. This response often requires dosages of isosorbide dinitrate of 160 to 320 mg daily. Transdermal preparations of nitroglycerin may give more constant blood levels but a large dosage is usually required to produce a sustained hemodynamic effect (40 to 80 cm2).(ABSTRACT TRUNCATED AT 250 WORDS)
Drug Therapy, Combination↗
Clinical implications of the hemodynamic effects of beta blockade.
Beta-adrenoceptor blockade produces a well-established constellation of hemodynamic effects at rest and during exercise. The beneficial clinical response in patients with hypertension and angina pectoris relates directly to these hemodynamic effects. A number of molecular modifications have accomplished more selective or additional circulatory effects designed to improve the efficacy and reduce the adverse effects of these drugs. In considering further clinical application of these agents, new data relating to the role of the sympathetic nervous system in the response to exercise, in the control of heart rate and in the progression of the syndrome of heart failure must be considered.
Adrenergic beta-Antagonists↗
Vascular hemodynamic impedance in congestive heart failure.
The objective of this study was to determine whether pulse-contour analysis could provide a measure of the differences in peripheral vascular state between patients with congestive heart failure (CHF) and healthy persons. Vascular hemodynamic impedance parameters were determined from brachial artery pressure waveforms recorded in 14 patients with CHF, aged 20 to 55 years (mean 36 +/- 12) and in 7 healthy control subjects, aged 22 to 55 years (mean 33 +/- 12). Cardiac output, heart sounds and electrocardiogram were also monitored. Cardiac output was 32% lower (p less than 0.01) and heart rate was 43% higher (p less than 0.001) in the CHF group than in the control group. The mean arterial pressure did not differ between groups. Systemic vascular resistance was 47% higher (p less than 0.05) and distal vascular compliance 73% lower (p less than 0.001) in the CHF group than in control group. Proximal vascular compliance was unchanged. These studies suggest that distal compliance assessed from pulse-contour analysis is a more sensitive and specific index than systemic vascular resistance to the vascular changes in CHF.
Adult↗
New concepts in the mechanisms and treatment of congestive heart failure. Introduction.
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Heart↗
Reduced atrial natriuretic factor after ligation of the left coronary artery in rats.
The diuretic-natriuretic responses of eight assay rats to extracts of atrial tissue obtained 3 months after left coronary ligation were less than the responses to extracts of tissue from sham-operated controls. The mean difference in diuresis (sham-operated response minus ligated response) was 370 (range 22 to 656) microliter/20 minutes (p less than 0.01) and in natriuresis 56 (range -92 to 222) microEq/20 minutes (p = 0.19). The differences in diuretic responses to these extracts was directly related to the severity of elevation of left ventricular end-diastolic pressure in these rats (r = -0.82, p = 0.01). These results in a model with varying degrees of left ventricular dysfunction suggest that myocardial damage is associated with a chronic decrease in atrial natriuretic factor. Reduced circulating atrial natriuretic factor therefore could contribute to the previously observed impaired ability of coronary ligated rats to excrete a saline load and to the sodium retention observed in clinical heart failure. Conclusive evidence will depend on the development of techniques to measure plasma levels of this hormone.
Animals↗
M-mode and two-dimensional echocardiographic analysis of the septum in experimental right ventricular infarction: correlation with hemodynamic alterations.
We investigated the changes that occur in the shape and the motion of the ventricular septum in experimental right ventricular (RV) infarction with M-mode and two-dimensional echocardiography. The echocardiographic findings were correlated with the hemodynamic alterations. Right ventricular infarction was produced by mercury embolization of the right coronary artery in five anesthetized closed-chest dogs. After embolization, the transseptal end-diastolic left-right ventricular pressure gradient reversed (3 +/- 1) to -1 +/- 1 mm Hg, p less than 0.001). The septal shape was altered by the flattening of the septum at end-diastole and a return to the normal septal shape during systole. Systolic septal motion was reversed after embolization (1 mm toward the left ventricle before embolization to 3 mm toward the RV after embolization, p less than 0.01). Septal thickening was not altered. We concluded that isolated RV free wall infarction results in the reversal of the transseptal end-diastolic pressure gradient and is associated with the flattening of the septum at end-diastole. During systole, the septum returns to its normal shape and moves toward the RV. In addition, systolic septal thickening is preserved. The motion of the septum toward the RV, together with normal septal thickening, may provide mechanical assistance to RV ejection with RV free wall infarction.
Animals↗
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↗
Relative attenuation of sympathetic drive during exercise in patients with congestive heart failure.
