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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.

INTRODUCTION: Fluctuations have long been known to dynamically shape microstate distributions in physical systems. Throughout engineering, “dithering” approaches that modulate fluctuations are used to enhance inefficient processes and, in chemistry, thermal fluctuations are amplified (e.g., by Bunsen burners) to accelerate reactions. In biology, a long-standing question is whether stochastic expression fluctuations originating from episodic transcription “bursts” play any physiologic role. RATIONALE: Stochastic fluctuations (noise), measured by the coefficient of variation, scale inversely with mean expression level. For example, transcriptional activators that increase the mean lead to decreased noise, whereas stressors that decrease the mean increase noise. However, this 1/mean “Poisson” scaling of transcriptional noise can be broken by certain processes (e.g., feedback) and, curiously, by small molecules such as pyrimidine nucleobases. We set out to determine the mechanism of action of nucleobases that amplify transcriptional noise independently of mean and explored their potential functional role. Specifically, we tested whether a noise-amplifying pyrimidine nucleotide and its naturally occurring base analogs decouple noise from the mean by disruption of a putative cellular noise control mechanism (i.e., a noise thermostat). RESULTS: We found that DNA surveillance and repair machinery decouple transcriptional noise from mean expression levels, homeostatically changing noise independently of mean, and this potentiates cell fate transitions in stem cells. Specifically, during removal of modified nucleotide substrates (e.g., idoxuri-dine) and naturally occurring nucleotide analogs [e.g., 5-hydroxymethylcytosine (hmC) and 5-hydroxymethyluridine (hmU)], transcriptional noise is amplified globally across the transcriptome. The amplified transcriptional noise is intrinsic (i.e., not cell extrinsic), independent of changes in the mean (i.e., occurs with minimal change in mean), and distinct from a stress response. Forward genetic screening identified AP endonuclease 1 (Apex1), a member of the base excision repair (BER) DNA surveillance pathway, as the essential mediator of homeostatic noise amplification, and up-regulation of BER enzymes upstream of Apex1 (e.g., glycosylases) also amplified noise. Single-molecule and live-cell imaging showed that this homeostatic noise amplification originated from shorter-duration, but higher-intensity, transcriptional bursts. Mechanistically, Apex1 amplified noise by altering DNA topology, i.e., by increasing negative DNA supercoiling, which impedes transcription but upon repair accelerates transcription, thereby homeostatically maintaining mean expression levels. We call this mechanism “discordant transcription through repair (“DiThR,” pronounced “dither”). Computational modeling predicted that DiThR could increase responsiveness to fate-determining stimuli and, indeed, experimental activation of DiThR potentiated both differentiation of embryonic stem cells into neural ectodermal cells and reprogramming of differentiated fibroblasts into induced pluripotent stem cells. CONCLUSION: Our data reveal that a DNA surveillance pathway uses the biomechanical link between supercoiling and transcription to homeostatically amplify transcriptional fluctuations. The resulting increase in expression excursions, or outliers, increases cellular responsiveness to diverse fate specification signals. Thus, DNA-processing activities that interrupt transcription could function in fate determination and may explain why naturally occurring base modifications, such as the oxidized nucleobase hmU, are enriched in embryonic stem cell DNA. The existence of a DiThR pathway that orthogonally regulates transcriptional fluctuations suggests that cells evolved mechanisms to exploit noise for the functional regulation of fate transitions and highlights the potential to harness these endogenous pathways for cellular reprogramming.

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).

Author(s): Desai, Ravi | Advisor(s): Weinberger, Leor S | Abstract: Stochastic fluctuations in gene expression (‘noise’) are often considered detrimental but, in other fields, fluctuations are harnessed for benefit (e.g., ‘dither’ or amplification of thermal fluctuations to accelerate chemical reactions). Here, we find that DNA base-excision repair amplifies transcriptional noise, generating increased cellular plasticity and facilitating reprogramming. The DNA-repair protein Apex1 recognizes modified nucleoside substrates to amplify expression noise—while homeostatically maintaining mean levels of expression—for virtually all genes across the transcriptome. This noise amplification occurs for both naturally occurring base modifications and unnatural base analogs. Single-molecule imaging shows amplified noise originates from shorter, but more intense, transcriptional bursts that occur via increased DNA supercoiling which first impedes and then accelerates transcription, thereby maintaining mean levels. Strikingly, homeostatic noise amplification potentiates fate-conversion signals during cellular reprogramming. These data suggest a functional role for the observed occurrence of modified bases within DNA in embryonic development and disease.

SUMMARYDifferentiation proceeds along a continuum of increasingly fate-restricted intermediates, referred to as canalization1–4. Canalization is essential for stabilizing cell fate, but the mechanisms underlying robust canalization are unclear. Here we show that deletion of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex ATPase gene Brm (encoding Brahma) results in a radical identity switch during directed cardiogenesis of mouse embryonic stem cells (ESCs). Despite establishment of well-differentiated precardiac mesoderm, Brm-null cells subsequently shifted identities, predominantly becoming neural precursors, violating germ layer assignment. Trajectory inference showed sudden acquisition of non-mesodermal identity in Brm-null cells, consistent with a new transition state inducing a fate switch referred to as a saddle-node bifurcation3,4. Mechanistically, loss of Brm prevented de novo accessibility of cardiac enhancers while increasing expression of the neurogenic factor POU3F1 and preventing expression of the neural suppressor REST. Brm mutant identity switch was overcome by increasing BMP4 levels during mesoderm induction, repressing Pou3f1 and re-establishing a cardiogenic chromatin landscape. Our results reveal BRM as a compensable safeguard for fidelity of mesoderm chromatin states, and support a model in which developmental canalization is not a rigid irreversible path, but a highly plastic trajectory that must be safeguarded, with implications in development and disease.

