Brahma safeguards canalization of cardiac mesoderm differentiation.

Differentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1,2. Canalization is essential for stabilizing cell fate, but the mechanisms that underlie robust canalization are unclear. Here we show that the BRG1/BRM-associated factor (BAF) chromatin-remodelling complex ATPase gene Brm safeguards cell identity during directed cardiogenesis of mouse embryonic stem cells. Despite the establishment of a well-differentiated precardiac mesoderm, Brm-/- cells predominantly became neural precursors, violating germ layer assignment. Trajectory inference showed a sudden acquisition of a non-mesodermal identity in Brm-/- cells. Mechanistically, the loss of Brm prevented de novo accessibility of primed cardiac enhancers while increasing the expression of neurogenic factor POU3F1, preventing the binding of the neural suppressor REST and shifting the composition of BRG1 complexes. The identity switch caused by the Brm mutation was overcome by increasing BMP4 levels during mesoderm induction. Mathematical modelling supports these observations and demonstrates that Brm deletion affects cell fate trajectory by modifying saddle-node bifurcations2. In the mouse embryo, Brm deletion exacerbated mesoderm-deleted Brg1-mutant phenotypes, severely compromising cardiogenesis, and reveals an in vivo role for Brm. Our results show that Brm is a compensable safeguard of the fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory.

Noise-driven cellular heterogeneity in circadian periodicity.

Nongenetic cellular heterogeneity is associated with aging and disease. However, the origins of cell-to-cell variability are complex and the individual contributions of different factors to total phenotypic variance are still unclear. Here, we took advantage of clear phenotypic heterogeneity of circadian oscillations in clonal cell populations to investigate the underlying mechanisms of cell-to-cell variability. Using a fully automated tracking and analysis pipeline, we examined circadian period length in thousands of single cells and hundreds of clonal cell lines and found that longer circadian period is associated with increased intercellular heterogeneity. Based on our experimental results, we then estimated the contributions of heritable and nonheritable factors to this variation in circadian period length using a variance partitioning model. We found that nonheritable noise predominantly drives intercellular circadian period variation in clonal cell lines, thereby revealing a previously unrecognized link between circadian oscillations and intercellular heterogeneity. Moreover, administration of a noise-enhancing drug reversibly increased both period length and variance. These findings suggest that circadian period may be used as an indicator of cellular noise and drug screening for noise control.

Quantification of pulmonary/systemic shunt ratio by single-acquisition phase-contrast cardiovascular magnetic resonance.

PURPOSE: Phase-contrast cardiovascular magnetic resonance (PC-CMR) quantification of intracardiac shunt (measuring the pulmonary to systemic flow ratio, Qp/Qs) is typically determined by measuring flow through planes perpendicular the pulmonary trunk (PA) and ascending aorta (Ao). This method is subject to error from presence of background velocity offsets and requires two scan acquisitions. We evaluated an alternate PC-CMR technique for quantifying Qp/Qs using a single modified plane that encompasses both the PA and Ao. MATERIAL AND METHODS: In 53 patients evaluated for intracardiac shunting, PC-CMR measurement in the individual Ao and PA planes and also in a single-acquisition plane was obtained and Qp/Qs calculated by each method. Bland-Altman analysis was performed to evaluate the agreement between the two methods. RESULTS: The 95% confidence limits of agreement ranged from -0.52 to +0.34 indicating good agreement between the two methods. There was excellent agreement on the clinically relevant threshold value of Qp/Qs ratio of 1.5 (representing criteria for surgical correction of shunt). CONCLUSIONS: Qp/Qs determined from the single-acquisition approach agrees well with that of the individual PA and Ao method and offers potential improved accuracy (due to background velocity offset).

Left ventricular torsion shear angle volume analysis in patients with hypertension: a global approach for LV diastolic function.

