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J N Cohn

Publications and source records attributed to J N Cohn.

At least 127 records · Page 7Linked to original sources
PubMed1994

Relative effects of alpha 1-adrenoceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog.

BACKGROUND: Progressive ventricular remodeling after myocardial damage is associated with a poor prognosis. Optimal prevention of the histopathological processes involved in remodeling requires a more complete understanding of the mechanisms involved in initiating and maintaining these structural changes. Since the sympathetic nervous system and the renin-angiotensin system may be involved in the remodeling process, the structural effects of pharmacological inhibitors have been evaluated in a canine model of localized myocardial injury resulting from transmyocardial DC shock. METHODS AND RESULTS: The study is comprised of two protocols run in series. In protocol 1, zofenopril (Z), a converting enzyme inhibitor (CEI), prevented the increase in left ventricular mass (LVM) and end-diastolic volume (LVV) observed in the control group (C) at 16 weeks (Z: LVM, 69.8 +/- 3.4 to 65.4 +/- 2.6 g, P = NS; LVV, 45.4 +/- 2.7 to 51.6 +/- 2.7 mL, P = NS; C: LVM, 68.4 +/- 3.2 to 91.4 +/- 2.9 g, P = .0001; LVV, 56.6 +/- 3.0 to 71.9 +/- 2.4 mL, P = .0003). Terazosin, an alpha 1-adrenoceptor antagonist, failed to prevent remodeling at 16 weeks despite continued receptor blockade. In protocol 2, the antiremodeling effect of full-dose CEI therapy with ramipril was confirmed. Low-dose ramipril that exerted no hemodynamic effect failed to prevent remodeling (LVM, 89.7 +/- 4.6 to 105.7 +/- 3.4 g, P = .01; LVV, 61.8 +/- 3.8 to 76.8 +/- 3.3 mL, P = .002). An angiotensin II subtype 1 receptor blocker also failed to prevent the increase in LVM or LVV (LVM, 89.0 +/- 4.6 to 109.7 +/- 5.3 g, P = .0001; LVV, 66.0 +/- 1.9 to 78.4 +/- 3.6 mL, P = .007). CONCLUSIONS: High-dose CEI therapy can prevent progressive structural changes resulting from localized myocardial damage induced by DC shock. the failure of alpha 1-adrenoceptor blockade and angiotensin II subtype 1 blockade to attenuate remodeling argues against an important direct role for norepinephrine acting through alpha 1-receptors or angiotensin II acting through the type 1 receptor in the remodeling process in this model.

Adrenergic alpha-Antagonists↗
PubMed1994

Vasodilators in heart failure. Conclusions from V-HeFT II and rationale for V-HeFT III.

The Veterans Affairs Vasodilator-Heart Failure Trials (V-HeFT I and II) provided information about heart failure treated with conventional therapy, and evaluated the long term efficacy of vasodilators. In V-HeFT I, the combination of hydralazine and isosorbide dinitrate provided a beneficial effect on prognosis in heart failure. V-HeFT II demonstrated that enalapril had a more favourable effect on 2-year survival than a combination of hydralazine plus isosorbide dinitrate. However, the hydralazine-isosorbide dinitrate combination exerted the most favourable short term impact on exercise performance and left ventricular ejection fraction. The V-HeFT studies showed that, although not all vasodilators are alike, their differing effects might be beneficial when used in combination. Determination of the potential additive effect of the calcium antagonist felodipine, a vasodilator, when used in combination with an ACE inhibitor, is the major goal of V-HeFT III.

Clinical Trials as Topic↗
PubMed1993

Nitrates versus angiotensin-converting enzyme inhibitors for congestive heart failure.

