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A clear, inclusive, and accurate approach to the collection of demographic information in clinical research and medical practice is critical to understanding the healthcare needs of the specific population. Inclusive demography constitutes appropriate and accurate characterization of an individual’s sexual orientation and gender identity (SOGI) data. Appropriate demography fosters sense of inclusion and belonging for those belonging to medically marginalized communities such as the lesbian, gay, bisexual, transgender, queer, intersex, asexual, and Indigenous Two-Spirit (LGBTQIA2S+) communities and improves health outcomes. Acquiring inclusive demographics in healthcare research is needed for the following critical reasons. First, LGBTQIA2S+ individuals experience undue psychological harm when their identities are not appropriately captured in survey data, promoting further alienation of the LGBTQIA2S+ community in medicine and research. Second, LGBTQIA2S+ populations are disproportionately burdened by several major cardiovascular and cardiovascular-associated diseases, including hypertension and diabetes. Failure to include these populations, and accurately characterize their participation, in research leads to failure to identify associations between identities and disease, resulting in worse health outcomes. Furthermore, this lack of precision in current data for sex, gender, and sexual orientation may lead to inaccurate data for all populations, not just the LGBTQIA2S+ community. Finally, there are currently major political and social threats and attacks on the LGBTQIA2S+ community and, in particular, on transgender and gender-diverse individuals. Proper medical inclusion and advocacy for the LGBTQIA2S+ community by the medical community may help protect the community from further undue harm through creating sense of belonging and reductions in marginalization-related health inequities.

Clinical algorithms stipulate that transthyretin amyloid cardiomyopathy (ATTR-CM) can be diagnosed noninvasively by technetium-99m pyrophosphate (PYP) imaging when light chain (AL) amyloidosis has been excluded. We sought to define the distribution of light chain abnormalities and final diagnosis of ATTR-CM among patients referred for PYP imaging. We conducted a retrospective cohort study of 378 sequential patients with suspected ATTR-CM, referred for PYP imaging from October 2014 to January 2019. PYP scans were adjudicated as per guidelines. We found that 97 patients (26%) had abnormal plasma cell dyscrasia (PCD) markers, including serum free light chain (FLC) and/or urine/serum immunofixation electrophoresis (IFE). After exclusions for incomplete data or known AL amyloidosis, the final study population with abnormal PCD testing was n = 82. Final adjudication of amyloidosis was determined by multidisciplinary clinical assessment and/or tissue biopsy. The median age of cohort was 75 (68 to 81) years, 88% were men, and 33% were Black. Of the 82 patients, 62 had positive PYP scans (76%) and 20 had negative PYP scans (24%). A total of 64 patients had adjudicated ATTR-CM, confirmed by tissue biopsy in 41 (64%). Of those with confirmed ATTR-CM, 44 (69%) had abnormal FLC ratio between 1.65 and 3.1 and normal IFE. In conclusion, among patients referred for technetium-99m-PYP imaging for suspected ATTR-CM, 26% exhibited abnormalities of PCD markers. An FLC ratio 1.65 to 3.1, with normal IFE was noted in 69% of those with ATTR-CM, suggesting that ATTR-CM can be diagnosed noninvasively without cardiac biopsy in patients with positive PYP scan and similar plasma cell testing results.

Diagnosis of pulmonary hypertension (PH) in systemic sclerosis (SSc) requires an invasive right heart catheterization (RHC), often based on an elevated estimated pulmonary artery systolic pressure on screening echocardiography. However, due to the poor specificity of echocardiography, a greater number of patients undergo RHC than necessary, exposing patients to potentially avoidable complication risks. The development of improved prediction models for PH in SSc may inform decision-making for RHC in these patients.We conducted a retrospective study of 130 patients with SSc; 66 (50.8%) were diagnosed with PH by RHC. We used data from pulmonary function testing, electrocardiography, echocardiography, and computed tomography to identify and compare the performance characteristics of three models predicting the presence of PH: 1) Random forest; 2) Classification and regression tree; and, 3) Logistic regression. For each model, we generated receiver operating curves and calculated sensitivity and specificity. We internally validated models using a train-test split of the data.The random forest model performed best with an area under the curve of 0.92 (95% CI: 0.83, 1.00), sensitivity of 0.95 (95% CI: 0.75, 1.00), and specificity of 0.80 (95% CI: 0.56, 0.94). The two most important variables in our random forest model were pulmonary artery diameter on chest computed tomography and diffusing capacity for carbon monoxide on pulmonary function testing.In patients with SSc, a random forest model can aid in the detection of PH with high sensitivity and specificity, and may allow for better patient selection for RHC, thereby minimizing patient risk. This article is protected by copyright. All rights reserved.

Although classified as group 1 pulmonary arterial hypertension (PAH), patients with systemic sclerosis-related pulmonary hypertension (SSc-PH) experience poorer clinical response to PAH therapy and increased mortality compared to those with idiopathic PAH. Due to heterogeneity in phenotypes, identifying patients likely to respond to therapy is challenging. The goal of this study was to determine clinical factors associated with hemodynamic response, defined by a 20% reduction in pulmonary vascular resistance on repeat right heart catheterization.We applied a time-to-event model using a retrospective cohort of 39 patients with precapillary SSc-PH, defined by a mean pulmonary artery pressure of ≥ 25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg on right heart catheterization.Patients with PAWP ≤ 8 mmHg were nearly fourfold more likely to achieve a hemodynamic response compared to those with PAWP 8 mmHg (HR 3.88; 95% CI: 1.20, 12.57); each 1 mmHg increase in PAWP was associated with a decreased hazard for hemodynamic response (HR 0.84; 95% CI: 0.70, 1.00).In patients with precapillary SSc-PH, PAWP was associated with time to hemodynamic response, suggesting the importance of subclinical cardiac disease in determining hemodynamic response to oral vasodilator therapy.

