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Biomedical subjects

J N Cohn

Publications and source records attributed to J N Cohn.

At least 19 recordsLinked to original sources
PubMed1992

Pharmacologic mechanisms of nitrates in myocardial ischemia.

Nitrates exert both hemodynamic and nonhemodynamic effects that help explain the mechanisms by which these drugs benefit patients with myocardial ischemia. The hemodynamic effects of nitrates include relaxation of conduit arteries, increased arterial compliance, increased venous capacitance, dilation of collateral vessels in the myocardium, and, possibly, increased myocardial compliance. A growing body of evidence suggests that the nonhemodynamic effects of these agents include inhibition of vascular smooth muscle growth and of myocyte hypertrophy and ventricular remodeling. Since endothelial function appears to be abnormal in patients with myocardial ischemia and nitrates replicate many of the effects of endothelium-derived relaxing factor, these drugs may be viewed as a pharmacologic replacement for deficient endogenous activity.

Hemodynamics↗
PubMed1992

Mechanisms of action and efficacy of nitrates in heart failure.

Nitrates exert hemodynamic and possibly nonhemodynamic effects that result in reduced cardiac filling pressures, increased cardiac output, reduced pulmonary vascular pressures, and improvement in symptoms and exercise tolerance in patients with heart failure. Combined with hydralazine, chronic oral administration of isosorbide dinitrate has been demonstrated to improve survival when added to digoxin and diuretic therapy. A long-term improvement in left ventricular ejection fraction in these clinical studies has raised the possibility that the nitrates may be acting at least in part by inhibiting left ventricular remodeling. The precise role of nitrates and the optimal dosing regimen in the therapeutic armamentarium for heart failure, particularly in patients already treated with a converting enzyme inhibitor, remains to be established.

Forecasting↗
PubMed1992

Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions.

BACKGROUND: It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity. We studied the effect of an angiotensin-converting--enzyme inhibitor, enalapril, on total mortality and mortality from cardiovascular causes, the development of heart failure, and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure. METHODS: Patients were randomly assigned to receive either placebo (n = 2117) or enalapril (n = 2111) at doses of 2.5 to 20 mg per day in a double-blind trial. Follow-up averaged 37.4 months. RESULTS: There were 334 deaths in the placebo group, as compared with 313 in the enalapril group (reduction in risk, 8 percent by the log-rank test; 95 percent confidence interval, -8 percent [an increase of 8 percent] to 21 percent; P = 0.30). The reduction in mortality from cardiovascular causes was larger but was not statistically significant (298 deaths in the placebo group vs. 265 in the enalapril group; risk reduction, 12 percent; 95 percent confidence interval, -3 to 26 percent; P = 0.12). When we combined patients in whom heart failure developed and those who died, the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group (630 vs. 818; risk reduction, 29 percent; 95 percent confidence interval, 21 to 36 percent; P less than 0.001). In addition, fewer patients given enalapril died or were hospitalized for heart failure (434 in the enalapril group; vs. 518 in the placebo group; risk reduction, 20 percent; 95 percent confidence interval, 9 to 30 percent; P less than 0.001). CONCLUSIONS: The angiotensin-converting--enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations, as compared with the rates in the group given placebo, among patients with asymptomatic left ventricular dysfunction. There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril.

Blood Pressure↗
PubMed1992

The effect of treatment on survival in congestive heart failure.

Congestive heart failure (CHF) is a disorder characterized by a variety of clinical, biochemical, electrophysiological, and hemodynamic abnormalities. During the past two decades, numerous drugs have been employed in the treatment of this complex syndrome, and many agents have been shown to improve symptoms and ventricular function in patients with CHF. Because CHF is associated with a high risk of death, treatment should be directed not only toward the relief of symptoms, but also toward a reduction in mortality. Many variables have been shown to be related to survival; taken individually, however, each is limited in its utility in predicting prognosis. In recent years, large-scale studies with large sample sizes have directly assessed the effects of treatment on mortality in CHF. Results from these trials indicate that vasodilators and angiotensin-converting enzyme (ACE) inhibitors may improve mortality in patients with symptoms of heart failure. Additional trials are now in progress to evaluate the effect of treatment on patients with asymptomatic left ventricular dysfunction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

A multicenter, randomized, double-blind, placebo-controlled trial of pimobendan, a new cardiotonic and vasodilator agent, in patients with severe congestive heart failure.

