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IMPORTANCE: The existing models predicting right ventricular failure (RVF) after durable left ventricular assist device (LVAD) support might be limited, partly due to lack of external validation, marginal predictive power, and absence of intraoperative characteristics. OBJECTIVE: To derive and validate a risk model to predict RVF after LVAD implantation. DESIGN, SETTING, AND PARTICIPANTS: This was a hybrid prospective-retrospective multicenter cohort study conducted from April 2008 to July 2019 of patients with advanced heart failure (HF) requiring continuous-flow LVAD. The derivation cohort included patients enrolled at 5 institutions. The external validation cohort included patients enrolled at a sixth institution within the same period. Study data were analyzed October 2022 to August 2023. EXPOSURES: Study participants underwent chronic continuous-flow LVAD support. MAIN OUTCOME AND MEASURES: The primary outcome was RVF incidence, defined as the need for RV assist device or intravenous inotropes for greater than 14 days. Bootstrap imputation and adaptive least absolute shrinkage and selection operator variable selection techniques were used to derive a predictive model. An RVF risk calculator (STOP-RVF) was then developed and subsequently externally validated, which can provide personalized quantification of the risk for LVAD candidates. Its predictive accuracy was compared with previously published RVF scores. RESULTS: The derivation cohort included 798 patients (mean [SE] age, 56.1 [13.2] years; 668 male [83.7%]). The external validation cohort included 327 patients. RVF developed in 193 of 798 patients (24.2%) in the derivation cohort and 107 of 327 patients (32.7%) in the validation cohort. Preimplant variables associated with postoperative RVF included nonischemic cardiomyopathy, intra-aortic balloon pump, microaxial percutaneous left ventricular assist device/venoarterial extracorporeal membrane oxygenation, LVAD configuration, Interagency Registry for Mechanically Assisted Circulatory Support profiles 1 to 2, right atrial/pulmonary capillary wedge pressure ratio, use of angiotensin-converting enzyme inhibitors, platelet count, and serum sodium, albumin, and creatinine levels. Inclusion of intraoperative characteristics did not improve model performance. The calculator achieved a C statistic of 0.75 (95% CI, 0.71-0.79) in the derivation cohort and 0.73 (95% CI, 0.67-0.80) in the validation cohort. Cumulative survival was higher in patients composing the low-risk group (estimated <20% RVF risk) compared with those in the higher-risk groups. The STOP-RVF risk calculator exhibited a significantly better performance than commonly used risk scores proposed by Kormos et al (C statistic, 0.58; 95% CI, 0.53-0.63) and Drakos et al (C statistic, 0.62; 95% CI, 0.57-0.67). CONCLUSIONS AND RELEVANCE: Implementing routine clinical data, this multicenter cohort study derived and validated the STOP-RVF calculator as a personalized risk assessment tool for the prediction of RVF and RVF-associated all-cause mortality.

IMPORTANCE: Heart failure with recovered ejection fraction (HFrecEF) is a recently recognized phenotype of patients with a history of reduced left ventricular ejection fraction (LVEF) that has subsequently normalized. It is unknown whether such LVEF improvement is associated with improvements in health status. OBJECTIVE: To examine changes in health-related quality of life in patients with heart failure with reduced ejection fraction (HFrEF) whose LVEF normalized, compared with those whose LVEF remains reduced and those with HF with preserved EF (HFpEF). DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study was conducted at a tertiary care hospital from November 2016 to December 2018. Consecutive patients seen in a heart failure clinic who completed patient-reported outcome assessments were included. Clinical data were abstracted from the electronic health record. Data analysis was completed from February to December 2020. MAIN OUTCOMES AND MEASURES: Changes in Kansas City Cardiomyopathy Questionnaire overall summary score, Visual Analog Scale score, and Patient-Reported Outcomes Measurement Information System domain scores on physical function, fatigue, depression, and satisfaction with social roles over 1-year follow-up. RESULTS: The study group included 319 patients (mean [SD] age, 60.4 [15.5] years; 120 women [37.6%]). At baseline, 212 patients (66.5%) had HFrEF and 107 (33.5%) had HFpEF. At a median follow-up of 366 (interquartile range, 310-421) days, LVEF had increased to 50% or more in 35 patients with HFrEF (16.5%). Recovery of systolic function was associated with heart failure–associated quality-of-life improvement, such that for each 10% increase in LVEF, the Kansas City Cardiomyopathy Questionnaire score improved by an mean (SD) of 4.8 (1.6) points (P = .003). Recovery of LVEF was also associated with improvement of physical function, satisfaction with social roles, and a reduction in fatigue. CONCLUSIONS AND RELEVANCE: Among patients with HFrEF in this study, normalization of left ventricular systolic function was associated with a significant improvement in health-related quality of life.

Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.

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The aim of this study was to evaluate the impact of a shared-care model on outcomes in patients with left ventricular assist devices (LVADs) living in remote locations.

Current continuous-flow left ventricular assist devices (LVADs) decrease peripheral vascular pulsatility, which may contribute to side effects such as bleeding and thrombotic events. However, the actual impact of manipulating LVAD pump speed, revolutions per minute (rpm), on peripheral (brachial) pulsatility index (brachial PI), in patients with heart failure implanted with a HeartWare (HVAD) or HeartMateII (HMII) LVAD is unknown. Therefore, blood velocities (Doppler ultrasound) in the brachial artery were recorded and brachial PI calculated across rpm manipulations which spanned the acceptable clinical outpatient range: 360 rpm (HVAD, n = 10) and 1200 rpm (HMII, n = 10). Left ventricular assist device-derived PIs were also recorded: HVAD maximal blood flow (HVADVmax), HVAD minimum blood flow (HVADVmin), and HMII PI (HMIIPI). Brachial PI changed significantly with rpm manipulations, from 2.3 ± 0.6 to 4.1 ± 0.8 (HVAD) and from 1.8 ± 0.5 to 3.6 ± 1.0 (HMII). Multilevel linear modeling with random intercepts revealed a 180 rpm decrease of the HVAD resulted in a 0.9 ± 0.1 (37 ± 4%, d= 2.65) increase in brachial PI and a 600 rpm decrease in the HMII resulted in a 0.8 ± 0.1 (38 ± 3%, d= 4.66) increase. Furthermore, a reduction in rpm resulted in a 20.0 ± 0.3% power savings, and a reduction in device reported blood flow of 9 ± 1%. Brachial PI was linearly related to HVADVmax, HVADVmin, their difference (R2= 0.42, R2= 0.65, and R2= 0.54, respectively), and HMIIPI (R2= 0.86). Manipulating LVAD pump speed, within a clinically acceptable outpatient range, resulted in a significant change in brachial PI, which was reflected by pump indices, documenting the potential for LVAD pump speed manipulations to improve LVAD outcomes.

The aim of this study was to assess the impact of continuous-flow left ventricular assist device (LVAD) type—axial flow (AX) versus centrifugal flow (CR)—on myocardial structural and functional response following mechanical unloading.

Introduction:Although significant cardiac reverse remodeling is a prerequisite for a left ventricular (LV) assist device (LVAD) patient to be considered for device weaning, multiple factors including patient goals, physician comfort, and center experience, weigh in on this complex decision. Existing predictive models defining recovery as device removal may under detect patients that could benefit from a targeted bridge to recovery strategy. We sought to derive and validate a predictive tool to identify patients prone to reverse remodel, independent of the complex decision of device explant.Methods:Heart failure patients (N=782) requiring LVAD were enrolled at the Utah Transplant Affiliated Hospitals (n=537) and 5 US programs (n=245). Baseline characteristics were recorded. The primary outcome was ‘responder’ incidence, defined as follow-up LV ejection fraction (LVEF) ≥40% and LV end-diastolic diameter (LVEDD) ≤6 cm within one year on LVAD support. Bootstrap imputation and lasso variable selection techniques were used to derive a predictive model which was then validated. A predictive calculator was developed and patients were classified into groups with varying potential for reverse remodeling.Results:Patients were predominantly white (84%), males (82%), aged 56±1 years. Overall, 14.8% patients were identified as responders. A subset of 10 pre-operative variables associated with reverse remodeling were included in the multivariate model achieving an optimism-corrected C-statistic of 0.75 (95% CI: 0.73-0.84) (Figure).Conclusions:The UCAR calculator is a machine learning-based multicenter and validated risk tool, implementing routine pre-operative clinical data, effectively stratifying patients into groups with varying potential for reverse remodeling. This tool can be useful in selecting patients to implement diagnostic and therapeutic protocols to promote reverse remodeling and myocardial recovery.

