The Subclinical Cardiomyopathy of Friedreich's Ataxia in a Pediatric Population.

BACKGROUND: Identification of a subclinical cardiomyopathy in pediatric patients with Friedreich's ataxia (FA) has not been well-described. METHODS: We performed echocardiography (Echo), cardiac magnetic resonance imaging (cMRI), and neurologic assessment in a cross-sectional analysis of 48 genetically confirmed FA subjects aged 9-17 years with moderate neurologic impairment but without a cardiovascular history. Echo- and cMRI-determined left ventricular mass were indexed (LVMI) to height in grams/m2.7. LV remodeling was categorized as concentric remodeling (CR), concentric hypertrophy (CH), or eccentric hypertrophy based upon Echo- determined relative LV wall thickness. RESULTS: Echo LVMI exceeded age-based normal values in 85% of subjects, and cMRI-determined LVMI correlated with depression of both diastolic and systolic tissue Doppler velocity (E': r = -0.65, P < .001, S': r = -0.46, P < .001) as well as increased early diastolic Doppler flow velocity/tissue velocity ratio (r= 0.55, P < .001), a marker of elevated LV filling pressure. Similar associations were found with echo-determined LV mass. Evidence of depressed LV relaxation and increased LV stiffness were observed in 88% and 71%, of subjects, respectively, despite a normal LV ejection fraction in almost all cases (mean = 60% + 7%). CR and CH were present in 40% and 44% of the study group, respectively, although significant depressions of E' and S' were observed only in subjects with CH (P < .005). CONCLUSIONS: A subclinical hypertrophic cardiomyopathy is common in pediatric FA patients and CH is associated with both diastolic and systolic dysfunction.

Effect of bucindolol on heart failure outcomes and heart rate response in patients with reduced ejection fraction heart failure and atrial fibrillation.

AIMS: There is little evidence of beta-blocker treatment benefit in patients with heart failure and reduced left ventricular ejection fraction (HFREF) and atrial fibrillation (AF). We investigated the effects of bucindolol in HFREF patients with AF enrolled in the Beta-blocker Evaluation of Survival Trial (BEST). METHODS AND RESULTS: A post-hoc analysis of patients in BEST with and without AF was performed to estimate the effect of bucindolol on mortality and hospitalization. Patients were also evaluated for treatment effects on heart rate and the influence of beta1-adrenergic receptor position 389 (ß(1)389) arginine (Arg) vs. glycine (Gly) genotypes. In the 303/2708 patients in AF, patients receiving bucindolol were more likely to achieve a resting heart rate ≤ 80 b.p.m. at 3 months (P < 0.005) in the absence of treatment-limiting bradycardia. In AF patients and sinus rhythm (SR) patients who achieved a resting heart rate ≤ 80 b.p.m., there were beneficial treatment effects on cardiovascular mortality/cardiovascular hospitalization [hazard ratio (HR) 0.61, P = 0.025, and 0.79, P = 0.002]. Without achieving a resting heart rate ≤ 80 b.p.m., there were no treatment effects on events in either group. ß(1)389-Arg/Arg AF patients had nominally significant reductions in all-cause mortality/HF hospitalization and cardiovascular mortality/hospitalization with bucindolol (HR 0.23, P = 0.037 and 0.28, P = 0.039), whereas Gly carriers did not. There was no evidence of diminished heart rate response in ß(1)389-Arg homozygotes. CONCLUSION: In HFREF patients with AF, bucindolol was associated with reductions in composite HF endpoints in those who achieved a resting heart rate ≤ 80 b.p.m. and nominally in those with the ß(1)389-Arg homozygous genotype.

Combinatorial pharmacogenetic interactions of bucindolol and ß1, α2C adrenergic receptor polymorphisms.

