Richard J. Rodeheffer

Effect of Oral Milrinone on Mortality in Severe Chronic Heart Failure

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 Patients treated with milrinone had more hospitalizations (44 vs. 39 percent, P = 0.041), were withdrawn from double-blind therapy more frequently (12.7 vs. 8.7 percent, P = 0.041), and had serious adverse cardiovascular reactions, including hypotension (P =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.

Plasma brain natriuretic peptide concentration: impact of age and gender

OBJECTIVES We wished to examine the effects of age and gender on plasma brain natriuretic peptide (BNP) concentration in a population-based study. BACKGROUND Measurement of BNP concentration is approved for use in the diagnosis of heart failure and may aid in the detection of left ventricular dysfunction. Although BNP is approved for clinical use, there are few data regarding the range of BNP observed in persons without cardiovascular disease or cardiac dysfunction. These data are essential for the interpretation of BNP. METHODS In 2,042 randomly selected residents of Olmsted County, Minnesota, >44 years old, BNP (Shionogi and Biosite assays), Doppler echocardiography, and medical record review were performed. A normal subset of subjects (n = 767) in sinus rhythm without cardiovascular, renal, or pulmonary disease or diabetes; on no cardiovascular medications; and with normal systolic, diastolic, and valvular function was identified. RESULTS Within the normal subset, the distribution of BNP differed by age, gender, and assay system. With both assays, BNP increased significantly with age and was significantly higher in women than men, leading to age-, gender-, and assay-specific reference ranges. Receiver operating characteristic analysis for the ability of BNP to detect an ejection fraction < or = 40% was performed in each age/gender stratum in the entire cohort (n = 2,042) and confirmed that discriminatory values for BNP for detection of reduced ejection fraction were higher in women and older persons and were different between the two assays. CONCLUSIONS Interpretation of BNP should include consideration of age-, gender-, and assay-specific partition values.

Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction: A Community-Based Study

OBJECTIVES This study sought to define the prevalence, severity, and significance of pulmonary hypertension (PH) in heart failure with preserved ejection fraction (HFpEF) in the general community. BACKGROUND Although HFpEF is known to cause PH, its development is highly variable. Community-based data are lacking, and the relative contribution of pulmonary venous versus pulmonary arterial hypertension (HTN) to PH in HFpEF is unknown. We hypothesized that PH would be a marker of symptomatic pulmonary congestion, distinguishing HFpEF from pre-clinical hypertensive heart disease. METHODS This community-based study of 244 HFpEF patients (age 76 +/- 13 years; 45% male) was followed up using Doppler echocardiography over 3 years. Control subjects were 719 adults with HTN without HF (age 66 +/- 10 years; 44% male). Pulmonary artery systolic pressure (PASP) was derived from the tricuspid regurgitation velocity and PH defined as PASP >35 mm Hg. Pulmonary capillary wedge pressure (PCWP) was estimated from the ratio of early transmitral flow velocity to early mitral annular diastolic velocity. RESULTS In HFpEF, PH was present in 83% and the median (25th, 75th percentile) PASP was 48 (37, 56) mm Hg. PASP increased with PCWP (r = 0.21; p < 0.007). Adjusting for PCWP, PASP was higher in HFpEF than HTN (p < 0.001). The PASP distinguished HFpEF from HTN with an area under the receiver-operating characteristic curve of 0.91 (p < 0.001) and strongly predicted mortality in HFpEF (hazard ratio: 1.3 per 10 mm Hg; p < 0.001). CONCLUSIONS PH is highly prevalent and often severe in HFpEF. Although pulmonary venous HTN contributes to PH, it does not fully account for the severity of PH in HFpEF, suggesting that a component of pulmonary arterial HTN also contributes. The potent effect of PASP on mortality lends support for therapies aimed at pulmonary arterial HTN in HFpEF.

The Frequency of Familial Dilated Cardiomyopathy in a Series of Patients with Idiopathic Dilated Cardiomyopathy

