Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure.

BACKGROUND: Arginine vasopressin may contribute to abnormalities in hemodynamics and fluid balance in heart failure through its actions on V(1A) (vascular and myocardial effects) and V(2) receptors (renal effects). Inhibiting the action of vasopressin may be beneficial in patients with heart failure. METHODS AND RESULTS: A total of 142 patients with symptomatic heart failure (New York Heart Association class III and IV) were randomized to double-blind, short-term treatment with conivaptan, a dual V(1a)/V(2) vasopressin receptor antagonist, at a single intravenous dose (10, 20, or 40 mg) or placebo. Compared with placebo, conivaptan at 20 and 40 mg significantly reduced pulmonary capillary wedge pressure (-2.6+/-0.7, -5.4+/-0.7, and -4.6+/-0.7 mm Hg for placebo and 20 and 40 mg groups, respectively; P<0.05) and right atrial pressure (-2.0+/-0.4, -3.7+/-0.4, and -3.5+/-0.4 mm Hg for placebo and 20 and 40 mg groups, respectively; P<0.05) during the 3- to 6-hour interval after intravenous administration. Conivaptan significantly increased urine output in a dose-dependent manner (-11+/-17, 68+/-17, 152+/-19, and 176+/-18 mL/hour for placebo and 10, 20, and 40 mg groups, respectively; P<0.001) during the first 4 hours after the dose. Changes in cardiac index, systemic and pulmonary vascular resistance, blood pressure, and heart rate did not significantly differ from placebo. CONCLUSIONS: In patients with advanced heart failure, vasopressin receptor antagonism with conivaptan resulted in favorable changes in hemodynamics and urine output without affecting blood pressure or heart rate. These data suggest that vasopressin is functionally significant in advanced heart failure and that further investigations are warranted to examine the effects of conivaptan on symptom relief and natural history in such patients.

Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure?

BACKGROUND: The diagnosis of diastolic heart failure is generally made in patients who have the signs and symptoms of heart failure and a normal left ventricular (LV) ejection fraction. Whether the diagnosis also requires an objective measurement of parameters that reflect the diastolic properties of the ventricle has not been established. METHODS AND RESULTS: We hypothesized that the vast majority of patients with heart failure and a normal ejection fraction exhibit abnormal LV diastolic function. We tested this hypothesis by prospectively identifying 63 patients with a history of heart failure and an echocardiogram suggesting LV hypertrophy and a normal ejection fraction; we then assessed LV diastolic function during cardiac catheterization. All 63 patients had standard hemodynamic measurements; 47 underwent detailed micromanometer and echocardiographic-Doppler studies. The LV end-diastolic pressure was >16 mm Hg in 58 of the 63 patients; thus, 92% had elevated end-diastolic pressure (average, 24+/-8 mm Hg). The time constant of LV relaxation (average, 51+/-15 ms) was abnormal in 79% of the patients. The E/A ratio was abnormal in 48% of the patients. The E-wave deceleration time (average, 349+/-140 ms) was abnormal in 64% of the patients. One or more of the indexes of diastolic function were abnormal in every patient. CONCLUSIONS: Objective measurement of LV diastolic function serves to confirm rather than establish the diagnosis of diastolic heart failure. The diagnosis of diastolic heart failure can be made without the measurement of parameters that reflect LV diastolic function.

Coronary angiographic findings in African-American and white patients from a single institution.

No data exist comparing clinical and angiographic findings in large numbers of contemporary African-American and white patients from the same hospital. Limited angiographic data on African Americans were obtained from hospitals serving predominantly minority patients, making the valid African-American:white comparisons difficult. The study included 2,624 consecutive white and 1,793 African-American patients who had angiography for diagnostic evaluation of presumed coronary artery disease at the Louisiana State University Medical Center in Shreveport between 1990 and 1997. Compared to whites of the same sex, a greater proportion of African-American patients had a history of hypertension, stroke, and heart failure. African Americans also had significantly higher systemic and left ventricular pressure, lower ejection fraction, greater echocardiographic left ventricular mass index, and more concentric hypertrophy. The overall proportion of patients with normal or minimal stenosis of coronary artery (<50% narrowing in the luminal diameter) was greater in African Americans than in whites for both men and women. This difference was predominately found in men aged > or = 55 years or older. Except among older men, African-American patients with coronary heart disease had a similar distribution of 1-, 2-, 3-vessel disease and mean stenosis score compared to whites. In conclusion, a higher frequency of normal coronaries and less frequent coronary stenosis were found in older African-American men. The African-American:white differences in angiographic findings were minimal in younger men and in women. However, African Americans had worse clinical profiles than whites.