The efficacy of nitrates versus that of angiotensin-converting enzyme (ACE) inhibitors in heart failure may be evaluated based on 3 treatment aims: hemodynamic improvement, symptom relief, and survival benefit. Nitrates used in conjunction with hydralazine produce a relatively large increase in stroke volume and a prominent reduction of left ventricular filling pressure, whereas ACE inhibitors produce a comparatively modest increase in stroke volume with a prominent reduction in filling pressure. The effect of these drugs on arterial compliance has been evaluated using a modified Windkessel model of the circulation to define their mechanism of action. Nitrates appear to affect the large arteries and arterial bed as well as the venous circulation. Intermediate-term response to therapy is often evaluated by changes in exercise tolerance. A review of multicenter trials reveals that, although both ACE inhibitors and hydralazine/nitrate have favorable hemodynamic actions, the effect of hydralazine/nitrate on exercise capacity appears to be slightly better. ACE inhibitors and nitrates both may reduce dysfunctional myocardial remodeling, as evaluated in a canine model of chronic left ventricular dysfunction. The increase in the ejection fraction by these drugs and the decrease of plasma norepinephrine levels by ACE inhibitors may contribute to improved long-term survival. It appears, therefore, that the long-term benefits of nitrates and ACE inhibitors in heart failure probably relate to their ability both to affect cardiac remodelling and to relax vascular smooth muscle.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Post-MI remodeling.

Two myocardial processes are initiated by acute myocardial infarction: hypertrophy of residual myocardium and a change in left ventricular chamber dimension. The sequence of these events appears to be critically dependent on the size of the infarct and its distensibility, on the load placed on the myocardium, on the metabolic state of adjacent and remote myocardium, and on the degree of activation of tissue hormone systems. Hypertrophy may occur transversely (concentric) or longitudinally (eccentric). The chamber may enlarge because of cell lengthening or slippage or because of infarct expansion. An increase in radius of curvature intensifies wall stress and metabolic demands, whereas increased wall thickness moderates stress. In a canine experimental model of acute regional myocardial necrosis, hypertrophy and dilatation appear to have a different time course, and both may be attenuated by pharmacologic intervention with either an angiotensin-converting enzyme (ACE) inhibitor or a nitrate. The relative contributions of load reduction, hormone inhibition, and the metabolic effect of pharmacologic intervention need further study. Targeting therapy to the prevention of detrimental ventricular remodeling may be a rational approach but one that needs clinical confirmation.

Animals↗
PubMed1993

ACE inhibitors.

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Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Efficacy of vasodilators in the treatment of heart failure.

Vasodilator drugs have been undergoing evaluation as therapy for heart failure for > 20 years. It has become clear that hemodynamic benefits, short-term improvement in exercise tolerance and long-term alteration in mortality are independent end points for efficacy of these drugs. Differing hemodynamic responses, variable effects on exercise capacity and differential effect on mortality of various vasodilator compounds raise the likelihood that vascular smooth muscle relaxation is not the sole mechanism of action of these drugs. Neurohormonal and antiproliferative effects of these agents may play a key role in the long-term response. Data from trials indicate that the vasodilator combination of hydralazine and isosorbide dinitrate as well as converting enzyme inhibitors can favorably affect all end points. The global efficacy of other vasodilators, such as calcium antagonists, has not yet been fully evaluated.

Clinical Trials as Topic↗
PubMed1993

Long-term oral nitrate therapy prevents chronic ventricular remodeling in the dog.

OBJECTIVES: The purpose of this experiment was to assess the long-term effects of oral nitrate therapy on ventricular remodeling in a canine model of discrete myocardial damage. BACKGROUND: A progressive increase in left ventricular mass and volume has been documented after experimental and clinical myocardial infarction. This ventricular remodeling has been associated with the development of congestive heart failure. Nitrate therapy, especially when combined with hydralazine, is effective in the management of clinical heart failure. Moreover, nitrates inhibit infarct expansion, one of the earliest manifestations of ventricular remodeling. Whether nitrates can attenuate chronic left ventricular remodeling is unknown. METHODS: Dogs with discrete myocardial necrosis produced 24 h earlier by transmyocardial direct current shock were randomized to receive isosorbide mononitrate, 30 mg twice daily (n = 10), or no treatment (n = 4); the latter group was augmented by 13 control dogs from a prior study in which an identical protocol was used. Ventricular structure was assessed with nuclear magnetic resonance imaging at baseline and at 1 and 16 weeks after myocardial damage. RESULTS: Left ventricular mass increased at 1 week in the control group (mean +/- SD 68.1 +/- 10.7 g to 80.1 +/- 12.1 g, p = 0.0001) but not in the nitrate-treated group (70.2 +/- 7.7 g to 69.6 +/- 7.3 g, p = NS). No change in left ventricular volume was observed in either group during the 1st week after myocardial damage. After 16 weeks of follow-up left ventricular mass had increased by 12.7 +/- 7.1 g (p = 0.001) in the control group and had decreased by 1.2 +/- 7.7 g in the nitrate group. Left ventricular volume was increased at 16 weeks by 14.2 +/- 10.3 ml in the control group but was decreased by 3.7 +/- 7.5 ml in the nitrate group. Isosorbide mononitrate produced transient hemodynamic effects with a return of most measured variables toward baseline within 2 h after administration of the drug. At 1 week there was no intergroup difference in rest hemodynamic variables assessed 12 h after drug administration. At 16 weeks, pulmonary capillary wedge pressure (15 +/- 4 vs. 8 +/- 3 mm Hg, p = 0.0001), pulmonary artery pressure (24 +/- 5 vs. 16 +/- 3 mm Hg, p = 0.0001) and right atrial pressure (10 +/- 3 vs. 6 +/- 3 mm Hg, p = 0.008) were all higher in the control group. CONCLUSIONS: Long-term oral nitrate therapy attenuates the early and late manifestations of ventricular remodeling after myocardial damage in the dog. Hemodynamic observations suggest the possibility that drug-induced preload or afterload reduction does not completely explain this effect.