BACKGROUND: Torsion shear angle φ is an important measure of left ventricular (LV) systolic and diastolic functions. Here we provide a novel index utilizing LV normalized torsion shear angle φ ^ volume V ^ loop to assess LV diastolic functional properties. We defined the area within φ ^ V ^ loop as torsion hysteresis area, and hypothesized that it may be an important global parameter of diastolic function. We evaluated the φ ^ changes to increased V ^ during early diastole - d φ ^ / d V ^ as a potential measure of LV suction. METHODS: Sixty resistant hypertension patients (HTN), forty control volunteers were studied using cardiovascular magnetic resonance with tissue tagging. Volumetric and torsional parameters were evaluated. RESULTS: HTN demonstrated concentric remodeling with preserved ejection fraction. HTN had significantly decreased normalized early filling rate, early diastolic mitral annulus velocity and E/A (1.33 ± 1.13 vs. 2.19 ± 1.07, P < 0.0001) vs. control. Torsion hysteresis area was greater (0.11 ± 0.07 vs. 0.079 ± 0.045, P < 0.001) and peak - d φ ^ / d V ^ at early diastole was higher (10.46 ± 8.51 vs. 6.29 ± 3.85, P = 0.002) than control. Torsion hysteresis area was significantly correlated with E/A (r = -0.23, P = 0.025). Thirteen HTN patients had both E/A ratio < 1.12 (Control mean E/A-1SD) and torsion hysteresis area > 0.12 (Control mean torsion hysteresis area + 1SD). CONCLUSIONS: Torsion hysteresis area and peak early diastolic - d φ ^ / d V ^ were significantly increased in hypertensive concentric remodeling. The φ ^ V ^ loop takes into account the active and passive recoil processes of LV diastolic and systolic phases, therefore provides a new global description of LV diastolic function.

Heart failure is a risk factor for incident driving cessation among community-dwelling older adults: findings from a prospective population study.

BACKGROUND: Heart failure (HF) patients often depend on driving for access to specialty care. We analyzed a public-use copy of the Cardiovascular Health Study (CHS) data to determine if HF is a risk factor for driving cessation and to identify other risk factors for driving cessation among those with HF. METHODS AND RESULTS: Of the 5,383 community-dwelling drivers aged ≥65 years (mean age 73 years, 55% women, 13% African American), 839 had HF: 246 had baseline prevalent HF and 593 developed incident HF before driving cessation during 9 years of follow-up. Incident driving cessation occurred at rates of 3,980 and 3,709 per 10,000 person-years of follow-up for those with and without HF, respectively (unadjusted hazard ratio [HR] associated with HF as a time-varying variable: 2.13, 95% confidence interval [CI] 1.83-2.47; P < .001). This association remained unchanged after multivariable risk adjustment (HR 1.43, 95% CI 1.21-1.68; P < .001). Among the 839 older drivers with HF, independent predictors for incident driving cessation were age ≥75 years (HR 1.99, 95% CI 1.44-2.73; P < .001), female gender (HR 1.93, 95% CI 1.37-2.74; P < .001), difficulty walking half a mile (HR 1.47 (1.04-2.08); P = .028), vision problems (HR 1.47, 95% CI 1.07-2.02; P = .018), and stroke as a time-varying covariate (HR 1.96, 95% CI 1.38-2.79; P < .001). CONCLUSIONS: HF is an independent risk factor for incident driving cessation among community-dwelling older drivers. Several patient characteristics predicted driving cessation in older HF patients, which may be targets for interventions to prevent driving cessation among these patients.

Unusual mechanism of tricuspid regurgitation in ventricular septal defect.

A 37-year-old woman was diagnosed to have a small ventricular septal defect (VSD) with high velocity tricuspid regurgitation (TR) that was attributed to atrio-VSD (Gerbode). Cardiac MR revealed a small subaortic VSD in the membranous portion of the interventricular septum. The atrioventricular portion was intact. Cardiac MR clearly showed flow jet through the VSD, impinging on the anterior tricuspid leaflet during systole, and bouncing back into the right atrium as TR. This ricochet mechanism of TR in VSD may be misinterpreted as Gerbode defect or as evidence of pulmonary hypertension.

A DNA repair pathway can regulate transcriptional noise to promote cell fate transitions.