BACKGROUND: Pharmacogenetics involves complex interactions of gene products affecting pharmacodynamics and pharmacokinetics, but there is little information on the interaction of multiple genetic modifiers of drug response. Bucindolol is a ß-blocker/sympatholytic agent whose efficacy is modulated by polymorphisms in the primary target (ß(1) adrenergic receptor [AR] Arg389 Gly on cardiac myocytes) and a secondary target modifier (α(2C) AR Ins [wild-type (Wt)] 322-325 deletion [Del] on cardiac adrenergic neurons). The major allele homozygotes and minor allele carriers of each polymorphism are respectively associated with efficacy enhancement and loss, creating the possibility for genotype combination interactions that can be measured by clinical trial methodology. METHODOLOGY: In a 1,040 patient substudy of a bucindolol vs. placebo heart failure clinical trial, we tested the hypothesis that combinations of ß(1)389 and α(2C)322-325 polymorphisms are additive for both efficacy enhancement and loss. Additionally, norepinephrine (NE) affinity for ß(1)389 AR variants was measured in human explanted left ventricles. PRINCIPAL FINDINGS: The combination of ß(1)389 Arg+α(2C)322-325 Wt major allele homozygotes (47% of the trial population) was non-additive for efficacy enhancement across six clinical endpoints, with an average efficacy increase of 1.70-fold vs. 2.32-fold in ß(1)389 Arg homozygotes+α(2C)322-325 Del minor allele carriers. In contrast, the minor allele carrier combination (13% subset) exhibited additive efficacy loss. These disparate effects are likely due to the higher proportion (42% vs. 8.7%, P = 0.009) of high-affinity NE binding sites in ß(1)389 Arg vs. Gly ARs, which converts α(2C)Del minor allele-associated NE lowering from a therapeutic liability to a benefit. CONCLUSIONS: On combination, the two sets of AR polymorphisms 1) influenced bucindolol efficacy seemingly unpredictably but consistent with their pharmacologic interactions, and 2) identified subpopulations with enhanced (ß(1)389 Arg homozygotes), intermediate (ß(1)389 Gly carriers+α(2C)322-325 Wt homozygotes), and no (ß(1)389 Gly carriers+α(2C)322-325 Del carriers) efficacy.

Determination of hospitalization type by investigator case report form or adjudication committee in a large heart failure clinical trial (ß-Blocker Evaluation of Survival Trial [BEST]).

BACKGROUND: End point committees are routinely used to adjudicate efficacy and safety end points in clinical trials. The 2,708-patient ß-Blocker Evaluation of Survival Trial (BEST) originally determined hospitalization type via investigator case report forms (CRFs), which captured whether a hospitalization was due to worsening heart failure (HF). Recently, the BEST End Points Committee (EPC) completed a blinded adjudication of all hospitalizations, allowing a comparison of the CRF method to the EPC method of determining hospitalization type. We sought to compare the investigator-determined mode of hospitalizations with the adjudicated events, to quantify the degree of agreement, and to compare the clinical trial results by method of event classification. METHODS: The BEST EPC reviewed all 5,086 hospitalizations that occurred in BEST. Events were identified using investigator-reported hospitalizations, as well as those documented by FDA Form 3500 (MedWatch) reports. RESULTS: The investigators identified more HF hospitalization events than adjudication (2,466 vs 1,729, P < .0001, paired analysis). Eight hundred thirty-four (34%) HF hospitalizations identified in CRFs were not confirmed by adjudication. Ninety-seven (6%) adjudicated events were not identified by the investigator reported method. One thousand six hundred thirty-two events were similarly identified by both methods. CONCLUSIONS: The EPC adjudication identified fewer HF hospitalizations than did the investigator reported method with no change in the hazard ratio for this end point. Our findings suggest that independent end point committees may improve reliability through reduced variance, thus providing similar outcome results with fewer events and no increase in CIs.

Correlation of echocardiographic findings with cerebral infarction in elderly adults: the AGES-Reykjavik study.

