<div><h4>Sex-Associated Differences in the Clinical Outcomes of Left Ventricular Assist Device Recipients: Insights From Interagency Registry for Mechanically Assisted Circulatory Support.</h4><i>Shetty NS, Parcha V, Abdelmessih P, Patel N, ... Arora G, Arora P</i><br /><b>Background</b><br />Sex-associated differences in clinical outcomes among left ventricular assist device recipients in the United States have been recognized. However, an investigation of the social and clinical determinants of sex-associated differences is lacking.<br /><b>Methods</b><br />Left ventricular assist device receiving patients enrolled in Interagency Registry for Mechanically Assisted Circulatory Support between 2005 and 2017 were included. The primary outcome was all-cause mortality. Secondary outcomes included heart transplantation and postimplantation adverse event rates. The cohort was stratified by the social subgroup of race and ethnicity (non-Hispanic White, non-Hispanic Black, non-Hispanic Asian, and Hispanic), and clinical subgroups of device strategy (destination therapy, bridge to transplant, and bridge to candidacy), and implantation center volume (low [≤20 implants/y], medium [21-30 implants/y], and high [>30 implants/y]). A multivariable-adjusted Cox proportional hazard model was used to assess the risk of death and heart transplantation with prespecified interaction testing. Poisson regression was used to estimate adverse events by sex across the various subgroups.<br /><b>Results</b><br />Among 18 525 patients, there were 3968 (21.4%) females. Compared with their male counterparts, Hispanic (adjusted hazard ratio [HR<sub>adj</sub>], 1.75 [1.23-2.47]) females had the highest risk of death followed by non-Hispanic White females (HR<sub>adj</sub>, 1.15 [1.07-1.25]; <i>P</i><sub>interaction</sub>=0.02). Hispanic (HR<sub>adj</sub>, 0.60 [0.40-0.89]) females had the lowest cumulative incidence of heart transplantation followed by non-Hispanic Black females (HR<sub>adj</sub>, 0.76 [0.67-0.86]), and non-Hispanic White females (HR<sub>adj</sub>, 0.88 [0.80-0.96]) compared with their male counterparts (<i>P</i><sub>interaction</sub><0.001). Compared with their male counterparts, females on the bridge to candidacy strategy (HR<sub>adj</sub>, 1.32 [1.18-1.48]) had the highest risk of death (<i>P</i><sub>interaction</sub>=0.01). The risk of death (<i>P</i><sub>interaction</sub>=0.44) and cumulative incidence of heart transplantation (<i>P</i><sub>interaction</sub>=0.40) did not vary by sex in the center volume subgroup. A higher incidence rate of adverse events after left ventricular assist device implantation was also seen in females compared with the males, overall, and across all subgroups.<br /><b>Conclusions</b><br />Among left ventricular assist device recipients, the risk of death, the cumulative incidence of heart transplantation, and adverse events differ by sex across the social and clinical subgroups.<br /><br /><br /><br /><small>Circ Heart Fail: 26 May 2023:e010189; epub ahead of print</small></div>

<div><h4>Sex-Specific Outcomes of Candidates Listed as the Highest Priority Status for Heart Transplantation.</h4><i>DeFilippis EM, Masotti M, Blumer V, Maharaj V, Cogswell R</i><br /><b>Background</b><br />While sex differences in heart transplantation (HT) waitlist mortality have been previously described, waitlist and HT outcomes by sex of patients in the highest urgency strata (Status 1) since implementation of the 2018 allocation system change in the United States are unknown. We hypothesized that women listed as Status 1 may have worse outcomes due to adverse events on temporary mechanical circulatory support.<br /><b>Methods</b><br />The analysis included adult, single-organ HT waitlist candidates listed as Status 1 at any time while listed, after the HT allocation system change (from October 18, 2018 through March 31, 2022). The primary outcome was the rate of HT by sex, assessed using multivariable competing risk analysis where waitlist removal for death or clinical deterioration was the competing event. Post-HT survival by sex of waitlist candidates transplanted as a Status 1 was also compared.<br /><b>Results</b><br />Of 1120 Status 1 waitlist candidates (23.8% women), women had a lower rate of HT compared to men (adjusted hazard ratio, 0.74 [95% CI, 0.62-0.88]; <i>P</i><0.001) and a higher rate of delisting for death or medical unsuitability (adjusted hazard ratio, 1.48 [95% CI, 1.05-2.09]; <i>P</i>=0.026). Calculated panel reactive antibody did not account for all the harm observed. Post-HT survival of Status 1 candidates by sex was similar (adjusted hazard ratio, 1.13 [95% CI, 0.62-2.06]; <i>P</i>=0.70).<br /><b>Conclusions</b><br />Women have a lower rate of HT and higher rate of delisting for death or clinical deterioration at the highest urgent status, which appears to be mediated but not fully explained by calculated panel reactive antibody levels. Further investigation into the safety profile of temporary mechanical circulatory support devices in women is needed.<br /><br /><br /><br /><small>Circ Heart Fail: 26 May 2023:e009946; epub ahead of print</small></div>