Stochastic fluctuations in gene expression ("noise") are often considered detrimental, but fluctuations can also be exploited for benefit (e.g., dither). We show here that DNA base excision repair amplifies transcriptional noise to facilitate cellular reprogramming. Specifically, the DNA repair protein Apex1, which recognizes both naturally occurring and unnatural base modifications, amplifies expression noise while homeostatically maintaining mean expression levels. This amplified expression noise originates from shorter-duration, higher-intensity transcriptional bursts generated by Apex1-mediated DNA supercoiling. The remodeling of DNA topology first impedes and then accelerates transcription to maintain mean levels. This mechanism, which we refer to as "discordant transcription through repair" ("DiThR," which is pronounced "dither"), potentiates cellular reprogramming and differentiation. Our study reveals a potential functional role for transcriptional fluctuations mediated by DNA base modifications in embryonic development and disease.

Cytoplasmic Amplification of Transcriptional Noise Generates Substantial Cell-to-Cell Variability.

Transcription is an episodic process characterized by probabilistic bursts, but how the transcriptional noise from these bursts is modulated by cellular physiology remains unclear. Using simulations and single-molecule RNA counting, we examined how cellular processes influence cell-to-cell variability (noise). The results show that RNA noise is higher in the cytoplasm than the nucleus in ∼85% of genes across diverse promoters, genomic loci, and cell types (human and mouse). Measurements show further amplification of RNA noise in the cytoplasm, fitting a model of biphasic mRNA conversion between translation- and degradation-competent states. This multi-state translation-degradation of mRNA also causes substantial noise amplification in protein levels, ultimately accounting for ∼74% of intrinsic protein variability in cell populations. Overall, the results demonstrate how noise from transcriptional bursts is intrinsically amplified by mRNA processing, leading to a large super-Poissonian variability in protein levels.

Risk of Heart Failure and Death After Prolonged Smoking Cessation: Role of Amount and Duration of Prior Smoking.

BACKGROUND: According to the 2004 Surgeon General's Report on Health Consequences of Smoking, after >15 years of abstinence, the cardiovascular risk of former smokers becomes similar to that of never-smokers. Whether this health benefit of smoking cessation varies by amount and duration of prior smoking remains unclear. METHODS AND RESULTS: Of the 4482 adults ≥65 years without prevalent heart failure (HF) in the Cardiovascular Health Study, 2556 were never-smokers, 629 current smokers, and 1297 former smokers with >15 years of cessation, of whom 312 were heavy smokers (highest quartile; ≥32 pack-years). Age-sex-race-adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for centrally adjudicated incident HF and mortality during 13 years of follow-up were estimated using Cox regression models. Compared with never-smokers, former smokers as a group had similar risk for incident HF (aHR, 0.99; 95% CI, 0.85-1.16) and all-cause mortality (aHR, 1.08; 95% CI, 0.96-1.20), but former heavy smokers had higher risk for both HF (aHR, 1.45; 95% CI, 1.15-1.83) and mortality (aHR, 1.38; 95% CI, 1.17-1.64). However, when compared with current smokers, former heavy smokers had lower risk of death (aHR, 0.64; 95% CI, 0.53-0.77), but not of HF (aHR, 0.97; 95% CI, 0.74-1.28). CONCLUSIONS: After >15 years of smoking cessation, the risk of HF and death for most former smokers becomes similar to that of never-smokers. Although this benefit of smoking cessation is not extended to those with ≥32 pack-years of prior smoking, they have lower risk of death relative to current smokers.

Radiculomyelitic rabies: can MR imaging help?

Radiculomyelitic (silent) rabies and acute disseminated encephalomyelitis have similar clinical presentations but distinct management and prognostic implications. It is thus important to differentiate between the two antemortem. Because of their distinct pathologic abnormalities, MR imaging may be helpful in distinguishing between the two entities. We report a case in which MR imaging helped us to diagnose silent rabies antemortem, which was subsequently confirmed at autopsy.

Infectious mononucleosis presenting as upper airway obstruction.

Upper airway obstruction though a common complication of infectious mononucleosis is rarely considered in differential diagnosis of stridor. We report a three-year-old child who had upper airway obstruction due to infectious mononucleosis, managed conservatively with oxygen, intravenous fluids and steroids.

Orthostatic hypotension and incident heart failure in community-dwelling older adults.