Effect of mibefradil, a T-type calcium channel blocker, on morbidity and mortality in moderate to severe congestive heart failure: the MACH-1 study. Mortality Assessment in Congestive Heart Failure Trial.

BACKGROUND: Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients. METHODS AND RESULTS: This multicenter, randomized, double-blind study compared mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (alpha=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (P=0.093). Treatment groups had similar cardiovascular mortality (P=0.246), cardiovascular morbidity/mortality (P=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of death. Substudies demonstrated no significant differences between treatments. CONCLUSIONS: When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.

A 65-year-old woman with heart failure.

The differential diagnosis for a 65-year-old woman with heart failure is discussed in the setting of a clinicopathological conference at Louisiana State University Medical Center in Shreveport. The discussion includes precipitating factors, pathophysiology, and etiologies of heart failure.

Influence of left ventricular geometric patterns on prognosis in patients with or without coronary artery disease.

OBJECTIVES: We sought to examine patterns of left ventricular (LV) geometry as determined by echocardiography and their association with mortality in patients with or without coronary artery disease (CAD). BACKGROUND: The independent prognostic role of LV geometry remains uncertain. METHODS: We performed a cohort study based on 988 consecutive patients who underwent both coronary arteriography for presumed CAD and echocardiography and were followed up for a mean of 9 years (range 5 to 13). Patients were classified into four LV geometry patterns: normal, concentric remodeling, eccentric LV hypertrophy (LVH) and concentric LVH. RESULTS: Patients with concentric LVH consistently showed the largest increase in LV posterior wall and septal thickness and LV mass index, as well as relative wall thickness (RWT), regardless of status of the coronary arteries. This pattern conferred the highest risk of both all-cause and cardiac mortality. Eccentric LVH moderately increased the risk of death compared with normal geometry; no substantial increase in mortality was noted in patients with concentric remodeling. When LV index and RWT were analyzed as continuous measures and considered in the same Cox proportional hazards model, increases in LV mass were independently associated with risk, but this outcome was less clear for RWT. CONCLUSIONS: In this series of patients referred to coronary angiography for suspected CAD, LVH conferred most of the predictive information from echocardiography. Patients with both LVH and abnormal RWT--concentric LVH--represent a group with the greatest mortality risk. Concentric remodeling may not be associated with increased risk of death because the predictive value of RWT is not as strong as for LV mass.

Heart failure in women.

Heart failure is a major and growing public health problem in the United States. Hospitalization and death for heart failure have risen dramatically and the proportion of women with heart failure, especially older women, is projected to be the predominant group in the next 3 decades. There is growing evidence that the etiology, pathophysiology, prognosis, and response to treatment may all be different in women. In addition, there is evidence that hypertension plays a more prominent role and that preserved left ventricular systolic function is more likely to be found in women. There are legitimate questions about the degree of benefit that women receive from standard medications. A major obstacle in our understanding of heart failure in women has been their underrepresentation in major clinical trials. Current emphasis on ensuring adequate representation in clinical trials should help to further our understanding of heart failure in women and its management.

Role of cytokines in the mechanism of action of amlodipine: the PRAISE Heart Failure Trial. Prospective Randomized Amlodipine Survival Evaluation.

