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Biomedical subjects

J N Cohn

Publications and source records attributed to J N Cohn.

At least 181 records · Page 10Linked to original sources
PubMed1990

Heart failure: mechanisms of cardiac and vascular dysfunction and the rationale for pharmacologic intervention.

Congestive heart failure is a complex clinical syndrome that has its basis in an abnormality of myocardial cell function resulting in impaired ventricular performance, exercise intolerance, and ventricular arrhythmias. The functional defect in myocardial performance may be related to alterations in receptor function, in regulatory proteins, or in biochemical mechanisms. Remodeling of the left ventricle has been observed to play an important role in the natural course of heart failure. The complex interplay between cellular elongation, reactive hypertrophy, and the influence of the change from ellipsoid to spheroidal shape of the left ventricle after acute myocardial infarction are just beginning to be understood. Prevention of this remodeling effect by pharmacologic intervention is being widely explored, although the mechanisms are poorly defined. Impedance to left ventricular ejection is also an important determinant of cardiac performance in heart failure. Constriction of arteriolar resistance vessels and reduction in compliance of arterial conductance vessels is a common manifestation of heart failure and may be under the influence of neural, hormonal, endothelial, and local regulatory factors. Increased tone of venous capacitance vessels contributes to a shift of blood centrally and to an increase in ventricular preload. Vasodilator drugs by relaxing the arterial, arteriolar, and venous vasculature result in a reduction in impedance and left ventricular afterload and a decrease in cardiac filling pressure and preload. Structural changes of hypertrophy and remodeling apparently contribute to the changes in resistance, compliance, and capacitance in the vasculature. Treatment of heart failure is aimed at relieving symptoms and prolonging life. Interventions to improve left ventricular function are critical to symptom relief. Vasodilators have been most effective for this purpose, and new positive inotropic drugs are being tested for efficacy. Long-term benefit may require interference with the myocardial and peripheral vascular remodeling processes that lead to progressive depression of ventricular performance. New insights into the cellular and subcellular mechanisms of this progression are critical to the development of innovative therapeutic strategies.

Cardiovascular System↗
PubMed1990

Cardiovascular and neurohormonal effects of atrial natriuretic peptide in conscious dogs with and without chronic left ventricular dysfunction.

Atrial natriuretic peptide (hANP 4-28) was infused for 1 h (0.3 microgram/kg/min) in 11 normal awake dogs and seven awake dogs with chronic left ventricular dysfunction, induced 16 weeks earlier by repetitive DC shock. The responses were similar in the two groups and included decreases in arterial pressure (107-99 mm Hg), heart rate (83-72 beats/min), and cardiac output (3.6-2.8 L/min), without changes in right or left ventricular filling pressures. Systemic vascular resistance (SVR) tended to rise during the infusion and was significantly increased (2,847-3,442 dyn s cm-5, p less than .05) during the postinfusion recovery period. Regional blood flows (microspheres) during infusion revealed a decrease in skin and splanchnic flow. Despite the apparent vasoconstrictor effect, plasma norepinephrine (PNE), renin activity (PRA), and arginine vasopressin (AVP) levels all fell during ANP infusion. These data suggest that ANP exerts a cardioinhibitory effect, possibly similar to that of arginine vasopressin (AVP), and that the net systemic vasoconstrictor effect of ANP in these dogs is mediated by a complex interrelationship between direct vascular effects, neurohormonal inhibition, and central reflex activation.

Animals↗
PubMed1990

Atrial natriuretic factor attenuates sympathetic reflexes during lower body negative pressure in normal men.

To assess further the effects of atrial natriuretic factor on autonomic nervous system reflexes in normal humans, the hemodynamic and neurohormonal responses to lower body negative pressure were measured at control and during infusions of atrial natriuretic factor and nitroglycerin in nine normal male subjects. The control -20 mm Hg lower body negative pressure was characterized by significant reductions in right atrial and pulmonary wedge pressures, as well as stroke volume and cardiac output. This was associated with a reflex increase in forearm vascular resistance and plasma norepinephrine. During the infusion of atrial natriuretic factor, the same -20 mm Hg lower body negative pressure produced a larger decrease in mean arterial pressure of 7.9 +/- 3.9 mm Hg (p less than 0.05), as well as a larger decrease in stroke volume (41.3 +/- 4.2 ml/beat) and cardiac output (2.0 +/- 0.3 L/min). Atrial natriuretic factor infusion did not affect the increase in forearm vascular resistance during lower body negative pressure, but did attenuate the increase in plasma norepinephrine. To control for nonspecific vasodilator actions, lower body negative pressure was also repeated during nitroglycerin infusion. Nitroglycerin infusion did not significantly change the responses of blood pressure, cardiac output, stroke volume, forearm vascular resistance, or plasma norepinephrine during lower body negative pressure. Thus, these data demonstrate that atrial natriuretic factor infusion can attenuate sympathetic nervous system reflexes evoked during lower body negative pressure. These inhibitory effects on the sympathetic nervous system may contribute to many of the observed hemodynamic actions of atrial natriuretic factor.