Patients with congestive heart failure have been considered to have augmented sympathetic drive both at rest and during dynamic exercise. The augmentation observed during exercise may be related to the state of near exhaustion experienced by patients with heart failure at relatively low work loads. To compare the response of the sympathetic nervous system to exercise in normal subjects and patients with heart failure when they are working in a comparable physiologic frame of reference, the data for both groups can be expressed as percent peak oxygen consumption achieved (percent peak VO2) rather than as a function of absolute oxygen consumption (VO2). Ten healthy control subjects and 31 patients with chronic clinical class II and III heart failure were studied during upright maximal bicycle exercise. Eighteen of the 31 patients had primary cardiomyopathy and 13 had ischemic cardiomyopathy. The average ejection fraction at rest was 24 +/- 10% (+/- SD) in the group with heart failure. Heart rate, systolic blood pressure, VO2 and plasma norepinephrine levels were measured at rest and throughout exercise. When the data were expressed as a function of percent peak VO2 achieved, patients with heart failure demonstrated a flatter slope (p = 0.004) than normal in the response of plasma norepinephrine to exercise, indicating a relative blunting of sympathetic drive. This was accompanied by attenuated heart rate (p = 0.001) and blood pressure (p less than 0.001) responses. These differences were not apparent when the data are expressed as a function of absolute VO2.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Reflex control of osmotically stimulated vasopressin in normal humans.
Previous studies have shown that in normal humans plasma arginine vasopressin (AVP) does not increase in response to unloading of cardiopulmonary and sinoaortic baroreceptors produced by lower body negative pressure (LBNP) unless hypotension occurs. To assess whether prior osmotic stimulation of AVP might bring out latent sensitivity to nonosmotic control mechanisms in humans we studied the response of plasma AVP to graded LBNP after a 105-min infusion of 5% saline in a group of eight normal individuals. During the infusion and before LBNP, serum osmolality increased from 288 +/- 9 to 300 +/- 10 mosmol/kg, and plasma AVP increased from 4.4 +/- 1.7 to 8.0 +/- 2.5 pg/ml. Neither osmolality nor AVP changed significantly during two stages of LBNP that first reduced central venous pressure alone and then reduced central venous pressure with accompanying tachycardia and narrowing of the pulse pressure. Time control studies performed in five individuals subjected to central venous catheterization and an identical hypertonic saline infusion failed to show significant spontaneous changes in AVP during a comparable interval after the infusions but without LBNP. Thus osmotic stimulation with hypertonic saline did not render AVP more sensitive to nonhypotensive unloading of cardiopulmonary and sinoaortic baroreceptors in normal humans.
Arginine Vasopressin↗
Effect of head-down tilt on basal plasma norepinephrine and renin activity in humans.
The effects of loading cardiopulmonary baroreceptors on basal norepinephrine and renin activity were studied in six normal subjects. Loading of cardiopulmonary baroreceptors was accomplished by a 60-min 30 degrees head-down tilt with small supplemental saline infusions. Central venous pressure was measured continuously by intrathoracic catheter; arterial pressure was measured indirectly by cuff. During the tilt, central venous pressure increased from 5.1 +/- 1.3 to 8.9 +/- 1.7 mmHg (P less than 0.001), whereas arterial pressure was unchanged. Plasma norepinephrine (185 +/- 85 pg/ml) and plasma renin activity (3.9 +/- 5.7 ng . ml-1 . h-1) did not change. Moderate sustained loading of cardiopulmonary baroreceptors is therefore without effect on unstressed plasma norepinephrine and renin activity in normal humans, suggesting that the tonic inhibitory effects of these receptors on these neurohumoral control systems are not readily increased in the basal state.
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↗
Ventricular myocardial catecholamines in primates.
We report myocardial catecholamine levels in primate ventricles assayed by high-pressure liquid chromatography with electrochemical detection. The norepinephrine content of the left ventricles of 11 monkeys (four rhesus and seven cynomolgus) was 1391 +/- 362 ng/gm (+/-SD) with a definite gradient from base (highest) to apex (lowest concentration). Dopamine and epinephrine were present in much lower concentrations (51.8 +/- 24.5 ng/gm and 59.2 +/- 20.0 ng/gm, respectively), but were similarly distributed throughout the left ventricle. There was considerable variation in norepinephrine concentration between animals, but the dopamine/norepinephrine ratio was very consistent within a given animal, averaging 3.7% +/- 1.4%. These values are probably indicative of what normal concentrations of catecholamines are likely to be in humans, and provide a basis for interpretation of results obtained in disease studies.
Animals↗
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↗
Unloading the heart in congestive heart failure.
Depressed contractile performance of the heart in congestive heart failure is aggravated by increases in preload and afterload related in part to arterial and venous constriction. Vasodilator drugs have a salutary effect on left ventricular performance by reducing aortic impedance and/or increasing venous capacitance resulting in an increase in stroke volume and a lowering of filling pressure. Vasodilators may act by counteracting the heightened neurohumoral vasoconstriction tone in heart failure (inhibition of the sympathetic nervous system, inhibition of the renin-angiotensin system) or by more directly affecting vascular smooth muscle tone (direct vasodilators, calcium antagonists). The immediate effects of these drugs on resting hemodynamics must be supplemented by knowledge of their effects on the circulatory response to exercise and of their efficacy during long-term administration before a rational choice can be made as to the ideal agent or combination of agents to use in the long-term management of congestive heart failure.
Calcium↗