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Bendopnea, or dyspnoea with bending forward, is a recently described symptom of heart failure that is associated with elevated ventricular filling pressures. Here, we describe a case of superior vena cava (SVC) stenosis that presented with bendopnea and resolved with SVC recanalisation. We suggest that SVC stenosis be considered in the differential diagnosis of patients who experience bendopnea.

The V122I variant in transthyretin (TTR) is the most common amyloidogenic mutation worldwide. The aim of this study is to describe the cardiac phenotype and risk for adverse cardiovascular outcomes of young V122I TTR carriers in the general population.TTR genotypes were extracted from whole-exome sequence data in participants of the Dallas Heart Study. Participants with African ancestry, available V122I TTR genotypes (N = 1818) and either cardiac magnetic resonance imaging (n = 1364) or long-term follow-up (n = 1532) were included. The prevalence of V122I TTR carriers (45 ± 10 years) was 3.2% (n/N = 59/1818). The V122I TTR carriers had higher baseline left ventricular wall thickness (8.52 ± 1.82 vs 8.21 ± 1.62 mm, adjusted P = .038) than noncarriers, but no differences in other cardiac magnetic resonance imaging measures (P.05 for all). Although carrier status was not associated with amino terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline (P = .79), V122I TTR carriers had a greater increase in NT-proBNP on follow-up than noncarriers (median 28.5 pg/mL, interquartile range 11.4-104.1 pg/mL vs median 15.9 pg/mL, interquartile range 0.0-43.0 pg/mL, adjusted P = .018). V122I TTR carriers were at a higher adjusted risk of heart failure (hazard ratio 3.82, 95% confidence interval 1.80-8.13, P.001), cardiovascular death (hazard ratio 2.65, 95% confidence interval 1.14-6.15, P = .023), and all-cause mortality (hazard ratio 1.95, 95% confidence interval 1.08-3.51, P = .026) in comparison with noncarriers.V122I TTR carrier status was associated with a greater increase in NT-proBNP, slightly greater left ventricular wall thickness, and a higher risk for heart failure, cardiovascular death, and all-cause mortality. These findings suggest the need to develop amyloidosis screening strategies for V122I TTR carriers.

Background Clinical congestion is associated with adverse outcomes in patients with heart failure. The pathophysiological mediators of this association remain uncertain. Methods and Results We prospectively enrolled a cohort of patients with heart failure and reduced left ventricular ejection fraction and performed a detailed clinical examination followed on the same day by an invasive right heart catheterization and blood sampling for biomarkers. High-sensitivity troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were measured. A clinical congestion score was calculated based on jugular venous pressure (cm H20 14 = 2 points), bendopnea (0 vs 1), a third heart sound (0 vs 1), or peripheral edema (0–2). Congestion was categorized into tiers as absent (0 points), mild (1 point), or moderate to severe (≥ 2 points). We tested for associations of high-sensitivity troponin T, NT-proBNP, and elevated ventricular filling pressures with clinical congestion in both univariate and multivariable analyses. Of 153 participants, 65 (42%) had absent, 35 mild (23%), and 53 (35%) had moderate to severe clinical congestion. Congestion tier was associated with higher NT-proBNP and hs-troponin levels, and the right atrial pressure and pulmonary capillary wedge pressure (P Conclusions Clinical congestion is a phenotype in which there is a high coexistent presence of elevated ventricular filling pressures, elevated natriuretic peptide levels, and subclinical myocardial injury. An elevated troponin was associated with clinical congestion in multivariable models that adjusted for ventricular filling pressures and natriuretic peptide levels. These data strengthen the evidence base for an association of elevated troponin with clinical congestion, suggesting that subclinical myocardial injury may be an important contributor to the pathophysiology of the congested state.

Patients with continuous flow destination therapy (DT) left ventricular assist devices (LVAD) comprise a heterogeneous population. We hypothesized that phenotypic clustering of individuals with DT LVADs by their implantation characteristics will be associated with different long-term risk profiles. We analyzed 5,999 patients with continuous flow DT LVADs in Interagency Registry for Mechanically Assisted Circulatory Support using 18 continuous variable baseline characteristics. We Z-transformed the variables and applied a Gaussian finite mixture model to perform unsupervised clustering resulting in identification of 4 phenogroups. Survival analyses considered the competing risk for cumulative incidence of transplant or the composite end point of death or heart transplant where appropriate. Phenogroup 1 (n = 1,163, 19%) was older (71 years) and primarily white (81%). Phenogroups 2 (n = 648, 11%) and 3 (n = 3,671, 61%) were of intermediate age (70 and 62 years), weight (85 and 87 kg), and ventricular size. Phenogroup 4 (n = 517, 9%) was younger (40 years), heavier (108 kg), and more racially diverse. The cumulative incidence of death, heart transplant, bleeding, LVAD malfunction, and LVAD thrombosis differed among phenogroups. The highest incidence of death and the lowest rate of heart transplant was seen in phenogroup 1 (p0.001). For adverse outcomes, phenogroup 4 had the lowest incidence of bleeding, whereas LVAD device thrombosis and malfunction were lowest in phenogroup 1 (p0.001 for all). Finally, the incidence of stroke, infection, and renal dysfunction were not statistically different. In conclusion, the present unsupervised machine learning analysis identified 4 phenogroups with different rates of adverse outcomes and these findings underscore the influence of phenotypic heterogeneity on post-LVAD implantation outcomes.

Aims Patients with obesity and ischaemic heart failure may counter‐intuitively have better outcomes compared with patients with normal body weight due to an ‘obesity paradox’. This study sought to determine if body mass index (BMI) impacts the treatment effects or safety outcomes of the treatment of ischaemic heart failure with coronary artery bypass grafting (CABG). Methods and results We obtained and reviewed the Surgical Treatment of Ischaemic Heart Failure (STICHES) data for 1212 patients. We categorized obesity by the World Health Organization (WHO) classes to define baseline characteristics and test for treatment interactions for the primary and secondary STICHES outcomes by treatment groups. While CABG decreased the risk of death, there was no evidence of treatment interaction by BMI per 5 kg/m2 (P = 0.83) or WHO obesity class. For the overall cohort, there was no interaction by WHO obesity class for the cumulative incidence of death in either the medical therapy or CABG plus medical therapy (P‐interaction = 0.90). There was a non‐significant trend for higher BMI and a lower risk of death [hazard ratio 0.92, 95% confidence interval (CI) 0.85–1.00, P = 0.051]. Increasing body size (per 5 kg/m2) was associated with return to the operating room (odds ratio 2.48, 95% CI 1.45–4.26, P