BACKGROUND AND PURPOSE: Chronic effects of hypertension may be observed in multiple end organs. Previous reports suggest that cardiovascular morphological features can mirror cerebral infarction. In this cross-sectional analysis of elderly subjects, we investigated the relationship of a comprehensive set of echocardiographic measures with cerebral infarction detected by MRI. METHODS: We compared echocardiographically determined left ventricular (LV) mass, left atrial volume, aortic root diameter, mitral annular calcification, and measures of diastolic function with cerebral infarction determined by MRI using logistic regression in a random sample drawn from the Age Gene/Environment Susceptibility-Reykjavik Study cohort. The model was first adjusted for age and gender, and then for age, gender, and vascular risk factors. RESULTS: Among 692 subjects aged 75 (standard deviation, 6) years, 28% had at least 1 cerebral infarct. When adjusted for age and gender, the presence of cerebral infarction was modestly related to LV mass (odds ratio [OR], 1.01; 95% confidence interval [CI], 1.00-1.02) and left atrial volume (OR, 1.03; 95% CI, 1.01-1.05), as well as the lowest quartile of early-to-late pulsed Doppler velocity ratio (early-to-late pulsed Doppler velocity ratio <0.75; OR, 1.87; 95% CI, 1.22-2.87). The latter relation remained significant after adjustment for vascular risk factors and LV ejection fraction (OR, 1.82; 95% CI, 1.16-2.86). CONCLUSIONS: Of all echocardiographic parameters, LV filling abnormality as indicated by low early-to-late pulsed Doppler velocity ratio displayed the strongest association with cerebral infarction and this relationship was independent of vascular risk factors. This simple marker of cerebral infarction may be useful when evaluating older patients.

Exercise capacity and idebenone intervention in children and adolescents with Friedreich ataxia.

OBJECTIVE: To determine the exercise capacity of children and adolescents with Friedreich's Ataxia (FA) and to evaluate the effects of 6 months of idebenone treatment on exercise capacity. DESIGN: Exploratory endpoint in a randomized double-blind, placebo-controlled, phase II clinical trial designed to investigate the effects of idebenone on a biomarker of oxidative stress. SETTING: Exercise physiology laboratory in a single clinical research center. PARTICIPANTS: Ambulatory subjects (N=48; age range, 9-17 y) with genetically confirmed FA. INTERVENTION: Idebenone administered orally 3 times a day for a total daily dose of approximately 5, 15, and 45 mg/kg or matching placebo for 6 months. MAIN OUTCOME MEASURES: Peak oxygen consumption per unit time (peak VO(2)) and peak work rate (WR) were measured during incremental exercise testing at baseline and after treatment. Echocardiography and neurologic assessments were also completed before and after treatment. RESULTS: Baseline mean peak VO(2) +/- SD was 746+/-246 mL/min (16.2+/-5.8 mL/kg/min), and WR was 40+/-23 W for all subjects. Peak VO(2) and WR were correlated with short guanine-adenine-adenine allele length and neurologic function. Relative left ventricular wall thickness was increased but left ventricular ejection fraction was normal in most subjects; there was no relationship between any exercise and echocardiographic measures. There were no significant changes in mean peak VO(2) or WR after idebenone treatment at any dose level relative to placebo. CONCLUSIONS: Exercise capacity in children and adolescents with FA was significantly impaired. The basis for the impairment appears to be multifactorial and correlated to the degree of neurologic impairment. Although idebenone has previously been shown potentially to improve features of FA, idebenone treatment did not increase exercise capacity relative to placebo.

Myocardial structure and function by echocardiography in relation to glucometabolic status in elderly subjects from 2 population-based cohorts: a cross-sectional study.