Administration, Oral↗
PubMed1993

Assessment of arterial compliance in hypertension.

Traditionally, hypertension has been defined in terms of an elevated resistance to flow confined predominantly to the precapillary vasculature. More recently, changes in arterial compliance have been used to estimate vascular adaptations in the larger conduit arteries. This review outlines and updates the many varied techniques employed to estimate arterial compliance changes during hypertension. Most measures of compliance assess changes in small segments of the arterial vasculature. Because hypertension is a disease that influences structure and reactivity in all parts of the systemic circulation, it is desirable that clinical techniques for monitoring vascular adaptations with disease should address the generalized changes in the systemic vasculature.

Animals↗
PubMed1993

Cardioreparation and the concept of modulating cardiovascular structure and function.

Hypertension and atherosclerotic cardiovascular disease represent major global health problems. Practising physicians are challenged daily by patients suffering adverse cardiovascular events, such as myocardial infarction, stroke, heart failure and sudden cardiac death. Major risk factors have been identified of which the most important is left ventricular hypertrophy. In recent years, growth factors, regulatory peptides and effector hormones of the renin-angiotensin-aldosterone system have been identified as important modulators of cell growth and behaviour. It therefore follows that a major emphasis has been placed on the importance of abnormalities in organ structure as the primary basis for impaired function of the heart and vasculature, including large and medium sized arteries and resistance vessels, or arterioles. The concept of reparation recognizes the importance of abnormalities in tissue structure to the functional basis of disease. It suggests that the structurally remodelled heart and vasculature can be restored to, or toward, normal structure and function by suitable therapy. Experimental and clinical trials which address this premise are reviewed herein.

Animals↗
PubMed1993

Neurohumoral activation in preclinical heart failure. Remodeling and the potential for intervention.