Background: A malignant subphenotype of left ventricular hypertrophy (LVH) has been described, in which minimal elevations in cardiac biomarkers identify individuals with LVH at high risk for developing heart failure (HF). We tested the hypothesis that a higher prevalence of malignant LVH among blacks may contribute to racial disparities in HF risk. Methods: Participants (n=15 710) without prevalent cardiovascular disease were pooled from 3 population-based cohort studies, the ARIC Study (Atherosclerosis Risk in Communities), the DHS (Dallas Heart Study), and the MESA (Multi-Ethnic Study of Atherosclerosis). Participants were classified into 3 groups: those without ECG-LVH, those with ECG-LVH and normal biomarkers (hs-cTnT (high sensitivity cardiac troponin-T) Results: Over the 10-year follow-up period, HF occurred in 512 (3.3%) participants, with 5.2% in black men, 3.8% in white men, 3.2% in black women, and 2.2% in white women. The prevalence of malignant LVH was 3-fold higher among black men and women versus white men and women. Compared with participants without LVH, the adjusted hazard ratio for HF was 2.8 (95% CI, 2.1–3.5) in those with malignant LVH and 0.9 (95% CI, 0.6–1.5) in those with LVH and normal biomarkers, with similar findings in each race/sex subgroup. Mediation analyses indicated that 33% of excess hazard for HF among black men and 11% of the excess hazard among black women was explained by the higher prevalence of malignant LVH in blacks. Of black men who developed HF, 30.8% had malignant LVH at baseline, with a corresponding population attributable fraction of 0.21. The proportion of HF cases occurring among those with malignant LVH, and the corresponding population attributable fraction, were intermediate and similar among black women and white men and lowest among white women. Conclusions: A higher prevalence of malignant LVH may in part explain the higher risk of HF among blacks versus whites. Strategies to prevent development or attenuate risk associated with malignant LVH should be investigated as a strategy to lower HF risk and mitigate racial disparities.

Background: In ≈25% of patients with heart failure and reduced left-ventricular ejection fraction, right-ventricular (RV), and left-ventricular (LV) filling pressures are discordant (ie, one is elevated while the other is not). Whether clinical assessment allows detection of this discordance is unknown. We sought to determine the agreement of clinically versus invasively determined patterns of ventricular congestion. Methods: In 156 heart failure and reduced LV ejection fraction subjects undergoing invasive hemodynamic assessment, we categorized patterns of ventricular congestion (no congestion, RV only, LV only, or both) based on clinical findings of RV (jugular venous distention) or LV (hepatojugular reflux, orthopnea, or bendopnea) congestion. Agreement between clinically and invasively determined (RV congestion if right atrial pressure [RAP] ≥10 mm Hg and LV congestion if pulmonary capillary wedge pressure [PCWP] ≥22 mm Hg) categorizations was the primary end point. Results: The frequency of clinical patterns of congestion was: 51% no congestion, 24% both RV and LV, 21% LV only, and 4% RV only. Jugular venous distention had excellent discrimination for elevated RAP (C=0.88). However, agreement between clinical and invasive congestion patterns was poor, к=0.44 (95% CI, 0.34–0.55). While those with no clinical congestion usually had low RAP and PCWP (67/79, 85%), over one-half (24/38, 64%) with isolated LV clinical congestion had PCWP Conclusions: While clinical examination allows accurate detection of elevated RAP, it does not allow accurate detection of discordant RV and LV filling pressures.

Aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) associate with structural heart disease and heart failure risk in individuals without known cardiovascular disease (CVD). However, few data are available regarding whether factors influencing levels of these two biomarkers are similar or distinct. We performed serial measurement of NT-proBNP and hs-cTnT in a contemporary multiethnic cohort with extensive phenotyping, with the goal of identifying their respective biological determinants in a population without known or suspected CVD. Methods: We evaluated 1877 participants of the Dallas Heart Study who had NT-proBNP and hs-cTnT measured and were free from clinical CVD at the each of its two examinations (2000–2002 and 2007–2009). Variables collected included demographic and risk factors, high-sensitivity C-reactive protein, body composition via dual-energy x-ray absorptiometry, coronary artery calcium by computed tomography, and cardiac dimensions and function by cardiac MRI. Linear regression was used to identify associations of these factors with each biomarker at baseline and with changes in biomarkers over follow-up. Results: NT-proBNP and hs-cTnT were poorly correlated at baseline (Spearman rho 0.083, p = 0.015), with only moderate correlation between change values (rho 0.18, p

Objectives The authors investigated the impact of coronary artery bypass grafting (CABG) on first and recurrent hospitalization in this population. Background In the STICH (Surgical Treatment for Ischemic Heart Failure) trial, CABG reduced all-cause death and hospitalization in patients with and ischemic cardiomyopathy and left ventricular ejection fraction Methods A total of 1,212 patients were randomized (610 to CABG + optimal medical therapy [CABG] and 602 to optimal medical therapy alone [MED] alone) and followed for a median of 9.8 years. All-cause and cause-specific hospitalizations were analyzed as time-to-first-event and as recurrent event analysis. Results Of the 1,212 patients, 757 died (62.4%) and 732 (60.4%) were hospitalized at least once, for a total of 2,549 total all-cause hospitalizations. Most hospitalizations (66.2%) were for cardiovascular causes, of which approximately one-half (907 or 52.9%) were for heart failure. More than 70% of all hospitalizations (1,817 or 71.3%) were recurrent events. The CABG group experienced fewer all-cause hospitalizations in the time-to-first-event (349 CABG vs. 383 MED, adjusted hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.74 to 0.98; p = 0.03) and in recurrent event analyses (1,199 CABG vs. 1,350 MED, HR: 0.78, 95% CI: 0.65 to 0.94; p Conclusions CABG reduces all-cause, CV, and HF hospitalizations in time-to-first-event and recurrent event analyses. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595)

Background Renin‐angiotensin‐system blockers (RASB) improve clinical outcomes in patients with chronic heart failure with reduced fraction; however, there remains ambiguity whether RASB therapy should be continued during the treatment of acute decompensated heart failure (ADHF). Hypothesis In comparison to patients with RASB use, RASB discontinuation in ADHF will be associated with worsening renal function, hypotension, and adverse long‐term clinical outcomes. Methods Patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization (ESCAPE) trial were separated into four groups based on RASB use at baseline and discharge: continuation (n = 316), discontinuation (n = 21), initiation (n = 42), and nonuse (n = 23). Post‐discharge outcomes were validated in an independent ADHF cohort admitted to the Cleveland Clinic (n = 253). Results RASB discontinuation and nonuse were associated with higher serial creatinine and blood urea nitrogen levels than RASB continuation or initiation (P