BACKGROUND: Left ventricular (LV) diastolic dysfunction has been associated with impaired glucometabolic status. However, studies of older subjects are lacking. We examined associations between echocardiographic indices of LV diastolic function and LV mass index (LVMI) and glucometabolic status among middle-aged and elderly subjects free from heart disease, hypothesizing that the associations would be comparative to younger cohorts. METHODS: We examined the Age Gene/Environment Susceptibility Reykjavik Study (Iceland; n = 607, 76 +/- 6 years) and the Malmö Preventive Project Re-Examination Study (MPP-RES) cohorts (Sweden; n = 1,519, 67 +/- 6 years), evaluating associations with multivariable regression analysis. RESULTS: In the Age Gene/Environment Susceptibility Reykjavik Study, LVMI was positively correlated with glycosylated hemoglobin (HbA1c) (P = .001). Otherwise, echocardiographic variables were not associated with glucometabolic status. In the MPP-RES, LVMI increased with increasing glucometabolic disturbance among both older (70-80 years) and middle-aged (57-69 years) subjects. Among older subjects, HbA1c was positively correlated with 2 variables reflecting LV diastolic function: late transmitral peak flow velocity (A) (P = .001) and early transmitral peak flow velocity (E)/early diastolic peak tissue velocity (Em) (P = .046). In middle-aged MPP-RES subjects, increasing glucometabolic disturbance was correlated with increasing late diastolic peak tissue velocity (Am) (P = .002) and, after age adjustment, with increasing A (P = .001) and decreasing Em/Am (P = .009). With age adjustment, Am and A were positively correlated with fasting glucose and HbA1c. CONCLUSIONS: Contrary to our hypothesis, in 2 independent cohorts of older individuals, associations between glucometabolic status and LV diastolic function were generally weak. These contrast with previous reports, as well as with observations among middle-aged subjects in the present study. Changes in LV diastolic function may be more age-related than associated with glucose metabolism in older subjects.

Exercise blood pressure and the risk of incident cardiovascular disease (from the Framingham Heart Study).

Exaggerated systolic blood pressure (BP) augmentation with exercise has been associated with impaired endothelial function and cardiovascular risk. However, previous studies were largely restricted to men, did not evaluate diastolic BP, and focused on peak exercise measures, which are influenced by effort and fitness level. The aim of this study was to determine the association of exercise BP responses with risk of incident cardiovascular disease (CVD). BP was assessed during stage 2 of the Bruce protocol and during recovery in 3,045 Framingham Study subjects (mean age 43 years; 53% women). The association between exercise BP and CVD events during 20 years of follow-up was examined using Cox proportional hazards models. In age- and sex-adjusted analyses, exercise systolic and diastolic BP were associated with incident CVD (adjusted hazard ratios [HRs] for top quintile 1.55, 95% confidence interval [CI] 1.18 to 2.04; and 1.77, 95% CI 1.35 to 2.31, respectively, relative to the lower 4 quintiles; p <0.005). After adjustment for BP at rest and conventional risk factors, exercise diastolic BP (HR 1.41, 95% CI 1.01 to 1.95, p = 0.04), but not exercise systolic BP (HR 0.97, 95% CI 0.68 to 1.38, p = 0.86), remained a significant predictor of CVD. Similarly, in recovery responses after exercise, only diastolic BP (HR 1.53, 95% CI 1.08 to 2.18, p = 0.02) predicted incident CVD in multivariable models. In conclusion, in middle-aged adults, diastolic BP during low-intensity exercise and recovery predicted incident CVD. Our findings support the concept that dynamic BP provides incremental information to BP at rest and suggest that exercise diastolic BP may be a better predictor than exercise systolic BP in this age group.

Ventilatory efficiency and resting hemodynamics in hypertrophic cardiomyopathy.