Significance Our findings have revealed a previously unrecognized link between circadian oscillations and intercellular variation and provide experimental evidence that stochastic transcriptional noise contributes significantly to cell-autonomous circadian periodicity. Interestingly, in separate studies, aging and cancer have been associated with increased transcriptional noise and less robust circadian rhythms. Here, we establish a direct association between transcriptional noise and circadian period. These findings may provide additional directions for researchers in the aging and cancer fields. Furthermore, circadian period may also be used as an indicator of variance in heterogeneity research and drug screening for noise control., 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.

Transcription is an episodic process characterized by probabilistic bursts; but how these bursts are modulated by cellular physiology remains unclear and has implications for how selection may act on these fluctuations. 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 amplified in the cytoplasm compared to the nucleus in ~85% of genes across diverse promoters, genomic loci, and cell types (human and mouse). Surprisingly, measurements show further amplification of RNA noise in the cytoplasm, fitting a model of biphasic mRNA conversion between translation- and degradation-competent states. The 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 transcriptional bursts are intrinsically amplified by mRNA processing and indicate mechanisms through which noise could act as a substrate for evolutionary selection.

Study question How well does multi-analyte steroid mass spectrometry (MS) profiling classify women with and without polycystic ovary syndrome (PCOS)? Summary answer Our liquid chromatography MS (LC-MS) steroid profiling only minimally improves discrimination of women with and without PCOS compared with a direct testosterone immunoassay (T_IA) and the free androgen index (FAI). What is known already Blood testosterone measured by direct (non-extraction) immunoassay overlaps between women with and without PCOS. Multi-analyte MS provides greater specificity and accuracy for steroid measurement so might improve the classification. Study design, size, duration An observational, cross-sectional study of women with PCOS (n = 152) defined by Rotterdam criteria and matched non-PCOS (n = 45) control women was conducted. Participants/materials, setting, methods Serum steroid profiles of testosterone (T), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), androstenedione (A4), estradiol (E2), estrone (E1), 17 hydroxy progesterone (17OHP4), progesterone (P4) and cortisol were measured by LC-MS; T_IA and sex hormone binding globulin were measured by immunoassay; and FAI, calculated free testosterone (cFT) and total androgen index (TAI) were calculated. Classification was based on logistic regression with corresponding univariate and multivariate C-statistics. Main results and the role of chance Serum testosterone by immunoassay demonstrated levels more than 100% higher than that measured by LC-MS. Compared with the controls, women with PCOS had higher serum T, DHEA, A4, TAI, T_IA, cFT, FAI and E2 but not serum DHT, E1, P4, 17OHP4 or cortisol. Univariate C-statistics were highest for FAI (0.89) and T_IA (0.82) compared with other androgens (T [0.72], DHT [0.40]), pro-androgens (A4 [0.74], DHEA[0.71]) or derivatives (cFT [0.75], TAI [0.60]). For all multivariate models, the overall correct predictions (81-86%) featured high sensitivity (92-96%) but low specificity (28-43%). and substituting LC-MS steroid measurements for T_IA and FAI produced only minimal improvements in classification. Limitations reasons for caution The study cohort is limited in size and only unconjugated steroids were measured. Wider implications of the findings Multi-analyte steroid profiling of unconjugated circulating steroids provides only limited improvement on direct T_IA in classifying women with and without PCOS. Study funding/competing interests None. Trial registration number N/A.

Our recent advancements in RNA nanotechnology introduced novel nanoscaffolds (nanorings); however, the potential of their use for biomedical applications was never fully revealed. As presented here, besides functionalization with multiple different short interfering RNAs for combinatorial RNA interference (e.g., against multiple HIV-1 genes), nanorings also allow simultaneous embedment of assorted RNA aptamers, fluorescent dyes, proteins, as well as recently developed RNA-DNA hybrids aimed to conditionally activate multiple split functionalities inside cells.

Control over the simultaneous delivery of different functionalities and their synchronized intracellular activation can greatly benefit the fields of RNA and DNA biomedical nanotechnologies and allow for the production of nanoparticles and various switching devices with controllable functions. We present a system of multiple split functionalities embedded in the cognate pairs of RNA–DNA hybrids which are programmed to recognize each other, re-associate and form a DNA duplex while also releasing the split RNA fragments which upon association regain their original functions. Simultaneous activation of three different functionalities (RNAi, Förster resonance energy transfer and RNA aptamer) confirmed by multiple in vitro and cell culture experiments prove the concept. To automate the design process, a novel computational tool that differentiates between the thermodynamic stabilities of RNA–RNA, RNA–DNA and DNA–DNA duplexes was developed. Moreover, here we demonstrate that besides being easily produced by annealing synthetic RNAs and DNAs, the individual hybrids carrying longer RNAs can be produced by RNA polymerase II-dependent transcription of single-stranded DNA templates.