OBJECTIVES: To examine the association of orthostatic hypotension with incident heart failure (HF) in older adults. METHODS: Of the 5,273 community-dwelling adults aged 65 years and older free of baseline prevalent HF in the Cardiovascular Health Study, 937 (18%) had orthostatic hypotension, defined as ≥20 mmHg drop in systolic or ≥10 mmHg drop in diastolic blood pressure from supine to standing position at 3 minutes. Of the 937, 184 (20%) had symptoms of dizziness upon standing and were considered to have symptomatic orthostatic hypotension. Propensity scores for orthostatic hypotension were estimated for each of the 5,273 participants and were used to assemble a cohort of 3,510 participants (883 participants with and 2,627 participants without orthostatic hypotension) who were balanced on 40 baseline characteristics. Cox regression models were used to estimate the association of orthostatic hypotension with centrally adjudicated incident HF and other outcomes during 13 years of follow-up. RESULTS: Participants (n = 3,510) had a mean (±standard deviation) age of 74 (±6) years, 58% were women, and 15% nonwhite. Incident HF occurred in 25% and 21% of matched participants with and without orthostatic hypotension, respectively (hazard ratio, 1.24; 95% confidence interval, 1.06-1.45; p = .007). Among matched participants, hazard ratios for incident HF associated with symptomatic (n = 173) and asymptomatic (n = 710) orthostatic hypotension were 1.57 (95% confidence interval, 1.16-2.11; p = .003) and 1.17 (95% confidence interval, 0.99-1.39; p = .069), respectively. CONCLUSIONS: Community-dwelling older adults with orthostatic hypotension have higher independent risk of developing new-onset HF, which appeared to be more pronounced in those with symptomatic orthostatic hypotension.

Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data.

BACKGROUND: Heart failure (HF) is the leading cause of hospitalization for Medicare beneficiaries. Nearly half of all HF patients have diastolic HF or HF with preserved ejection fraction (HF-PEF). Because these patients were excluded from major randomized clinical trials of neurohormonal blockade in HF there is little evidence about their role in HF-PEF. METHODS: The aims of the American Recovery & Reinvestment Act-funded National Heart, Lung, and Blood Institute-sponsored "Neurohormonal Blockade and Outcomes in Diastolic Heart Failure" are to study the long-term effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists in four separate propensity-matched populations of HF-PEF patients in the OPTIMIZE-HF (Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure) registry. Of the 48,612 OPTIMIZE-HF hospitalizations occurring during 2003-2004 in 259 U.S. hospitals, 20,839 were due to HF-PEF (EF ≥40%). For mortality and hospitalization we used Medicare national claims data through December 31, 2008. RESULTS: Using a two-step (hospital-level and hospitalization-level) probabilistic linking approach, we assembled a cohort of 11,997 HF-PEF patients from 238 OPTIMIZE-HF hospitals. These patients had a mean age of 75 years, mean EF of 55%, were 62% women, 15% African American, and were comparable with community-based HF-PEF cohorts in key baseline characteristics. CONCLUSIONS: The assembled Medicare-linked OPTIMIZE-HF cohort of Medicare beneficiaries with HF-PEF with long-term outcomes data will provide unique opportunities to study clinical effectivenss of various neurohormonal antagonists with outcomes in HF-PEF using propensity-matched designs that allow outcome-blinded assembly of balanced cohorts, a key feature of randomized clinical trials.

Reduced right ventricular ejection fraction and increased mortality in chronic systolic heart failure patients receiving ß-blockers: insights from the BEST trial.

BACKGROUND: Right ventricular ejection fraction (RVEF) < 20% is an independent predictor of poor outcomes in patients with advanced chronic systolic heart failure (HF). The aim of this study was to examine if the adverse effect of abnormally reduced RVEF varies by the receipt of beta-blockers. METHODS: In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 patients with chronic advanced HF and left ventricular ejection fraction < 35%, receiving standard background therapy with renin-angiotensin inhibition, digoxin, and diuretics, were randomized to receive bucindolol or placebo. Of these 2008 had data on baseline RVEF, and 14% (146/1017) and 13% (125/991) of the patients receiving bucindolol and placebo respectively had RVEF < 20%. RESULTS: Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF ≥ 20% and < 20% respectively (unadjusted hazard ratios {HR}, 1.33; 95% confidence intervals {CI}, 0.99-1.78; p = 0.055 and adjusted HR, 0.99; 95% CI, 0.71-1.37; p = 0.934). Among those receiving bucindolol, all-cause mortality occurred in 28% and 49% of patients with RVEF ≥ 20% and < 20% respectively (unadjusted HR, 2.15; 95% CI, 1.65-2.80; p < 0.001 and adjusted HR, 1.50; 95% CI, 1.08-2.07; p = 0.016). These differences were statistically significant (unadjusted and adjusted p for interaction, 0.016 and 0.053 respectively). CONCLUSIONS: In ambulatory patients with chronic advanced systolic HF receiving renin-angiotensin inhibition, digoxin, and diuretics, RVEF < 20% had no intrinsic association with mortality. However, in those receiving additional therapy with bucindolol, RVEF < 20% had a significant independent association with increased risk of mortality.