Background There is limited data on electrocardiographic (ECG) abnormalities and their prognostic significance in women with peripartum cardiomyopathy (PPCM). We sought to characterize ECG findings in PPCM and explore the association of ECG findings with myocardial recovery and clinical outcomes. Hypothesis We hypothesized that ECG indicators of myocardial remodeling would portend worse systolic function and outcomes. Methods Standard 12-lead ECGs were obtained at enrollment in the Investigations of Pregnancy-Associated Cardiomyopathy study and analyzed for 88 women. Left ventricular ejection fraction (LVEF) was measured by echocardiography at baseline, 6 months, and 12 months. Women were followed for clinical events (death, mechanical circulatory support, and/or cardiac transplantation) until 1 year. Results Half of women had an "abnormal" ECG, defined as atrial abnormality, ventricular hypertrophy, ST-segment deviation, and/or bundle branch block. Women with left atrial abnormality (LAA) had lower LVEF at 6 months (44% vs 52%, P = 0.02) and 12 months (46% vs 54%, P = 0.03). LAA also predicted decreased event-free survival at 1 year (76% vs 97%, P = 0.008). Neither left ventricular hypertrophy by ECG nor T-wave abnormalities predicted outcomes. A normal ECG was associated with recovery in LVEF to ≥50% (84% vs 49%, P = 0.001) and event-free survival at 1 year (100% vs 85%, P = 0.01). Conclusions ECG abnormalities are common in women with PPCM, but a normal ECG does not rule out the presence of PPCM. LAA predicted lower likelihood of myocardial recovery and event-free survival, and a normal ECG predicted favorable event-free survival.

Plasma volume expansion is clinically and prognostically relevant in individuals with heart failure. Prior cohorts either excluded or had limited representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between calculated plasma volume status (PVS) and outcomes in HFpEF.We included enrollees from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) with available haematocrit and weight data (n = 3414). Plasma volume was derived from the Hakim formula and compared to estimates of ideal plasma volume to generate a relative PVS. Multivariable Cox proportional hazards models tested the association of PVS with clinical outcomes. The median PVS was -11.9% (25th-75th percentile: -17.2% to -6.4%) and the majority (91.1%) had PVS consistent with relative volume contraction (PVS ≤ 0%) as opposed to volume expansion (8.9%, PVS 0%). After multivariable adjustment, each 5% increment in PVS was associated with a ∼11%, 14%, and 12% higher risk for the primary composite endpoint, all-cause death, and heart failure hospitalization, respectively (P 0.002 for all), but not cardiovascular death (P = 0.051). After additional adjustment for natriuretic peptides, PVS only remained associated with heart failure hospitalization (HR 1.10, 95% confidence interval 1.001-1.21, P = 0.047). There were no significant interactions between spironolactone use and the PVS-risk relationship for any endpoint (P 0.1 for all).Higher calculated estimates of PVS were independently associated with a higher risk of long-term clinical outcomes in HFpEF, and particularly, heart failure hospitalization.

Orthotropic heart transplantation remains the most effective therapy for patients with end-stage heart failure, with a median survival of ≈13 years. Yet, a number of complications are observed after orthotropic heart transplantation, including atrial and ventricular arrhythmias. Several factors contribute to arrhythmias, such as autonomic denervation, effect of the surgical technique, acute and chronic rejection, and transplant vasculopathy among others. To minimize risk of future arrhythmias, the bicaval technique and minimizing ischemic time are current surgical standards. Sinus node dysfunction is the most common indication for early (within 30 days) pacemaker implantation, whereas atrioventricular block incidence increases as time from transplant increases. Atrial fibrillation can occur in the first few weeks following transplantation but is uncommon in the long term unless secondary to a precipitant such as acute rejection. The most common atrial arrhythmias are atrial flutters, which are mainly typical, but atypical circuits can be observed such as those that involve the remnant donor atrium in regions immediately adjacent to the atrioatrial anastomosis suture line. Choosing the appropriate pharmacological therapy requires careful consideration due to the potential interaction with immunosuppressive agents. Despite historical concerns, adenosine is effective and safe at reduced doses if administered under cardiac monitoring. Catheter ablation has emerged as an effective treatment strategy for symptomatic supraventricular tachycardias, including ablation of atypical flutter circuits. Cardiac allograft vasculopathy is an important risk factor for sudden cardiac death, yet the role of prophylactic implantable cardioverter-defibrillator implant for sudden death prevention is unclear. Current indications for implantable cardioverter-defibrillator implantation are as in the nontransplant population. A number of questions for future research are posed.

Purpose of Review The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resulted in the coronavirus 2019 (COVID-19) global pandemic. While primarily a respiratory virus, SARS-CoV-2 can cause myocardial injury. The pattern of injury, referred to as acute COVID-19 cardiovascular syndrome (ACovCS), is defined by cardiac troponin leak in the absence of obstructive coronary artery disease. Although the etiology of the injury is unknown, many speculate that a cytokine release syndrome (CRS) may be an important factor. We aim to review recent data concerning markers of cardiac injury in ACovCS and its relation to the CRS. Recent Findings Cardiac injury was common in patients hospitalized for COVID-19, with both cardiac troponin and B-type natriuretic peptide (BNP) being elevated in this population. Biomarkers were correlated with illness severity and increased mortality. Cytokines such as IL-6 were more often elevated in patients with ACovCS. Myocarditis evident on cardiac MR following COVID-19 may be associated with cardiac troponin levels. The impact of dexamethasone and remdesivir, two therapies shown to have clinical benefit in COVID-19, on myocardial injury is unknown. Summary Biomarkers of cardiac stress and injury in COVID-19 may be used to stratify risk in the future. Currently, there is no evidence that inhibition of cytokine release will reduce myocardial injury in patients with COVID-19.

Background Physical inactivity and low cardiorespiratory fitness (CRF) are associated with higher risk of heart failure. However, the independent contributions of objectively measured sedentary time, physical activity, and CRF toward left ventricular (LV) structure and function are not well established. Methods and Results We included 1368 participants from the DHS (Dallas Heart Study) (age, 49 years; 40% men) free of cardiovascular disease who had physical activity and sedentary time measured by accelerometer, CRF estimated from submaximal treadmill test, and cardiac magnetic resonance imaging performed using 3‐T magnetic resonance imaging. A series of linear regression models were constructed to evaluate the associations of sedentary time, moderate physical activity, vigorous physical activity, and CRF with LV parameters after adjustment for established cardiovascular risk factors. We observed a modest correlation between CRF levels and objectively measured moderate (correlation coefficient, 0.17; P P Conclusions Vigorous physical activity and CRF are significantly associated with cardiac structure and function parameters. Future studies are needed to determine if interventions aimed at improving CRF levels may favorably modify cardiac structure and function.