BACKGROUND Dilated cardiomyopathy is characterized by an increase in ventricular size and impairment of ventricular function. Most cases are believed to be sporadic, and familial dilated cardiomyopathy is usually considered to be a rare and distinct disorder. We studied the proportion of cases of idiopathic dilated cardiomyopathy that were familial in a large sequential series of patients whose first-degree relatives were investigated regardless of whether these relatives had cardiac symptoms. METHODS We studied relatives of 59 index patients with idiopathic dilated cardiomyopathy of obtaining a family history and performing a physical examination, electrocardiography, and two-dimensional, M-mode, and Doppler echocardiography. A total of 315 relatives were examined. RESULTS Eighteen relatives from 12 families were shown to have dilated cardiomyopathy. Thus, 12 of the 59 index patients (20.3 percent) had familial disease. There was no difference in age, sex, severity of disease, exposure to selected environmental factors, or electrocardiographic or echocardiographic features between the index patients with familial disease and those with nonfamilial disease. A noteworthy finding was that 22 of 240 healthy relatives (9.2 percent) with normal ejection fractions had increased left ventricular diameters during systole or diastole (or both), as compared with 2 of 112 healthy control subjects (1.8 percent) who were studied separately. CONCLUSIONS Dilated cardiomyopathy was found to be familial in at least one in five of the patients in this study, a considerably higher percentage than in previous reports. This finding has important implications for family screening and provides direction for further investigation into the causes and natural history of dilated cardiomyopathy.

Endothelin in human congestive heart failure

BACKGROUND Although recent investigations report the elevation of plasma endothelin (ET) in congestive heart failure (CHF), it remains unclear if this elevation is that of the biologically active peptide ET-1 or of its precursor big-ET. Furthermore, it is unclear if such elevation is associated with increased myocardial ET and if the molecular form from cardiac tissue is altered ET. Last, it remains to be established whether circulating ET is increased at the earliest stage of CHF in patients with asymptomatic left ventricular dysfunction and correlates with the magnitude of ventricular dysfunction. METHODS AND RESULTS The present study was designed to investigate concentrations and molecular forms of ET in plasma and cardiac tissue in healthy subjects and CHF patients with New York Heart Association (NYHA) class I through IV using cardiac radionuclide angiogram, cardiac myocardial biopsy, radioimmunoassay, gel permeation chromatography (GPC), and immunohistochemical staining (IHCS). Plasma ET was increased only in patients with moderate (NYHA class III) or severe (NYHA class IV) CHF compared with healthy subjects and individuals with asymptomatic (NYHA class I) or mild (NYHA class II) CHF. The elevation of circulating ET in CHF showed a negative correlation with left ventricular ejection fraction and cardiac index and a positive correlation with functional class and left ventricular end-diastolic volume index. GPC demonstrated that immunoreactive plasma ET was ET-1 in healthy subjects and both mature ET-1 and its precursor big-ET in severe CHF patients, with big-ET the predominant molecular form. Cardiac tissue concentrations and IHCS revealed ET presence in healthy atrial and ventricular tissue, which were not different in severe CHF. GPC revealed that the molecular form of cardiac ET was ET-1 in both healthy and CHF hearts. CONCLUSIONS The present study establishes for the first time that the elevation of plasma ET in severe human CHF represents principally elevation of big-ET. Second, ET is present in healthy and failing myocardia, and its activity by both immunohistochemistry and radioimmunoassay is not changed in CHF. Furthermore, the elevated plasma ET is characteristic of severe CHF and not asymptomatic or mild CHF. In addition, the degree of plasma elevation of ET correlates with the magnitude of alterations in cardiac hemodynamics and functional class. The present study confirms and extends previous investigations of ET in human CHF and establishes the evolution of circulating and local cardiac ET in the spectrum of human CHF.

Age- and Gender-Related Ventricular-Vascular Stiffening A Community-Based Study

Background— Increases in vascular (Ea), ventricular systolic (Ees), and ventricular diastolic (Ed) elastance (stiffness) may contribute to the pathogenesis of heart failure (HF) with preserved ejection fraction (HFnlEF). The prevalence of HFnlEF increases strikingly with age, particularly in women. We hypothesized that ventricular-vascular stiffening may occur with age and be more pronounced in women in the general community. Methods and Results— In a cross-sectional sample of Olmsted County, Minn, residents ≥45 years old (n=2042), clinical data, Doppler echocardiography, and blood pressure (BP) measurements were obtained. Ea was calculated from stroke volume and systolic BP and indexed to body size (EaI). Ees was calculated by a modified single-beat method using systolic and diastolic BP, stroke volume, ejection fraction, timing intervals, and an estimated normalized ventricular elastance at arterial end diastole. Operant Ed was calculated from Doppler indices reflective of atrial pressures and the diastolic filling volume. EaI, Ees, and Ed all increased with age in men and in women (P<0.0001 for all). Ees increased more steeply with age in women (P=0.002). Adjusted for age, EaI, Ees, and Ed were higher in women than in men (P<0.0001 for all). Findings were similar in those without known or suspected cardiovascular disease (n=623). Conclusions— In the community, advancing age and female gender are associated with increases in vascular and ventricular systolic and diastolic stiffness even in the absence of cardiovascular disease. We speculate that this combined ventricular-vascular stiffening may contribute to the increased prevalence of HFnlEF in elderly persons and particularly in elderly women.