<div><h4>Long-Term Outcomes of Early Coronary Artery Disease Testing After New-Onset Heart Failure.</h4><i>Zheng J, Heidenreich PA, Kohsaka S, Fearon WF, Sandhu AT</i><br /><b>Background</b><br />Coronary artery disease (CAD) testing remains underutilized in patients with newly diagnosed heart failure (HF). The longitudinal clinical impact of early CAD testing has not been well-characterized. We investigated changes in clinical management and long-term outcomes after early CAD evaluation in patients with incident HF.<br /><b>Methods</b><br />We identified Medicare patients with incident HF from 2006 to 2018. The exposure variable was early CAD testing within 1 month of initial HF diagnosis. Covariate-adjusted rates of cardiovascular interventions after testing, including CAD-related management, were modeled using mixed-effects regression with clinician as a random intercept. We assessed mortality and hospitalization outcomes using landmark analyses with inverse probability-weighted Cox proportional hazards models. Falsification end points and mediation analysis were employed for bias assessment.<br /><b>Results</b><br />Among 309 559 patients with new-onset HF without prior CAD, 15.7% underwent early CAD testing. Patients who underwent prompt CAD evaluation had higher adjusted rates of subsequent antiplatelet/statin prescriptions and revascularization, guideline-directed therapy for HF, and stroke prophylaxis for atrial fibrillation/flutter than controls. In weighted Cox models, 1-month CAD testing was associated with significantly reduced all-cause mortality (hazard ratio, 0.93 [95% CI, 0.91-0.96]). Mediation analyses indicated that ≈70% of this association was explained by CAD management, largely from new statin prescriptions. Falsification end points (outpatient diagnoses of urinary tract infection and hospitalizations for hip/vertebral fracture) were nonsignificant.<br /><b>Conclusions</b><br />Early CAD testing after incident HF was associated with a modest mortality benefit, driven mostly by subsequent statin therapy. Further investigation on clinician barriers to testing and treating high-risk patients may improve adherence to guideline-recommended cardiovascular interventions.<br /><br /><br /><br /><small>Circ Heart Fail: 22 May 2023:e010426; epub ahead of print</small></div>

<div><h4>Dapagliflozin Improves Heart Failure Symptoms and Physical Limitations Across the Full Range of Ejection Fraction: Pooled Patient-Level Analysis From DEFINE-HF and PRESERVED-HF Trials.</h4><i>Nassif ME, Windsor SL, Gosch K, Borlaug BA, ... Sharma K, Kosiborod MN</i><br /><b>Background</b><br />Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear.<br /><b>Methods</b><br />Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression.<br /><b>Results</b><br />Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6-7.5]; <i>P</i><0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0-8.1]; <i>P</i>=0.01), >40 to ≤60 (4.9 points [95% CI, 0.8-9.0]; <i>P</i>=0.02) and >60% (6.8 points [95% CI, 1.5-12.1]; <i>P</i>=0.01; <i>P</i><sub>interaction</sub>=0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously (<i>P</i><sub>interaction</sub>=0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all <i>P</i><sub>interaction</sub>values nonsignificant).<br /><b>Conclusions</b><br />In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifiers: NCT02653482 and NCT03030235.<br /><br /><br /><br /><small>Circ Heart Fail: 19 May 2023:e009837; epub ahead of print</small></div>