Aged↗
PubMed1990

Abnormalities of peripheral sympathetic nervous system control in congestive heart failure.

The sympathetic nervous system (SNS) is activated in patients with heart failure. Hemodynamic and metabolic abnormalities probably serve as the afferent stimulus for this response. This chronic activation is accompanied by an attenuation of reflex responsiveness to unloading of the central baroreceptors and mechanoreceptors. Loss of the buffering capacity of these afferent receptors may contribute to the sustained SNS stimulation. The renin-angiotensin system is uncoupled from the SNS, probably because the intrarenal mechanisms subserving renin release are preserved. Chronic activation of the SNS may contribute to disturbed hemodynamics as well as to long-term structural changes that may influence the natural history of the syndrome. A relation between plasma norepinephrine and mortality raises the possibility of a direct adverse effect of SNS activation on survival. Therapeutic approaches to inhibit the SNS include agents that block receptors, enhance the response to baroreceptor loading, inhibit presynaptic norepinephrine release, or act centrally to inhibit sympathetic outflow. The benefit-to-risk ratio for each of these possible interventions needs to be assessed in controlled long-term trials.

Heart Failure↗
PubMed1990

Heart failure with normal ejection fraction. The V-HeFT Study. Veterans Administration Cooperative Study Group.

In patients with clinical heart failure entered into the Veterans Administration Cooperative Study (V-HeFT) trial, 83 of 623 who had a baseline radionuclide measurement of left ventricular ejection fraction exhibited an ejection fraction of at least 0.45. When compared with the patients with an ejection fraction of less than 0.45, these subjects with apparent predominant diastolic dysfunction had a lower incidence of coronary artery disease (26.5% vs. 47.2%, p less than 0.001) and a higher incidence of preexisting hypertension (53.0% vs. 39.4%, p less than 0.02). In the normal ejection fraction group, systolic blood pressure was higher (129.7 vs. 117.7 mm Hg, p = 0.0001), heart rate slower (75.0 vs. 83.2 beats/min, p = 0.0001), cardiothoracic ratio smaller (0.512 vs. 0.536, p = 0.002), echocardiographic left ventricular dimension smaller in diastole (61.7 vs. 69.2 mm, p = 0.0001) and in systole (47.4 vs. 58.1 mm, p = 0.0001), and posterior wall thickness greater (9.0 vs. 7.9 mm, p = 0.004). Exercise tolerance was only slightly better in the normal ejection fraction group (peak oxygen consumption, 15.5 vs. 14.6 ml/kg/min, p = 0.04). Prognosis in the normal ejection fraction patients (annual mortality rate, 8.0%) was significantly better than in the low ejection fraction group (annual mortality rate, 19.0%) (p = 0.0001). Ventricular tachycardia on Holter monitor was a poor prognostic sign in these patients, and severe reduction in exercise tolerance also tended to predict poor outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise Test↗
PubMed1989

Effect of dobutamine on plasma potassium in congestive heart failure secondary to idiopathic or ischemic cardiomyopathy.

Dobutamine was administered in a dose of 10 +/- 1 micrograms/kg/min to 13 patients with severe idiopathic or ischemic dilated cardiomyopathy. Acute hemodynamic improvement was noted in all patients. All patients had a significant decrease in plasma potassium (4.6 +/- 0.1 to 4.2 +/- 0.2 mEq/liter, p less than 0.0001) at peak infusion. The decrease in potassium persisted for at least 45 minutes after discontinuing the infusion. Three patients had exacerbation of baseline ventricular arrhythmias that resolved with infusion discontinuation. Changes in plasma norepinephrine could not explain the potassium decrease or arrhythmia production, which also significantly decreased in these patients (771 +/- 123 to 524 +/- 73 pg/ml, p less than 0.01). It is concluded that dobutamine causes a significant decrease in plasma potassium and that the decrease persists at least 45 minutes after the infusion is discontinued.