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.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.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.In septuagenarian patients with atrial fibrillation, compared with rhythm-control, a rate-control strategy was associated with significantly lower mortality and hospitalization.

Whether prediabetes is an independent risk factor for incident heart failure (HF) in non-diabetic older adults remains unclear.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.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).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.

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 β-blocker therapy, the BEST protocol prespecified a post hoc analysis to determine whether the effect of bucindolol varied by baseline SBP.In the BEST, 2706 patients with chronic systolic (left ventricular ejection fraction35%) 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 SBP120 mm Hg at baseline.Among patients with SBP120 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 SBP120 and ≤ 120 mm Hg, respectively.Bucindolol, a nonselective β-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 SBP120 mm Hg.

Objectives The goal of this study was to define the mechanism of preserved ejection fraction (EF) despite depressed myocardial strains in hypertension (HTN). Background Concentric left ventricular (LV) remodeling in HTN may have normal or supranormal EF despite depressed myocardial strains. The reason for such discordance is not clear. The aim of this study was to comprehensively evaluate the LV mechanics in a well-defined HTN population to define underlying reasons for such a paradox. Methods Sixty-seven patients with resistant HTN and 45 healthy control subjects were studied by cardiac magnetic resonance imaging and tissue tagging with 3-dimensional analysis. Amplitude and directional vector of longitudinal (Ell), circumferential (Ecc), and principal strain for maximal shortening (E3) were computed at basal, mid, and distal LV levels, respectively. LV torsion, defined as the rotation angle of apex relative to base, and LV twist, which accounts for the effects of differential LV remodeling on torsion for comparison among the 2 groups, were also calculated. Results LV mass index and LV mass/LV end-diastolic volume ratio were significantly higher in the HTN group compared with controls, consistent with concentric LV remodeling. Ell and Ecc were significantly decreased in amplitude with altered directional vector in HTN compared with controls. However, the amplitude of E3 was similar in the 2 groups. Torsion and twist were significantly higher in HTN, which was mainly due to increase in apical rotation. The HTN group demonstrated significantly increased LV wall thickening compared with controls that resulted in greater LVEF in the HTN group compared with controls (70% vs. 65%, p Conclusions In compensated LV remodeling secondary to HTN, there is increased LV wall thickening with preserved E3 and increased torsion compared with normal controls. This, therefore, contributes to supranormal LVEF in HTN despite depressed longitudinal and circumferential strains.

Reduced right ventricular ejection fraction (RVEF) is associated with poor outcomes in patients with chronic systolic heart failure (HF). Although most HF patients are older adults, little is known about the relationship between low RVEF and outcomes in older adults with systolic HF.Of the 2008 Beta-Blocker Evaluation of Survival Trial (BEST) participants with systolic HF (left ventricular ejection fraction ≤ 35%) 822 were ≥ 65 years and had data on baseline RVEF estimated by gated-equilibrium radionuclide ventriculography. Using RVEF ≥ 40% (n = 308) as reference, we examined association of RVEF 30-39% (n = 214), 20-29% (n = 206) and20% (n = 94) with outcomes using Cox regression models.All-cause mortality occurred in 36%, 40%, 39% and 56% of patients with RVEF ≥ 40%, 30-39%, 20-29% and20% respectively. Compared with RVEF ≥ 40%, unadjusted hazard ratios (HR) and 95% confidence intervals (CI) for all-cause mortality associated with RVEF 30-39%, 20-29% and20% were 1.19 (0.90-1.57; P = 0.220), 1.13 (0.84-1.51; P = 0.423) and 1.97 (1.43-2.73; P0.001) respectively. Respective multivariable-adjusted HR's (95% CI's) for all-cause mortality were 1.19 (0.88-1.60; P = 0.261), 1.00 (0.73-1.39; P = 0.982) and 1.70 (1.14-2.53; P = 0.009). Adjusted HR's (95% CI's) associated with RVEF20% (versus ≥ 40%) for cardiovascular mortality and HF mortality were 1.79 (1.17-2.76; P = 0.008) and 1.97 (1.02-3.83; P = 0.045) respectively. RVEF had no independent association with sudden cardiac death, all-cause or HF hospitalization.Abnormally low RVEF is a significant independent predictor of mortality, but not of HF hospitalization, in older adults with systolic HF.

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.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 fraction35%), 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.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).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.

Diabetes mellitus (DM) is a risk factor for incident heart failure (HF) in older adults. However, the extent to which this association is independent of other risk factors remains unclear. Of 5,464 community-dwelling adults ≥65 years old in the Cardiovascular Health Study without baseline HF, 862 had DM (fasting plasma glucose levels ≥126 mg/dl or treatment with insulin or oral hypoglycemic agents). Propensity scores for DM were estimated for each of the 5,464 participants and were used to assemble a cohort of 717 pairs of participants with and without DM who were balanced in 65 baseline characteristics. Incident HF occurred in 31% and 26% of matched participants with and without DM, respectively, during >13 years of follow-up (hazard ratio 1.45 for DM vs no DM, 95% confidence interval [CI] 1.14 to 1.86, p = 0.003). Of the 5,464 participants before matching unadjusted and multivariable-adjusted hazard ratios for incident HF associated with DM were 2.22 (95% CI 1.94 to 2.55, p

Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure 12 years of median follow-up, centrally adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension, respectively (hazard ratio associated with isolated diastolic hypotension: 1.33 [95% CI: 1.10–1.61]; P =0.004). Among the 5376 prematch individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% CI: 1.09–1.53; P =0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure.

