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Biomedical subjects

J N Cohn

Publications and source records attributed to J N Cohn.

At least 109 records · Page 6Linked to original sources
PubMed1995

Plasma norepinephrine and mortality.

Plasma norepinephrine levels, which reflect sympathetic nervous system activity, are almost universally elevated in patients with left ventricular dysfunction. This elevation occurs in patients with overt, symptomatic heart failure (HF) and in patients with asymptomatic left ventricular dysfunction. Evidence suggests that the elevation in plasma norepinephrine levels can be at least partly attributed to an increase in sympathetic nervous system activity. It has become evident that elevated plasma norepinephrine levels are directly related to prognosis; patients with levels > 900 pg/ml have a poor prognosis and shortened life expectancy. However, plasma norepinephrine levels bear little relationship to physiologic and clinical variables observed in HF, including ejection fraction and exercise capacity. Data from the V-HeFT II show that at 2-year follow-up, a progressive rise of plasma norepinephrine was observed in both treatment arms, suggesting that disease progresses despite treatment with either an angiotensin-converting enzyme inhibitor, enalapril, or vasodilator therapy with hydralazine/isosorbide dinitrate. It is possible that interventions aimed at the progressive neurohormonal activation that occurs in HF may improve the course of illness. Further study is needed to test this hypothesis.

Enalapril↗
PubMed1995

Critical review of heart failure: the role of left ventricular remodeling in the therapeutic response.

Recent clinical investigations have provided new insights into physiologic alterations taking place as heart failure progresses. As a result, new end points may be more relevant to monitor in patients, rather than the classical assessment of severity based on subjective evaluation of functional capacity. Structural changes of the myocardium, referred to as remodeling, have profound effects on the performance of the left ventricle and on long-term prognosis. Left ventricular ejection fraction may serve as a clinical marker for remodeling changes. Remodeling changes involve hypertrophy of the muscle mass, dilation of the left ventricle, and a change in the shape of the ventricle. Histologically, these changes are produced by myocyte lengthening, interstitial growth, and myocyte slippage. The consequences of remodeling include an abnormal bio-energetic state because of the augmented wall stress and accentuated myocardial oxygen consumption. The elevated wall stress promotes further hypertrophy. Superimposed on the remodeling changes is neurohormonal activation. Both remodeling and neurohormonal activation are directly related to mortality. An experimental canine model has been used successfully to investigate the potential impact of pharmacologic intervention on remodeling. Angiotensin-converting enzyme inhibitors and the combination of hydralazine and isosorbide dinitrate have been shown in clinical trials to reduce long-term mortality and increase ejection fraction. The effects of these drugs appear to be mediated in part by alterations in remodeling and neurohormonal activation. Thus, left ventricular ejection fraction can be used as a clinical marker for remodeling processes, and plasma norepinephrine levels can be used as a marker for neurohormonal activation.

Animals↗
PubMed1995

New concepts regarding events that lead to end-stage heart disease.

Cardiac dysfunction is a progressive process that eventuates in end-stage heart failure. This progression involves dilatation and hypertrophy of the left ventricle, characterized as left ventricular remodeling. This remodeling results in a falling left ventricular ejection fraction, worsening heart failure, and increased risk of lethal ventricular arrhythmias. Increased aortic impedance due to vasoconstriction, neurohormonal stimulation, and bioenergetic abnormalities all may contribute to the remodeling process. Therapeutic efforts aimed at halting this progressive process, especially if initiated early in the course of the disease, are most likely to exert a favorable effect.

Disease Progression↗
PubMed1995

Interobserver discordance in the classification of mechanisms of death in studies of heart failure.