Introduction:Existing models predicting right ventricular failure (RVF) after durable left ventricular assist device (LVAD) support are limited due to lack of multicenter validation, absence of intraoperative characteristics, and marginal predictive power. We sought to derive and validate a risk model to predict post-LVAD RVF.Methods:Advanced heart failure (HF) patients (N=798) requiring continuous-flow LVAD were enrolled at the Utah Transplant Affiliated Hospitals (n=477), Inova Heart & Vascular Institute (n=183), and Henry Ford Medical Center (n=138). Baseline clinical and intraoperative characteristics were recorded. The primary outcome was RVF incidence, defined as the need for right VAD (RVAD) or intravenous inotropes for >14 days. Bootstrap imputation and lasso variable selection were used to derive a predictive model which was then validated. A risk calculator was developed classifying patients into risk groups, and survival was compared.Results:Patients were predominantly white (72%), males (84%), aged 56±13 years. Patients in the RVF and non-RVF groups were comparable in terms of sex, age, and LVAD indication, while RVF patients more commonly had a history of systemic hypertension, non-ischemic cardiomyopathy, lower INTERMACS profiles, and more commonly required inotropic or temporary circulatory support pre-LVAD. Overall, 193 (24.2%) patients developed RVF with 109 (56.5%) requiring inotropes and 84 (43.5%) an RVAD. Multivariable predictors for RVF are shown in the Figureand achieved a c-statistic of 0.74 (95% CI: 0.70-0.78). Inclusion of intraoperative characteristics did not improve model performance. Cumulative survival was higher in the minimal risk group compared to low, moderate, and high.Conclusions:The STOP-RVF calculator effectively stratifies the risk for RVF after LVAD support by implementing routinely collected clinical data. It could impact patient selection and peri-operative management of advanced HF patients.

Advanced heart failure (AHF) is the late stage of the heart failure syndrome that is associated with significant morbidity, high mortality, and rising costs that pose a significant burden for the different health care systems in the United States and worldwide. Despite advances in pharmacologic and device therapy, patients with AHF frequently require complex therapies, such as continuous infusion with inotropic agents, mechanical circulatory support, and heart transplant. This article summarizes the team-based approach to care of patients with AHF and those supported by left ventricular assist devices.

Bleeding is an important cause of morbidity and mortality in patients with continuous-flow left ventricular assist devices (LVADs). Reduced pulsatility has been implicated as a contributing cause. The aim of this study was to assess the effects of different degrees of pulsatility on the incidence of nonsurgical bleeding.

Patients with human immunodeficiency virus (HIV) infection are at increased risk of accelerated coronary artery disease (CAD) and cardiovascular events. Stress echocardiography (SE) is routinely used for risk stratification and prognosis of patients with known or suspected CAD. The prognostic value of SE in this high-risk group is unknown. The purpose of this study was to evaluate the prognostic value of SE in HIV-infected patients with known or suspected CAD.

Introduction:Accurate assessment of the risk of adverse outcomes can assist in the management of patients with heart failure (HF).Hypothesis:Health-related quality of life (HRQoL) can improve prediction of HF outcomes beyond that of the more traditional clinical disease characteristics.Methods:We included consecutive patients with HF with reduced ejection fraction (HFrEF) who were seen in the HF clinic and completed patient reported outcome assessment (PROs) as part of routine care. Elastic net and gradient boosting regression analysis were used to build predictive models for HF hospitalization, heart transplant, left ventricular assist device implantation or death (composite outcome), including a range of clinical variables and PRO results as covariates.Results:There were 1,165 patients with HFrEF (mean age 60.5±16.2, 65% male) with median follow-up time of 490 days. Addition of PROs to more traditional risk factors improved model performance, as analyzed by C-statistics. The gradient boosting regression was chosen as the final model based on superior prediction performance - c-statistic 0.733 and favorable stratification of patient risk - Figure 1A. The Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ) and PROMIS dimensions of Satisfaction with social roles and activities and Physical function were covariates with high variable importance measure in the model. The predictive value of PROs was also confirmed by determining freedom from the composite endpoint in the 20th, 50th and 80th percentiles of PRO strata, while assigning the remaining clinical variables a median value (Figure 1B). In this analysis, PROs discriminated outcomes independent of other clinical characteristics.Conclusions:HRQoL appears to significantly modify outcome in HFrEF. Routine assessment of PROs could help to more accurately assess risk of adverse outcomes and personalize informed treatment decisions.

