John M. Nicklas

Acute Hemodynamic and Clinical Effects of Levosimendan in Patients With Severe Heart Failure

BackgroundWe determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure. Methods and ResultsOne hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21±1%) who had a pulmonary capillary wedge pressure ≥15 mm Hg and a cardiac index ≤2.5 L · min−1 · m−2 were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1 to intravenous infusion of levosimendan or placebo. Drug infusions were uptitrated over 4 hours from an initial infusion rate of 0.1 &mgr;g · kg−1 · min−1 to a maximum rate of 0.4 &mgr;g · kg−1 · min−1 and maintained at the maximal tolerated infusion rate for an additional 2 hours. Levosimendan caused dose-dependent increases in stroke volume and cardiac index beginning with the lowest infusion rate and achieving maximal increases in stroke volume and cardiac index of 28% and 39%, respectively. Heart rate increased modestly (8%) at the maximal infusion rate and was not increased at the 2 lowest infusion rates. Levosimendan caused dose-dependent decreases in pulmonary capillary wedge, right atrial, pulmonary arterial, and mean arterial pressures. Levosimendan appeared to improve dyspnea and fatigue, as assessed by the patient and physician, and was not associated with a significant increase in adverse events. ConclusionsLevosimendan caused rapid dose-dependent improvement in hemodynamic function in patients with decompensated heart failure. These hemodynamic effects appeared to be accompanied by symptom improvement and were not associated with a significant increase in the number of adverse events. Levosimendan may be of value in the short-term management of patients with decompensated heart failure.

Prognostic Importance of Marital Quality for Survival of Congestive Heart Failure

Mounting evidence indicates that social support is associated with better outcomes of cardiovascular disease and reduced all-cause mortality. Much less is known about the specific contribution of marital functioning to these outcomes, and the potential prognostic significance of marital quality for congestive heart failure (CHF) has not been explored. Interview and observational measures of marital quality obtained from 189 patients with CHF (139 men and 50 women) and their spouses were examined as predictors of patient survival up to 48 months after assessment and compared with prediction based on illness severity (New York Heart Association [NYHA] class). Four-year survival rates were 52.5% and 68% for male patients and female patients, respectively. In Cox regression analyses, a composite measure of marital quality predicted 4-year survival as well as the patients concurrent NYHA class did (both p <0.001). Adjusting for CHF severity did not diminish the prognostic significance of marital functioning, and prediction of survival from marital quality appeared stronger for female than for male patients. Thus, when marital quality and NYHA class are considered jointly, they both make independent, statistically significant contributions to the prediction of patient mortality.

Relation of neurohumoral activation to clinical variables and degree of ventricular dysfunction: A report from the registry of studies of left ventricular dysfunction☆

OBJECTIVES This study examined the relation between neurohumoral activation and severity of left ventricular dysfunction and congestive heart failure in a broad group of patients with depressed left ventricular function who were not recruited on the basis of eligibility for a therapeutic trial. BACKGROUND Previous studies have established the presence of neurohumoral activation in patients with severe congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to an impairment in left ventricular function. METHODS From the 6,273 patients recruited into the Studies of Left Ventricular Dysfunction Registry (SOLVD), a subgroup of 859 patients were randomly selected, and their plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were correlated with clinical findings, New York Heart Association functional class, left ventricular ejection fraction and drug use. RESULTS There was a weak but significant correlation between ejection fraction and an increase in plasma norepinephrine (rho = -0.18, p < 0.0001), plasma renin activity (rho = -0.24, p < 0.0001) and arginine vasopressin (rho = -0.12, p < 0.003). The only exception was atrial natriuretic peptide, which showed the best correlation to ejection fraction (rho = -0.37, p < 0.0001). Deterioration in functional class was associated more with increases in atrial natriuretic peptide (p = 0.0003) and plasma renin activity (p = 0.0003) and less with an increase in plasma norepinephrine. Of the clinical variables, elevated jugular venous pressure and third heart sound (S3) gallop were significantly associated with increased levels of plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. We then compared the relation of neurohormones with clinical signs, functional status, ejection fraction and drug therapy and controlled for mutual interactive effects. After adjustment, a decrease in ejection fraction was still significantly related to an increase in plasma norepinephrine, plasma renin activity and atrial natriuretic peptide. In contrast, only a difference between functional classes I and III/IV was associated with an increase in plasma renin activity and atrial natriuretic peptide levels. CONCLUSIONS Neurohumoral activation in patients with heart failure is related to severity of left ventricular functional depression, and this relation is independent of functional class or concomitant drug therapy.

Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure

BACKGROUND Elevated plasma endothelin-1 (ET-1) levels in patients with chronic heart failure correlate with pulmonary artery pressures and pulmonary vascular resistance. ET(A) receptors on vascular smooth muscle cells mediate pulmonary vascular contraction and hypertrophy. We determined the acute hemodynamic effects of sitaxsentan, a selective ET(A) receptor antagonist, in patients with chronic stable heart failure receiving conventional therapy. METHODS AND RESULTS This multicenter, double-blind, placebo-controlled trial enrolled 48 patients with chronic New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) treated with ACE inhibitors and diuretics. Patients with a baseline pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index </=2.5 L. min(-1). m(-2) were randomized to 1 of 3 doses (1.5, 3.0, or 6.0 mg/kg) of sitaxsentan or placebo as an intravenous infusion over 15 minutes. Hemodynamic responses were assessed by catheterization of the right side of the heart for 6 hours. Sitaxsentan decreased pulmonary artery systolic pressure, pulmonary vascular resistance, mean pulmonary artery pressure, and right atrial pressure (P</=0.001, 0.003, 0.017, and 0.031, respectively) but had no effect on heart rate, mean arterial pressure, pulmonary capillary wedge pressure, cardiac index, or systemic vascular resistance. Plasma ET-1 levels were elevated at baseline and decreased with sitaxsentan. CONCLUSIONS In patients with moderate to severe heart failure receiving conventional therapy, acute ET(A) receptor blockade caused selective pulmonary vasodilation associated with a reduction in plasma ET-1. Sitaxsentan may be of value in the treatment of patients with pulmonary hypertension secondary to chronic heart failure.

Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: Results of the studies of left ventricular dysfunctions (SOLVD) registry

Abstract Objectives . The aim of this study was to determine the differences in neurohumoral responses between patients with pulmonary congestion with and without impaired left ventricular ejection fraction. Background . Previous studies have established the presence of neurohumoral activation in patients with congestive heart failure. It is not known whether the activation of these neurohumoral mechanisms is related to the impairment in systolic contractility. Methods . The 898 patients recruited into the Studies of Left Ventricular Dysfunction (SOLVD) Registry substudy were examined to identify those patients with pulmonary congestion on chest X-ray film who had either unpaired ( 45%, group II) left ventricular ejection fraction. Plasma norepinephrine, plasma renin activity, arginine vasopressin and atrial natriuretic peptide levels were measured in these two groups of patients and compared with values in matched control subjects, Results . Distribution of the New York Heart Association symptom classification was the same in the two groups of patients. Compared with control subjects, patients in group II with pulmonary congestion and preserved ejection fraction had no activation of the neurohumoral mechanisms, except for a small but statistically significant increase in arginine vasopressin and plasma renin activity. Compared with patients in group II, those in group I with pulmonary congestion and unpaired ejection fraction had significant increases in plasma norepinephrine (p Conclusions . The results point to the importance of the decrease in left ventricular ejection fraction as one of the mechanisms for activation of neurohormones in patients with heart failure.

Prospective, double-blind, placebo-controlled trial of low-dose amiodarone in patients with severe heart failure and asymptomatic frequent ventricular ectopy

Sudden cardiac death is a common cause of mortality in patients with congestive heart failure. To determine if low-dose amiodarone could reduce sudden death among these patients, a prospective, placebo-controlled, double-blind pilot trial was conducted. One hundred one patients with ejection fractions less than 30%, New York Heart Association class III or IV symptoms, and frequent but asymptomatic spontaneous ventricular ectopy (Lown class II to V) were randomly assigned to treatment with low-dose amiodarone (400 mg/day for 4 weeks and then 200 mg/day) or placebo. Mean follow-up was 357 days (range 4 to 1009 days). Side effects were infrequent and there was no difference in the incidence of side effects between the treatment groups. The frequency of spontaneous ventricular ectopy in the group receiving amiodarone fell from 4992 +/- 1240 beats/24 hours at baseline to 1135 +/- 494 beats/24 hours after 1 month of treatment (p = 0.02) and remained low after 6 months, while there was no change in ventricular ectopy among the patients receiving placebo. Despite the reduction in ectopy, there was no improvement in mortality or decrease in the incidence of sudden death. One-year mortality by Kaplan-Meier analysis was 28% in the group receiving amiodarone and 19% in the group receiving placebo (p = NS). One-year mortality in patients with greater than 75% reduction in ventricular ectopy after 1 month of treatment was 31% versus 17% in patients with less than or equal to 75% ectopic suppression (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Couples coping with congestive heart failure: Role and gender differences in psychological distress

Psychological distress and marital quality were assessed with male (n = 128) and female (n = 49) congestive-heart-failure (CHF) patients and their spouses. Hopkins Symptom Check List--25 scores were in the distressed range for 57% of patients and 40% of spouses. This role difference was greater for men than for women, and a gender difference (more distress in women than men) was greater for spouses than for patients. The patients distress, but not the spouses, reflected the severity of the patients illness, and distress for both partners correlated negatively with ratings of marital quality. Female-patient couples reported better relationship quality than male-patient couples, however, and a mediation analysis indicated that the gender difference in spouse distress could be explained by marital quality. Results highlight the contextual nature of CHF distress and suggest that role differences in distress vary by gender.