Pimobendan, a new oral cardiotonic and vasodilator agent, increases myocardial contractile force through specific inhibition of phosphodiesterase type III and increased calcium sensitivity of the myocardial contractile elements. The effects of pimobendan on left ventricular performance and maximal exercise capacity were studied in a multicenter, randomized, double-blind, placebo-controlled trial involving 52 patients with severe congestive heart failure despite diuretics, digoxin, and angiotensin-converting enzyme inhibitors. The acute hemodynamic evaluation included three single doses of 2.5, 5.0, and 10.0 mg of oral pimobendan, which was subsequently administered at a daily dose of 5 or 10 mg for 4 weeks. Acute administration of pimobendan significantly increased the resting cardiac index and lowered pulmonary capillary wedge pressure in a dose-dependent manner, whereas heart rate and systemic arterial pressure were not substantially altered. Patients receiving pimobendan, 5 and 10 mg daily, had a significantly greater increase in maximal exercise duration than those receiving placebo, that is, 144 +/- 30 and 124 +/- 33 seconds versus 58 +/- 25 seconds (p = 0.05). Peak oxygen uptake increased by 1.7 +/- 0.8 and 2.2 +/- 1.3 ml/kg/min in patients receiving pimobendan at a daily dose of 5 and 10 mg, respectively, whereas it decreased by 0.1 +/- 0.6 ml/kg/min in patients receiving placebo (p = 0.06). Thus pimobendan acutely improves resting left ventricular performance and chronically increases exercise duration and peak oxygen uptake in patients with severe congestive heart failure concomitantly treated with digoxin, diuretics, and angiotensin-converting enzyme inhibitors.

Cardiotonic Agents↗
PubMed1992

Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: reliability and validity during a randomized, double-blind, placebo-controlled trial of pimobendan. Pimobendan Multicenter Research Group.

To determine the reliability and validity of a patient outcome questionnaire for chronic heart failure, a randomized, double-blind, placebo-controlled, 3-month trial of pimobendan, an investigational medication with inotropic and vasodilator activities, was performed. Evaluated were 198 ambulatory patients with primarily New York Heart Association (NYHA) class III heart failure from 20 referral centers. Baseline therapy included digoxin, diuretics and, in 80%, a converting enzyme inhibitor. Oral pimobendan at 2.5 (n = 49), 5.0 (n = 51), or 10 (n = 49) mg daily or matching placebo (n = 49) was administered. The Minnesota Living with Heart Failure (LIhFE) questionnaire was a primary outcome measure, along with an exercise test. Interitem correlations identified subgroups of questions representing physical and emotional dimensions. Repeated baseline scores were highly correlated (r = 0.93), as were the physical (r = 0.89) and emotional (r = 0.88) dimension scores. Placebo did not have a significant effect with median (25th, 75th percentile) changes from baseline scores of 1 (-3, 5), 1 (-2, 3), and 0 (-1, 2), respectively (all p values greater than 0.10). The 5 mg dose significantly improved the total score, 7.5 (0, 18; p = 0.01) and the physical dimension, 4 (0, 8; p = 0.01), compared with placebo. Changes in the total (r = 0.33; p less than 0.01) and physical (r = 0.35; p less than 0.01) scores were weakly related to changes in exercise times, but corresponded well with changes in patients' ratings of dyspnea and fatigue.(ABSTRACT TRUNCATED AT 250 WORDS)

Activities of Daily Living↗
PubMed1992

Hemodynamic, left ventricular structural and hormonal changes after discrete myocardial damage in the dog.