<div><h4>Fibrotic Plaque and Microvascular Dysfunction Predict Early Cardiac Allograft Vasculopathy Progression After Heart Transplantation: The Early Post Transplant Cardiac Allograft Vasculopathy Study.</h4><i>Chih S, Chong AY, Džavík V, So DY, ... Beanlands RSB, Ross HJ</i><br /><b>Background</b><br />Early cardiac allograft vasculopathy (CAV) prognostication is needed to improve long-term outcomes after heart transplantation. We characterized first year posttransplant coronary anatomic-physiologic alterations to determine predictors of early CAV progression.<br /><b>Methods</b><br />Heart transplant recipients at 2 institutions (enrolled January 2018 to March 2021) underwent prospective evaluation 3 and 12-month posttransplant with angiography and left anterior descending artery intravascular ultrasound, optical coherence tomography, fractional flow reserve, coronary flow reserve, and index of microcirculatory resistance measurements. CAV progression was assessed by intravascular ultrasound change in percentage intimal volume from baseline to 12-month follow-up.<br /><b>Results</b><br />Eighty-two patients (mean age, 51 years; 60% men) completed evaluation at mean 13.8 and 56.3 weeks posttransplant. Donor atherosclerosis (baseline intravascular ultrasound maximal intimal thickness, ≥0.5 mm) was evident in 50%. De novo (follow-up maximal intimal thickness, ≥0.5 mm) and rapidly progressive CAV (maximal intimal thickness, ≥0.5-mm increase from baseline) developed in 24% and 13%, respectively. On optical coherence tomography, baseline to follow-up median intimal volume increased 42% (0.58 mm<sup>3</sup>/mm), percentage intimal volume increased 44% (4.6%), vessel volume decreased 4% (-0.50 mm<sup>3</sup>/mm) and lumen volume decreased 9% (-1.02 mm<sup>3</sup>/mm); <i>P</i><0.05 for all. Fibrotic plaque was the predominant morphology: baseline, 29% and follow-up, 50%. Coronary physiology was abnormal in 41% at baseline and 45% at follow-up, with 1 in 5 patients having microvascular dysfunction (index of microcirculatory resistance, ≥25). On multivariable linear regression analysis, recipient male sex, fibrotic plaque, and index of microcirculatory resistance were independent predictors of coronary disease progression.<br /><b>Conclusions</b><br />Fibrotic plaque on optical coherence tomography and index of microcirculatory resistance early posttransplant predict CAV progression in the first year of transplantation.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT03217786.<br /><br /><br /><br /><small>Circ Heart Fail: 11 May 2023:e010173; epub ahead of print</small></div>

<div><h4>Echocardiographic Features Beyond Ejection Fraction and Associated Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction.</h4><i>Peters AE, Clare RM, Chiswell K, Felker GM, ... Mentz R, DeVore AD</i><br /><b>Background</b><br />Heart failure (HF) guidelines recommend assessment of left ventricular ejection fraction (LVEF) to classify patients and guide therapy implementation. However, LVEF alone may be insufficient to adequately characterize patients with HF, especially those with mildly reduced or preserved LVEF. Recommendations on additional testing are lacking, and there are limited data on use of echocardiographic features beyond LVEF in patients with heart failure with mildly reduced or preserved LVEF.<br /><b>Methods</b><br />In patients with HF with mildly reduced or preserved LVEF identified in a large US health care system, the association of the following metrics with mortality was evaluated: LV global longitudinal strain (LV GLS>-16), left atrial volume index (>28 mL/m<sup>2</sup>), left ventricular hypertrophy (LVH), and E/e´>13 and e´<9. A multivariable model for mortality was constructed including age, sex, and key comorbidities followed by stepwise selection of echocardiographic features. Characteristics and outcomes of subgroups with normal versus abnormal LV GLS and LVEF were evaluated.<br /><b>Results</b><br />Among 2337 patients with complete echocardiographic data assessed between 2017 and 2020, the following features were associated with all-cause mortality on univariate analysis over 3 years of follow-up: E/e´+e´, LV GLS, left atrial volume index (all <i>P</i><0.01). In the multivariable model (<i>C</i>-index=0.65), only abnormal LV GLS was independently associated with all-cause mortality (HR, 1.35 [95% CI, 1.11-1.63]; <i>P</i>=0.002). Among patients with LVEF>55%, 498/1255 (40%) demonstrated abnormal LV GLS. Regardless of specific LVEF, patients with abnormal LV GLS demonstrated a higher burden of multiple comorbidities and higher event rates compared with patients with normal LV GLS.<br /><b>Conclusions</b><br />In a large, real-world HF with mildly reduced or preserved LVEF population, echocardiographic features, led by LV GLS, were associated with adverse outcomes irrespective of LVEF. A large proportion of patients demonstrate adverse myocardial function by LV GLS despite preserved LVEF and may represent a key cohort of interest for HF medical therapies and future clinical studies.<br /><br /><br /><br /><small>Circ Heart Fail: 01 May 2023; 16:e010252</small></div>