Arrhythmias, Cardiac↗
PubMed1989

Alpha 2-receptor-mediated vasoconstriction in patients with congestive heart failure.

alpha 2-Adrenoceptors exist postsynaptically to subserve vasoconstriction and presynaptically to modulate norepinephrine release into the synaptic cleft. Because adrenoceptors may down-regulate in response to chronic stimulation, we investigated the activity of alpha 2-receptor-mediated vasoconstriction in patients with congestive heart failure, who had increased levels of plasma norepinephrine. We used the isolated forearm model and intra-arterial infusions of subsystemic doses of yohimbine, a specific alpha 2-blocker, in 11 patients with heart failure and in 15 normal subjects. Yohimbine produced a dose-related increase in forearm blood flow and decrease in forearm vascular resistance. These findings were consistent with a direct vasodilator effect mediated by blockade of the postsynaptic alpha 2-vascular receptor. Furthermore, the vasodilator responses in patients with heart failure were similar to the normal subjects in terms of the percent increase in forearm blood flow, the dose-response relation, and the fractional response to hyperemia and phentolamine; thus, alpha 2-receptor-mediated vasoconstriction is neither enhanced nor down-regulated in heart failure. In addition, in patients with heart failure and in normal subjects, yohimbine produced an increase in the forearm venous norepinephrine concentration, consistent with an inhibition of the presynaptic alpha 2-receptor resulting in an augmented release of norepinephrine into the synaptic cleft. Thus, these data suggest that the postsynaptic alpha 2-receptor is an important mediator of vasoconstriction in patients with heart failure. Despite chronic elevations in plasma norepinephrine in patients with heart failure, alpha 2-receptor mechanisms subserving vasoconstriction and inhibition of norepinephrine release into the synaptic cleft are still functional in heart failure.

Female↗
PubMed1989

The sympathetic nervous system in heart failure.

The syndrome of clinical heart failure (CHF) is characterized by increased activity of the sympathetic nervous system (SNS), which may contribute in part to the heightened vascular tone that adversely affects left ventricular systolic performance. The increased resting SNS activity is accompanied by an attenuated SNS response to physiological stress, including orthostasis, hypotension, and maximal exercise. Since heart transplantation appears to reverse the increased resting activity and the deficient reflex responsiveness, these abnormalities appear to be functional. The degree of SNS activation appears to be directly related to mortality in CHF, thus suggesting that heightened SNS activity is either a marker or a risk factor for a lethal outcome in this syndrome. Pharmacologic inhibition of the SNS is an attractive therapeutic option for evaluation in CHF.

Heart Failure↗
PubMed1989

Left ventricular function after myocardial infarction.

After acute myocardial infarction, left ventricular filling pressure is elevated because of systolic and/or diastolic dysfunction. The severity of the left ventricular dysfunction is influenced not only by infarct size and location but also by biochemical, neurohormonal, and peripheral vascular responses to infarction. Short-term vasodilator therapy improves left ventricular dysfunction and may influence favorably long-term prognosis in the presence of severe systolic dysfunction but not with predominant diastolic dysfunction. The chronic systolic dysfunction which may follow acute myocardial infarction also is influenced favorably by chronic vasodilator therapy.

Heart↗
PubMed1989

Sympathetic nervous system activity and the heart.

The sympathetic nervous system has been viewed as the critical mechanism for cardiovascular response to increased circulatory needs during acute stress, augmenting cardiac rate and contractility and changing peripheral vascular tone. These physiologic responses, however, are increasingly thought to cause long-term adverse effects--such as altered myocardial function; renal, systemic, and coronary vasoconstriction; ventricular arrhythmias; and left ventricular hypertrophy--for some patients with cardiovascular disease. How the sympathetic nervous system affects the pathophysiology of cardiovascular diseases is not fully understood, although new techniques for assessing plasma catecholamines and for quantitating sympathetic activity are adding to our knowledge. Nevertheless, a review of the physiologic responses to sympathetic nervous system stimulation reveals much about their possible role in the cardiovascular disease process.

Animals↗
PubMed1988

Prognosis of congestive heart failure and predictors of mortality.

The interaction of physiologic variables that appear to be predictive of prognosis in patients with severe congestive heart failure was examined in a series of 139 patients referred to a heart failure service. Left ventricular ejection fraction, peak oxygen consumption during a progressive maximal exercise test and resting plasma norepinephrine concentration were identified as the strongest univariate predictors of prognosis. Examination of their interaction was accomplished by stratifying each variable into quartiles and then pooling quartiles for bivariate analysis. The data demonstrate that ejection fraction has the most profound effect on survival calculated from maximal oxygen consumption and norepinephrine concentration, but that each of the variables provides additional independent prognostic information when added to survival estimated from any of the other variables. Therefore, ventricular function, exercise tolerance and sympathetic nervous system activation appear to provide independent insight into the prognosis of patients with heart failure.

Female↗