Whether heteroplasmic mitochondrial genetic variants in readily accessible tissues (blood, skeletal muscle) reflect those in the human heart (atrial appendage, left ventricle) is unknown. Using next generation sequencing data from paired tissue samples (n=233) collected postmortem in the Genotype-Tissue Expression project, we identified 558 unique heteroplasmic mitochondrial genetic variants across the four tissues, of which only 13% were shared across all four tissue sites. Between the two cardiac sites, 61% of heteroplasmic mitochondrial genetic variants were unique to one site. A greater proportion of the heteroplasmic variants were non-synonymous or frameshift variants in the muscle sites compared to blood or those variants shared across all four tissues. Compared to blood, the total number of heteroplasmic variants was higher in cardiac tissue, which was associated with advancing age. Our findings suggest that human cardiac tissue has unique heteroplasmic mtDNA variants and may be relevant to aging-related diseases.

High-dose melphalan and stem cell transplantation (HDM/SCT) is an effective treatment for selected patients with AL amyloidosis. We report the long-term outcomes of 648 patients with AL amyloidosis treated with HDM/SCT over 25 years. Hematologic CR was achieved by 39% of patients. The median duration of hematologic CR was 12.3 years, and 45% of patients with a hematologic CR had no evidence of a recurrent plasma cell dyscrasia at 15 years after HDM/SCT. With a median follow-up interval of 8 years, the median event-free survival (EFS) and overall survival (OS) were 3.3 and 7.6 years, respectively. Patients with a hematologic CR had a median OS of 15 years, and 30% of these patients survived20 years. On multivariable analysis, dFLC180 mg/L and BM plasma cells10% were independently associated with shorter EFS, whereas BNP81 pg/mL, troponin I 0.1 ng/mL, and serum creatinine2.0 mg/dL were independently associated with shorter OS. We developed a prognostic score for EFS, which incorporated dFLC180 mg/L and BMPC%10% as adverse risk factors. Patients with low-risk (0 factors), intermediate-risk (1 factor), and high-risk (2 factors) disease had median EFS estimates of 5.3, 2.8, and 1.0 years, respectively (p .001). The 100-day treatment-related mortality rate was 3% in the latest treatment period (2012-2021), and the 25-year risk of t-MDS/AML was 3%. We conclude that HDM/SCT induces durable hematologic responses and prolonged survival with improved safety in selected patients with AL amyloidosis.

Introduction: The American Heart Association’s framework “ideal cardiovascular health” (CVH) focuses on modifiable risk factors to reduce the overall burden of cardiovascular disease (CVD). Metabolomics provide important pathobiological insights into risk factors and CVD development. Whether circulating metabolites relate to CVH status and mediate the relations of CVH score with atrial fibrillation (AF) and heart failure (HF) has not been explored. Hypothesis: We hypothesized: a) CVH score associates with metabolites; and b) metabolites mediate the relation of CVH score with incident AF and HF. Methods and Results: We analyzed 3056 adults (mean age 54 years; 54% women) in FHS Offspring Cohort (Exam 5); 2059 participants had metabolomics data. Each metabolite measurement was log transformed and standardized for data normalization. Using linear mixed models, CVH score was associated with 144 metabolites (false discovery rate, q-value < 0.05), adjusting for age, sex, estimated glomerular filtration rate (eGFR) and family structure. Of these 144 metabolites, 65 metabolites overlapped with key cardiometabolic components of the CVH score (body mass index, blood pressure, and fasting blood sugar). In mediation analyses (adjusting for age, sex, eGFR), no metabolites mediated the relation between CVH score and incident AF. However, 11 metabolites (C36:4 phosphatidylcholine, isocitrate, glycerol, ornithine, aminoadipate, 3-indolepropionic acid, cystathionine, asparagine, alpha-hydroxybutyrate, phosphorylated saccharides, and C52:5 triacylglycerol) partially mediated the association between CVH score and incident HF in multivariable-adjusted models. Conclusion: Multiple metabolites associate with the CVH score and many of the metabolites are specifically associated with the cardiometabolic components of the CVH score. Several metabolic signatures, particularly lipids and tricarboxylic acid cycle intermediates, partially mediated the relation between CVH score and incident HF. Our findings lend insight into the role of metabolites in the relations of modifiable cardiovascular risk factors with incident HF.

Diflunisal is a non-steroidal anti-inflammatory drug that stabilises transthyretin (TTR) and reduces neurologic deterioration in patients with polyneuropathy caused by hereditary transthyretin amyloidosis (ATTRv). We conducted a retrospective cohort study of patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) treated with diflunisal for at least one year between 2009 and 2016 at the Boston University Amyloidosis Centre. Baseline and one year follow up characteristics were measured, including plasma chemistries and echocardiography. Cox proportional hazards analysis assessed the primary outcome of all-cause mortality. A total of 104 ATTRwt-CM patients were evaluated with 35 patients receiving diflunisal. Patients in the diflunisal group were younger (73.8 vs 76.8 years, p = 0.034), with lower B-type natriuretic peptide (BNP, 335 +/- 67 vs. 520 +/- 296 pg/mL, p = 0.006), similar troponin I (0.1 +/- 0.1 vs 0.2 +/- 0.3 ng/mL, p = 0.09), and better renal function (eGFR 67 +/- 17 vs 53 +/- 18 mL/min/1.73m2, p = 0.0002) at baseline. Over a median follow-up of 3.2 years, 52 deaths occurred. Diflunisal administration was associated with improved survival in unadjusted analysis (HR 0.13, 95% CI 0.05 − 0.36, p < 0.001) that persisted after adjustment for age, baseline BNP, eGFR, troponin I, interventricular septal thickness, and left ventricular ejection fraction (HR 0.18, 95% CI 0.06 − 0.51, p = 0.0006). Over the observation period, no significant changes in BNP, troponin I, interventricular septal thickness or left ventricular ejection fraction were observed with diflunisal treatment. A total of 14 patients (40%) discontinued diflunisal in this study, but only 3 within the first year. Mean eGFR in treated patients was 59 ml/min/1.73m2 at 1 year (change from baseline p = 0.03). Diflunisal administration in ATTRwt-CM was associated with improved survival and overall stability in clinical and echocardiographic markers of disease with decrement renal function.