Introduction:In the phase 2 MAVERICK-HCM study in patients (pts) with non-obstructive hypertrophic cardiomyopathy (nHCM), mavacamten, a cardiac myosin inhibitor, was well tolerated and associated with significant reduction in biomarkers of myocardial wall stress and injury over 16 weeks (wks). Long-term efficacy and safety of mavacamten are being evaluated in MAVA-LTE.Methods:Pts who completed MAVERICK-HCM were eligible to enroll in the MAVERICK-LTE cohort of MAVA-LTE. Pts who received mavacamten in MAVERICK-HCM continued on the same dose; pts on placebo were randomized (1:1) to 1 of 2 target mavacamten plasma concentration groups (~200 or ~500 ng/mL) and started on 5 mg, with dose titration at Wk 6 (dosing not based on clinical response). Pts were evaluated at Wks 8, 12, 16, 24, and every 12 wks thereafter. An interim analysis was performed (longest follow-up at data cutoff, 96 wks; efficacy data presented through Wk 48).Results:At the data cutoff, 43 pts were enrolled in MAVERICK-LTE (mean age, 54 yrs; 65% female; mean dose, 7.6 mg/day). Median NT-proBNP significantly decreased by 58% at Wk 24 and by 67% at Wk 48 (Table). Significant reductions were also observed in tissue Doppler E/e’ at Wks 24 and 48 and in left atrial volume index (LAVI) at Wk 48. There was a modest reduction in left ventricular ejection fraction (LVEF) of 5.4% at Wk 48 without significant changes in LV stroke volume (Wk 48 mean ± SD change, 0.0 ± 8.5 mL). Most treatment-emergent adverse events were considered mild or moderate and unrelated to treatment. Nine pts temporarily discontinued treatment due to LVEF <50% (range, 36%-49%); 7 were asymptomatic, 8 resumed treatment at a lower dose after recovery of LVEF ≥50%, and 1 permanently discontinued.Conclusions:Consistent with the parent study, longer-term mavacamten was well tolerated and demonstrated sustained reduction in NT-proBNP in pts with nHCM. Improvements in LV relaxation and diastolic function by mavacamten were evidenced by lower E/e’ and LAVI.

Introduction:Sociodemographic factors (SDFs) are known to influence clinical outcomes in patients treated for various diseases. To what extent SDFs affect health-related quality of life (HRQoL) in heart failure (HF) has not been fully described.Methods:HRQoL impairment was assessed in consecutive patients in a large HF clinic using patient reported outcome (PRO) instruments - the HF specific Kansas City Cardiomyopathy Questionnaire (KCCQ-12) and the generic Visual Analogue Scale (VAS); scales 0-100. We dichotomized both scales based on severity of QoL impairment: severe to very severe (0-50) and mild to moderate (51-100). The SDFs of interest were age (continuous), sex, race (white vs non-white), partnership status (partnered vs not partnered) and health insurance type (Medicare vs Medicaid vs self-pay vs commercial). We examined associations of SDFs with KCCQ-12 and VAS in univariate analyses and multivariable adjusted logistic regression models.Results:A total of 1,016 patients were included, of whom 52.3% had severe to very severe QoL limitation by KCCQ-12 and 50.6% by VAS. After adjusting for covariates including type of HF, substance abuse and a comorbidity score, health insurance was the only SDF independently associated with HRQoL. Compared to commercial insurance, patients enrolled in Medicaid (OR = 2.58; 95% CI: 1.57, 4.25) and Medicare (OR = 1.86; 95% CI: 1.31, 2.65) had higher odds of severe to very severe HF related QoL impairment as measured by KCCQ-12. Similarly, patients enrolled in Medicaid (OR = 1.72; 95% CI: 1.21, 2.44) and Medicare (OR = 1.99; 95% CI: 1.23, 3.22) had higher odds of severe to very severe general HRQoL impairment as measured by VAS.Conclusions:In a large cross-sectional sample of HF patients, health insurance type was a SDF independently associated with HRQoL. Understanding potentially modifiable factors linked to health insurance type may identify targets to improve HRQoL in HF for Medicare and Medicaid enrollees.

Introduction:Pioneering studies have uncovered an array of developmental programs in end-stage heart failure (HF), but the central regulatory mechanisms that drive this cardiac transcriptional reprogramming remain poorly-understood. We thus examined whether the cardiac epigenome, specifically DNA methylation, encodes a pathological shift in cardiac gene expression in HF.Methods:We used paired-end whole-genome bisulfite sequencing and next-generation RNA sequencing of left ventricle tissue obtained from 7 patients with end-stage HF and 3 non-failing donor hearts. Experimental groups comprised of a broad and equivalent distribution of ages (34 - 62 years) and Body Mass Indices (23 - 43 kg/m2).Results:Differential methylation in HF localized to promoter-associated CpG islands. Hyper-methylated promoters were associated with suppression of genes involved in oxidative metabolism (67% enrichment, P< 0.001), whereas promoter hypo-methylation enriched glycolytic metabolic pathways (39% enrichment, P< 0.001). Furthermore, we identified DNA methyltransferase 3A (DNMT3A) as an induced (30%, P< 0.05) putative epigenetic regulator. To better understand its role in the metabolic alterations of HF, we used an in vitrooverexpression of plasmid-derived DNMT3A in H9c2 cardiomyoblasts, which repressed ASCL1 (28.4%, P< 0.05), ASCL5 (10%, P< 0.05), HADHA (12.5%, P< 0.05), and NDUFA5 (21.3%,P< 0.05). Lastly, we identified binding-site competition via hyper-methylation of the Nuclear Respiratory Factor 1 (NRF1) motif (P= 10-76), offering preliminary insight into a putative mechanism whereby DNA methylation regulates mitochondrial biogenesis.Conclusion:Altogether, these findings depict an etiology-independent shift in cardiac DNA methylation that corresponds with metabolic gene reprogramming in end-stage human HF. Targeting these epigenetic mechanisms may therefore unveil novel approaches to the clinical management of end-stage HF.