Warfarin is often used in patients with systolic heart failure (HF) to prevent adverse outcomes. However, its long-term effect remains controversial. The objective of this study was to determine the association of warfarin use and outcomes in patients with advanced chronic systolic HF without atrial fibrillation (AF), previous thromboembolic events, or prosthetic valves. Of the 2,708 BEST patients, 1,642 were free of AF without a history of thromboembolic events and without prosthetic valves at baseline. Of these, 471 patients (29%) were receiving warfarin. Propensity scores for warfarin use were estimated for each patient and were used to assemble a matched cohort of 354 pairs of patients with and without warfarin use who were balanced on 62 baseline characteristics. Kaplan-Meier and Cox regression analyses were used to estimate the association between warfarin use and outcomes during 4.5 years of follow-up. Matched participants had a mean age ± SD of 57 ± 13 years with 24% women and 24% African-Americans. All-cause mortality occurred in 30% of matched patients in the 2 groups receiving and not receiving warfarin (hazard ratio 0.86, 95% confidence interval 0.62 to 1.19, p = 0.361). Warfarin use was not associated with cardiovascular mortality (hazard ratio 0.97, 95% confidence interval 0.68 to 1.38, p = 0.855), or HF hospitalization (hazard ratio 1.09, 95% confidence interval 0.82 to 1.44, p = 0.568). In conclusion, in patients with chronic advanced systolic HF without AF or other recommended indications for anticoagulation, prevalence of warfarin use was high. However, despite a therapeutic international normalized ratio in those receiving warfarin, its use had no significant intrinsic association with mortality and hospitalization.

Presence of concentric left ventricular (LV) geometry has important pathophysiologic and prognostic implications. However, little is known about its natural history in older adults. Of the 5,795 community-dwelling adults ≥65 years of age in the Cardiovascular Health Study, 1,871 without baseline heart failure had data on baseline and 7-year echocardiograms. Of these 343 (18%) had baseline concentric LV geometry (concentric remodeling 83%, concentric LV hypertrophy [LVH] 17%) and are the focus of the present study. LV geometry at year 7 was categorized into 4 groups based on LVH (LV mass indexed for height51 g/m²·⁷) and relative wall thickness (RWT): eccentric hypertrophy (RWT ≤0.42 with LVH), concentric hypertrophy (RWT0.42 with LVH), concentric remodeling (RWT0.42 without LVH), and normal (RWT ≤0.42 without LVH). At year 7, LV geometry normalized in 57%, remained unchanged in 35%, and transitioned to eccentric hypertrophy in 7% of participants. Incident eccentric hypertrophy occurred in 4% and 25% of those with baseline concentric remodeling and concentric hypertrophy, respectively, and was associated with increased LV end-diastolic volume and decreased LV ejection fraction at year 7. Previous myocardial infarction and baseline above-median LV mass (39 g/m²·⁷) and RWT (0.46) had significant unadjusted associations with incident eccentric LVH; however, only LV mass39 g/m²·⁷ (odds ratio 17.52, 95% confidence interval 3.91 to 78.47, p0.001) and previous myocardial infarction (odds ratio 4.73, 95% confidence interval 1.16 to 19.32, p = 0.031) had significant independent associations. In conclusion, in community-dwelling older adults with concentric LV geometry, transition to eccentric hypertrophy was uncommon but structurally maladaptive.

Summary 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.

Background— The left ventricular (LV) dilatation of isolated mitral regurgitation (MR) is associated with an increase in chymase and a decrease in interstitial collagen and extracellular matrix. In addition to profibrotic effects, chymase has significant antifibrotic actions because it activates matrix metalloproteinases and kallikrein and degrades fibronectin. Thus, we hypothesize that chymase inhibitor (CI) will attenuate extracellular matrix loss and LV remodeling in MR. Methods and Results— We studied dogs with 4 months of untreated MR (MR; n=9) or MR treated with CI (MR+CI; n=8). Cine MRI demonstrated a >40% increase in LV end-diastolic volume in both groups, consistent with a failure of CI to improve a 25% decrease in interstitial collagen in MR. However, LV cardiomyocyte fractional shortening was decreased in MR versus normal dogs (3.71±0.24% versus 4.81±0.31%; P Conclusions— These results suggest that chymase disrupts cell surface–fibronectin connections and FAK phosphorylation that can adversely affect cardiomyocyte myofibrillar structure and function. The greater effect of CI on epicardial versus endocardial titin and noncollagen cell surface proteins may be responsible for the increase in torsion angle in chronic MR.

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.