Background Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an underappreciated cause of heart failure that results from misfolded TTR (prealbumin) protein. Diflunisal is an approved non-steroidal anti-inflammatory drug that stabilizes TTR, with limited data available regarding effects on cardiac structure and function. Methods and Results ATTR-CM patients (n=81, 41% treated with 250 mg twice-daily diflunisal by clinical practice) were retrospectively identified with baseline and follow-up (median interval 1 year) serum biomarker and echocardiographic data compared, including global longitudinal strain (GLS). Chi-squared and Wilcoxon tests assessed differences between subjects, divided by treatment group, and univariable and multivariable linear regression was performed. At baseline, patients treated with diflunisal were younger (68 vs 77 years, P = .0001), with lower B-type natriuretic peptide (BNP; 249 vs 545 pg/mL, P = .009) and serum creatinine (1.1 vs 1.2 mg/dL, P = .04), but similar TTR concentration (P = .31), cardiac troponin I (P = .06), and GLS (P = .67). At follow-up, diflunisal untreated versus treated patients showed differences in TTR concentration (19 vs 33 mg/dL, P = .01) and favorable differences in left atrial volume index (+4.6 vs −1.4 mL/m2, P = .002) and cardiac troponin I (+0.03 vs −0.01 ng/mL, P = .01) for the entire cohort. Among the subset with wild-type ATTR (n=53), diflunisal treatment was associated with differences in GLS (+1.2% untreated vs +0.1% treated, P = .03). Changes in wall thickness (P = .2), left ventricular ejection fraction (P = .71), and BNP (P = .42) were similar between groups. Conclusions In ATTR-CM, diflunisal treatment resulted in measurable differences in some parameters of cardiac structure and function after only 1 year of administration. Further longer-term analysis is warranted.

Introduction: Cardiopulmonary exercise testing (CPET) is a prognostic tool for advanced heart failure. Whether exercise metrics can provide incremental mortality prediction in ATTRwt-CM has not been well-studied. Hypothesis: We hypothesize CPET metrics improve mortality prediction in ATTRwt-CM. Methods: A retrospective review was conducted in ATTRwt-CM patients evaluated at the BU Amyloidosis Center between 2009-2019 who underwent CPET testing. Baseline demographic, clinical, and mortality data was collected. Continuous and categorical variables were compared using paired t-testing and chi-square testing, respectively. Baseline variable association with mortality was evaluated using logistic regression. Kaplan-Meier curves were used for survival estimation and Hazard ratios (HR) were estimated using Cox proportional hazards regression analysis. Results: A total of 136 patients with ATTRwt-CM were analyzed with median follow-up of 4 years (IQR 2.4, 5.6) with 43% deaths (n=59) during follow-up. Differences in baseline characteristics and metrics between individuals with and without mortality are shown in the table. Peak VO 2 , V E /VCO 2 , ventilatory threshold, heart rate recovery, and OUES were significantly associated with mortality. Using backwards stepwise regression, only OUES remained significantly associated with mortality among CPET variables. Using multivariable Cox survival analysis (adjusting for age, NYHA, eGFR, LVEF, troponin I, and BNP), OUES remained significantly associated with mortality (HR 0.25, 95% CI 0.08 - 0.77; p=0.02). The addition of OUES to troponin I, BNP, GLS, and eGFR increased the Wald chi-square statistic from 22.5 to 26.5 (p=0.01). Conclusions: The addition of OUES in ATTRwt-CM improves mortality prediction when added to current disease staging biomarkers: troponin I, BNP, GLS, and eGFR. This study highlights the incremental strength in outcome prediction using an exercise parameter, OUES, in ATTRwt-CM.

OBJECTIVE: Systemic sclerosis-related pulmonary hypertension (SSc-PH) is a common complication of SSc associated with accelerated mortality. We hypothesized that cardiac axis deviation may indicate abnormalities in cardiac function allowing for prognostication of disease severity and mortality. METHODS: This was a retrospective study where electrocardiograms (ECGs) were reviewed for cardiac axis deviation and their association with echocardiography and cardiopulmonary hemodynamics on right heart catheterization. The primary outcome observed was all-cause mortality from the time of PH diagnosis. RESULTS: ECGs were reviewed from 169 patients with SSc-PH. Right axis deviation (RAD) and left axis deviation (LAD) occurred in 28.4% and 30.8% of patients with SSc-PH, respectively. Compared to those without, patients with RAD exhibited predominantly right-sided cardiac disease on echocardiography and increased PH severity by cardiopulmonary hemodynamics including a greater mean pulmonary artery pressure (42.0 ± 12.5 mm Hg vs. 29.8 ± 7.0 mm Hg) and pulmonary vascular resistance (645.6 ± 443.2 dyns/cm(5) vs. 286.3 ± 167.7 dyn·s/cm(5)). LAD was associated with predominantly left-sided cardiac disease on echocardiography but was not associated with PH severity on cardiopulmonary hemodynamics. Both RAD (HR: 10.36; 95% CI: 4.90 - 21.93; p < 0.001) and LAD (HR: 2.94; 95% CI: 1.53 – 5.68; p = 0.001) were associated with an increased hazard for all-cause mortality. CONCLUSION: RAD and LAD reflect structural cardiac abnormalities and are associated with poor prognosis in patients with SSc-PH. These findings support the importance of electrocardiography, an inexpensive, widely available non-invasive test, in risk stratification.

The global prevalence of atrial fibrillation (AF) and heart failure (HF) is rising. Population-based studies have observed that AF and HF often coexist, predispose to each other, and share risk factors. Age is the most potent risk factor for both AF and HF, but race plays an important role. Although AF and HF share common risk factors, adjusting for these risk factors does not explain the higher risk of AF patients developing HF and vice versa. Common pathophysiologic mechanisms may explain this linkage. The morbidity and mortality outcomes with combined AF and HF are substantial and warrant improved preventive strategies.

