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Biomedical subjects

M Packer

Publications and source records attributed to M Packer.

At least 19 recordsLinked to original sources
PubMed1992

Long-term strategies in the management of heart failure: looking beyond ventricular function and symptoms.

Therapeutic approaches to the management of heart failure have traditionally focused on shortterm hemodynamic and symptomatic goals, but present evidence suggests that most therapeutic decisions have long-term consequences. Treatment may change the rate of disease progression, modify the need for additional therapy, influence the number of hospitalizations, and alter the risk of death. However, there may be little relation between a drug's short-term effect on cardiac function or cardiovascular symptoms and its long-term effect on survival. Some therapeutic interventions favorably influence the outcome of patients with heart failure, even though they exert negative inotropic effects; others adversely affect the outcome of patients, even though they markedly improve cardiac performance. This discordance might be explained if the most important predictor of response to a therapeutic intervention in heart failure were the effect of the pharmacologic agent on neurohormonal systems rather than on hemodynamic variables. In general, drugs that decrease the effects of the sympathetic nervous system (digitalis glycosides) and the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitors) reduce the risk of worsening heart failure. Conversely, drugs that potentiate the effects, or increase the activity, of the sympathetic nervous system (phosphodiesterase inhibitors) or the renin-angiotensin system (calcium antagonists) increase cardiovascular morbidity and mortality. These observations suggest that physicians should no longer focus on short-term hemodynamic or symptomatic goals in the treatment of heart failure but, instead, should manage patients to improve both the quality and quantity of life.

Cardiotonic Agents↗
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

The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure.

Because physicians have traditionally considered heart failure to be a hemodynamic disorder, they have described the syndrome of heart failure using hemodynamic concepts and have designed treatment strategies to correct the hemodynamic derangements of the disease. However, although hemodynamic abnormalities may explain the symptoms of heart failure, they are not sufficient to explain the progression of heart failure and, ultimately, the death of the patient. Therapeutic interventions may improve the hemodynamic status of patients but adversely affect their long-term outcome. These findings have raised questions about the validity of the hemodynamic hypothesis and suggest that alternative mechanisms must play a primary role in advancing the disease process. Several lines of evidence suggest that neurohormonal mechanisms play a central role in the progression of heart failure. Activation of the sympathetic nervous system and renin-angiotensin system exerts a direct deleterious effect on the heart that is independent of the hemodynamic actions of these endogenous mechanisms. Therapeutic interventions that block the effects of these neurohormonal systems favorably alter the natural history of heart failure, and such benefits cannot be explained by the effect of these treatments on cardiac contractility and ejection fraction. Conversely, pharmacologic agents that adversely influence neurohormonal systems in heart failure may increase cardiovascular morbidity and mortality, even though they exert favorable hemodynamic effects. These observations support the formulation of a neurohormonal hypothesis of heart failure and provide the basis for the development of novel therapeutic strategies in the next decade.

Adrenergic beta-Antagonists↗
PubMed1992

Lack of relation between ventricular arrhythmias and sudden death in patients with chronic heart failure.

Although both asymptomatic ventricular arrhythmias and sudden death are common in patients with chronic heart failure, there is little evidence that patients who have frequent or complex ventricular arrhythmias are at increased risk of sudden death. Two hypotheses may explain the lack of an arrhythmia-sudden death relation in this disorder. First, complex ventricular arrhythmias may be a nonspecific manifestation of a dying left ventricle rather than an indication of a specific arrhythmogenic substrate. In fact, during long-term follow-up, patients with mild heart failure who have nonsustained ventricular tachycardia are more likely to develop clinical progression of the disease rather than sudden death. Second, sudden death may be related to events other than a malignant ventricular arrhythmia. The most common myocardial ischemia, whereas the terminal event in patients with an idiopathic dilated cardiomyopathy is commonly a severe bradyarrhythmia or electromechanical dissociation. Neither outcome can be predicted by a prior history of ventricular arrhythmias on ambulatory electrocardiographic monitoring. If asymptomatic ventricular arrhythmias do not lead to sudden death, then there would appear to be little reason to expect that antiarrhythmic drugs could prevent cardiac arrest in patients with chronic heart failure. This may explain why drugs that suppress ambulatory arrhythmias do not prevent sudden death in these patients, whereas interventions may reduce the risk of unexpected circulatory collapse in this disorder without suppressing ventricular ectopic activity. To make matters more complicated, the desirable actions of antiarrhythmic drugs are attenuated and their negative inotropic and proarrhythmic actions are enhanced in patients with severe cardiac dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗
PubMed1991

Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group.