Background: Atrial fibrillation (AF) is the most common arrhythmia in patients undergoing cardiac valve surgery. AF in patients undergoing surgery can be categorized as preoperative AF (PPAF) or postsurgical AF (PSAF). Objective: To determine whether PSAF in patients undergoing valve surgery had an impact on mortality compared with patients in sinus rhythm or PPAF. Methods: A total of 556 consecutive patients who underwent valve surgery were reviewed. Patients were divided into three cohorts: sinus rhythm before and after surgery (n=293); PPAF (n=139); and sinus rhythm before and AF after the surgery (PSAF) (n=124). Baseline characteristics, surgical details and outcomes were recorded. Results: Compared with patients in sinus rhythm (mean [± SD] age 67.8±12.5 years), patients in the PPAF and PSAF groups were significantly older (73.1±9.9 years and 72.4±9.9 years, respectively). Hospital stay was significantly longer in the PPAF and PSAF groups (10.5±6.1 days and 11.3±8.3 days, respectively) compared with patients with sinus rhythm (7.12±4.9 days). During a follow-up of 51 months, all-cause mortality was significantly higher in both the PPAF and PSAF groups. This was irrespective of concomitant coronary bypass surgery. On multivariate Cox regression analysis, the adjusted risk for all-cause mortality for PPAF and PSAF was 1.93 (95% CI 1.18 to 3.17; P=0.01) and 1.64 (95% CI 1.07 to 2.53; P=0.02), respectively. Conclusion: Patients with PSAF and PPAF have longer hospital stays and higher long-term mortality rates than patients in sinus rhythm. Long-term mortality was similar between PPAF and PSAF.

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. (Echocardiography 2011;28:E36-E38)

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 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$ \left(\widehat{\varphi}\right) $$ \end{document} volume \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$ \left(\widehat{V}\right) $$ \end{document} loop to assess LV diastolic functional properties. We defined the area within \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$ \widehat{\varphi}\widehat{V} $$ \end{document} loop as torsion hysteresis area, and hypothesized that it may be an important global parameter of diastolic function. We evaluated the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$ \widehat{\varphi} $$ \end{document} changes to increased \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$ \widehat{V} $$ \end{document} during early diastole \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$ \left(-d\widehat{\varphi}/d\widehat{V}\right) $$ \end{document} 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 0.12 (Control mean torsion hysteresis area + 1SD). Conclusions Torsion hysteresis area and peak early diastolic \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$ -d\widehat{\varphi}/d\widehat{V} $$ \end{document} were significantly increased in hypertensive concentric remodeling. The \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document} $$ \widehat{\varphi}\widehat{V} $$ \end{document} 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.

Introduction: Left ventricular ejection fraction (LVEF) is a predictor of incident heart failure (HF). However, baseline LVEF is often unavailable in population studies of HF. Material and methods: Of the 5324 Cardiovascular Health Study (CHS) participants free of baseline HF, 143 (3%) had LVEF < 45% and 1091 (21%) developed HF during 13 years of follow-up. Using public-use copies of the CHS data, we compared two predictor models of incident HF, with and without adjustment for baseline LVEF. Results: Baseline impaired LVEF was a strong independent predictor of incident HF (adjusted hazard ratio, 2.78; P < 0.001) but had no impact on the direction, magnitude or significance of independent associations of the other predictors of incident HF such as age, sex, race, coronary artery disease, hypertension and diabetes. Conclusion: Baseline LVEF is an important predictor for incident HF but is not essential in population studies of risk factors for incident HF.

To examine the association of orthostatic hypotension with incident heart failure (HF) in older adults.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.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.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.

A 41 year-old African-American male presented with syncope preceded by shortness of breath at outside facility and transferred to us for management of extensive pulmonary embolism with unstable vital signs. Electrocardiogram showed sinus tachycardia with S1Q3T3 pattern. A transthoracic echocardiogram revealed a freely mobile strand like mass in the left atrium. A transoesophageal echocardiogram showed a very large freely mobile thrombus extending from a patent foramen ovale in to the left atrium. He underwent emergent surgery for the extraction of clot followed by thromboembolectomy from both pulmonary arteries. He made a remarkable recovery and was discharged after seven days of hospital stay.

Background Torsion is an important determinant of left ventricular (LV) systolic and diastolic function. We hypothesized that the area within the torsion volume loop, called the torsional hysteresis (TH), may be an important parameter of diastolic function (DD). Methods 60 resistant hypertension (HTN) patients, 40 healthy controls were studied using cardiac MRI with tissue tagging. Volumetric and torsional parameters were evaluated.

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.

Aims To test the hypothesis that baseline hypoalbuminaemia is associated with incident heart failure (HF) in community-dwelling older adults. Methods and results Of the 5795 community-dwelling adults aged ≥65 years in the Cardiovascular Health Study, 5450 were free of centrally adjudicated prevalent HF at baseline, and also had data on baseline serum albumin. Of these, 599 (11%) had hypoalbuminaemia, defined as baseline serum albumin levels ≤3.5 mg/dL. Propensity scores for hypoalbuminaemia were calculated for each patient and used to assemble a matched cohort of 582 pairs of participants with and without hypoalbuminaemia, who were well balanced on 58 baseline characteristics. Using Cox regression models, we estimated the association of hypoalbuminaemia with centrally adjudicated incident HF during 9.6 years of median follow-up. Matched participants had a mean (±SD) age of 74 (±6) years, 62% were women, and 16% were African Americans. Incident HF occurred in 25 and 20% of matched participants with and without hypoalbuminaemia, respectively [hazard ratio when hypoalbuminaemia was compared with normoalbuminaemia, 1.40; 95% confidence interval, 1.05–1.85; P = 0.020]. Pre-match unadjusted, multivariable-adjusted, and propensity-adjusted hazard ratios (95% confidence intervals) for incident HF associated with hypoalbuminaemia were 1.33 (1.12–1.58; P = 0.001), 1.33 (1.11–1.60; P = 0.002), and 1.25 (1.04–1.50; P= 0.016), respectively. The combined endpoint of incident HF or all-cause mortality occurred in 59 and 50% of matched participants with and without hypoalbuminaemia, respectively (hazard ratio, 1.33; 95% confidence interval, 1.11–1.61; P= 0.002). Conclusions Among community-dwelling older adults without HF, baseline hypoalbuminaemia was associated with increased risk of incident HF during 10 years of follow-up.