<div><h4>Use of a Cardiac Scale to Predict Heart Failure Events: Design of SCALE-HF 1.</h4><i>Fudim M, Yazdi D, Egolum U, Haghighat A, ... Smith S, DeVore AD</i><br /><b>Background</b><br />There is a need for simple, noninvasive solutions to remotely monitor and predict worsening heart failure (HF) events. SCALE-HF 1 (Surveillance and Alert-Based Multiparameter Monitoring to Reduce Worsening Heart Failure Events) is a prospective, multicenter study that will develop and assess the accuracy of the heart function index-a composite algorithm of noninvasive hemodynamic biomarkers from a cardiac scale-in predicting worsening HF events.<br /><b>Methods</b><br />Approximately 300 patients with chronic HF and recent decompensation will be enrolled in this observational study for model development. Patients will be encouraged to take daily cardiac scale measurements.<br /><b>Results</b><br />Approximately 50 HF events, defined as an urgent, unscheduled clinic, emergency department, or hospitalization for worsening HF will be used for model development. The composite index will be developed from hemodynamic biomarkers derived from ECG, ballistocardiogram, and impedance plethysmogram signals measured from the cardiac scale. Biomarkers of interest include weight, peripheral impedance, pulse rate and variability, and estimates of stroke volume, cardiac output, and blood pressure captured through the cardiac scale. The sensitivity, unexplained alert rate, and alerting time of the index in predicting worsening HF events will be evaluated and compared with the performance of simple weight-based rule-of-thumb algorithms (eg, weight increase of 3 lbs in 1 day or 5 lbs in 7 days) that are often used in practice.<br /><b>Conclusions</b><br />SCALE-HF 1 is the first study to develop and evaluate the performance of a composite index derived from noninvasive hemodynamic biomarkers measured from a cardiac scale in predicting worsening HF events. Subsequent studies will validate the heart function index and assess its ability to improve patient outcomes.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT04882449.<br /><br /><br /><br /><small>Circ Heart Fail: 01 May 2023; 16:e010012</small></div>

<div><h4>Rethinking Donor and Recipient Risk Matching in Europe and North America: Using Heart Transplant Predictors of Donor and Recipient Risk.</h4><i>Moayedi Y, Rodenas-Alesina E, Mueller B, Fan CS, ... Ross HJ, Khush KK</i><br /><b>Background</b><br />In Europe, there is greater acceptance of hearts from higher-risk donors for transplantation, whereas in North America, the donor heart discard rate is significantly higher. A Donor Utilization Score (DUS) was used to compare European and North American donor characteristics for recipients included in the International Society for Heart and Lung Transplantation registry from 2000 to 2018. DUS was further evaluated as an independent predictor for 1-year freedom from graft failure, after adjusting for recipient risk. Lastly, we assessed donor-recipient risk matching with the outcome of 1-year graft failure.<br /><b>Methods</b><br />DUS was applied to the International Society for Heart and Lung Transplantation cohort using meta-modeling. Posttransplant freedom from graft failure was summarized by Kaplan-Meier survival. Multivariable Cox proportional hazard regression was applied to quantify the effects of DUS and Index for Mortality Prediction After Cardiac Transplantation score on the 1-year risk of graft failure. We present 4 donor/recipient risk groups using the Kaplan-Meier method.<br /><b>Results</b><br />European centers accept significantly higher-risk donor hearts compared to North America. DUS 0.45 versus 0.54, <i>P</i><0.005). DUS was an independent predictor for graft failure with an inverse linear relationship when adjusted for covariates (<i>P</i><0.001). The Index for Mortality Prediction After Cardiac Transplantation score, a validated tool to assess recipient risk, was also independently associated with 1-year graft failure (<i>P</i><0.001). In North America, 1-year graft failure was significantly associated with donor-recipient risk matching (log-rank <i>P</i><0.001). One-year graft failure was highest with pairing of high-risk recipients and donors (13.1% [95% CI, 10.7%-13.9%]) and lowest among low-risk recipients and donors (7.4% [95% CI, 6.8%-8.0%]). Matching of low-risk recipients with high-risk donors was associated with significantly less graft failure (9.0% [95% CI, 8.3%-9.7%]) than high-risk recipients with low-risk donors (11.4% [95% CI, 10.7%-12.2%]) Conclusions: European heart transplantation centers are more likely to accept higher-risk donor hearts than North American centers. Acceptance of borderline-quality donor hearts for lower-risk recipients could improve donor heart utilization without compromising recipient survival.<br /><br /><br /><br /><small>Circ Heart Fail: 01 May 2023; 16:e009994</small></div>