Studies of the mechanism of death in heart failure are dependent on the reliability and validity of classification of deaths as pump failure or arrhythmias (sudden). Two recent trials differed in that the Vasodilator Heart Failure Trial II (V-HeFT II) reported a higher incidence of sudden death than the Studies of Left Ventricular Dysfunction Treatment Trial (SOLVD) and an effect of enalapril on sudden death was not observed in SOLVD. A similar classification system was used in the two studies, but deaths in V-HeFT were classified centrally from a narrative summary, whereas deaths in SOLVD were classified in the field by individual investigators. To examine reliability, 10 narratives used to classify V-HeFT deaths were independently classified by 21 SOLVD investigators. In only 5 of 10 cases did 75% of SOLVD investigators agree with the V-HeFT classification. In no deaths were all SOLVD investigators in agreement on classification. Although V-HeFT classified 5 of 10 cases as sudden death, 16 of 21 SOLVD investigators classified less than 5 deaths as sudden and 1 classified none as sudden. The kappa statistic for interobserver agreement of 0.22 (P < or = .01) indicated interobserver agreement only slightly better than chance agreement. Therefore, the incidence of sudden death in heart failure is critically dependent on the bias of the investigator. Central classification will minimize inconsistencies, but it does not solve the problem that the mechanism of death is difficult to assign. Total mortality may be the only reliable endpoint in heart failure trials.

Adult↗
PubMed1995

ACE inhibitors in non-ischaemic heart failure: results from the MEGA trials.

Large-scale trials have demonstrated a consistent mortality reduction from angiotensin converting enzyme (ACE) inhibitor therapy for chronic heart failure. Nonetheless, the pharmacologic and physiologic mechanisms of this favourable affect and the appropriate target population remain controversial. ACE inhibitors exert vasodilator, neurohormonal inhibiting and growth inhibiting effects that may contribute to the clinical response. They improve pump function and prevent ventricular remodelling, but they also may exert an antiarrhythmic effect. They may prevent coronary ischaemic events but appear to reduce cardiovascular event rates even more in non-ischaemic than in ischaemic heart disease. Their efficacy in early stages of asymptomatic heart disease and the optimal dose of the drugs for long-term benefit require further study.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Noninvasive pulse wave analysis for the early detection of vascular disease.

A noninvasive technique has been developed and validated for calculating capacitive and oscillatory systemic arterial compliance with the use of pulse wave analysis and a modified Windkessel model. Application of the technique to subjects with hypertension, postmenopausal women with symptomatic coronary artery disease, and appropriate control subjects has confirmed a reduction of oscillatory compliance in the disease states and an increase in capacitive and oscillatory compliances in response to vasodilator drugs. This method should be useful in screening subjects for early evidence of vascular disease and in monitoring the response to therapy.

Blood Pressure↗
PubMed1994

Has the problem of heart failure been solved?

Emphasis on the management of heart failure has shifted from attempts to alter hemodynamics and symptoms to attempts to interfere with the natural history of the disease. This shift in emphasis has been stimulated by the recognition that heart failure progresses despite therapy and that shortened life expectancy makes the disease as lethal as most cancers. Most recent trials have therefore focused on mortality and have evaluated therapies designed to impact on progression of the syndrome. In this article the results of several recent trials are discussed, as well as the future of effective therapy.

Heart Failure↗
PubMed1994

Myocardial bioenergetic abnormalities in a canine model of left ventricular dysfunction.

OBJECTIVES: The purpose of this study was to assess high energy phosphate compound metabolism in remodeled left ventricular myocardium. BACKGROUND: The development of heart failure several years after myocardial infarction is often unexplained. Certain abnormalities of remodeled myocardium suggest that structural changes occurring in viable myocardium after discrete myocardial damage may contribute to the later appearance of heart failure. Whether these abnormalities alter metabolism in the surviving muscle and thereby possibly contribute to ventricular dysfunction is unknown. METHODS: High energy phosphate compound metabolism was assessed using spatially localized phosphorus-31 nuclear magnetic resonance spectroscopy. Eleven dogs with documented left ventricular dysfunction, resulting from infarction produced by transmyocardial direct current shock, were compared with eight normal dogs. Analyses were performed at baseline and during coronary hyperperfusion induced by intravenous adenosine. Myocardial blood flow was measured with radioactive microspheres. RESULTS: The creatine phosphate/adenosine triphosphate (CP/ATP) ratio was significantly reduced in the left ventricular dysfunction group in both the subepicardium ([mean +/- SE] 1.94 +/- 0.08 vs. 2.32 +/- 0.13, p = 0.019) and the subendocardium (1.71 +/- 0.07 vs. 2.05 +/- 0.07, p = 0.004). Intravenous adenosine produced significant coronary hyperemia in both groups but was less marked in dogs with left ventricular dysfunction. The improvement in myocardial perfusion was accompanied by a significant increase in the subendocardial CP/ATP ratio (from 1.71 +/- 0.07 to 1.92 +/- 0.08, p = 0.01) in dogs with left ventricular dysfunction. CONCLUSIONS: An abnormal transmural distribution of high energy phosphate compounds is evident in remodeled myocardium. This abnormality may be related in part to mismatch of oxygen delivery and demand.