Left Atrial Volume as an Index of Left Atrial Size: A Population-Based Study

OBJECTIVES We studied left atrial volume (LAV) as an index of atrial size. BACKGROUND Increased left atrial dimension (LAD) measured by M-mode echocardiography is a risk factor for atrial fibrillation, stroke, and death. METHODS A random sample of residents of Olmsted County, Minnesota, age > or =45 years (n = 2,042) underwent Doppler echocardiography with assessment of LAD and LAV. A subgroup of the population (n = 767) with no cardiovascular disease and normal systolic and diastolic function was used to develop reference ranges for LAD and LAV. In the total population, the prevalence of left atrial enlargement and the association between cardiovascular disease and left atrial size as determined by both indexes were assessed. RESULTS In the normal subgroup, both indexes were associated with gender and body size, thus models controlling for body size were used to determine gender-specific reference ranges for LAD and LAV. In the total population, left atrial enlargement was common, with a prevalence of 18% (men) and 12% (women) using LAD/body surface area (BSA) and of 16% (men and women) using LAV/BSA. The agreement between the indexes was only fair (kappa = 0.53). Adjusting for age and gender, LAV/BSA was more strongly associated with the presence of cardiovascular diseases than LAD/BSA. CONCLUSIONS We described a simple technique of measuring LAV, examined methods for indexing LAV, and described its normal range in a large, healthy reference cohort. Further, we find that in the community, left atrial enlargement is common and reflects the burden of cardiovascular disease.

Cardiac Structure and Ventricular–Vascular Function in Persons With Heart Failure and Preserved Ejection Fraction From Olmsted County, Minnesota

Background— Mechanisms purported to contribute to the pathophysiology of heart failure with normal ejection fraction (HFnlEF) include diastolic dysfunction, vascular and left ventricular systolic stiffening, and volume expansion. We characterized left ventricular volume, effective arterial elastance, left ventricular end-systolic elastance, and left ventricular diastolic elastance and relaxation noninvasively in consecutive HFnlEF patients and appropriate controls in the community. Methods and Results— Olmsted County (Minn) residents without cardiovascular disease (n=617), with hypertension but no heart failure (n=719), or with HFnlEF (n=244) were prospectively enrolled. End-diastolic volume index was determined by echo Doppler. End-systolic elastance was determined using blood pressure, stroke volume, ejection fraction, timing intervals, and estimated normalized ventricular elastance at end diastole. Tissue Doppler e velocity was used to estimate the time constant of relaxation. End-diastolic volume (EDV) and Doppler-derived end-diastolic pressure (EDP) were used to derive the diastolic curve fitting (α) and stiffness (β) constants (EDP=αEDVβ). Comparisons were adjusted for age, sex, and body size. HFnlEF patients had more severe renal dysfunction, yet smaller end-diastolic volume index and cardiac output and increased EDP compared with both hypertensive and healthy controls. Arterial elastance and ventricular end-systolic elastance were similarly increased in hypertensive controls and HFnlEF patients compared with healthy controls. In contrast, HFnlEF patients had more impaired relaxation and increased diastolic stiffness compared with either control group. Conclusions— From these cross-sectional observations, we speculate that the progression of diastolic dysfunction plays a key role in the development of heart failure symptoms in persons with hypertensive heart disease.

Natriuretic peptide system in human heart failure.

BACKGROUND Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are a family of structurally related peptides that participate in the integrated control of renal and cardiovascular function. Previous studies suggest a functional role for these hormonal peptides in cardiorenal regulation in congestive heart failure (CHF). METHODS AND RESULTS The present studies were performed in normal subjects (n = 6) and in patients with mild (New York Heart Association [NYHA] class I to II, n = 20) and severe (NYHA class III to IV, n = 20) CHF by use of radioimmunoassay and immunohistochemical staining (IHCS). Plasma ANP was significantly increased in both mild and severe CHF compared with normal subjects. In contrast, plasma BNP was only moderately increased in the severe CHF group, and plasma CNP concentration was unchanged in CHF compared with normal subjects. Atrial tissue concentrations of the natriuretic peptides did not parallel circulating concentrations. ANP predominated in normal atrial tissue, but BNP predominated in CHF. In ventricular tissue, IHCS staining was present for all three peptides in normal ventricular myocardium and was markedly enhanced in CHF. CONCLUSIONS These studies support a differential regulation of ANP, BNP, and CNP circulating concentrations and tissue activity in human CHF.

Prevalence and etiology of idiopathic dilated cardiomyopathy (summary of a National Heart, Lung, and Blood Institute Workshop)

Idiopathic dilated cardiomyopathy (IDC) is the primary indication for cardiac transplantation, with associated costs of approximately