Congestive heart failure is often preceded by a latent or preclinical phase in which patients are relatively asymptomatic. During this period, there is neuroendocrine activation, left ventricular dysfunction, and remodeling of the heart. The extent to which these activities are interrelated is unclear, but it appears from experimental studies that myocardial damage is associated with chronic sympathetic nervous system activation, left ventricular hypertrophy, and a subsequent increase in left ventricular volume. The nondamaged myocardial tissue demonstrates enhanced messenger RNA for angiotensinogen and angiotensin converting enzyme activity. Angiotensin II along with other trophic signals may prime the cell for "growth." Alteration of left ventricular function may produce unusual loading conditions on the myocardium. Stretch of membrane-bound ion channels may impart mechanical signals that may be transduced and expressed as cellular hypertrophy. Interstitial collagenase may be activated, leading to disruption of the collagen-supporting network. Elongated cells (eccentric hypertrophy), cell slippage, and cell dropout may contribute to the dilatative process. The end product is cardiac dilatation, inefficient left ventricular performance, and congestive heart failure. We have observed that an increase in left ventricular mass is the initial morphological response to acute myocardial damage in a canine model. This occurs at 1 week and is followed by progressive activation of the sympathetic nervous system, left ventricular dilatation, and modest left ventricular dysfunction, a condition that mimics preclinical heart failure in patients. The remodeling process in the canine model, including the increase in mass and volume, may be blocked by angiotensin converting enzyme inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The influence of atrial fibrillation on prognosis in mild to moderate heart failure. The V-HeFT Studies. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: Atrial fibrillation occurs commonly in heart failure; however, its importance in terms of prognosis is controversial. METHODS AND RESULTS: We assessed the relation of atrial fibrillation on first Holter monitor to morbidity and mortality in mild to moderate heart failure in 632 patients in the Veterans Affairs Vasodilator-Heart Failure Trial (V-HeFT) I and 795 patients in V-HeFT II: Ninety-nine patients in atrial fibrillation and 533 patients in sinus rhythm were followed for a mean of 2.5 years (range, 6 months to 5.7 years) in V-HeFT I; 107 patients in atrial fibrillation and 688 patients in sinus rhythm in V-HeFT II were followed for a mean of 2.5 years (range, 6 months to 5.0 years). V-HeFT I compared treatment with prazosin, hydralazine-isosorbide dinitrate, and placebo, whereas V-HeFT II compared hydralazine-isosorbide dinitrate with enalapril. Follow-up evaluations included serial Holter monitors, serial metabolic exercise testing, hospitalization data, and clinical examinations. In V-HeFT I, cumulative mortality at 2 years was 0.34 for patients with atrial fibrillation and 0.30 for patients in sinus rhythm (p = 0.25). Overall cumulative mortality was 0.54 for atrial fibrillation patients and 0.64 for sinus rhythm patients (p = 0.86). In V-HeFT II, cumulative mortality at 2 years was 0.20 for patients with atrial fibrillation and 0.21 for patients with sinus rhythm (p = 0.68), and overall cumulative mortality was 0.46 for atrial fibrillation patients and 0.52 for those in sinus rhythm (p < 0.46). Sudden death was not increased with atrial fibrillation in V-HeFT I patients (p = 0.64) or in V-HeFT II (p = 0.68). By multivariate analysis, the relative mortality risk for atrial fibrillation was 0.95 in V-HeFT I and 0.76 in V-HeFT II: Metabolic exercise testing, showed no significant difference in mean change in peak oxygen consumption between patients with atrial fibrillation and those with sinus rhythm in V-HeFT I and a slight decrease late in V-HeFT II: Hospitalization rate for heart failure was not increased in either study. The embolic event rate was not increased for atrial fibrillation patients: 3% versus 4.9% of patients in sinus rhythm (p = 0.41) in V-HeFT I and 4.0% versus 6.0% in V-HeFT II patients (p = 0.44). A secondary analysis compared mortality of patients in atrial fibrillation with that of patients in sinus rhythm on all Holters: Mortality was not increased overall (p = 0.72 in V-HeFT I and p = 0.35 in V-HeFT II). CONCLUSIONS: Atrial fibrillation does not increase major morbidity or mortality in mild to moderate heart failure.

Atrial Fibrillation↗
PubMed1993

Influence of age on mechanisms and prognosis of heart failure. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: Advanced age is commonly thought to carry a poor prognosis in congestive heart failure, but the case has not been established. The Department of Veterans Affairs Cooperative Vasodilator-Heart Failure Trials (V-HeFT I and II) provided a large data base to assess the effect of age on hemodynamic profiles and survival in the failing heart. METHODS AND RESULTS: Patients were stratified into four categories according to age: < or = 55, 56-60, 61-65, and > 65 years. The distributions of treatments and baseline characteristics from history, physical findings, and laboratory data were analyzed for differences across age categories. Survival curves were calculated for age strata according to treatment, presence or absence of coronary artery disease, ejection fraction, and peak oxygen consumption. Risk ratios for age and treatment categories showed no consistent trend of treatment effect on mortality. Age was significantly associated with coronary artery disease, hypertension, rhythm disturbances, systolic blood pressure, ejection fraction, and peak oxygen uptake, but successive age strata did not show incremental changes. Survival curves did not show progressively steeper slopes with advancing age. In V-HeFT I, the oldest patients did have the poorest survival, but age interacted with the presence of coronary artery disease and randomization into the placebo group. CONCLUSIONS: Contrary to intuitive thinking, age alone did not shorten the survival in congestive heart failure patients who were < 75 years old and receiving optimal therapy.