OBJECTIVES: We sought to determine whether the beneficial effects of amlodipine in heart failure may be mediated by a reduction in tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels. We postulated that TNF-alpha and IL-6 levels may also have predictive value in patients with congestive heart failure (CHF). BACKGROUND: The molecular mechanism for progression of CHF may involve cytokine overexpression. The effect of amlodipine on cytokine levels in patients with CHF is unknown. METHODS: In the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial, we used enzyme-linked immunosorbent assay to measure plasma levels of TNF-alpha in 92 patients and IL-6 in 62 patients in New York Heart Association functional classes III and IV randomized to receive amlodipine (10 mg/day) or placebo. Blood samples were obtained for cytokine measurement at baseline and at 8 and 26 weeks after enrollment. RESULTS: The baseline amlodipine and placebo groups did not differ in demographics and cytokine levels. Mean (+/- SD) plasma levels of TNF-alpha were 5.69 +/- 0.32 pg/ml, and those of IL-6 were 9.23 +/- 1.26 pg/ml at baseline. These levels were elevated 6 and 10 times, respectively, compared with those of normal subjects (p < 0.001). Levels of TNF-alpha did not change significantly over the 26-week period (p = 0.69). However, IL-6 levels were significantly lower at 26 weeks in patients treated with amlodipine versus placebo (p = 0.007 by the Wilcoxon signed-rank test). An adverse event-CHF or death-occurred more commonly in patients with higher IL-6 levels. CONCLUSIONS: Amlodipine lowers plasma IL-6 levels in patients with CHF. The beneficial effect of amlodipine in CHF may be due to a reduction of cytokines such as IL-6.

Prediction of mortality risk by different methods of indexation for left ventricular mass.

OBJECTIVES: We sought to compare the predictive value of echocardiographically determined left ventricular hypertrophy on death from all causes and cardiac mortality using various methods of indexation for left ventricular mass. BACKGROUND: Considerable controversy exists regarding the optimal method for indexing left ventricular mass to body size in the clinical setting. METHODS: The study included 988 consecutive patients who had both coronary angiograms and echocardiographic examinations in an inner-city public hospital in Chicago, Illinois. Patients were followed up for a mean of 7 years (range 2 to 11). RESULTS: Various left ventricular mass indexes (e.g., mass indexed for height, height2, height2.13, height2.7, body surface area and body surface area1.5 were highly correlated (r = 0.90 to 0.99). Used as a continuous measure, an increase in any left ventricular mass index was associated with similar risk of death from all causes and cardiac diseases. Although left ventricular hypertrophy assessed by mass indexed for body surface area using the published conventional partition values provided somewhat better prediction, the adjusted relative risk was in general not significantly different from hypertrophy based on other indexes. Patients with left ventricular hypertrophy defined concordantly by indexes based on both body surface area and height (or height2.7) had, by definition, the highest average mass indexes among all groups and experienced as much as a threefold greater risk of death than those without hypertrophy. A small proportion of patients (12%) who were classified into the hypertrophy group by height-based indexes alone, but not by body surface area, had a moderate increase in mass and showed no increase in risk, even though being overweight was extremely prevalent in this group. CONCLUSIONS: Because of the high correlation among various body size indexes, left ventricular hypertrophy, defined by different indexes for left ventricular mass, similarly confers increased risk of mortality in patients with or without coronary artery disease.

Patterns of physician use of angiotensin converting enzyme inhibitors in the inpatient treatment of congestive heart failure.

Randomized clinical trails have demonstrated that angiotensin-converting enzyme (ACE) inhibitors reduce mortality, improve symptoms, and decrease hospitalization rates in congestive heart failure (CHF) patients with impaired left ventricular systolic function. Guidelines from the Agency for Healthcare Policy and Research (AHCPR) endorse the use of ACE inhibitors in eligible CHF patients and note their underutilization in practice. Randomly selected records of 1,212 Medicare CHF patients in Louisiana, discharged between July 1993 and October 1993, were reviewed. Abstracted data were used to characterize practice patterns and pertinent clinical factors influencing current ACE inhibitor utilization by practicing physicians in eligible Medicare CHF patients admitted to acute care hospitals. A total of 1,133 patients admitted were discharged alive; mean age was 77.6 years (64% female; 68% white). One third of the patients (34%) were already receiving ACE inhibitors on admission; of these, 85% were discharged on ACE inhibitors. The remaining 66% of patients were not on an ACE inhibitor on admission; only 35% of these are documented to have been placed on an ACE inhibitor(s) at discharge. Overall, a significantly large number of CHF patient charts (48%) lacked documentation of LV systolic function assessments. On multivariate logistic regression modeling, the following key clinical variables were positively related to the prescription of ACE inhibitors: low ejection fraction, dyspnea and orthopnea, normal creatinine levels, high diastolic blood pressure, cardiomegaly, and increasing age. Among patients with low ejection fraction, factors contributing to not being discharged on ACE inhibitors included: high creatinine levels, history of myocardial infarction or ischemic heart disease, renal failure, and being African American. This study documents the underutilization of ACE inhibitors in patients with impaired left ventricular systolic function. Results suggest the need for increased physician-based educational efforts concerning the use of ACE inhibitors in CHF patients, and also for increasing left ventricular systolic function assessments and documentation of findings in patient charts.