Introduction: Hereditary transthyretin amyloid cardiomyopathy (pV142I hATTR-CM) is an under-recognized cause of heart failure (HF) in elderly patients of African origin. While we have previously demonstrated that the endogenous TTR ligand retinol binding protein 4 (RBP4) identifies patients with hATTR-CM, its capacity to predict outcomes is unexplored. Further, comparative data are lacking describing clinical outcomes in hATTR-CM vs. matched patients with HF. Hypothesis: Reduced survival is associated with pV142I hATTR-CM when compared to an age, race, sex matched patients with HF. Methods: Retrospective, single center, cohort study of self-reported African American patients ≥ 60 years of age with normal TTR genotype, HF, and LV wall thickness ≥ 12mm (n=84) were compared to a cohort with biopsy-proven pV142I hATTR-CM (n=30). Patients did not receive ATTR-specific therapies, as study occurred prior to FDA approvals. Baseline laboratory values were measured. All-cause mortality was estimated and compared between groups based on a median followup of 45.4 months. Analyses were conducted with Fisher Exact, Kruskal Wallis, and Kaplan-Meier with log-rank testing. Results: hATTR-CM patients were slightly older but less likely to have concomitant HTN or DM (Table 1). Baseline RBP4 concentration was lower while troponin level higher in patients with hATTR-CM (Table 1). hATTR-CM patients had a higher hazard of all-cause mortality after adjusting for age (HR=3.5, 95% CI: 1.8 – 6.7, p Conclusions: Patients pV142I hATTR-CM demonstrate significantly reduced survival (a 3.5-fold increased risk of death, 43% 4-year survival) compared to control subjects with HF in the absence of amyloidosis. Baseline RBP4 concentration did not associate with survival. These data suggest that hATTR-CM recognition is essential to permit implementation of available therapies that can improve survival.

Relief of congestion is the primary goal of initial therapy for acute decompensated heart failure (ADHF). Early measurement of urine sodium concentration (UNa) may be useful to identify patients with diminished response to diuretics. The aim of this study was to determine if the first spot UNa after diuretic initiation could select patients likely to require more intensive therapy during hospitalization.At the time of admission, 103 patients with ADHF were identified prospectively, and UNa was measured after the first dose of intravenous diuretic. Clinical outcomes were compared for patients with UNa60 mmol/L and UNa of ≤60 mmol/L, with the primary outcome of a composite of death at 90 days, mechanical circulatory support during admission, and requirement of inotropic support at discharge.Patients with UNa ≤60 had lower admission blood pressure, had less chronic neurohormonal antagonist prior to admission, and were more than twice as likely to experience the primary end point (hazard ratio 2.40, 95% CI 1.02-5.66, P = .045), which was marginally significant after adjusting for renal function and baseline home loop diuretic. Worsening renal function was significantly more common in patients with UNa60 (23.6% vs 6.5%, P = .05). Although the initial assessment of congestion was similar at admission, patients with low early UNa had a longer length of stay (11 vs 6 days, P .006) than patients with UNa60.Assessment of spot UNa after initial intravenous loop diuretic administration may facilitate identification and triage of a population of HF patients at increased risk for adverse events and prolonged hospitalization.

Introduction Our aim was to investigate if the accuracy of diagnosing mild cognitive impairment (MCI) using the Mini–Mental State Examination (MMSE) and logical memory (LM) test could be enhanced by adding MRI data. Methods Data of individuals with normal cognition and MCI were obtained from the National Alzheimer Coordinating Center database (n = 386). Deep learning models trained on MRI slices were combined to generate a fused MRI model using different voting techniques to predict normal cognition versus MCI. Two multilayer perceptron (MLP) models were developed with MMSE and LM test results. Finally, the fused MRI model and the MLP models were combined using majority voting. Results The fusion model was superior to the individual models alone and achieved an overall accuracy of 90.9%. Discussion This study is a proof of principle that multimodal fusion of models developed using MRI scans, MMSE, and LM test data is feasible and can better predict MCI.

Background Heart Failure (HF) the most frequent MS-DRG resulting in 30 day readmission is a major focus of readmission reduction initiatives. Achieving meaningful and sustained reductions in HF readmissions in a Safety Net Hospital is particularly challenging. Boston Medical Center achieved this goal through designing a robust slate of multidisciplinary interventions tapping existing institutional resources in new ways. Objectives Design a slate of multidisciplinary interventions that lower BMC’s average 30 day Medicare HF readmission to less than 19% by May 2019. Methods Using PDSA methodology a multidisciplinary team implemented interventions addressing care processes, co-morbidities and social determinants of health. Effectiveness was monitored through automated performance dashboards. Interventions included (1) Inpatient HF Consult Criteria patients not on Cardiology teams; (2) Standardized RN Teach Back and EPIC smart phrases discharge documentation; (3) VNA support HF home discharges, preferential respite admission when homelessness; (4) HF Clinic Nurse Practitioner follow up appointments within 7–14 days discharge ;(5) Scripted call day prior Cardiology appointment to mitigate barriers to arrival;(6) Concurrent Renal consultation CKD IV or V patients not on hemodialysis. Results In the six month prior to QI initiative, BMC’s Medicare 30 day HF readmission rate averaged 26.85% which decreased to 15.2% (12/1/18–6/30/19) as the slate of interventions fully activated. Total HF readmissions showed similar decrease from 23.9% to 17.2%. Conclusions BMC demonstrates that meaningful Heart Failure readmission reductions can be achieved Safety Net Hospitals by tapping into existing institutional resources in new ways. Planning permanent accountable team, automated dashboards and robust feedback loops insure reductions seen are sustained.

OBJECTIVE Metabolic syndrome (MetS) can lead to myocardial fibrosis, diastolic dysfunction, and eventual heart failure. This study evaluated alterations in myocardial microstructure in people with MetS by using a novel algorithm to characterize ultrasonic signal intensity variation. METHODS Among 254 participants without existing cardiovascular disease (mean age 42 ± 11 years, 75% women), there were 162 with MetS, 47 with obesity without MetS, and 45 nonobese controls. Standard echocardiography was performed, and a novel validated computational algorithm was used to investigate myocardial microstructure based on sonographic signal intensity and distribution. The signal intensity coefficient (SIC [left ventricular microstructure]) was examined. RESULTS The SIC was significantly higher in people with MetS compared with people with (P

The review’s main focus centers on the genetics of hereditary cardiac amyloidosis, highlighting the opportunities and challenges posed by the widespread availability of genetic screening and diagnostic cardiac imaging. Advancements in cardiac imaging, heightened awareness of the ATTR amyloidosis diagnosis, and greater access to genetic testing have all led to an increased appreciation of the prevalence of ATTR cardiac amyloidosis. Elucidation of the TTR molecular structure and effect of mutations on TTR function have allowed for novel TTR therapy development leading to clinical implementation of transthyretin stabilizers and transthyretin gene silencers. The transthyretin amyloidoses are a diverse group of protein misfolding disorders with cardiac and peripheral/autonomic nervous system manifestations due to protein deposition. Genetic screening allows for the early identification of asymptomatic TTR mutation carriers. With the advent of TTR-specific therapeutics, clinical guidance is necessary for the management of individuals with mutations in the TTR gene without evidence of disease.