Effect of long-term Enalapril therapy on neurohormones in patients with left ventricular dysfunction

Abstract The aim of this study was to compare the long-term effects of treatment with enalapril or placebo on plasma neurohormones in patients with left ventricular (LV) dysfunction. Elevated neurohormonal levels are associated with increased mortality in patients with congestive heart failure. Multiple studies have shown that angiotensin-converling enzyme inhibitors decrease mortality and morbidity in these patients. In Studies of Left Ventricular Dysfunction (SOLVD), enalapril significantly reduced mortality in patients with symptomatic LV dysfunction (treatment trial). In contrast, in patients with asymptomatic LV dysfunction (prevention trial), there was no significant reduction in mortality with enalapril therapy. The effect of enalapril was examined in 333 prevention trial and 129 treatment trial patients. Plasma norepinephrine (NE) and plasma renin activity were measured in these patients at baseline, and at 4 and 12 months of follow-up. In a subset of these patients, atrial natriuretic peptide (ANP) and arginine vasopressin were also measured. Analysis of covariance models were used to determine the effect of enalapril on each neurohormone. Participants in the treatment trial had significantly higher neurohormonal levels when compared with those in the prevention trial or normal control subjects. In the treatment trial, patients taking enalapril had a greater decrease in plasma NE levels than patients taking placebo (p

Treatment of cardiogenic shock with the hemopump left ventricular assist device

A multiinstitutional study is in progress to evaluate the Hemopump in the treatment of cardiogenic shock. Fifty-three patients with refractory cardiogenic shock were selected for Hemopump assistance. The hemodynamic definition of cardiogenic shock included (1) a cardiac index of less than 2.0 L.min-1.m-2, (2) pulmonary capillary wedge pressure of greater than 18 mm Hg, and (3) a systolic blood pressure of less than 90 mm Hg or a left ventricular work index of less than 1,500 g-m.m-2.min-1. The Hemopump was successfully inserted in 41 of 53 patients (77.3%). A significant improvement in the hemodynamic status was seen during Hemopump assistance. A minimal level of hemolysis was observed. No leg ischemia was observed. The 30-day overall survival of the Hemopump group was 31.7%. Criteria establishing indications for use and clinical utility are proposed. We conclude that the Hemopump provides significant hemodynamic support of the patient in cardiogenic shock allowing for recovery from ventricular stunning in marginal ventricles, and that in select patients the Hemopump may offer a major improvement in survival over conventional therapy.

Effects of repeated brief coronary occlusion on regional left ventricular function and dimension in dogs

The cumulative effects of repeated, brief episodes of regional ischemia on myocardial function and dimension were examined in 14 open-chest dogs. The left anterior descending coronary artery was occluded for 5 minutes, followed by 10 minutes of reflow, repeated 16 times, and then 1 hour recovery. Systolic function decreased progressively in segments made repetitively ischemic and remained depressed even after 1 hour of recovery. Average systolic shortening decreased 20% from baseline after recovery from the first occlusion, 82% after the 8th, 91% after the 16th, and 104% after the 1 hour recovery (p less than 0.015, analysis of variance). End-diastolic segment length progressively increased in regions made repetitively ischemic, lengthening 4% after the first occlusion, 10% after the third occlusion, 19% after the sixteenth occlusion, and 16% after 1 hour of recovery (p less than 0.02). Nonischemic end-diastolic segment length also showed a smaller but parallel increase, while non-ischemic systolic function showed compensatory improvement. After the dogs were killed, myocardial staining with triphenyl tetrazolium chloride revealed no necrosis. Electron microscopy, performed in 5 dogs, showed scattered mitochondrial swelling in both postischemic and nonischemic regions, but no evidence of irreversible injury. The ratio of myocardial blood flow in the region made repetitively ischemic to nonischemic flow, as measured with microspheres, was 1.00 +/- 0.02 before the occlusions and 0.90 +/- 0.03 just before death (difference not significant). Thus, in the dog progressively abnormal regional systolic function and regional and global diastolic dilatation can be produced by repetitive, brief, coronary occlusions, which are not associated with histochemical or ultrastructural evidence of myocardial necrosis.