Objectives Optimal medical therapy in patients with heart failure and coronary artery disease is associated with improved outcomes. However, whether this association is influenced by the performance of coronary artery bypass grafting is less well established. Thus, the aim of this study was to determine the possible relationship between coronary artery bypass grafting and optimal medical therapy and its effect on the outcomes of patients with ischemic cardiomyopathy. Methods The Surgical Treatment for Ischemic Heart Failure trial randomized 1212 patients with coronary artery disease and left ventricular ejection fraction 35% or less to coronary artery bypass grafting with medical therapy or medical therapy alone with a median follow-up over 9.8 years. For the purpose of this study, optimal medical therapy was collected at baseline and 4 months, and defined as the combination of 4 drugs: angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, beta-blocker, statin, and 1 antiplatelet drug. Results At baseline and 4 months, 58.7% and 73.3% of patients were receiving optimal medical therapy, respectively. These patients had no differences in important parameters such as left ventricular ejection fraction and left ventricular volumes. In a multivariable Cox model, optimal medical therapy at baseline was associated with a lower all-cause mortality (hazard ratio, 0.78; 95% confidence interval, 0.66-0.91; P = .001). When landmarked at 4 months, optimal medical therapy was also associated with a lower all-cause mortality (hazard ratio, 0.82; 95% confidence interval, 0.62-0.99; P = .04). There was no interaction between the benefit of optimal medical therapy and treatment allocation. Conclusions Optimal medical therapy was associated with improved long-term survival and lower cardiovascular mortality in patients with ischemic cardiomyopathy and should be strongly recommended.

In this document, we propose a universal definition of heart failure (HF) as the following: HF is a clinical syndrome with symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and or objective evidence of pulmonary or systemic congestion. We propose revised stages of HF as follows. At-risk for HF (Stage A), for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-HF (stage B), for patients without current or prior symptoms or signs of HF, but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C), for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality. Advanced HF (Stage D), for patients with severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT), refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). The classification includes HF with reduced EF (HFrEF): HF with an LVEF of ≤40%; HF with mildly reduced EF (HFmrEF): HF with an LVEF of 41% to 49%; HF with preserved EF (HFpEF): HF with an LVEF of ≥50%; and HF with improved EF (HFimpEF): HF with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of >40%.

In this document, we propose a universal definition of heart failure (HF) as the following: HF is a clinical syndrome with symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and or objective evidence of pulmonary or systemic congestion. We propose revised stages of HF as follows. At-risk for HF (Stage A), for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-HF (stage B), for patients without current or prior symptoms or signs of HF, but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C), for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality. Advanced HF (Stage D), for patients with severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT), refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). The classification includes HF with reduced EF (HFrEF): HF with an LVEF of ≤40%; HF with mildly reduced EF (HFmrEF): HF with an LVEF of 41% to 49%; HF with preserved EF (HFpEF): HF with an LVEF of ≥50%; and HF with improved EF (HFimpEF): HF with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of40%.

Heart transplant (HT) recipients are at higher risk of varicella zoster virus (VZV) reactivation. Risk factors for VZV reactivation are currently not well defined, impeding the ability to design and implement strategies to minimize the burden of this illness in this population. Automated data extraction tools were used to retrieve data from the electronic health record (EHR) of all adult HT recipients at our center between 2010 and 2016. Information from the Organ Procurement and Transplantation Network Standard Analysis and Research Files was merged with the extracted data. Potential cases were manually reviewed and adjudicated using consensus definitions. Cumulative incidence and risk factors for VZV reactivation in HT recipients were assessed by the Kaplan-Meier method and Cox modeling, respectively. In 203 HT recipients, the cumulative incidence of VZV reactivation at 8-years post-transplantation was 26.4% (95% CI: 17.8-38.0). The median time to VZV reactivation was 2.1 years (IQR, 1.5-4.1). Half (14/28) of the cases experienced post-herpetic neuralgia (PHN). Post-transplant CMV infection (HR 9.05 [95% CI: 3.76-21.77) and post-transplant pulse-dose steroids (HR 3.19 [95% CI: 1.05-9.68]) were independently associated with a higher risk of VZV reactivation in multivariable modeling. Identification of risk factors will aid in the development of targeted preventive strategies.

Background: Obesity may contribute to adverse outcomes in coronavirus disease 2019 (COVID-19). However, studies of large, broadly generalizable patient populations are lacking, and the effect of body mass index (BMI) on COVID-19 outcomes— particularly in younger adults—remains uncertain. Methods: We analyzed data from patients hospitalized with COVID-19 at 88 US hospitals enrolled in the American Heart Association’s COVID-19 Cardiovascular Disease Registry with data collection through July 22, 2020. BMI was stratified by World Health Organization obesity class, with normal weight prespecified as the reference group. Results: Obesity, and, in particular, class III obesity, was overrepresented in the registry in comparison with the US population, with the largest differences among adults ≤50 years. Among 7606 patients, in-hospital death or mechanical ventilation occurred in 2109 (27.7%), in-hospital death in 1302 (17.1%), and mechanical ventilation in 1602 (21.1%). After multivariable adjustment, classes I to III obesity were associated with higher risks of in-hospital death or mechanical ventilation (odds ratio, 1.28 [95% CI, 1.09–1.51], 1.57 [1.29–1.91], 1.80 [1.47–2.20], respectively), and class III obesity was associated with a higher risk of in-hospital death (hazard ratio, 1.26 [95% CI, 1.00–1.58]). Overweight and class I to III obese individuals were at higher risk for mechanical ventilation (odds ratio, 1.28 [95% CI, 1.09–1.51], 1.54 [1.29–1.84], 1.88 [1.52–2.32], and 2.08 [1.68–2.58], respectively). Significant BMI by age interactions were seen for all primary end points ( P -interaction70 years. Severe obesity (BMI ≥40 kg/m 2 ) was associated with an increased risk of in-hospital death only in those ≤50 years (hazard ratio, 1.36 [1.01–1.84]). In adjusted analyses, higher BMI was associated with dialysis initiation and with venous thromboembolism but not with major adverse cardiac events. Conclusions: Obese patients are more likely to be hospitalized with COVID-19, and are at higher risk of in-hospital death or mechanical ventilation, in particular, if young (age ≤50 years). Obese patients are also at higher risk for venous thromboembolism and dialysis. These observations support clear public health messaging and rigorous adherence to COVID-19 prevention strategies in all obese individuals regardless of age.

Introduction: Amyloid cardiomyopathy (ACM) is recognized increasingly as a cause of advanced heart failure. There are limited data describing clinical outcomes for ACM patients who receive durable mechanical circulatory support (MCS). Methods: This analysis included adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) with a primary diagnosis of dilated cardiomyopathy (DCM, N=19,921), non-amyloid restrictive cardiomyopathy (RCM, N=248), or ACM (N=48) who received durable MCS of any type or strategy from 2005-2017. We compared baseline characteristics and adverse events for the 3 groups. The primary endpoint was death with heart transplantation as a competing risk with follow-up censored at device explantation. Results: Patients with ACM (N=48) were older (61 y [IQR 55-69] versus 58 y [IQR 49-66] for DCM and 55 y [IQR 46-62] for non-amyloid RCM, P Conclusion: Compared to DCM or non-amyloid RCM patients, those with durable MCS for ACM have the highest risk of early adverse events and lowest survival. These data highlight concerns with durable MCS for ACM.