Adenosine↗
PubMed1994

Treatment of infarct related heart failure: vasodilators other than ACE inhibitors.

Vasodilator drugs, particularly intravenously infused nitroprusside and an orally administered combination of hydralazine and isosorbide dinitrate, exert a profoundly favorable hemodynamic effect in the setting of heart failure complicating a prior myocardial infarction. Although these oral drugs also may relieve symptoms and improve exercise tolerance, the long-term benefits appear to be related to inhibition or reversal of the left ventricular dilation that results in a progressive fall in left ventricular ejection fraction. The long-term efficacy of both ACE inhibitors and hydralazine-nitrate in symptomatic heart failure makes the vasodilator combination a rational alternative to an ACE inhibitor and possibly an effective agent for cotherapy with an ACE inhibitor. Trials are needed to test the additive efficacy of this vasodilator combination and to develop other safe and effective drugs that target the progressive remodeling process in heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Interaction of intravenous atrial natriuretic factor with furosemide in patients with heart failure.

Furosemide is frequently administered intravenously to patients with chronic heart failure. However, use of diuretics may cause neuroendocrine activation and by itself may not consistently afford diuresis. Atrial natriuretic factor (ANF) in pharmacologic doses is a vasodilator and has favorable neuroendocrinologic effects in patients with congestive heart failure. To examine whether exogenous ANF might enhance the effects of acute furosemide injection, we studied 14 patients with chronic stable heart failure and measured the effects of the combination of ANF and furosemide on hemodynamics, neuroendocrine activation, and urine output. Eight patients were randomly assigned to receive placebo plus furosemide (1.3 mg/kg intravenously). Six patients received ANF (2 micrograms/kg intravenously) plus furosemide at the same dose in a double-blind manner. The group receiving placebo plus furosemide exhibited a slight increase in mean arterial pressure (92 to 96 mm Hg; p < 0.03), systemic vascular resistance (1989 to 2271 dynes.sec.cm-5; p = 0.0007), and pulmonary capillary wedge pressure (22 to 24 mm Hg; p < 0.04) from baseline to 10 minutes. The group receiving ANF plus furosemide exhibited no change in mean arterial pressure and systemic vascular resistance from baseline to 10 minutes. Pulmonary capillary wedge pressure and mean pulmonary pressure were unchanged. In the group receiving placebo plus furosemide.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Angiotensin-converting enzyme inhibition and beta-adrenoceptor blockade regress established ventricular remodeling in a canine model of discrete myocardial damage.

OBJECTIVES: This study was designed to assess the effect of angiotensin-converting enzyme inhibition and beta-adrenoreceptor blockade on established ventricular remodeling. BACKGROUND: Angiotensin-converting enzyme inhibitor therapy attenuates the development of ventricular remodeling when given shortly after myocardial infarction. However, regression of established ventricular remodeling after infarction has received little attention. METHODS: The relative effects of angiotensin-converting enzyme inhibitor therapy and beta-adrenoceptor blockade on established ventricular remodeling were assessed in a canine model characterized by increased left ventricular mass and chamber dilation as a result of localized myocardial necrosis produced by transmyocardial direct current shock. Dogs were randomly assigned to 3 months of therapy with captopril (25 mg twice daily, n = 7) or metoprolol (100 mg twice daily, n = 7) or to a control group with no intervention (n = 6), 11 +/- 4 (mean +/- SD) months after acute myocardial damage. RESULTS: Compared with the control group, dogs in both the captopril and metoprolol groups had reduced left ventricular mass as measured by magnetic resonance imaging (-8.1 +/- 3.8 vs. 1.7 +/- 2.8 g, p = 0.003 and -9.6 +/- 5.6 vs. 1.7 +/- 2.8 g, p = 0.001), respectively. Captopril and metoprolol also produced a reduction in left ventricular end-diastolic volume (-7.6 +/- 6.0 and -6.0 +/- 5.8 ml, respectively) compared with the control value (-1.6 +/- 3.8 ml) (p = 0.14 [NS]). Both agents reduced mean arterial pressure but had disparate effects on pulmonary wedge pressure and right atrial pressure. There was no significant correlation between change in ventricular mass or volume and change in any measured hemodynamic or neurohormonal variable. CONCLUSIONS: These data suggest that pharmacologic intervention with angiotensin-converting enzyme inhibition or beta-adrenoceptor blockade can result in regression of established ventricular remodeling. The mechanism of this response will require further study, but these data did not support a close association between regression of remodeling and hemodynamic unloading of the ventricle or systemic neuroendocrine factors.