PURPOSE: In patients with systolic heart failure, the ability of cardiopulmonary exercise testing (CPX) variables to reflect pathophysiology is well established. The relationship between CPX and pathophysiology has, however, not been thoroughly investigated in patients with nonobstructive hypertrophic cardiomyopathy (NHCM). The objective of this study was to assess the ability of CPX variables to reflect resting hemodynamics in patients with nonobstructive hypertrophic cardiomyopathy NHCM. METHODS: We performed CPX and right heart catheterization on 83 subjects with NHCM (51 male/32 female, mean age = 38 +/- 10 yr, NYHA I-III mean = 1.7). Peak oxygen consumption ( O2) and minute ventilation/carbon dioxide ratio (V E/VCO2) at peak exercise were compared to resting hemodynamics including pulmonary artery systolic, diastolic and mean pressures (PASP, PADP and MPAP), and pulmonary capillary wedge pressure (PCWP). RESULTS: Elevations in PCWP (> or = 15 mm Hg), PASP (> or =30 and > or = 40 mm Hg), PADP (> 15 mm Hg) and MPAP (> or = 20 mm Hg) were detected in 22, 33, 10, and 23% of subjects, respectively. Peak V E/VCO2 (positive correlation) and peak VO2 (negative correlation) correlated modestly with all pressure measurements (r = 0.33-0.51, P < 0.01 for all measurements). By receiver operating curve analysis, a V E/VCO2 >35.5 exhibited the best diagnostic accuracy with a curve areas of 0.81 for PAP > or = 30 mm Hg (sensitivity/specificity = 86%/67%), 0.87 for PAP > or = 40 mm Hg (77%/100%), 0.86 for MPAP > 20 mm Hg (83%/79%), and 0.84 for PCWP > or = 15 mm Hg (80%/76%). CONCLUSIONS: CPX can accurately identify abnormal resting hemodynamics in patients with NHCM. Further testing of this modality in other forms of diastolic dysfunction may be warranted.

Adaptive postprocessing techniques for myocardial tissue tracking with displacement-encoded MR imaging.

UNLABELLED: The purpose of this study was to prospectively assess the effects of two adaptive postprocessing techniques on the evaluation of myocardial function with displacement-encoded magnetic resonance (MR) imaging, including sensitivity for abnormal wall motion, with two-dimensional echocardiography as the reference standard. Sixteen patients (11 men, five women; age range, 26-74 years) and 12 volunteers (six men, six women; age range, 29-53 years) underwent breath-hold MR imaging. Institutional review board approval and informed consent were obtained. Adaptive phase-unwrapping and spatial filtering techniques were compared with conventional phase-unwrapping and spatial filtering techniques. Use of the adaptive techniques led to a reduced rate of failure with the phase-unwrapping technique from 18.9% to 0.6% (P < .001), resulted in lower variability of segmental strain measurements among healthy volunteers (P < .001 to P = .02), and increased the sensitivity of quantitative detection of abnormal segments in patients from 82.5% to 87.7% (P = .034). The adaptive techniques improved the semiautomated postprocessing of displacement-encoded cardiac images and increased the sensitivity of detection of abnormal wall motion in patients. SUPPLEMENTAL MATERIAL: http://radiology.rsnajnls.org/cgi/content/full/246/1/229/DC1.

Antiangiogenic and antitumor effects of bevacizumab in patients with inflammatory and locally advanced breast cancer.

PURPOSE: Vascular endothelial growth factor (VEGF) is a potent molecule that mediates tumor angiogenesis primarily through VEGF receptor 2 (VEGFR2). Bevacizumab, a recombinant humanized monoclonal antibody to VEGF, was administered to previously untreated patients to evaluate parameters of angiogenesis. PATIENTS AND METHODS: Twenty-one patients with inflammatory and locally advanced breast cancer were treated with bevacizumab for cycle 1 (15 mg/kg on day 1) followed by six cycles of bevacizumab with doxorubicin (50 mg/m(2)) and docetaxel (75 mg/m(2)) every 3 weeks. After locoregional therapy, patients received eight cycles of bevacizumab alone, and hormonal therapy when indicated. Tumor biopsies and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were obtained at baseline, and after cycles 1, 4, and 7. RESULTS: A median decrease of 66.7% in phosphorylated VEGFR2 (Y951) in tumor cells (P = .004) and median increase of 128.9% in tumor apoptosis (P = .0008) were seen after bevacizumab alone. These changes persisted with the addition of chemotherapy. There were no significant changes in microvessel density or VEGF-A expression. On DCE-MRI, parameters reflecting reduced angiogenesis, a median decrease of 34.4% in the inflow transfer rate constant (P = .003), 15.0% in the backflow extravascular- extracellular rate constant (P = .0007) and 14.3% in extravascular-extracellular volume fraction (P = .002) were seen after bevacizumab alone. CONCLUSION: Bevacizumab has inhibitory effects on VEGF receptor activation and vascular permeability, and induces apoptosis in tumor cells.