Left ventricular diastolic dysfunction (LVDD) has been reported to have strong correlation with exercise capacity. However, this relationship has not been studied extensively in community-dwelling older adults. Data on pulse and tissue Doppler echocardiographic estimates of resting early (E) and atrial (A) transmitral peak inflow and early (Em) mitral annular velocities, and six-minute walk test were obtained from 89 community-dwelling older adults (mean age, 74; range, 65-93 years; 54% women), without a history of heart failure. Overall, 47% had cardiovascular morbidity and 60% had normal diastolic function (E/A 0.75-1.5 and E:Em10). Among the 36 individuals with LVDD, 83%, 14% and 3% had grade I (E/A0.75, regardless of E/E(m)), II (E/A 0.75-1.5 and E/E(m) ≥10) and III (E/A1.5 and E/E(m) ≥10) LVDD, respectively. Those with LVDD were older (77 versus 73 years; p = 0.001) and had a trend for higher prevalence of cardiovascular morbidity (58% versus 40%; p = 0.083). LVDD negatively correlated with six-minute walk distance (1013 versus 1128 feet; R = -0.25; p = 0.017). This association remained significant despite adjustment for cardiovascular morbidity (R = -0.35; p = 0.048), but lost significance when adjusted for age (R = -0.32; p = 0.105), age and cardiovascular morbidity (R = -0.38; p = 0.161), and additional adjustment for sex, race, body mass index, and systolic blood pressure (R = -0.44; p = 0.365). In conclusion, most community-dwelling older adults without heart failure had normal left ventricular diastolic function or grade-I LVDD. Although LVDD was associated with decreased performance on a six-minute walk test, that association was no longer evident after adjustment for age, body mass index and cardiovascular morbidity.

Anticoagulation has been shown to decrease ischemic stroke in atrial fibrillation (AF). However, concerns remain regarding their safety and efficacy in those ≥70 years of age who constitute most patients with AF. Of the 4,060 patients (mean age 65 years, range 49 to 80) in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 2,248 (55% of 4,060) were 70 to 80 years of age, 1,901 of whom were receiving warfarin. Propensity score for warfarin use, estimated for each of the 2,248 patients, was used to match 227 of the 347 patients not on warfarin (in 1:1, 1:2, or 1:3 sets) to 616 patients on warfarin who were balanced in 45 baseline characteristics. All-cause mortality occurred in 18% and 33% of matched patients receiving and not receiving warfarin, respectively, during up to 6 years (mean 3.4) of follow-up (hazard ratio [HR] when warfarin use was compared to its nonuse 0.58, 95% confidence interval [CI] 0.43 to 0.77, p0.001). All-cause hospitalization occurred in 64% and 67% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use 0.93, 95% CI 0.77 to 1.12, p = 0.423). Ischemic stroke occurred in 4% and 8% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use 0.57, 95% CI 0.31 to 1.04, p = 0.068). Major bleeding occurred in 7% and 10% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use 0.73, 95% CI 0.44 to 1.22, p = 0.229). In conclusion, warfarin use was associated with decreased mortality in septuagenarian patients with AF but had no association with hospitalization or major bleeding.

Methods: Of the 5795 community-dwelling adults ≥65 years in the Cardiovascular Health Study, 5273 had data on OH and were also free of prevalent HF at baseline. OH was deined as a drop of ≥20 mm Hg in systolic blood pressure (BP) and/or ≥10 mm Hg in diastolic BP from the supine to the standing position at 3 minutes. Propensity scores for OH were calculated for each of the 5273 participants and were used to assemble a cohort of 3510 participants (883 and 2627 of those with and without OH respectively) who were balanced on 40 baseline characteristics. Cox regression models were used to estimate the association of OH with centrally-adjudicated incident HF.

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.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).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.

We studied the impact of baseline systolic blood pressure (SBP) on outcomes in patients with mild to moderate chronic systolic and diastolic heart failure (HF) in the Digitalis Investigation Group trial using a propensity-matched design. Of 7,788 patients, 7,785 had baseline SBP data and 3,538 had SBP ≤ 120 mm Hg. Propensity scores for SBP ≤ 120 mm Hg, calculated for each of the 7,785 patients, were used to assemble a matched cohort of 3,738 patients with SBP ≤ 120 and >120 mm Hg who were well-balanced in 32 baseline characteristics. All-cause mortality occurred in 35% and 32% of matched patients with SBPs ≤ 120 and >120 mm Hg respectively, during 5 years of follow-up (hazard ratio [HR] when SBP ≤ 120 was compared to >120 mm Hg 1.10, 95% confidence interval [CI] 0.99 to 1.23, p = 0.088). HRs for cardiovascular and HF mortalities associated with SBP ≤ 120 mm Hg were 1.15 (95% CI 1.01 to 1.30, p = 0.031) and 1.30 (95% CI 1.08 to 1.57, p = 0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBPs ≤ 120 and > 120 mm Hg, respectively (HR 1.13, 95% CI 1.03 to 1.24, p = 0.008). HRs for all-cause and HF hospitalizations associated with SBP ≤ 120 mm Hg were 1.10 (95% CI 1.02 to 1.194, p = 0.017) and 1.21 (95% CI 1.07 to 1.36, p = 0.002). In conclusion, in patients with mild to moderate long-term systolic and diastolic HF, baseline SBP ≤ 120 mm Hg was associated with increased cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations that was independent of other baseline characteristics.