The global prevalence of atrial fibrillation (AF) and heart failure (HF) is rising. Population-based studies have observed that AF and HF often coexist, predispose to each other, and share risk factors. Age is the most potent risk factor for both AF and HF, but race plays an important role. Although AF and HF share common risk factors, adjusting for these risk factors does not explain the higher risk of AF patients developing HF and vice versa. Common pathophysiologic mechanisms may explain this linkage. The morbidity and mortality outcomes with combined AF and HF are substantial and warrant improved preventive strategies.

Background Obesity is a precursor to heart failure with preserved ejection fraction. Biomarkers that identify preclinical metabolic heart disease ( MHD ) in young obese patients would help identify high‐risk individuals for heart failure prevention strategies. We assessed the predictive value of GAL3 (galectin–3), FSTL3 (follistatin‐like 3 peptide), and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) to identify stage B MHD in young obese participants free of clinically evident cardiovascular disease. Methods and Results Asymptomatic obese patients (n=250) and non‐obese controls (n=21) underwent echocardiographic cardiac phenotyping. Obese patients were classified as MHD positive ( MHD ‐ POS ; n=94) if they had abnormal diastolic function or left ventricular hypertrophy and had estimated pulmonary artery systolic pressure ≥35 mm Hg. Obese patients without such abnormalities were classified as MHD negative (MHD‐NEG; n=52). Serum biomarkers timed with echocardiography. MHD ‐ POS and MHD‐NEG individuals were similarly obese, but MHD ‐ POS patients were older, with more diabetes mellitus and metabolic syndrome. Right ventricular coupling was worse in MHD ‐ POS patients ( P GAL 3 levels were higher in MHD ‐ POS versus MHD ‐NEG patients (7.7±2.3 versus 6.3±1.9 ng/mL, respectively; P GAL 3 and FSTL 3 levels correlated with diastolic dysfunction and increased pulmonary artery systolic pressure but not with left ventricular mass. In multivariate models including all 3 biomarkers, only GAL 3 remained associated with MHD (odds ratio: 1.30; 95% CI , 1.01–1.68; P =0.04). Conclusions In young obese individuals without known cardiovascular disease, GAL 3 is associated with the presence of preclinical MHD . GAL 3 may be useful in screening for preclinical MHD and identifying individuals with increased risk of progression to obesity‐related heart failure with preserved ejection fraction.

Introduction: Cardioembolic events are common in cardiac amyloidosis (CA) in the absence of atrial fibrillation. In sinus rhythm (SR), marked reduction in the atrial component of left ventricular filling confers a physiology of atrial electromechanical disassociation (EMD), an entity well-recognized in CA. Presently, there are no effective tools to predict risk for atrial EMD. Hypothesis: We hypothesized that detection of blunted left atrial (LA) mechanics by strain imaging would provide increased sensitivity to detect abnormal LA contraction mechanics and associate with embolic events/intracardiac thrombus among CA patients in SR. Methods: Baseline echocardiograms were analyzed for LA strain (TomTec, Unterschleissheim, Germany) from a retrospectively identified cohort of n=46 CA patients, of whom n=17 developed an embolic event/intercardiac thrombus (event+) and n=29 did not (event-). Patients with prior/active atrial fibrillation or flutter or administration of anticoagulation were excluded by electrocardiographic or medical record review. Comparisons between groups applied Student’s t test utilizing equal variance assumption testing. Results: No significant differences were identified in standard structural echocardiographic parameters (between event+ vs. event- groups), including LVEF (44 vs. 50%, p=0.11), transmitral A velocity (51 vs. 49 cm/s, p=0.84), LA volume index (41 vs. 40 mL/m 2 , p=0.77), and diastolic dysfunction grade (Grade III in 47 vs. 52%, p=0.53). In patients with light-chain CA, LA contraction mechanics were significantly decreased among event+ persons compared to event- persons (Figure). Conclusions: LA contraction mechanics are significantly blunted in light-chain CA patients who experienced an embolic event/intracardiac thrombus despite normal SR. These data suggest that LA strain assessment may afford a means to guide anticoagulation treatment in high-risk CA patients.

Metabolic syndrome (MetS) can lead to myocardial fibrosis, diastolic dysfunction, and eventual heart failure. This study evaluated alterations in myocardial microstructure in people with MetS by using a novel algorithm to characterize ultrasonic signal intensity variation.Among 254 participants without existing cardiovascular disease (mean age 42 ± 11 years, 75% women), there were 162 with MetS, 47 with obesity without MetS, and 45 nonobese controls. Standard echocardiography was performed, and a novel validated computational algorithm was used to investigate myocardial microstructure based on sonographic signal intensity and distribution. The signal intensity coefficient (SIC [left ventricular microstructure]) was examined.The SIC was significantly higher in people with MetS compared with people with (P 0.001) and without obesity (P = 0.04), even after adjustment for age, sex, body mass index, hypertension, diabetes mellitus, and the ratio of triglyceride (TG) to high-density lipoprotein (HDL) cholesterol (P 0.05 for all). Clinical correlates of SIC included TG concentrations (r = 0.21, P = 0.0007) and the TG/HDL ratio (r = 0.2, P = 0.001).This study's findings suggest that preclinical MetS and dyslipidemia in particular are associated with altered myocardial signal intensity variation. Future studies are needed to determine whether the SIC may help detect subclinical diseases in people with metabolic disease, with the ultimate goal of targeting preventive efforts.