Is functional capacity related to left atrial contractile function in nonobstructive hypertrophic cardiomyopathy?

The mechanisms underlying reduced exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy (NHCM) could include perturbations of ventricular relaxation, diastolic compliance, or compensatory atrial systolic function. We hypothesized that a loss of atrial contractility in NHCM patients leads to reduced functional capacity. To test this hypothesis, we compared resting noninvasive left atrial ejection phase indices in 49 consecutive patients with NHCM (ages 36+/-10 years; 41% female) and normal left ventricular ejection fraction (mean, 68%+/-8%) with objective metabolic exercise parameters. Left atrial active emptying fraction, ejection force, and kinetic energy failed to predict exercise capacity. Only left atrial total and active emptying volumes correlated weakly with minute volume/CO2 production slope (r=0.31 and r=0.33; p<0.05 for both). Furthermore, when subjects were stratified by New York Heart Association symptomatology, exercise parameters--but not atrial contractility--differed between groups. These data, obtained at rest, fail to suggest that NHCM-related heart failure symptoms are due to an atrial myopathy.

Magnetic resonance imaging assessment of myocardial elastic modulus and viscosity using displacement imaging and phase-contrast velocity mapping.

Approximately half of patients experiencing congestive heart failure present with a normal left ventricular ejection fraction. Perturbations in material properties affecting ventricular pressure/volume relationships likely play an important role in the "stiff heart syndrome" yet noninvasive tools permitting the accurate assessment of myocardial elasticity are extremely limited. We developed an MRI-based technique to examine regional left ventricular stress/strain relationships by incorporating displacement-encoding with stimulated-echoes (DENSE) and phase-contrast (PC) velocity mapping and compared regional elastic moduli (EM) and viscous delay time constants (VDTCs) (N=10) with immediate postmortem direct strain gauge measurements (N=8) and global chamber compliance (literature) in normal dogs. EMs by MRI were significantly greater in papillary muscle columns when compared with lateral wall and septal locations by MRI (7.59+/-1.65 versus 3.40+/-0.87 versus 2.55+/-0.93 kPa, P<0.0001) and were in agreement with direct strain gauge measurements (3.78+/-0.93 and 2.96+/-0.88 kPa for the lateral wall and the septum, P=ns for both versus MRI). MRI-determined VDTCs were similar in the three regions (VDTC=-1.15+/-12.37 versus 3.04+/-7.25 versus 4.17+/-5.76 ms, P=ns) and did not differ from lateral and septal wall strain gauge assessment (VDTC=3.09+/-0.40 and 4.57+/-1.86 ms, P=ns for both versus MRI). Viscoelastic measurements obtained in six normal volunteers demonstrated the feasibility of this technique in humans. Noninvasive, regional assessment of myocardial stiffness using DENSE and PC velocity mapping techniques is accurate in a canine model and feasible in humans.

Left atrial volumetric remodeling is predictive of functional capacity in nonobstructive hypertrophic cardiomyopathy.

BACKGROUND: The left atrium is afterload sensitive, responding to immediate changes in left ventricular (LV) diastolic pressure, and left atrial volumetric remodeling has been reported in conditions associated with abnormal diastolic function. We examined the relationship between left atrial volumetric remodeling and objective measures of exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy (HCM). METHODS: We compared LA volume indices, other 2-dimensional and Doppler echocardiographic parameters, invasive hemodynamic measures, and magnetic resonance imaging (MRI)-derived LV mass with exercise duration, maximal oxygen uptake (MV* O2), anaerobic threshold (AT), and ventilatory efficiency (VE/V* CO2 slope) in 43 patients with nonobstructive HCM. Patients underwent cardiac catheterization within 48 hours and metabolic stress testing within 1 week of their echocardiogram and MRI examinations. RESULTS: Left atrial volume at end-ventricular systole (LA max) and end-atrial emptying (LA min) correlated with MV* O2 (r = -0.39, P < .01 for both), AT (r = -0.42, r = -0.39, respectively, P < .01 for both), and VE/V* CO2 slope (r = 0.45, P = .003; r = 0.41, P = .008). Patients with an LA max > or =33 mL/m2 had significantly lower MV* O2 (P = .025) and AT levels (P = .017) and higher VE/V* CO2 slope levels (P = .004) as compared with patients with a smaller LA size. In multivariate analysis, MRI-determined LV mass, which was not a univariate correlate of exercise tolerance, provided additional effect when combined with LA volume index. CONCLUSIONS: Left atrial volumetric remodeling predicts exercise capacity in nonobstructive HCM and may reflect chronic LV diastolic burden. This simple noninvasive measure of LA size may provide a long-term indication of the effects of chronically elevated filling pressures in patients with HCM and further studies testing its prognostic value are necessary.