Rate-control versus rhythm-control strategies and outcomes in septuagenarians with atrial fibrillation.

BACKGROUND: The prevalence of atrial fibrillation substantially increases after 70 years of age. However, the effect of rate-control versus rhythm-control strategies on outcomes in these patients remains unclear. METHODS: In the randomized Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 4060 patients (mean age 70 years, range 49-80 years) with paroxysmal and persistent atrial fibrillation were randomized to rate-control versus rhythm-control strategies. Of these, 2248 were 70-80 years, of whom 1118 were in the rate-control group. Propensity scores for rate-control strategy were estimated for each of the 2248 patients and were used to assemble a cohort of 937 pairs of patients receiving rate-control versus rhythm-control strategies, balanced on 45 baseline characteristics. RESULTS: Matched patients had a mean age of 75 years; 45% were women, 7% were nonwhite, and 47% had prior hospitalizations due to arrhythmias. During 3.4 years of mean follow-up, all-cause mortality occurred in 18% and 23% of matched patients in the rate-control and rhythm-control groups, respectively (hazard ratio [HR] associated with rate control, 0.77; 95% confidence interval [CI], 0.63-0.94; P = .010). HRs (95% CIs) for cardiovascular and noncardiovascular mortality associated with rate control were 0.88 (0.65-1.18) and 0.62 (0.46-0.84), respectively. All-cause hospitalization occurred in 61% and 68% of rate-control and rhythm-control patients, respectively (HR 0.76; 95% CI, 0.68-0.86). HRs (95% CIs) for cardiovascular and noncardiovascular hospitalization were 0.66 (0.56-0.77) and 1.07 (0.91-1.27), respectively. CONCLUSION: In septuagenarian patients with atrial fibrillation, compared with rhythm-control, a rate-control strategy was associated with significantly lower mortality and hospitalization.

Prediabetes is not an independent risk factor for incident heart failure, other cardiovascular events or mortality in older adults: findings from a population-based cohort study.

BACKGROUND: Whether prediabetes is an independent risk factor for incident heart failure (HF) in non-diabetic older adults remains unclear. METHODS: Of the 4602 Cardiovascular Health Study participants, age≥65 years, without baseline HF and diabetes, 2157 had prediabetes, defined as fasting plasma glucose (FPG) 100-125 mg/dL. Propensity scores for prediabetes, estimated for each of the 4602 participants, were used to assemble a cohort of 1421 pairs of individuals with and without prediabetes, balanced on 44 baseline characteristics. RESULTS: Participants had a mean age of 73 years, 57% were women, and 13% African American. Incident HF occurred in 18% and 20% of matched participants with and without prediabetes, respectively (hazard ratio {HR} associated with prediabetes, 0.90; 95% confidence interval {CI}, 0.76-1.07; p=0.239). Unadjusted and multivariable-adjusted HRs (95% CIs) for incident HF associated with prediabetes among 4602 pre-match participants were 1.22 (95% CI, 1.07-1.40; p=0.003) and 0.98 (95% CI, 0.85-1.14; p=0.826), respectively. Among matched individuals, prediabetes had no independent association with incident acute myocardial infarction (HR, 1.02; 95% CI, 0.81-1.28; p=0.875), angina pectoris (HR, 0.93; 95% CI, 0.77-1.12; p=0.451), stroke (HR, 0.86; 95% CI, 0.70-1.06; p=0.151) or all-cause mortality (HR, 0.99; 95% CI, 0.88-1.11; p=0.840). CONCLUSIONS: We found no evidence that prediabetes is an independent risk factor for incident HF, other cardiovascular events or mortality in community-dwelling older adults. These findings question the wisdom of routine screening for prediabetes in older adults and targeted interventions to prevent adverse outcomes in older adults with prediabetes.