BACKGROUND: Milrinone, a phosphodiesterase inhibitor, enhances cardiac contractility by increasing intracellular levels of cyclic AMP, but the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined. METHODS: We randomly assigned 1,088 patients with severe chronic heart failure (New York Heart Association class III or IV) and advanced left ventricular dysfunction to double-blind treatment with (40 mg of oral milrinone daily (561 patients) or placebo (527 patients). In addition, all patients received conventional therapy with digoxin, diuretics, and a converting-enzyme inhibitor throughout the trial. The median period of follow-up was 6.1 months (range, 1 day to 20 months). RESULTS: As compared with placebo, milrinone therapy was associated with a 28 percent increase in mortality from all causes (95 percent confidence interval, 1 to 61 percent; P = 0.038) and a 34 percent increase in cardiovascular mortality (95 percent confidence interval, 6 to 69 percent; P = 0.016). The adverse effect of milrinone was greatest in patients with the most severe symptoms (New York Heart Association class IV), who had a 53 percent increase in mortality (95 percent confidence interval, 13 to 107 percent; P = 0.006). Milrinone did not have a beneficial effect on the survival of any subgroup. Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P = 0.006) and syncope (P = 0.002), more often than the patients given placebo. CONCLUSIONS: Our findings indicate that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure. The mechanism by which the drug exerts its deleterious effects is unknown.

Aged↗
PubMed1991

Activation of neurohumoral systems following acute myocardial infarction.

Previous studies have indicated that patients with an acute myocardial infarction have marked activation of all neurohumoral systems on admission to the hospital. This activation begins to subside within the first 72 hours so that by 7-10 days, all plasma neurohormones have returned to normal. The only documented exceptions were found to occur in patients with left ventricular dysfunction and overt heart failure, where both plasma renin activity and atrial natriuretic peptide were increased, and in patients with left ventricular dysfunction but no overt heart failure, where only atrial natriuretic peptide was increased. Although these studies suggest that neurohumoral activation rarely occurs at the time of hospital discharge, they were small and may have missed an important subgroup of patients with persistent neurohumoral activation. In the Survival and Ventricular Enlargement (SAVE) study, 522 patients had plasma neurohumoral levels measured at a mean of 12 days postinfarction. All SAVE patients had left ventricular dysfunction (left ventricular ejection fraction less than or equal to 40%), but no overt heart failure. In this group of patients, all neurohumoral levels (plasma renin activity, norepinephrine, arginine vasopressin, and atrial natriuretic peptide) were found to be increased compared with age-matched control subjects. These results indicate that, in fact, a subgroup of patients without overt heart failure has persistent neurohumoral activation at the time of hospital discharge postinfarction, and that this activation involves several neurohumoral systems. Since patients with persistent neurohumoral activation postinfarction are likely those most at risk of developing complications and the ones most likely to benefit from pharmacologic interventions blunting the effects of neurohumoral activation, measurement of predischarge neurohumoral levels may be useful.

Humans↗
PubMed1991

Sex differences in the management of coronary artery disease. Survival and Ventricular Enlargement Investigators.

BACKGROUND: Despite the fact that coronary artery disease is the leading cause of death among women, previous studies have suggested that physicians are less likely to pursue an aggressive approach to coronary artery disease in women than in men. To define this issue further, we compared the care previously received by men and women who were enrolled in a large postinfarction intervention trial. METHODS: We assessed the nature and severity of anginal symptoms and the use of antianginal and antiischemic interventions before enrollment in the 1842 men and 389 women with left ventricular ejection fractions less than or equal to 40 percent after an acute myocardial infarction who were randomized in the Survival and Ventricular Enlargement trial. RESULTS: Before their index infarction, women were as likely as men to have had angina and to have been treated with antianginal drugs. However, despite reports by women of symptoms consistent with greater functional disability from angina, fewer women had undergone cardiac catheterization (15.4 percent of women vs. 27.3 percent of men, P less than 0.001) or coronary bypass surgery (5.9 percent of women vs. 12.7 percent of men, P less than 0.001). When these differences were adjusted for important covariates, men were still twice as likely to undergo an invasive cardiac procedure as women, but bypass surgery was performed with equal frequency among the men and women who did undergo cardiac catheterization. CONCLUSIONS: Physicians pursue a less aggressive management approach to coronary disease in women than in men, despite greater cardiac disability in women.