Transmyocardial direct-current (DC) shock produces localized left ventricular myocardial necrosis without obstruction to coronary blood flow. In 43 dogs sequential measurements of hemodynamic, neuroendocrine and myocardial structural changes were made at baseline and for 16 weeks after DC shock. Six dogs (14%) died in the peri-shock period. By 1 week after shock, left ventricular mass, as measured by nuclear magnetic resonance imaging, had increased from a mean value +/- SD of 67.9 +/- 10.1 to 82.5 +/- 12.9 g (p = 0.0001). Left ventricular end-diastolic volume was unchanged at 1 week but increased at 16 weeks from 56.1 +/- 10.3 to 70.3 +/- 10.7 ml (p = 0.0003). Left ventricular mass demonstrated a further increase at 12 months (107.8 +/- 14.8 g). Rest cardiac output was significantly decreased at 4 months (3.67 +/- 1.23 to 3.18 +/- 0.81 liters/min, p less than 0.01) as was stroke volume (43 +/- 9 to 37 +/- 7 ml, p less than or equal to 0.01). Left ventricular ejection fraction decreased progressively from 73% to 38% at 1 year. At 4 months there were increases in mean pulmonary artery pressure (18 +/- 4 to 23 +/- 4 mm Hg, p less than 0.01), pulmonary capillary wedge pressure (9 +/- 3 to 15 +/- 3 mm Hg, p less than 0.01) and right atrial pressure (5 +/- 4 to 9 +/- 3 mm Hg, p less than 0.01). Plasma norepinephrine was increased at 4 months (318 +/- 190 to 523 +/- 221 pg/ml, p = 0.0003), whereas plasma renin activity was not significantly changed (4.3 +/- 2.6 vs. 5.2 +/- 3.4 ng/ml per h). Microsphere regional blood flow studies demonstrated a 50% reduction in skeletal muscle blood flow at 4 months (0.06 +/- 0.06 ml/min per g compared with 0.12 +/- 0.09 in normal dogs, p = 0.05), and a reduction in the endocardial/epicardial blood flow ratio (1.11 +/- 0.13 compared with 1.24 +/- 0.13 in normal dogs, p = 0.02). Therefore, in this model of acute left ventricular damage, left ventricular hypertrophy precedes progressive left ventricular dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Rapid, accurate and simultaneous noninvasive assessment of right and left ventricular mass with nuclear magnetic resonance imaging using the snapshot gradient method.

Left ventricular, and possibly also right ventricular, mass is an important determinant of prognosis in cardiovascular disease. Consequently, noninvasive estimation of ventricular mass may be an important clinical investigation. The ideal technique for this purpose would be widely available and accurate, employ short study times and avoid exposure to contrast agents and radiation. Conventional nuclear magnetic resonance (NMR) imaging fulfills most of these criteria, but it is time-consuming and expensive. Moreover, its accuracy in estimating right ventricular mass has yet to be assessed. Accordingly, high speed NMR imaging using the snapshot gradient echo technique was used to assess right and left ventricular mass in 10 dogs and the results were compared with values obtained at autopsy, which ranged from 26.1 to 52.9 and 61 to 119.8 g, respectively. The mean absolute difference between the NMR imaging estimates and autopsy findings was 2 +/- 1.2 g (range 0.4 to 4.2) for right ventricular mass and 4.4 +/- 1.7 g (range 1.8 to 6.6) for left ventricular mass. Total NMR imaging time was less than or equal to 5 min. These data demonstrate that high speed NMR imaging can be used to accurately estimate right as well as left ventricular mass.

Animals↗
PubMed1992

Role of neurohumoral control of the circulation in determining exercise capacity in patients with heart failure.

The weak relationship between left ventricular function and exercise capacity in heart failure has stimulated interest in neurohumoral mechanisms as possibly contributing to exercise intolerance. Although chronic activation of neuroendocrine systems is characteristic of heart failure and is accompanied by impaired reflex responsiveness to physiologic stimuli, data from clinical trials do not support the hypothesis that the abnormal neurohumoral state is directly related to exercise intolerance. Thus, these systems may play an important role in the natural history of the disease and its high mortality, but they may not be critical to the impaired exercise capacity.

Blood Circulation↗
PubMed1992

First- and third-order models for determining arterial compliance.

BACKGROUND: Engineering models of the arterial vasculature have been used to describe vascular properties of resistance and compliance. These approaches have used either Fourier frequency analysis, based on transmission line equations, or time domain analysis of the circuit equations describing modified Windkessel models of the vasculature. DESIGN: A third-order, four-element modified Windkessel model can reproduce arterial pressure waveforms, including both exponential and oscillatory pressure decays observed during the diastolic portion of the cardiac cycle. METHOD: A method to determine both capacitive and oscillatory compliance of the arterial vasculature was developed, and the effect of these compliance properties on the blood pressure waveform was examined.

Arteries↗
PubMed1992

Abnormalities of vascular compliance in hypertension, aging and heart failure.

AIM: Diastolic arterial pulse wave analysis and a modified Windkessel model were used to evaluate the vascular response to hypertension, heart failure and aging. RESULTS: Compared to age-matched normal subjects, arterial compliance was reduced in patients with hypertension and heart failure, particularly in the vessels that contribute to resonances or oscillations in the pulse wave. In elderly subjects, the capacitive function of the arteries and compliance of the smaller arteries that contribute to oscillations were both reduced. CONCLUSION: These small-vessel structural or functional abnormalities may serve as a marker for disease and for the response to therapy.

Aging↗
PubMed1991

A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.