Introduction: Left Ventricular Assist Devices (LVAD) decrease cardiac mechanical work and metabolic demand and may decrease cardiomyocyte oxidative stress, followed by cell cycle re-entry and cell regeneration. We tested whether LVAD long-term support is associated with myocardial regeneration. Methods: Viability fluorodeoxyglucose (18FDG) - positron-emission tomography scans were performed >3 months after LVAD implantation and every 6 months thereafter. 4 patients aged 18-70 with end-stage non-ischemic (NICM, n=3) or ischemic cardiomyopathy (ICM, n=1) were included. Low metabolic activity myocardial regions of interest (ROI) at Results: LV ejection fraction ranged 0-35% at baseline. Two patients (LVAD speed 2660 rotations per minute - RPM, output 3.4-4.1 and 5.6-5.9 liters per minute (LPM), respectively) underwent 2 scans before cardiac transplantation, exhibiting borderline increased global signal (1-4%) and significantly increased 18FDG signal in the baseline low-intensity ROI on the follow-up scan (67.7, 75.7%). The other 2 patients (LVAD parameters: 5600 RPM/ 4.6-5.8 LPM; 9200 RPM/ 4.3-4.8 LPM) exhibited decreased global 18FDG signal (10-16%) and increased signal in the co-registered baseline low-intensity ROIs (1.7-21.5%) (Figure). Conclusions: LVAD long-term support is associated with a global decrease in myocardial 18FDG uptake signal over time, and with increased viability signal in baseline low-intensity ROIs, suggestive of myocardial regeneration in metabolically inactive regions. Future research is required to identify patient subgroups that are most likely to exhibit high regeneration potential upon long-term LVAD support.

Background: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder characterized by progressive muscle degeneration. The leading cause of death is complications from the development of DMD-associated cardiomyopathy. The majority of DMD patients have skeletal abnormalities that limit the quality of echocardiograms (ECHO). Although cardiac magnetic resonance imaging (cMRI) is the gold standard cardiac imaging tool, the vast majority of DMD patients are evaluated by ECHO rather than cMRI. We hypothesized that when compared to ECHO, cMRI more accurately assesses cardiac function and provides more valuable data for the diagnosis of DMD-associated cardiomyopathy. Methods: We undertook a retrospective study of 20 DMD patients referred to the UT Southwestern Adult Neuromuscular Cardiomyopathy Clinic who had undergone both an ECHO and cMRI within 15 months of each other. We assessed the proportion of studies demonstrating reduced left ventricular (LV) function [cMRI LVEF Results: Amongst these patients, 10% of cMRIs and 85% of ECHOs were technically difficult. By cMRI, 30% of the studies were normal (LVEF 64±2 %), while 70% showed reduced function (LVEF: 44±12%). By ECHO, 75% of the studies were normal (FS 32±5), while 25% showed reduced function (FS: 15±8). Of the patients with truly reduced function by cMRI, 64% were considered normal by ECHO. Finally, 61% of cMRI studies showed LGE (50% with normal LVEF and 67% with reduced LVEF). Conclusions: In summary, cMRI is superior to ECHO in assessing cardiac function in DMD. ECHO underestimates left ventricular dysfunction, likely due to the poor quality of studies obtained in this patient population. In addition, cMRI identifies LGE, a marker associated with increased mortality, irrespective of cardiac function. Earlier utilization of cMRI will expedite the diagnosis of DMD-associated cardiomyopathy and enable the cardiologist to initiate aggressive guideline-directed medical therapy at an earlier age.

Introduction: Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder. DMD-associated cardiomyopathy is the primary mode of premature death in the majority of male DMD patients, but the prevalence of cardiomyopathy and its clinical significance in female DMD carriers is less well characterized. Hypothesis: We hypothesized that a significant proportion of DMD carriers develop maladaptive left ventricular (LV) structural remodeling and cardiomyopathy over time. Methods: A cross-sectional study was undertaken comparing cardiac magnetic resonance imaging (cMRI) and cardiopulmonary stress test (CPX) parameters between DMD carriers and healthy age- and sex-matched controls from the Dallas Heart Study (DHS). Demographic data, cMRI parameters, and CPX parameters were collected retrospectively on 30 consecutive DMD carriers and 26 control DHS subjects. Results: Overall, DMD carriers had a significantly lower LVEF compared to DHS controls (58+8% vs 70+7%, p< 0.0001). The overall prevalence of reduced LVEF in DMD carriers (defined as LVEF 2 vs 58+7, p< 0.0001; 31+10 ml/m 2 vs 17+5, p< 0.0001; respectively). LV concentricity was also significantly lower among all DMD carriers compared to DHS controls (3.10+0.65 g/mL 0.67 vs 3.73+0.79, p =0.002). LV concentricity was significantly lower in DMD carriers with reduced EF compared to controls (3.09+0.51 g/mL 0.67 vs 3.73+0.79, p = 0.012), while DMD carriers with preserved EF also had reduced concentricity compared to controls (3.12+0.86 vs 3.73+0.79, p = 0.054). Finally, peak VO 2 was lower in DMD carriers compared to DHS controls (23+6 ml/kg/min vs 25+4, p =0.076), though this difference did not reach statistical significance. Conclusions: Collectively, the data suggest that middle-aged female DMD carriers are at greater risk of developing left ventricular systolic dysfunction and cardiomyopathy associated with decreased exercise capacity. A possible mechanism driving the development of this cardiomyopathy is progressive, maladaptive left ventricular dilatation and cardiac atrophy.

Background: Muscular dystrophies (MD) are genetic disorders that cause progressive peripheral skeletal myopathies. The majority of MD patients will develop atrial and ventricular arrhythmias and/or an associated cardiomyopathy with a high degree of morbidity and mortality. However, it remains unknown the degree of atrial remodeling that may also occur in MD patients. We hypothesize maladaptive atrial remodeling occurs in MD patients. Methods: Utilizing the UT Southwestern Cardiomyopathy Clinic, MD [total: 79 patients (34 females, 45 males)] and non-ischemic cardiomyopathy (NICM) [total: 81 patients (29 females, 52 males)] patients were identified who underwent a cardiac MRI (cMRI) between 2011 and 2015. A matched, healthy control cohort from the Dallas Heart Study (DHS) [total: 101 patients (40 females, 61 males)] were identified. Most MD patients had Duchenne/Becker MD, Limb-Girdle MD or myotonic MD. Two blinded, independent readers made volumetric measurements from cMRIs to assess right atrial (RA) and left atrial (LA) dimensions with low inter-reader variability. A third independent investigator analyzed the RA and LA data with aggregate data presented in the Table. The statistical significance of the data (p Results: Analysis of the cMRI data revealed significant differences in both the structure and function of the RA and the LA between MD and NICM patients. In addition, the data revealed significant differences in the LA but not the RA emptying fraction in MD patients as compared to the DHS patients. Conclusion: Collectively, the data suggests MD patients develop significant maladaptive remodeling of the LA but not the RA, predisposing these patients to atrial arrhythmias. Investigation into differences in atrial remodeling as a function of gender and the type of MD need to be explored.