Animals↗
PubMed1994

Modern strategies to prevent coronary sequelae and stroke in hypertensive patients differ from the JNC V Consensus Guidelines.

In recent years, government agencies of many countries have established consensus guidelines for the evaluation and treatment of hypertension. Once published, guidelines tend to be perceived as directives by a variety of health care providers. Unfortunately, these guidelines often do not reflect the practices of most hypertension experts. This report summarizes the opinions of seven hypertension experts concerning the impact of "official" guidelines on clinical practice. In addition, the individual therapeutic recommendations of these panel members are summarized. Their different treatment strategies reflect the diversity of first rate treatment plans that aim to reduce the cardiovascular sequelae in individual patients with essential hypertension. Most importantly, not one of these seven treatment strategies followed the "preferred" treatment of the U.S. guidelines, which recommend diuretics and beta-blockers as first-line therapy. The present authors approach the treatment of hypertension as a means to reduce cardiovascular events. Thus, reduction of blood pressure is not the most important therapeutic endpoint. The panel believes that whereas many different drugs can produce effective blood pressure reduction, the modern primary goal of antihypertensive drug therapy is to select a regimen most likely to prolong the quality and duration of life. In real terms, this means that the primary goal of treatment is the prevention of the major vascular sequelae of hypertension (heart attack, ventricular remodeling, hypertrophy, heart failure, and stroke) that shorten useful life. There are a number of effective hypertensive treatments, which can be selected based on individual patient requirements. However, many consensus guidelines do not allow the flexibility required to optimize individual patient treatment. As a result, health care providers should not feel compelled to regard the preferences of "official" guidelines as the best, modern, state-of-the-art therapy for an individual patient. All seven experts who are deeply involved in the daily care of patients preferred drugs other than beta-blockers and diuretics (the Joint National Committee [JNC] choices) for first-line therapy of hypertension.

Cardiovascular Diseases↗
PubMed1994

Prognosis in congestive heart failure.

Prognostic variables such as the ejection fraction and peak oxygen consumption can be used to place patients with heart failure in risk strata. Some vasodilators have been shown to improve survival at all stages of heart failure with the probability of benefit increasing as the prognosis worsens. Quantitative estimates of survival among groups defined by prognostic variables and treatments should be used to make more informed benefit-to-risk assessments.

Death, Sudden, Cardiac↗
PubMed1994

Fish oil improves arterial compliance in non-insulin-dependent diabetes mellitus.

In a double-blind, placebo-controlled study we investigated the effects of dietary fish oil supplementation on arterial wall characteristics in 20 patients with non-insulin-dependent diabetes mellitus. Estimates reflecting compliance values in the large arteries and more peripheral vasculature, as measured by pulse-contour analysis, improved significantly after 6 weeks of fish oil therapy compared with values recorded at baseline and after 6 weeks' administration of olive oil. The large-artery compliance estimate increased from 1.50 (confidence interval [CI], 1.31 to 1.69) mL/mm Hg at baseline to 1.68 (CI, 1.52 to 1.84) mL/mm Hg after fish oil administration (P < .01). The oscillatory compliance value increased from 0.015 (CI, 0.011 to 0.019) mL/mm Hg at baseline to 0.022 (CI, 0.016 to 0.028) mL/mm Hg after fish oil ingestion (P < .05). No changes occurred in arterial blood pressure, cardiac output, stroke volume, or systemic vascular resistance with either intervention. The improved compliance estimates with fish oil ingestion occurred without altering fasting blood glucose and cholesterol concentrations. These results support the hypothesis that fish oils alter vascular reactivity and favorably influence arterial wall characteristics in patients with non-insulin-dependent diabetes mellitus. These direct vascular effects, expressed at the level of the vessel wall, may contribute to the cardioprotective actions of fish oil in humans.

Arteries↗