Angina Pectoris↗
PubMed1991

The erythrocyte sedimentation rate in congestive heart failure.

BACKGROUND AND METHODS: Physicians have long believed that the erythrocyte sedimentation rate is low in patients with congestive heart failure, but this concept is based on a misinterpretation of the results in a single report published in 1936. To reevaluate this concept in the modern era, we measured the sedimentation rate in 242 patients who were referred for treatment of chronic heart failure. RESULTS: The sedimentation rate was low (less than 5 mm per hour) in only 24 patients (10 percent) but was increased (above 25 mm per hour) in 50 percent. Patients with low or normal sedimentation rates (less than or equal to 25 mm per hour) had more severe hemodynamic abnormalities than patients with elevated rates: lower cardiac index (mean +/- SEM, 1.7 +/- 0.1 vs. 2.0 +/- 0.1 liters per minute per square meter of body-surface area) and higher mean right atrial pressure (mean +/- SEM, 12 +/- 1 vs. 9 +/- 1 mm Hg) (both P less than 0.0001). New York Heart Association functional class IV symptoms were present in 66 percent of the patients with a low or normal sedimentation rate, as compared with 42 percent of those with elevated rates (P less than 0.0001). After one to three months of therapy, patients whose sedimentation rates decreased showed little hemodynamic or clinical response to treatment, whereas both cardiac performance and functional status improved in patients whose rates increased (P less than 0.02 for the comparison between groups). The sedimentation rate was correlated with the plasma fibrinogen level (r = 0.64, P = 0.0025), and changes in the sedimentation rate during treatment were correlated inversely with changes in mean right atrial pressure (r = -0.57, P = 0.0002). During long-term follow-up, patients with low or normal sedimentation rates had a worse one-year survival than patients with elevated rates (41 vs. 66 percent, P = 0.01). CONCLUSIONS: These data indicate that the erythrocyte sedimentation rate is correlated with the severity of illness in patients with chronic heart failure. Because of its lack of discriminatory power, however, the test is of limited value in the clinical management of this disorder.

Blood Sedimentation↗
PubMed1991

Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure.

Previous efforts to block the renin-angiotensin system in patients with chronic congestive heart failure (CHF) have focused on 2 distal sites in the system, the angiotensin-converting enzyme and the angiotensin II receptor. Recent work, however, has led to the development of agents that directly inhibit renin, the proximal step in the cascade. In this study, we investigated the hemodynamic effects of renin inhibition in 9 patients with chronic CHF by using enalkiren, a primate-selective, dipeptide renin inhibitor, which has been previously shown to suppress plasma renin activity and to lower blood pressure in hypertensive patients. The acute intravenous administration of enalkiren (1.0 mg/kg) produced increases in cardiac index (2.0 +/- 0.3 to 2.3 +/- 0.1 liter/min/m2) and stroke volume index (26 +/- 3 to 34 +/- 4 ml/m2) and decreases in left ventricular filling pressure (31 +/- 3 to 25 +/- 3 mm Hg), mean right atrial pressure (15 +/- 1 to 13 +/- 2 mm Hg), heart rate (78 +/- 5 to 72 +/- 6 beats/min) and systemic vascular resistance (2,199 +/- 594 to 1,339 +/- 230 dynes.s.cm-5) (all p less than 0.01 to 0.05). These observations indicate that renin inhibition produces hemodynamic benefits in patients with chronic CHF and could potentially provide a novel approach to interfering with the renin-angiotensin system in patients with this disorder.

Adult↗
PubMed1990

Elevated circulating levels of tumor necrosis factor in severe chronic heart failure.