Background: Many patients with amyloid cardiomyopathy (ACM) develop advanced heart failure, and durable mechanical circulatory support (MCS) may be a consideration. However, data describing clinical outcomes after MCS in this population are limited. Methods: Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support with dilated cardiomyopathy (DCM, n=19 921), nonamyloid restrictive cardiomyopathy (RCM, n=248), or ACM (n=46) between 2005 and 2017 were included. Patient and device characteristics were compared between cardiomyopathy groups. The primary end point was the cumulative incidence of death with heart transplantation as a competing risk. Results: Patients with ACM (n=46) were older (61 years [interquartile range, 55–69 years] versus 58 years [interquartile range, 49–66 years] for DCM and 55 years [interquartile range, 46–62 years] for nonamyloid RCM, P P =0.04) at device implantation. Use of biventricular support (biventricular assist device or total artificial heart) was the highest for patients with ACM (41.3% versus 6.7% and 19.4% for patients with DCM and nonamyloid RCM, respectively, P =0.014). The cumulative incidence of death was highest for patients with ACM relative to those with DCM or nonamyloid RCM ( P Conclusions: Compared with patients with DCM or nonamyloid RCM who received durable MCS, those with ACM experienced the highest use of biventricular support and the worst survival. These data highlight concerns with the use of durable MCS for patients with ACM.

Background Current strategies for cardiovascular disease ( CVD ) risk assessment focus on 10‐year or longer timeframes. Shorter‐term CVD risk is also clinically relevant, particularly for high‐risk occupations, but is under‐investigated. Methods and Results We pooled data from participants in the ARIC (Atherosclerosis Risk in Communities study), MESA (Multi‐Ethnic Study of Atherosclerosis), and DHS (Dallas Heart Study), free from CVD at baseline (N=16 581). Measurements included N‐terminal pro‐B‐type natriuretic peptide (>100 pg/mL prospectively defined as abnormal); high‐sensitivity cardiac troponin T (abnormal >5 ng/L); high‐sensitivity C‐reactive protein (abnormal >3 mg/L); left ventricular hypertrophy by ECG (abnormal if present); carotid intima‐media thickness, and plaque (abnormal >75th percentile for age and sex or presence of plaque); and coronary artery calcium (abnormal >10 Agatston U). Each abnormal test result except left ventricular hypertrophy by ECG was independently associated with increased 3‐year risk of global CVD (myocardial infarction, stroke, coronary revascularization, incident heart failure, or atrial fibrillation), even after adjustment for traditional CVD risk factors and the other test results. When a simple integer score counting the number of abnormal tests was used, 3‐year multivariable‐adjusted global CVD risk was increased among participants with integer scores of 1, 2, 3, and 4, by ≈2‐, 3‐, 4.5‐ and 8‐fold, respectively, when compared with those with a score of 0. Qualitatively similar results were obtained for atherosclerotic CVD (fatal or non‐fatal myocardial infarction or stroke). Conclusions A strategy incorporating multiple biomarkers and atherosclerosis imaging improved assessment of 3‐year global and atherosclerotic CVD risk compared with a standard approach using traditional risk factors.

This study examines the concordance of jugular venous pressure assessments taken at the bedside vs remotely and compares these with invasively measured right atrial pressure.

AIMS Prior cohorts demonstrating the importance of serum chloride levels in heart failure either excluded or had partial representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between serum chloride concentration and outcomes in HFpEF. METHODS AND RESULTS We included participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) who met the following criteria: met inclusion by the natriuretic peptide stratum, had recorded serum chloride levels, and were from the Americas (n = 942). Multivariable Cox proportional hazards models tested the association of serum chloride with clinical outcomes, and mixed effects modelling tested the association of spironolactone or loop diuretic on serial serum chloride levels. The median serum chloride level was 102 [25th-75th percentile 100-105 mmol/L (range 84-114 mmol/L)]. After multivariable adjustment, every standard deviation decrease in serum chloride (4.05 mmol/L) was associated with ∼50% increased risk for cardiovascular death [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.11-2.06, P = 0.008] and ∼30% increased risk for all-cause death (HR 1.29, 95% CI 1.02-1.62, P = 0.04), but not with the primary composite endpoint or heart failure hospitalization (P > 0.3 for both). There were no significant interactions between spironolactone use and the serum chloride-risk relationship (P > 0.1) for each endpoint. Spironolactone was not (P = 0.33) but loop diuretic use was associated with lower serial serum chloride levels (P

Physical examination of jugular venous pressure is used to estimate right atrial (RA) pressure and infer left-sided filling pressure to assist volume management. Previous studies in advanced heart failure patients showed about 75% concordance between RA and pulmonary capillary wedge (PCW) pressures. We sought to determine the relationship between mean RA and mean PCW pressure and assess the clinical significance in a broad population of patients undergoing invasive right heart catheterization (RHC).We examined 4135 RHC cases at a single academic medical center from February 2007 to December 2014, analyzing baseline variables, hemodynamic data, and in-hospital mortality.The overall Pearson correlation for mean RA and PCW pressures was 0.68 with 70% concordance between dichotomized pressures (RA ≥10 and PCW ≥22 mmHg). Results were similar in subgroups with heart failure (r=0.67, 72%), STEMI/NSTEMI (r=0.60, 69%), unstable angina (r=0.78, 69%), stable/no angina (r=0.72, 67%), and valvular disease (r=0.61, 72%; Chi-square P=.15). Mean RA pressure was independently associated with in-hospital mortality in multivariate analysis (OR 1.12 [95% CI 1.081-1.157] per 1 mmHg increase, P.001). The RA/PCW ratio was not independently associated with in-hospital mortality. Mean RA pressure was also weakly associated with worse renal function (rho=-0.16, P.001).In patients undergoing right catheterization for diverse indications, the mean RA and PCW pressures correlated moderately well, but there was discordance in a sizable minority, in whom assessment of left-sided filling pressures using estimated jugular venous pressure may be misleading. Elevated right atrial pressure is a marker for in-hospital mortality.