Little is known about the association of rheumatic heart disease (RHD) with incident heart failure (HF) among older adults.Cardiovascular Health Study, a prospective cohort study.Of the 4,751 community-dwelling adults ≥ 65 years, free of prevalent HF at baseline, 140 had RHD, defined as self-reported physician-diagnosed RHD along with echocardiographic evidence of left-sided valvular disease. Propensity scores for RHD, estimated for each of the 4,751 participants, were used to assemble a cohort of 720, in which 124 and 596 participants with and without RHD, respectively, were balanced on 62 baseline characteristics.Incident HF developed in 33% and 22% of matched participants with and without RHD, respectively, during 13 years of follow-up (hazard ratio when RHD was compared to no-RHD 1.60; 95% confidence interval 1.13-2.28; P = 0.008). Pre-match unadjusted, multivariable-adjusted, and propensity-adjusted hazard ratios (95% confidence intervals) for RHD-associated incident heart failure were 2.04 (1.54-2.71; P0.001), 1.32 (1.02-1.70; P = 0.034), and 1.55 (1.14-2.11; P = 0.005), respectively. RHD was not associated with all-cause mortality (HR 1.09; 95% CI 0.82-1.45; P = 0.568).RHD is an independent risk factor for incident HF among community-dwelling older adults free of HF, but has no association with mortality.

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.

Aims Abnormally low right ventricular ejection fraction (RVEF) is a predictor of poor outcomes in chronic heart failure (HF) patients with low left ventricular ejection fraction (LVEF). However, little is known about the relationship between LVEF and RVEF in these patients. Methods and results Of the 2707 Beta-blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF, New York Heart Association class III–IV symptoms, and LVEF ≤35%, 2008 patients had gated-equilibrium radionuclide angiographic data on baseline LVEF and RVEF. Patients were categorized into quartiles by LVEF ≥29% (n= 507), 23–28% (n= 513), 17–22% (n= 538), and

Increased serum uric acid (UA) is associated with incident heart failure (HF). However, whether it is a direct effect of UA or an effect of increased xanthine oxidase (XO) is unknown. Because hyperuricemia in hyperinsulinemia is primarily due to impaired renal UA excretion, its association with incident HF would suggest a direct UA effect. In contrast, hyperuricemia in normoinsulinemia is likely due to increased UA production and thus its association with incident HF would suggest an XO effect. To clarify this, we examined the association of hyperuricemia with centrally adjudicated incident HF in Cardiovascular Health Study participants with and without hyperinsulinemia. Of the 5,411 participants ≥ 65 years of age without baseline HF, 1,491 (28%) had hyperuricemia (serum UA ≥ 6 mg/dl for women and ≥ 7 mg/dl for men). Propensity scores for hyperuricemia were estimated using 63 baseline characteristics. Mean serum UA levels were 6.0 and 5.3 mg/dl in those with (n = 2,731) and those without (n = 2,680) hyperinsulinemia (median serum insulin ≥ 13 mU/L), respectively (p0.001). Propensity-adjusted hazard ratios (95% confidence intervals) for hyperuricemia-associated incident HF during 8 years of median follow-up were 0.99 (0.83 to 1.18, p = 0.886) and 1.32 (1.04 to 1.67, p = 0.021) for those with and without hyperinsulinemia respectively (p for interaction = 0.014). In conclusion, the absence of an association of hyperuricemia with incident HF in those with hyperinsulinemia (despite a significantly higher mean serum UA) and a significant association in normoinsulinemia suggest that UA has no intrinsic association with incident HF and that it may predict incident HF when it is a marker of increased of XO activity.

A 46-year-old female with recurrent syncope and sinus arrest documented on an implanted loop recorder was referred for implantation of pacemaker. Initial attempts at lead deployment were unsuccessful due to an abnormal cardiac anatomy so cardiac magnetic resonance (CMR) examination was obtained to define the anatomy. Cardiac magnetic resonance revealed dextrocardia with the apices of both ventricles positioned in the right hemithorax. The liver, lung, and …