BACKGROUND: To define better the efficacy of vasodilator therapy in the treatment of chronic congestive heart failure, we compared the effects of hydralazine and isosorbide dinitrate with those of enalapril in 804 men receiving digoxin and diuretic therapy for heart failure. The patients were randomly assigned in a double-blind manner to receive 20 mg of enalapril daily or 300 mg of hydralazine plus 160 mg of isosorbide dinitrate daily. The latter regimen was identical to that used with a similar patient population in the effective-treatment arm of our previous Vasodilator-Heart Failure Trial. RESULTS: Mortality after two years was significantly lower in the enalapril arm (18 percent) than in the hydralazine-isosorbide dinitrate arm (25 percent) (P = 0.016; reduction in mortality, 28.0 percent), and overall mortality tended to be lower (P = 0.08). The lower mortality in the enalapril arm was attributable to a reduction in the incidence of sudden death, and this beneficial effect was more prominent in patients with less severe symptoms (New York Heart Association class I or II). In contrast, body oxygen consumption at peak exercise was increased only by hydralazine-isosorbide dinitrate treatment (P less than 0.05), and left ventricular ejection fraction, which increased with both regimens during the 2 years after randomization, increased more (P less than 0.05) during the first 13 weeks in the hydralazine-isosorbide dinitrate group. CONCLUSIONS: The similar two-year mortality in the hydralazine-isosorbide dinitrate arms in our previous Vasodilator-Heart Failure Trial (26 percent) and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent) strengthen the conclusion that vasodilator therapy should be included in the standard treatment for heart failure. The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.

Adolescent↗
PubMed1991

Future directions in vasodilator therapy for heart failure.

Vasodilator therapy has become a major pharmacologic approach for improving left ventricular function, and consequently, vasodilator drugs are being used increasingly in the treatment of heart failure. Ideally, vasodilator drugs used in the long-term management of heart failure should show clearly defined pharmacodynamic effects. These include reduced impedance to left ventricular ejection, increased venous capacitance, increased left ventricular ejection fraction and reduced heart size, absence of neurohormonal stimulation, and slowed progression of left ventricular dysfunction. The mechanisms of action and sites of activity of the various vasodilator drugs currently available vary considerably, and none as yet has proved ideal for the treatment of heart failure or hypertension. The complexity surrounding the multiple vasoconstrictor mechanisms involved in heart failure has led to a rationale for combined vasodilator therapy and certain combinations are discussed. From a therapeutic standpoint, the development of drugs with multiple mechanisms of action is particularly attractive. Flosequinan is a new vasodilator agent whose cellular mechanism of action remains uncertain. Flosequinan has the advantage of being able to relax both arterial and venous beds and as such may be particularly beneficial in the treatment of heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Reduced vascular compliance as a marker for essential hypertension.

In 38 patients with established essential hypertension and 32 age-matched normotensive control subjects proximal and distal arterial compliance were determined by computer-based assessment of the diastolic decay of a brachial arterial tracing and a modified Windkessel model of the circulation. In the hypertensive subjects compared to the normotensive subjects mean arterial pressure was 25% higher (P less than .001), systemic vascular resistance 23% higher (P less than .01), proximal compliance 19% lower (P less than .01), and distal compliance 72% lower (P less than .001). The reduction in distal compliance was highly age-dependent. In the youngest age range (45 to 54 years) little overlap appeared between hypertensive and normotensive groups, whereas in the oldest subjects studied (65 to 75 years) distal compliance was comparably low in the two groups. Thus, distal vascular compliance provides a sensitive and specific marker for the abnormal vasculature associated with hypertension and may be particularly useful in identifying the disease in young individuals with borderline blood pressure.

Aged↗
PubMed1991

Lessons from V-HeFT: questions for V-HeFT II and the future therapy of heart failure.

V-HeFT, the first mortality trial in patients with heart failure, has provided important insights regarding trial design, including patient selection and efficacy criteria. Planning of V-HeFT II, the trial comparing hydralazine-isosorbide dinitrate and enalapril, has raised additional issues regarding the power to detect mortality effects and the relative value of non-mortality endpoints for efficacy. V-HeFT has demonstrated that some vasodilator regimens can prolong life in heart failure. Hydralazine + isosorbide dinitrate reduced mortality by 27% compared to placebo in patients treated with digoxin and diuretics. The possibility of a non-vasodilator mechanism for long-term benefit of these interventions is raised by the apparently poor relationship between the magnitude of vasodilation and the favorable long-term effects. These issues need to be explored in subsequent trials. In future long-term trials, however, the need for background therapy with drugs that have been effective in reducing mortality will make the identification of life prolongation from new therapies more difficult to demonstrate.

Enalapril↗