Glenn N. Levine, MD, FACC, FAHA, Chair Patrick T. O’Gara, MD, FACC, FAHA, Chair-Elect Jonathan L. Halperin, MD, FACC, FAHA, Immediate Past Chair [‡‡][1] Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD

Background: Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD. Methods: We included participants from MESA (Multi-Ethnic Study of Atherosclerosis) (n=6621) and the Dallas Heart Study (n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein. Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction, stroke, coronary or peripheral revascularization, incident heart failure, or atrial fibrillation) and ASCVD (fatal or nonfatal myocardial infarction or stroke) were assessed over >10 years of follow-up. Multivariable analyses for the primary global CVD end point adjusted for traditional risk factors plus statin use and creatinine (base model). Results: Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results ( P P =0.001), significant integrated discrimination improvement (0.07, 95% confidence interval [CI] 0.06–0.08, P P =0.003) were observed, and the model was well calibrated (χ 2 =12.2, P =0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted hazard ratio, 1.9; 95% CI, 1.4–2.6), 2 (hazard ratio, 3.2; 95% CI, 2.3–4.4), 3 (hazard ratio, 4.7; 95% CI, 3.4–6.5), and ≥4 (hazard ratio, 7.5; 95% CI, 5.2–10.6). Findings replicated in the Dallas Health Study were similar for the ASCVD outcome. Conclusions: Among adults without known CVD, a novel multimodality testing strategy using left ventricular hypertrophy by ECG, coronary artery calcium, N-terminal pro B-type natriuretic peptide, high-sensitivity cardiac troponin T, and high-sensitivity C-reactive protein significantly improved global CVD and ASCVD risk assessment.

A young man with Duchenne muscular dystrophy presented to the UT Southwestern Neuromuscular Cardiomyopathy Clinic with advanced heart failure. Despite maximal medical therapy, his cardiac function continued to decline requiring initiation of inotrope therapy. Given the patient's clinical deterioration, a left ventricular assist device (LVAD) was implanted as destination therapy after undergoing a multidisciplinary assessment. The patient tolerated the surgical implantation of the LVAD without any significant complications, and he has had a relatively unremarkable course 38 months post-LVAD implantation. A critical factor contributing to the long-term success of this patient was the decision to select an LVAD that would not disrupt the diaphragm and thus preserve the respiratory muscle strength. This case demonstrates that permanent mechanical LVADs should be considered for appropriately selected Duchenne muscular dystrophy patients with medically refractory end-stage cardiomyopathy.

Recently, the symptom of bendopnea, that is, shortness of breath when bending forwards such as when putting on shoes, has been described in heart failure patients and found to be associated with higher ventricular filling pressures, particularly in the setting of low cardiac index. However, it is not known whether bendopnea is associated with clinical outcomes.In a prospective convenience sample of 179 patients followed in our heart failure disease management clinic, we determined the presence of bendopnea at the time of enrollment and ascertained clinical outcomes through 1 year of follow-up. We performed univariate and stepwise multivariable modeling to test the association of bendopnea with clinical outcomes.Bendopnea was present in 32 of 179 (18%) subjects. At 1 year, those with versus without bendopnea were at increased risk of the composite endpoint of death, heart failure admission, inotrope initiation, left ventricular assist device implantation, or cardiac transplantation in univariate (hazard ratio [HR] 1.9, P.05) but not multivariable (HR 1.9, P = .11) analysis. Bendopnea was more strongly associated with short-term outcomes including heart failure admission at 3 months in both univariate (HR 3.1, P.004) and multivariable (HR 2.5, P = .04) analysis.Bendopnea was associated with an increased risk of adverse outcomes in ambulatory patients with heart failure, particularly heart failure admission at 3 months.

Hypothesis Because there may be signals of sex-based differences in response to HFpEF therapy according to left ventricular ejection fraction, we hypothesize that there will be a prognostic difference in clinical outcomes by sex according to global longitudinal strain (GLS) in HFpEF and this may be associated with treatment heterogeneity with spironolactone. Methods Participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial with core lab strain echo data (N=477) were stratified into 4 categories based on sex and GLS relative to the median. Cox-proportional hazards models adjusted for age, race, atrial fibrillation, NYHA class, stroke, and creatinine determined the association of sex/GLS categories with the composite primary endpoint (cardiovascular death, heart failure hospitalization, or aborted cardiac arrest), heart failure hospitalization, cardiovascular death, and all-cause mortality. Results In this cohort (age 70±20 y, 46% male, LVEF 60±16%) the median GLS was -15.6%. Kaplan-Meier estimates for the primary composite outcome stratified by the four sex/GLS groups are shown below (Figure). In adjusted Cox-proportional hazards models, both sex groupings with above-median (e.g. impaired) GLS were associated with a higher risk for the composite primary endpoint, cardiovascular death, and heart failure hospitalizations, but not all cause mortality in comparison with men with below-median GLS (e.g. preserved). However, there was no significant difference in the risk of any of the endpoints between men and women with below-median GLS. Lastly, sex/GLS groupings did not impact the treatment effect of spironolactone vs placebo for any of the endpoints (P-interaction>0.05 for all). ConclusionS The prognostic importance of systolic dysfunction as measured by GLS in HFpEF did not appear to be impacted by sex, and grouping by sex and GLS did not modify the effect of spironolactone on long-term outcomes.

Background: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m 2 , and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. Results: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036–1238) vs 1191 pg/dL (95% CI 1089–1304), P =0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P =0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98–3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1–3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). Conclusions: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT 02653482.

Background The practice of induction therapy with either rabbit anti-thymocyte globulin (r-ATG) or interleukin-2 receptor antagonists (IL-2RA) is common among heart transplant recipients. However, its benefits in the setting of contemporary maintenance immunosuppression with tacrolimus/mycophenolic acid (TAC/MPA) are unknown. Methods We compared post-transplant mortality among three induction therapy strategies (r-ATG vs IL2-RA vs no induction) in a retrospective cohort analysis of heart transplant recipients maintained on TAC/MPA in the Organ Procurement Transplant Network (OPTN) database between the years 2006 and 2015. We used a multivariable model adjusting for clinically important co-morbidities, and a propensity score analysis using the inverse probability weighted (IPW) method in the final analysis. Results In multivariable IPW analysis, r-ATG (HR = 1.23; 95% CI = 1.05-1.46, P = 0.01) remained significantly associated with a higher mortality. There was a trend toward having a higher mortality in the IL2-RA (HR = 1.11; 95% CI = 1.00-1.24, P = 0.06) group. Subgroup analyses failed to show a patient survival benefit in using either r-ATG or IL2-RA among any of the subgroups analyzed. Conclusion In this contemporary cohort of heart transplant recipients receiving TAC/MPA, neither r-ATG nor IL2-RA were associated with a survival benefit. On the contrary, adjusted analyses showed a significantly higher mortality in the r-ATG group and a trend toward higher mortality in the IL2-RA group. While caution is needed in interpreting treatment effects in an observational cohort, these data call into question the benefit of induction therapy as a common practice and highlight the need for more studies.