Background:Significant improvements in myocardial structure and function have been reported in some advanced heart failure (HF) patients (Responders-R) upon left ventricular assist devices (LVAD)- induced mechanical unloading. This is reported to affect the energy balance, suggesting its potential to reverse the deleterious metabolic adaptations of the failing heart. Specifically, our prior work demonstrated a post-LVAD glycolysis upregulation with no subsequent increase in pyruvate mitochondrial oxidation through the TCA cycle. The underlying mechanisms responsible for this mismatch are not known.Aim:We hypothesized that the upregulated glycolytic intermediates are channeled instead of the TCA cycle into metabolic cardioprotective and repair pathways driving the observed myocardial recovery in Responders.Methods:We prospectively obtained LV apical myocardial tissue obtained from normal donors and HF patients at LVAD implant (Pre-LVAD) and transplantation (Post-LVAD) and segregated them as R and Non-R based on post-LVAD clinical recovery.Results:Western blot analysis of the key PPP and OCM enzymes, glucose-6-phosphate dehydrogenase and transketolase, phosphoglycerate dehydrogenase and mitochondrial serine hydroxymethyl transferase showed significant increase in Post-R as compared to post-Non-responders. In agreement with the elevated enzyme levels, the metabolite levels of the enzyme substrates such as sedoheptulose-6-phosphate (PPP) and serine and glycine (OCM) were decreased in post-R. Furthermore, post-R had significantly reduced ROS levels, high NADPH levels, improved mitochondrial dynamics and enhanced ECM protein, ?-dystroglycan, further indicating increased flux of glucose into PPP and OCM and its correlation with recovery.Conclusions:The recovering human heart appears to direct the increased glycolytic metabolites into PPP and OCM, both of which play a role in cardioprotection by generating NADPH thereby reducing ROS and metabolites for repair. Further confirmation of these findings with metabolic flux studies are warranted.

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Aims Echocardiographic contrast (EC) improves the diagnostic accuracy of suboptimal echocardiograms. In October 2007, the Food and Drug Administration (FDA) placed a black box warning on the label of the perflutren-based agents Definity and Optison, contraindicating their use in patients with pulmonary hypertension (PHT) and unstable cardiopulmonary status, after serious cardiopulmonary reactions occurred in temporal relation to EC administration. In 2008 and 2011, the FDA revised the black box warning allowing their use in this same population. However, limited data exist regarding the safety profile of these agents in patients with PHT. Methods and results Consecutive hospitalized patients with PHT who were referred for echocardiographic evaluation, but required the use of EC, were included. All our patients received the EC agent Definity. We evaluated these patients for serious adverse events (respiratory decompensation, hypotension, syncope, convulsions, arrhythmias, anaphylactic reactions, or death) occurring within 24 h of EC administration. The study group included 1513 patients (age 69 ± 14 years, 55% males, BMI 33 ± 9 kg/m2), of which 911 (60%) had mild PHT, 515 (34%) had moderate PHT, and 87 (6%) had severe PHT. The mean pulmonary artery systolic pressures (PASP) in the groups with mild, moderate, and severe PHT were 41 ± 4 (range 35–49) mmHg, 55 ± 5 (range 50–69) mmHg, and 78 ± 9 (range 70–122) mmHg, respectively. The incidence of adverse events in all subgroups was rare (0.002%) and they were not attributed to EC because of temporal and clinical considerations. Conclusion The use of the EC agent Definity is safe in hospitalized patients with PHT.

PURPOSETo compare the utilization of evidence-based (EB) cardiac therapies and clinical outcomes of cardiac care on general medicine inpatient services under teaching and nonteaching services at an academic hospital.