Objective Systemic sclerosis (SSC; scleroderma)–associated pulmonary arterial hypertension (PAH) is a major cause of mortality in SSc patients and represents an important diagnostic and therapeutic target. Our aims were to evaluate the relationship between echocardiogram-derived right-sided heart hemodynamics and gold standard right-sided heart catheterization (RHC) measurements in a scleroderma population and to investigate whether this relationship is modified by a subset of pulmonary hypertension. Methods We performed RHC and echocardiography on the same day, with pulmonary function testing in 21 consecutive subjects with scleroderma and precapillary pulmonary hypertension (mean ± SD age 57 ± 10 years, 81% women). Results RHC measures, including pulmonary arterial systolic and mean pressure and pulmonary vascular resistance (PVR), correlated strongly with echocardiogram-derived data. RHC-derived PVR was negatively associated with right ventricular (RV) systolic performance, as measured by tricuspid annular plane systolic excursion (TAPSE; rho = −0.70, P < 0.001), tissue Doppler tricuspid s′ velocity (rho = −0.68, P = 0.002), and RV fractional area change (rho = −0.78, P < 0.001). Correlations with TAPSE and s′ velocity were strengthened when forced vital capacity %/diffusing capacity of the lung for carbon monoxide % ≥1.6 was used to identify pure PAH phenotypes in SSc. Bland-Altman analyses demonstrated strong agreement between RHC and echocardiogram-derived hemodynamic measures. Conclusion Our findings suggest that echocardiography may play a clinical role in identifying pulmonary hypertension and RV dysfunction noninvasively, particularly in a subset of SSc patients stratified by pulmonary function testing. This method may establish specific disease phenotypes with differential cardiovascular impact and prove useful as a marker of disease progression/risk stratification in SSC patients that warrants further investigation in larger cohorts.

Background: Although decongestion is the primary focus of acute heart failure (HF) management, the degree of natriuretic response to diuretic therapy varies and may predict length of stay (LOS) and early outcomes. We hypothesize that a UNa &lt60 mmol/L, measured after initial intravenous (IV) diuretic administration, would be associated with longer duration of IV diuretic, longer LOS, increased use of inotropic therapy in hospital and higher risk of death. Methods and Results: From July 1, 2014-May 30, 2015, we enrolled 100 unique patients hospitalized to the advanced HF service for decompensated HF. Dose of IV diuretic was based on their daily oral home dose. Spot urine samples were collected within a median of 98 (0-187) minutes after initial diuretic therapy. Patients with UNa &lt60 mmol/L (n=30) had significantly lower serum sodium and higher admission NT-proBNP than those with UNa &gt60 mmol/L (n=70). As well, they were more commonly rated with hemodynamic profile C (“cold and wet”, 40.0 vs.11.4%, p=0.002) and INTERMACS profile 3-4 (30.0 vs. 12.9%, p= 0.04). During the hospital stay, patients with low initial UNa required longer use of IV diuretic therapy (9.5 vs. 5.0 days, p&lt0.0001) and had a longer median LOS (12.0 vs. 6.0 days, p&lt 0.0001) than those with high UNa. After adjusting for eGFR, UNa &lt60 mmol/L was still associated with a higher likelihood of inotropic usage in hospital (hazard ratio [HR] 9.91 (3.27-30.05); p&lt0.0001) and death (HR 3.14 (1.20-8.23); p=0.004) at a median follow-up period of 85 (38-159) days (figure 1). Conclusions: Low UNa after initial IV diuretic administration identifies a population of acute HF patients with advanced disease who have longer LOS and are at high risk for death. Measurement of UNa after first diuretic therapy may help to facilitate triage of patients with heart failure and anticipate the need for advanced HF therapies

Background How serum albumin levels are associated with risk for heart failure (HF) in the elderly is unclear. Methods We evaluated 2,907 participants without HF (age 73.6 ± 2.9 years, 48.0% male, 58.7% white) from the community-based Health ABC Study. The association between baseline albumin and incident HF was assessed with standard and competing risks proportional hazards models controlling for HF predictors, inflammatory markers, and incident coronary events. Results During a median follow-up of 9.4 years, 342 (11.8%) participants developed HF. Albumin was a time-dependent predictor of HF, with significance retained for up to 6 years (baseline hazard ratio [HR] per −1 g/L 1.14, 95% CI 1.06-1.22, P P = .001). This association persisted in models controlling for HF predictors, inflammatory markers, and incident coronary events (baseline HR per −1 g/L 1.13, 95% CI 1.05-1.22, P = .001; annual rate of HR decline 1.8%, 95% CI 0.5%-3.0%, P = .008) and when mortality was accounted for in adjusted competing risks models (baseline HR per −1 g/L 1.13, 95% CI 1.05-1.21, P = .001; annual rate of HR decline 1.9%, 95% CI 0.7%-3.1%, P = .002). The association of albumin with HF risk was similar in men (HR per −1 g/L 1.13, 95% CI 1.05-1.23, P = .002) and women (HR per −1 g/L 1.12, 95% CI 1.04-1.22, P = .005) and in whites and blacks (HR per −1 g/L 1.13, 95% CI 1.04-1.22, P Conclusions Low serum albumin levels are associated with increased risk for HF in the elderly in a time-dependent manner independent of inflammation and incident coronary events.

Incident atrial fibrillation (AF) resulting in hypotension and ICU care is a significant occurrence complicating stem cell transplantation (SCT) for AL amyloidosis. We have reported that while a history of AF predicted post-SCT AF, echocardiographic parameters were not associated with incident AF.

Background— Despite the substantial overlap of obesity and metabolic disease, there is heterogeneity with respect to cardiovascular risk. We sought to investigate preclinical differences in systolic and diastolic function in obesity, and specifically compare obese individuals with and without metabolic syndrome (MS). Methods and Results— Obese individuals without cardiac disease with (OB/MS+, n=124) and without (OB/MS−, n=37) MS were compared with nonobese controls (n=29). Diastolic function was assessed by transmitral and tissue Doppler. Global longitudinal strain (LS) and time-based dyssynchrony were assessed by speckle tracking. Both OB/MS− and OB/MS+ groups had similar ejection fraction but worse systolic mechanics as assessed by LS and dyssynchrony when compared with nonobese controls. Specifically, OB/MS− had 2.5% lower LS (SE, 0.7%; P =0.001 in multivariable-adjusted analyses) and 10.8 ms greater dyssynchrony (SE, 3.3 ms; P =0.002), and OB/MS+ had 1.0% lower LS (SE, 0.3%; P P Conclusions— Obesity is associated with subclinical differences in both systolic and diastolic function regardless of the presence or absence of MS although MS seems to be associated with worse diastolic dysfunction. When compared with controls, metabolically healthy obese had lower LS, greater dyssynchrony, and early diastolic dysfunction, supporting the notion that obesity per se may have adverse cardiovascular effects regardless of metabolic disease.