Symptomatic improvement through decongestive therapy is a cornerstone for treatment of acute decompensated heart failure (ADHF). Visual analog scales (VAS) are instruments that can capture patients' perceptions of dyspnea (DVAS) or global well-being (GVAS). However, the clinical implications of these instruments and their changes over time during treatment for ADHF need further clarification. DVAS and GVAS were collected in 657 patients randomized in the DOSE-AHF and ROSE-AHF trials. To determine factors associated with symptom change, multivariable predictors of changes in DVAS and GVAS over 72 hours were determined. In addition, time-to-event analyses determined the association between these assessments and post-discharge clinical outcomes. The median baseline DVAS and GVAS scores were 54 (interquartile range 35 to 76) and 50 (30 to 66), respectively. These scores increased from baseline to 72 hours (ΔDVAS 16 [0 to 35] and ΔGVAS 19 [2 to 37]). Although changes in both scales were associated with their baseline values, 72-hour change in NT-proBNP was associated with each scale in multivariable analysis. However, there were additional variables associated with 72-hour change in GVAS including 72-hour change in creatinine, implantable cardioverter-defibrillator presence, baseline loop diuretic dose, and 72-hour total loop diuretic dose. There were no consistent associations between DVAS or GVAS and clinical composite outcomes at 60 days. In conclusion, DVAS and GVAS may be related to different clinical factors during treatment for ADHF and VAS scores were not consistently associated with clinical outcomes in ADHF. These findings inform the utility of the DVAS and GVAS instruments as measurements of symptom change for future ADHF clinical trials and registries.

Background The prognostic interrelationship between natriuretic peptide ( NP ) levels and body mass index ( BMI ) among patients with chronic stable heart failure with preserved ejection fraction is not well characterized. Methods and Results Participants from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial enrolled in the Americas meeting inclusion by the NP stratum were stratified into 4 data‐derived categories by BMI and standardized NP ‐z score. Adjusted Cox‐proportional models determined the independent association of BMI , NP ‐z score, and BMI / NP categories with composite primary end point, heart failure hospitalization, and all‐cause mortality. The study population included 997 participants. There was a U‐shaped relationship between BMI and NP with elevated NP levels noted at extremes of BMI distribution. There was also a U‐shaped relationship between BMI and risk of adverse clinical outcomes with the lowest risk among patients approximating a BMI of 25 kg/m 2 . In contrast, higher NP levels were linearly associated with higher risk of adverse clinical outcomes. For BMI / NP ‐based categories, participants in the high BMI /high NP group had greater prevalence of cardiac structural and functional abnormalities and the highest risk of adverse clinical outcomes (hazard ratio for primary end point; 95% confidence interval: 2.29 [1.36–3.84] Reference: low BMI /low NP ). Conclusions There is a U‐shaped association between BMI and NP levels among patients with chronic heart failure with preserved ejection fraction. Higher NP levels are independently associated with a higher risk of mortality across both high and low BMI strata. Among obese patients with heart failure with preserved ejection fraction, elevated NP levels identify a higher risk phenotype with a significantly increased incidence of both mortality and heart failure hospitalization.

Purpose The thermodilution (Td) method is routinely used for measurement of cardiac output although its accuracy in low-output states remains uncertain. Criteria for designating heart transplant listing status in the contemporary allocation system is incumbent on meeting strict cardiac index (CI) cutoffs. We aimed to assess the agreement between Td and direct Fick (dFick) CI in patients with low CI. Methods In this retrospective analysis of 535 patients who underwent right heart catheterization with dFick CI measurement as part of clinically indicated hemodynamic evaluation using the gold-standard Douglas bag technique, 253 patients had both Td/dFick CI measurements. Three saline injections were typically used and averaged in Td CI measurements. We included 118 patients who specifically had a CI of Results Among the 118 patients included (Mean [SD] age 60 [12.2] years, 42.3% female), Median (interquartile range, IQR) overall dFick and Td CI values differed significantly (1.86 [1.65, 2.1] and 2.03 [1.78, 2.31] L/min/m2, respectively; P 25% in 33.1% of patients. Conclusion The agreement of Td with the gold-standard dFick CI measurements in patients with low CI was suboptimal. These data are important consider in in clinical scenarios such as heart transplant listing status where strict hemodynamic cutoffs guide urgency.

Jonathan L. Halperin, MD, FACC, FAHA, Chair Glenn N. Levine, MD, FACC, FAHA, Chair-Elect Sana M. Al-Khatib, MD, MHS, FACC, FAHA Kim K. Birtcher, PharmD, MS, AACC Biykem Bozkurt, MD, PhD, FACC, FAHA Ralph G. Brindis, MD, MPH, MACC Joaquin E. Cigarroa, MD, FACC Lesley H. Curtis, PhD, FAHA

Purpose of review Left ventricular hypertrophy (LVH), an important consequence of hypertension, is traditionally classified as either concentric or eccentric based on the presence or absence of increased relative wall thickness. In 2010, we proposed a novel four-tiered classification that accounted for LV dilatation in addition to LV wall thickness. The purpose of this review is to discuss the rationale for this revised classification and highlight subsequent studies that have assessed its utility. Recent findings A series of recent observational studies have tested whether the four-tiered classification identifies subphenotypes of LVH with differential risk of adverse outcomes, including incident heart failure. The majority have confirmed that eccentric hypertrophy can be subdivided into a high-risk and a low-risk group based on whether LV dilatation is present. Additional studies have shown that LV dilatation is an independent risk factor for the development of heart failure. Summary Incorporation of LV dilatation into the assessment of LVH identifies important subphenotypes within the standard two-tiered classification that have differential risk. Such refinements in the classification of LVH may yield new insights into how LVH progresses to heart failure, help identify risk factors for this transition, and improve therapeutic efforts to prevent its occurrence.

Bloodstream infections (BSIs) are common in patients with continuous-flow left ventricular assist devices (CF-LVADs). Whether CF-LVADs modulate the febrile response to BSIs is unknown. We retrospectively compared the febrile response to BSIs in patients with heart failure (HF) with CF-LVADs versus a control population of patients with HF receiving inotropic infusions. BSIs were adjudicated using the Centers for Disease Control and Prevention and the National Healthcare Safety Network criteria. Febrile status (temperature ≥38°C, 100.4 °F), temperature at presentation with BSI, and the highest temperature within 72 hours (Tmax) were collected. We observed 59 BSIs in LVAD patients and 45 BSIs in controls. LVAD patients were more likely to be afebrile and to have a lower temperature at presentation than control (88% vs 58%, p=0.002, and 37°C ±0.7 vs 37.7°C ±1.0, p=0.0009, respectively). By 72 hours, the difference in afebrile status diminished (53% vs 44%, p=0.42), and the Tmax was similar between the LVAD and control groups (37.9°C±0.9 vs 38.2°C±0.8, respectively, p=0.10). In conclusion, at presentation with a BSI, the vast majority of CF-LVAD patients were afebrile, an event which occurred at a higher frequency when compared with patients with advanced HF on chronic inotropes via an indwelling venous catheter. These data alert clinicians to have a very low threshold to obtain blood cultures in CF-LVAD patients even in the absence of fever. Further study is needed to determine whether a delayed or diminished febrile response represents another pathophysiological consequence of CF-LVADs.