Age Factors↗
PubMed1993

Prognostic significance of serial changes in left ventricular ejection fraction in patients with congestive heart failure. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: In congestive heart failure patients, a single measurement of left ventricular ejection fraction (LVEF) provides important prognostic information. The importance, if any, of improvement or worsening in serial LVEF has not been defined. The Department of Veterans Affairs Cooperative Vasodilator-Heart Failure Trials (V-HeFT) data base was analyzed to determine the prognostic importance of LVEF changes. METHODS AND RESULTS: The data bases for V-HeFT I (n = 642) and V-HeFT II (n = 804) were analyzed. All patients had heart failure with documented exercise intolerance and abnormal LVEF or cardiac dilatation by chest x-ray or echocardiography. Radionuclide LVEF was obtained at baseline, within 6 months, and at least yearly after randomization to treatment. Cumulative survival subsequent to LVEF follow-up measurements was calculated for strata defined by LVEF change from baseline. In V-HeFT I, patients treated with hydralazine/isosorbide dinitrate (H-I) experienced a significant (p < 0.001) increase in LVEF and a survival advantage over those treated with placebo and prazosin. In V-HeFT II, both treatment groups showed significant improvements in LVEF, with the increase with H-I greater than that with enalapril, and enalapril provided a significant survival advantage over H-I. Change (> 5) in LVEF from baseline at 6 months (V-HeFT I) and 1 year (V-HeFT II) were the strongest predictors of mortality among the serial measurements and were significant after adjustment for therapy and baseline LVEF. Baseline clinical variables were not helpful in predicting the patients who would experience an improvement in LVEF. CONCLUSIONS: In patients with heart failure, serial measurements of LVEF provide additional important prognostic information. Vasodilator therapy with H-I is associated with an improvement in LVEF and prognosis. Vasodilator therapy with enalapril improves LVEF less than H-I but provides an additional survival benefit.

Drug Therapy, Combination↗
PubMed1993

Mechanism of death in heart failure. The Vasodilator-Heart Failure Trials. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: The Vasodilator-Heart Failure Trial (V-HeFT) data base provides information on the mechanism of death of male veterans entered into two trials that evaluated the effect of vasodilator therapy on survival in heart failure. METHODS AND RESULTS: Men aged 18-75 years with heart failure were recruited at 13 Department of Veterans Affairs Medical Centers. In V-HeFT I, 283 of 642 patients (44%) died during follow-up (average, 2.3 years), and in V-HeFT II, 285 of 804 randomized patients (35.5%) died during follow-up (average, 2.5 years). Mechanism of death was established centrally using a standardized classification. In V-HeFT I, 124 of the 283 deaths (43.8%) were sudden with no worsening of symptoms; in V-HeFT II, 104 of the 285 deaths (36.5%) were sudden. An average of 31.5% of the deaths (31.4% and 31.6%, respectively) in the two trials was due to pump failure. The proportion of sudden deaths that occurred without worsening of symptoms was similar in patients with and without ischemic heart failure. Sudden deaths tended to occur earlier and pump failure deaths later in both V-HeFT studies. There was a trend for a lower percentage of cardiac deaths from pump failure and a higher percentage from sudden death in subgroups with higher peak exercise oxygen consumption (VO2), higher ejection fraction, and lower plasma norepinephrine levels. The proportion of deaths that occurred suddenly was similar in placebo, prazosin, and hydralazine plus isosorbide dinitrate treatment groups but was significantly lower in the enalapril treatment group. In V-HeFT I, measures of cardiac function and VO2 predicted pump failure death and sudden death. In V-HeFT II, VO2 and cardiothoracic ratio were independent predictors of all-cause deaths and pump failure deaths; only ejection fraction was an independent predictor of both pump failure and sudden death. CONCLUSION: Although mechanistically distinct terminal events can be identified in patients with heart failure and physiological measurements can provide some insight into the risk of these disparate events, sudden death and pump failure death both appear largely to be linked to the severity of cardiac dysfunction and symptoms. Strategies to identify individuals for selective preventive therapy are not yet practical.

Cause of Death↗