Echocardiographic predictors of morbidity and mortality in patients with advanced heart failure: the Beta-blocker Evaluation of Survival Trial (BEST).

OBJECTIVES: The aim of this study was to determine echocardiographic predictors of outcome in patients with advanced heart failure (HF) due to severe left ventricular (LV) systolic dysfunction in the Beta-blocker Evaluation of Survival Trial (BEST). BACKGROUND: Previous studies indicate that echocardiographic measurements of LV size and function, mitral deceleration time, and mitral regurgitation (MR) predict adverse outcomes in HF. However, complete quantitative echocardiograms evaluating all of these parameters have not been reported in a prospective randomized clinical trial in the era of modern HF therapy. METHODS: Complete echocardiograms were performed in 336 patients at 26 sites and analyzed by a core laboratory. A Cox proportional-hazards regression model was used to determine which echocardiographic variables predicted the primary end point of death or the secondary end point of death, HF hospitalization, or transplant. Significant variables were then entered into a multivariable model adjusted for clinical and demographic covariates. RESULTS: On multivariable analysis adjusted for clinical covariates, only LV end-diastolic volume index predicted death (events = 75), with a cut point of 120 ml/m(2). Three echocardiographic variables predicted the combined end point of death (events = 75), HF hospitalization (events = 97), and transplant (events = 9): LV end-diastolic volume index, mitral deceleration time, and the vena contracta width of MR. Optimal cut points for these variables were 120 ml/m(2), 150 ms, and 0.4 cm, respectively. CONCLUSIONS: Echocardiographic predictors of outcome in advanced HF include LV end-diastolic volume index, mitral deceleration time, and vena contracta width. These variables indicate that LV remodeling, increased LV stiffness, and MR are independent predictors of outcome in patients with advanced HF.

Impact of nonfatal myocardial infarction on outcomes in patients with advanced heart failure and the effect of bucindolol therapy.

We sought to identify the clinical characteristics and outcomes of patients who had advanced heart failure and nonfatal myocardial infarction (MI) in the beta-Blocker Evaluation of Survival Trial (BEST) and to investigate whether bucindolol alters the risk of developing nonfatal MI. Of the 2,708 patients enrolled in the study, 142 had suspected MI and 69 had confirmed MI; there were 860 deaths overall. The rate of nonfatal MI in the BEST was low over the 4.1 years of follow-up (4.8% had suspected events and 2.4% had adjudicated events) and was similar to that in high-risk populations. Cox's proportional hazard model with 23 prespecified candidate variables associated advanced age, heart failure symptoms, male gender, ischemic etiology, diabetes, and hypertension with nonfatal MI or cardiovascular death. The 2-year mortality rate was 56% for the cohort that had suspected nonfatal MI versus 30% for the cohort that did not (p = 0.01). Likewise, the risk of hospitalization for congestive heart failure was twofold greater. Beta-blocker therapy with bucindolol resulted in a 52% decrease in suspected nonfatal MI (2.9% vs 5.5%, p = 0.001). In conclusion, nonfatal MI occurs at low rates but increases the risks for mortality and hospitalization in patients who have advanced heart failure. Beta-blocker therapy with bucindolol appears to attenuate the risk of nonfatal MI in this population.