Venous thromboembolism in patients with heart failure: in-hospital and chronic use of anti-coagulants for prevention.

Heart failure (HF) is a common clinical syndrome characterized by high morbidity and frequent hospitalizations. HF is an independent and major risk factor for venous thromboembolism (VTE) and VTE occurring in patients with HF carries a worse prognosis. The present review will focus on short and long term role of anti-coagulants in prevention of venous thrombosis in HF patients. We will also be discussing the recently investigated and patented anti-coagulants which could have a role in this specific population.

Bucindolol, systolic blood pressure, and outcomes in systolic heart failure: a prespecified post hoc analysis of BEST.

BACKGROUND: In the Beta-Blocker Evaluation of Survival Trial (BEST), systolic blood pressure (SBP) ≤ 120 mm Hg was an independent predictor of poor prognosis in ambulatory patients with chronic systolic heart failure (HF). Because SBP is an important predictor of response to ß-blocker therapy, the BEST protocol prespecified a post hoc analysis to determine whether the effect of bucindolol varied by baseline SBP. METHODS: In the BEST, 2706 patients with chronic systolic (left ventricular ejection fraction < 35%) HF and New York Heart Association class III (92%) or IV (8%) symptoms and receiving standard background therapy were randomized to receive either bucindolol (n = 1354) or placebo (n = 1354). Of these, 1751 had SBP ≤ 120 mm Hg, and 955 had SBP > 120 mm Hg at baseline. RESULTS: Among patients with SBP > 120 mm Hg, all-cause mortality occurred in 28% and 22% of patients receiving placebo and bucindolol, respectively (hazard ratio when bucindolol was compared with placebo, 0.77; 95% confidence interval [CI], 0.59-0.99; P = 0.039). In contrast, among those with SBP ≤ 120 mm Hg, 36% and 35% of patients in the placebo and bucindolol groups died, respectively (hazard ratio, 0.95; 95% CI, 0.81-1.12; P = 0.541). Hazard ratios (95% CIs; P values) for HF hospitalization associated with bucindolol use were 0.70 (0.56-0.89; P = 0.003) and 0.82 (0.71-0.95; P = 0.008) for patients with SBP > 120 and ≤ 120 mm Hg, respectively. CONCLUSION: Bucindolol, a nonselective ß-blocker with weak α(2)-blocking properties, significantly reduced HF hospitalization in systolic HF patients regardless of baseline SBP. However, bucindolol reduced mortality only in those with SBP > 120 mm Hg.

Outcomes in younger and older adults with chronic advanced systolic heart failure: a propensity-matched study.

BACKGROUND: Older age is an independent predictor of all-cause mortality in patients with mild to moderate heart failure (HF). Whether older age is also an independent predictor of mortality in patients with more advanced HF is unknown. METHODS: Of the 2707 Beta-Blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF (New York Heart Association class III/IV and left ventricular ejection fraction <35%), 1091 were elderly (≥ 65 years). Propensity scores for older age, estimated for each of the 2707 patients, were used to assemble a cohort of 603 pairs of younger and older patients, balanced on 66 baseline characteristics. RESULTS: All-cause mortality occurred in 33% and 36% of younger and older matched patients respectively during 4 years of follow-up (hazard ratio {HR} associated with age ≥ 65 years, 1.05; 95% confidence interval {CI}, 0.87-1.27; P=0.614). HF hospitalization occurred in 38% and 40% of younger and older matched patients respectively (HR, 1.01; 95% CI, 0.84-1.21; P=0.951). Among 603 pairs of unmatched and unbalanced patients, all-cause mortality occurred in 28% and 36% of younger and older patients respectively (HR, 1.34; 95% CI, 1.10-1.64; P=0.004) and HF hospitalization occurred in 34% and 40% of younger and older unmatched patients respectively (HR, 1.24; 95% CI, 1.03-1.50; P=0.024). CONCLUSION: Significant bivariate associations suggest that older age is a useful marker of poor outcomes in patients with advanced chronic systolic HF. However, lack of significant independent associations suggests that older age per se has no intrinsic effect on outcomes in these patients.