Background Associations between coronary artery disease (CAD) and outcomes in systolic heart failure (HF) and that between coronary artery bypass graft (CABG) surgery and outcomes in patients with HF and CAD have not been examined using propensity-matched designs. Methods Of the 2707 patients with advanced chronic systolic HF in the Beta-Blocker Evaluation of Survival Trial (BEST), 1593 had a history of CAD, of whom 782 had prior CABG. Using propensity scores for CAD we assembled a cohort of 458 pairs of CAD and no-CAD patients. Propensity scores for prior CABG in those with CAD were used to assemble 500 pairs of patients with and without CABG. Matched patients were balanced on 68 baseline characteristics. Results All-cause mortality occurred in 33% and 24% of matched patients with and without CAD respectively, during 26months of median follow-up (hazard ratio {HR} when CAD was compared with no-CAD, 1.41; 95% confidence interval {CI}, 1.11–1.81; P =0.006). HR's (95% CIs) for CAD-associated cardiovascular mortality, HF mortality, and sudden cardiac death (SCD) were 1.53 (1.17–2.00; P =0.002), 1.44 (0.92–2.25; P =0.114) and 1.76 (1.21–2.57; P =0.003) respectively. CAD had no association with hospitalization. Among matched patients with HF and CAD, all-cause mortality occurred in 32% and 39% of those with and without prior CABG respectively (HR for CABG, 0.77; 95% CI, 0.62–0.95; P =0.015). Conclusions In patients with advanced chronic systolic HF, CAD is associated with increased mortality, and in those with CAD, prior CABG seems to be associated with reduced all-cause mortality but not SCD.

The impact of baseline systolic blood pressure (SBP) on outcomes in patients with advanced chronic systolic heart failure (HF) has not been studied using a propensity-matched design. Of the 2,706 participants in the Beta-Blocker Evaluation of Survival Trial (BEST) with chronic HF, New York Heart Association class III to IV symptoms and left ventricular ejection fractionor =35%, 1,751 had SBPor =120 mm Hg (median 108, range 70 to 120) and 955 had SBP120 mm Hg (median 134, range 121 to 192). Propensity scores for SBP120 mm Hg, calculated for each patient, were used to assemble a matched cohort of 545 pairs of patients with SBPsor =120 and120 mm Hg who were balanced in 65 baseline characteristics. Matched Cox regression models were used to estimate associations between SBPor =120 mm Hg and outcomes over 4 years of follow-up. Matched participants had a mean age +/- SD of 62 +/- 12 years, 24% were women, and 24% were African-American. HF hospitalization occurred in 38% and 32% of patients with SBPsor =120 and120 mm Hg, respectively (hazard ratio 1.33 SBPor =120 was compared to120 mm Hg, 95% confidence interval 1.04 to 1.69, p = 0.023). All-cause mortality occurred in 28% and 30% of matched patients with SBPsor =120 and120 mm Hg, respectively (hazard ratio 1.13 SBPor =120 compared to120 mm Hg, 95% confidence interval 0.86 to 1.49, p = 0.369). In conclusion, in patients with advanced chronic systolic HF, baseline SBPor =120 mm Hg is associated with increased risk of HF hospitalization, but had no association with all-cause mortality.

We sought to demonstrate the distinguishing features between interarterial and intraseptal courses of an anomalous left coronary artery from the right sinus of Valsalva (RSV) on X-ray angiography, using an ex vivo model.An anomalous left main coronary artery (LMCA) arising from the RSV can take prepulmonary, retro-aortic, interarterial (IA) or intraseptal (IS) courses, of which only the IA course is associated with sudden death. Anomalous LMCA is usually identified during catheter angiography. On Xray angiography, IA and IS courses have common characteristics that makes their distinction challenging. We hypothesized that the cranialcaudal orientation of the vessel on X-ray angiography allows these pathways to be distinguished, and tested this hypothesis using an ex vivo heart model.Plastic tubing was inserted along the IA and IS courses in an ex vivo normal pig heart. X-ray imaging in standard views and MRI on a 3-T scanner were performed.In a normally formed heart, an anomalous LMCA with IA path must take a cephalad course, superior to the pulmonary valve. Conversely, an IS vessel will pass caudally, at or below the level of the infundibular septum. These findings were demonstrated in the X-ray angiograms and confirmed by magnetic resonance imaging.X-ray angiography can differentiate IA and IS courses of an anomalous LMCA in the normally formed heart. This may obviate the need for further cross-sectional imaging in many cases.

Mast cells are increased in isolated mitral regurgitation (MR) in the dog and may mediate extracellular matrix loss and left ventricular (LV) dilatation. We tested the hypothesis that mast cell stabilization would attenuate LV remodeling and improve function in the MR dog.MR was induced in adult dogs randomized to no treatment (MR, n = 5) or to the mast cell stabilizer, ketotifen (MR + MCS, n = 4) for 4 months. LV hemodynamics were obtained at baseline and after 4 months of MR and magnetic resonance imaging (MRI) was performed at sacrifice. MRI-derived, serial, short-axis LV end-diastolic (ED) and end-systolic (ES) volumes, LVED volume/mass ratio, and LV 3-dimensional radius/wall thickness were increased in MR and MR + MCS dogs compared with normal dogs (n = 6) (P.05). Interstitial collagen was decreased by 30% in both MR and MR + MCS versus normal dogs (P.05). LV contractility by LV maximum time-varying elastance was significantly depressed in MR and MR + MCS dogs. Furthermore, cardiomyocyte fractional shortening was decreased in MR versus normal dogs and further depressed in MR + MCS dogs (P.05). In vitro administration of ketotifen to normal cardiomyocytes also significantly decreased fractional shortening and calcium transients.Chronic mast cell stabilization did not attenuate eccentric LV remodeling or collagen loss in MR. However, MCS therapy had a detrimental effect on LV function because of a direct negative inotropic effect on cardiomyocyte function.

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.