Background Metabolic disease can lead to intrinsic pulmonary hypertension in experimental models. The contributions of metabolic syndrome (MetS) and obesity to pulmonary hypertension and right ventricular dysfunction in humans remain unclear. We investigated the association of MetS and obesity with right ventricular structure and function in patients without cardiovascular disease. Methods and Results A total of 156 patients with MetS (mean age 44 years, 71% women, mean body mass index 40 kg/m 2 ), 45 similarly obese persons without MetS, and 45 nonobese controls underwent echocardiography, including pulsed wave Doppler measurement of pulmonary artery acceleration time ( PAAT ) and ejection time. Pulmonary artery systolic pressure was estimated from PAAT using validated equations. MetS was associated with lower tricuspid valve e′ (right ventricular diastolic function parameter), shorter PAAT , shorter ejection time, and larger pulmonary artery diameter compared with controls ( P PAAT was 42±12 mm Hg in participants with MetS compared with 32±9 and 32±10 mm Hg in obese and nonobese controls ( P for ANOVA PAAT (β=−20.4, SE=6.5, P =0.002 versus obese). This association persisted after accounting for left ventricular structure and function and after exclusion of participants with obstructive sleep apnea. Conclusions MetS is associated with abnormal right ventricular and pulmonary artery hemodynamics, as shown by shorter PAAT and subclinical right ventricular diastolic dysfunction. Estimated pulmonary artery systolic pressures are higher in MetS and preclinical metabolic heart disease and raise the possibility that pulmonary hypertension contributes to the pathophysiology of metabolic heart disease.

Introduction: Metabolic syndrome (MetS) is associated with preclinical metabolic heart disease (MHD) as reflected by left ventricular (LV) diastolic dysfunction. Very little is known about right ventricular (RV) function and/or pulmonary hypertension in MetS or early MHD. Hypothesis: We tested the hypothesis that that MetS is associated with subclinical RV dysfunction and pulmonary hypertension. Methods: A total of 164 subjects with MetS but without cardiovascular disease (mean age 45 years, 71% women, mean BMI 41 kg/m 2 ), 40 similarly obese controls without MetS, and 36 non-obese healthy controls underwent echocardiography, including pulsed-wave Doppler measurement of pulmonary artery acceleration time (PAAT) and ejection time (ET). PA systolic pressure was estimated from PAAT using validated equations. Results: MetS was associated with lower tricuspid valve e', shorter PAAT, shorter ET, and larger PA diameter compared with controls (Table). A total of 24% of individuals with MetS had an abnormal PAAT (Table ). After adjustment for age, sex, hypertension, diabetes, and body-mass index, MetS remained associated with shorter PAAT (P=0.03 vs healthy; P=0.0005 vs obese). Among MetS, PAAT was correlated with mitral mean e’ (r=0.20, P=0.004), E/A ratio (r=0.21, P=0.008), and tricuspid e’ (r=0.20, P=0.04). A total of 40% of participants with abnormal PAAT also had low mean e’ ( Conclusions: MetS is associated with abnormal RV hemodynamics as evidenced by shorter PAAT, which correlates with measures of LV diastolic function. Estimated PA systolic pressures are significantly higher in preclinical MetS and MHD, and raise the possibility that pulmonary hypertension contributes to the pathophysiology of MHD.

BACKGROUND Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described. METHODS We measured plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995–1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT >1.5 mm), and mean common carotid artery IMT. We carried out multivariable regressions for carotid measurements vs biomarkers using linear and logistic models; P < 0.0056 was deemed statistically significant. RESULTS Maximal ICA IMT was significantly associated with plasma GDF-15 [β-estimate 0.04 per 1-U increase in log(GDF-15), SE 0.01, P < 0.0001]. Similarly, the odds of having carotid plaque increased 33% [odds ratio 1.33 per 1-U increase in log(GDF-15), 95% CI 1.20–1.48, P < 0.0001]. In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the 3 biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together. CONCLUSIONS Increased GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted.

Metabolic syndrome (MS) is commonly associated with left ventricular (LV) diastolic dysfunction and LV hypertrophy. We sought to examine whether preclinical LV diastolic dysfunction can occur independent of LV hypertrophy in MS. We recruited 90 consecutive participants with MS and without cardiovascular disease (mean age 46 years, 78% women) and 26 controls (no risk factors for MS; mean age 43 years, 65% women). Participants underwent echocardiography with tissue Doppler imaging. In age- and gender-adjusted analyses, MS was associated with higher left atrial (LA) diameter, higher LV mass, lower E/A ratio, and lower mean e' (p0.001 for all). These associations remained significant after further adjusting for blood pressure, antihypertensive medication use, and body mass index. After adjusting for LV mass, MS remained independently associated with higher LA diameter, lower E/A ratio, and lower mean e' (p ≤0.01 for all). Specifically, subjects with MS had a 1.8 cm/s lower mean e' compared with controls (p = 0.01). Notably, differences in mean e' between those with and without MS were more pronounced at younger ages (p for interaction = 0.003). In conclusion, MS was associated with preclinical LV diastolic dysfunction independent of LV mass, as reflected by higher LA diameter, lower E/A ratio, and lower mean e'. This suggests that MS can lead to the development of diastolic dysfunction through mechanisms independent of hypertrophy. Differences in diastolic function were more pronounced at younger ages, highlighting the potential importance of early risk factor modification and preventive strategies in MS.