A new interference in some digoxin assays: anti-murine heterophilic antibodies.

BACKGROUND: We describe a patient with cirrhotic liver disease and atrial fibrillation who was treated with spironolactone and digoxin. He was hospitalized because of an incidental finding of a high serum digoxin level (4.2 micrograms/L), but he remained asymptomatic without emerging arrhythmias. Despite discontinuation of both drugs, his serum digoxin level persisted at or above 3.0 micrograms/L for approximately 5 weeks, drawing into question the accuracy of the digoxin assay. METHODS: Additional digoxin methods gave lower, discrepant results, providing evidence of an assay interference, and several possible sources of digoxin false positivity were evaluated. This included assessment of the contribution of digoxin-like immunoreactive factor (DLIF), digoxin metabolites, and spironolactone. Because the routine digoxin assay used a monoclonal antibody, we also tested for another hypothetical interference: human heterophilic ("anti-mouse") antibodies. RESULTS: We found no contribution from DLIF, digoxin antibodies, or spironolactone to the apparent digoxin results. However, the use of protein A to complex and selectively remove immunoglobulin G molecules markedly lowered the apparent digoxin value, as did the less specific process of ultrafiltration. CONCLUSIONS: These results suggest a previously unreported cause of digoxin false positivity: heterophilic antibodies, which have been reported to bind murine monoclonal antibodies in other assays. Because newer digoxin assays now use murine monoclonal antibodies, the possible presence of heterophilic, anti-mouse antibodies should now be considered in the interpretation of a high digoxin level.

Effect of amlodipine on morbidity and mortality in severe chronic heart failure. Prospective Randomized Amlodipine Survival Evaluation Study Group.

BACKGROUND: Previous studies have shown that calcium-channel blockers increase morbidity and mortality in patients with chronic heart failure. We studied the effect of a new calcium-channel blocker, amlodipine, in patients with severe chronic heart failure. METHODS: We randomly assigned 1153 patients with severe chronic heart failure and ejection fractions of less than 30 percent to double-blind treatment with either placebo (582 patients) or amlodipine (571 patients) for 6 to 33 months, while their usual therapy was continued. The randomization was stratified on the basis of whether patients had ischemic or nonischemic causes of heart failure. The primary end point of the study was death from any cause and hospitalization for major cardiovascular events. RESULTS: Primary end points were reached in 42 percent of the placebo group and 39 percent of the amlodipine group, representing a 9 percent reduction in the combined risk of fatal and nonfatal events with amlodipine (95 percent confidence interval, 24 percent reduction to 10 percent increase; P=0.31). A total of 38 percent of the patients in the placebo group died, as compared with 33 percent of those in the amlodipine group, representing a 16 percent reduction in the risk of death with amlodipine (95 percent confidence interval, 31 percent reduction to 2 percent increase; P=0.07). Among patients with ischemic heart disease, there was no difference between the amlodipine and placebo groups in the occurrence of either end point. In contrast, among patients with nonischemic cardiomyopathy, amlodipine reduced the combined risk of fatal and nonfatal events by 31 percent (P=0.04) and decreased the risk of death by 46 percent (P<0.001). CONCLUSIONS: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.