BACKGROUND AND METHODS: Although cachexia often accompanies advanced heart failure, little is known about the causes of the cachectic state. To assess the potential role of tumor necrosis factor in the pathogenesis of cardiac cachexia, we measured serum levels of the factor in 33 patients with chronic heart failure, 33 age-matched healthy controls, and 9 patients with chronic renal failure. RESULTS: Mean (+/- SEM) serum levels of tumor necrosis factor were higher in the patients with heart failure (115 +/- 25 U per milliliter) than in the healthy controls (9 +/- 3 U per milliliter; P less than 0.001). Nineteen of the patients with chronic heart failure had serum levels of tumor necrosis factor greater than or equal to 39 U per milliliter (greater than 2 SD above the mean value for the control group), whereas the remaining 14 patients had serum levels of tumor necrosis factor below this level. The patients with high levels of tumor necrosis factor were more cachectic than those with low levels (82 +/- 3 vs. 95 +/- 6 percent of ideal body weight, respectively; P less than 0.05) and had more advanced heart failure, as evidenced by their higher values for plasma renin activity (2.92 +/- 0.53 vs. 1.06 +/- 0.53 ng per liter per second [10.5 +/- 1.9 vs. 3.8 +/- 1.9 ng per milliliter per hour]; P less than 0.01) and lower serum sodium concentration (135 +/- 1 vs. 138 +/- 1 mmol per liter; P less than 0.05). The group with high levels of tumor necrosis factor also had lower hemoglobin levels (7.82 +/- 0.2 vs. 8.69 +/- 0.4 mmol per liter [12.6 +/- 0.4 vs. 14.0 +/- 0.6 g per deciliter]) and higher values for blood urea nitrogen (19.5 +/- 2.2 vs. 12.5 +/- 1.8 mmol per liter) than the group with low levels of tumor necrosis factor (P less than 0.05 for both). The high levels of tumor necrosis factor were not due solely to decreased renal clearance, however, since the levels in the patients with heart failure were considerably higher than those in the nine patients with chronic renal failure (115 +/- 25 vs. 45 +/- 25 U per milliliter; P less than 0.05). CONCLUSIONS: These findings indicate that circulating levels of tumor necrosis factor are increased in cachectic patients with chronic heart failure and that this elevation is associated with the marked activation of the renin-angiotensin system seen in patients with end-stage cardiac disease.

Adult↗
PubMed1990

Potential role of potassium as a determinant of morbidity and mortality in patients with systemic hypertension and congestive heart failure.

Prehistoric animals and humans consumed a diet low in sodium but high in potassium, and thus, evolutionary forces fostered the development of physiologic systems that conserved sodium and excreted potassium. With the advent of civilized societies, food cooking and processing have greatly increased the sodium but decreased the potassium content of the diet. However, there has been little time for physiologic systems to adapt. The resulting excess of sodium has been implicated as an important factor in the development of hypertension and congestive heart failure. This traditional focus on sodium has ignored the potential role that an inadequate dietary intake of potassium might play in the degenerative diseases of the heart, brain and kidney. Yet dietary potassium may be as powerful a determinant of cardiovascular morbidity and mortality as dietary sodium. In experimental and clinical hypertension, an increased intake of potassium (without a change in dietary sodium) can reduce blood pressure, may suppress the activity of the sympathetic nervous and renin-angiotensin systems, and can prevent the development of vascular injury; conversely, potassium depletion has been associated with an increase in stroke and sudden death. In patients with chronic heart failure, potassium can modify both the mechanical and electrical properties of the heart, it can exert diuretic effects, and it can reduce the frequency and complexity of potentially lethal ventricular tachyarrhythmias. Given this central role, the effects of many pharmacologic interventions on the morbidity and mortality of patients with hypertension or chronic heart failure can be enhanced or diminished by the effect that these treatments might have on potassium homeostasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Heart Failure↗
PubMed1990

The placebo effect in heart failure.

Many patients who are enrolled in controlled clinical trials of new drugs for the treatment of heart failure show favorable hemodynamic and clinical responses to placebo therapy. This "placebo effect" results from both the creation of a supportive therapeutic environment and the spontaneous improvement that is commonly seen when measurements of symptoms and cardiac function are repeated frequently over long intervals of time. Three months of treatment with a placebo produces a reduction in symptoms in 25% to 35% of patients, an increase in cardiac output and a decrease in pulmonary wedge pressure, and an increase in exercise tolerance of up to 90 to 120 seconds. Physicians commonly seek to maximize the "placebo effect," since the goal of treatment in the clinical setting is to improve the quality of the patient's life. On the other hand, clinical investigators seek to minimize the "placebo effect," since the goal of a research study is to test the hypothesis that the new drug is superior to a placebo.

Heart Failure↗