Systemic sclerosis (SSC; scleroderma)-associated pulmonary arterial hypertension (PAH) is a major cause of mortality in SSc patients and represents an important diagnostic and therapeutic target. Our aims were to evaluate the relationship between echocardiogram-derived right-sided heart hemodynamics and gold standard right-sided heart catheterization (RHC) measurements in a scleroderma population and to investigate whether this relationship is modified by a subset of pulmonary hypertension.We performed RHC and echocardiography on the same day, with pulmonary function testing in 21 consecutive subjects with scleroderma and precapillary pulmonary hypertension (mean ± SD age 57 ± 10 years, 81% women).RHC measures, including pulmonary arterial systolic and mean pressure and pulmonary vascular resistance (PVR), correlated strongly with echocardiogram-derived data. RHC-derived PVR was negatively associated with right ventricular (RV) systolic performance, as measured by tricuspid annular plane systolic excursion (TAPSE; rho = -0.70, P0.001), tissue Doppler tricuspid s' velocity (rho = -0.68, P = 0.002), and RV fractional area change (rho = -0.78, P0.001). Correlations with TAPSE and s' velocity were strengthened when forced vital capacity %/diffusing capacity of the lung for carbon monoxide % ≥1.6 was used to identify pure PAH phenotypes in SSc. Bland-Altman analyses demonstrated strong agreement between RHC and echocardiogram-derived hemodynamic measures.Our findings suggest that echocardiography may play a clinical role in identifying pulmonary hypertension and RV dysfunction noninvasively, particularly in a subset of SSc patients stratified by pulmonary function testing. This method may establish specific disease phenotypes with differential cardiovascular impact and prove useful as a marker of disease progression/risk stratification in SSC patients that warrants further investigation in larger cohorts.

Background Galectin‐3 ( GAL ‐3), a β‐galactoside–binding protein, is a new clinical biomarker believed to reflect cardiac remodeling/fibrosis in patients with heart failure ( HF ). Plasma GAL ‐3 is inversely related to renal function. It is not known whether the relationship between renal function and GAL ‐3 is influenced by clinical decompensation, type of HF , or the presence or absence of clinical HF . Methods and Results Patients were prospectively categorized as having acute decompensated HF or stable HF on the basis of clinical status and as having HF with reduced left ventricular ejection fraction or HF with preserved left ventricular ejection fraction. Plasma GAL ‐3 was measured by enzyme‐linked immunosorbent assay in patients with HF (n=75), control patients without HF (n=32), and control patients without HF with moderate renal insufficiency (n=12). Compared to controls without HF (14±4 ng/mL), GAL ‐3 was higher in patients with both acute decompensated HF (23±11 ng/mL) and stable HF (22±10 ng/mL) ( P HF and stable HF ( P =0.75). Likewise, GAL ‐3 was elevated in both HF with preserved left ventricular ejection fraction (23±9 ng/mL) and HF with reduced left ventricular ejection fraction (22±11 ng/mL) ( P P =0.37). GAL ‐3 correlated strongly with estimated glomerular filtration rate, both in patients with HF ( r =−0.75, P HF ( r =−0.82, P HF . Conclusions Plasma GAL ‐3 is inversely related to renal function in patients with and without clinical HF . Concentrations of plasma GAL ‐3 do not seem to depend on the level of compensation or type of HF . Furthermore, the relationship between GAL ‐3 and renal function seems to be affected little or not at all by the presence or absence of clinical HF .

BackgroundAlthough there is evidence linking smoking and heart failure (HF), the association between lifetime smoking exposure and HF in older adults and the strength of this association among current and past smokers is not well known.MethodsWe examined the association between smoking status, pack-years of exposure, and incident HF risk in 2,125 participants of the Health, Aging, and Body Composition Study (age 73.6 ± 2.9 years, 69.7% women, 54.2% whites) using proportional hazard models.ResultsAt inception, 54.8% of participants were nonsmokers, 34.8% were past smokers, and 10.4% were current smokers. During follow-up (median 9.4 years), HF incidence was 11.4 per 1,000 person-years in nonsmokers, 15.2 in past smokers (hazard ratio [HR] vs nonsmokers 1.33, 95% CI 1.01-1.76, P = .045), and 21.9 in current smokers (HR 1.93, 95% CI 1.30-2.84, P = .001). After adjusting for HF risk factors, incident coronary events, and competing risk for death, a dose-effect association between pack-years of exposure and HF risk was observed (HR 1.09, 95% CI 1.05-1.14, P < .001 per 10 pack-years). Heart failure risk was not modulated by pack-years of exposure in current smokers. In past smokers, HR for HF was 1.05 (95% CI 0.64-1.72) for 1 to 11 pack-years, 1.23 (95% CI 0.82-1.83) for 12 to 35 pack-years, and 1.64 (95% CI 1.11-2.42) for >35 pack-years of exposure in fully adjusted models (P < .001 for trend) compared with nonsmokers.ConclusionsIn older adults, both current and past cigarette smoking increase HF risk. In current smokers, this risk is high irrespective of pack-years of exposure, whereas in past smokers, there was a dose-effect association.

Patients with heart failure (HF) develop metabolic derangements including increased adipokine levels, insulin resistance, inflammation and progressive catabolism. It is not known whether metabolic dysfunction and adipocyte activation worsen in the setting of acute clinical decompensation, or conversely, improve with clinical recovery.We assessed insulin resistance using homeostasis model assessment of insulin resistance (HOMA-IR), and measured plasma levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), adiponectin, visfatin, resistin, leptin, and tumor necrosis factor (TNF) α in 44 patients with acute decompensated HF (ADHF) due to left ventricular (LV) systolic dysfunction and again early (1 wk) and late (6 mo) after clinical recovery, in 26 patients with chronic stable HF, and in 21 patients without HF. NT-proBNP was not increased in control subjects, mildly elevated in patients with stable HF, markedly elevated in patients with ADHF, and decreased progressively early and late after treatment. Compared to control subjects, plasma adiponectin, visfatin, leptin, resistin, and TNF-α were elevated in patients with chronic stable HF and increased further in patients with ADHF. Likewise, HOMA-IR was increased in chronic stable HF and increased further during ADHF. Adiponectin, visfatin, and HOMA-IR remained elevated at the time of discharge from the hospital, but returned to chronic stable HF levels. Adipokine levels were not related to body mass index in HF patients. HOMA-IR correlated positively with adipokines and TNF-α in HF patients.ADHF is associated with worsening of insulin resistance and elevations of adipokines and TNF-α, indicative of adipocyte activation. These metabolic abnormalities are reversible, but they temporally lag behind the clinical resolution of decompensated HF.