<div><h4>Pulmonary Artery Pressure-Guided Heart Failure Management Reduces Hospitalizations in Patients With Chronic Kidney Disease.</h4><i>Raval NY, Valika A, Adamson PB, Williams C, Brett ME, Costanzo MR</i><br /><b>Background</b><br />Hemodynamic-guided heart failure management is a superior strategy to prevent decompensation leading to hospitalization compared with traditional clinical methods. It remains unstudied if hemodynamic-guided care is effective across severities of comorbid renal insufficiency or if this strategy impacts renal function over time.<br /><b>Methods</b><br />In the CardioMEMS US PAS (Post-Approval Study), heart failure hospitalizations were compared from 1 year before and after pulmonary artery sensor implantation in 1200 patients with New York Heart Association class III symptoms and a previous hospitalization. Hospitalization rates were evaluated in all patients grouped into baseline estimated glomerular filtration rate (eGFR) quartiles. Chronic kidney disease progression was evaluated in patients with renal function follow-up data (n=911).<br /><b>Results</b><br />Patients with stage 2 or greater chronic kidney disease at baseline exceeded 80%. Heart failure hospitalization risk was lower in all eGFR quartiles ranging from a hazard ratio of 0.35 (0.27-0.46; <i>P</i><0.0001) in patients with eGFR >65 mL/min per 1.73 m<sup>2</sup> to 0.53 (0.45-0.62; <i>P</i><0.0001) in patients with eGFR ≤37 mL/min per 1.73 m<sup>2</sup>. Renal function was preserved or improved in most patients. Survival was different between quartiles and lower in quartiles with more advanced chronic kidney disease.<br /><b>Conclusions</b><br />Hemodynamic-guided heart failure management using remotely obtained pulmonary artery pressures is associated with lower hospitalization rates and general preservation of renal function in all eGFR quartiles or chronic kidney disease stages.<br /><br /><br /><br /><small>Circ Heart Fail: 01 May 2023; 16:e009721</small></div>

<div><h4>Protein Biomarkers of New-Onset Heart Failure: Insights From the Heart Omics and Ageing Cohort, the Atherosclerosis Risk in Communities Study, and the Framingham Heart Study.</h4><i>Girerd N, Levy D, Duarte K, Ferreira JP, ... Rossignol P, Zannad F</i><br /><b>Background</b><br />We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone.<br /><b>Methods</b><br />A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871).<br /><b>Results</b><br />In single protein analysis, after adjusting for matching variables and clinical risk factors (and correcting for multiple testing), 62 proteins were associated with incident HF in ARIC, 16 in FHS, and 116 in HOMAGE cohort. Proteins associated with incident HF in all cohorts were BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), eukaryotic translation initiation factor 4E-BP1 (4E-binding protein 1), hepatocyte growth factor (HGF), Gal-9 (galectin-9), TGF-alpha (transforming growth factor alpha), THBS2 (thrombospondin-2), and U-PAR (urokinase plasminogen activator surface receptor). The increment in <i>C</i>-index for incident HF based on a multiprotein biomarker approach, in addition to clinical risk factors and NT-proBNP, was 11.1% (7.5%-14.7%) in ARIC, 5.9% (2.6%-9.2%) in FHS, and 7.5% (5.4%-9.5%) in HOMAGE cohort, all <i>P</i><0.001), each of which was a larger increase than that for NT-proBNP on top of clinical risk factors. Complex network analysis revealed a number of overrepresented pathways related to inflammation (eg, tumor necrosis factor and interleukin) and remodeling (eg, extracellular matrix and apoptosis).<br /><b>Conclusions</b><br />A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.<br /><br /><br /><br /><small>Circ Heart Fail: 01 May 2023; 16:e009694</small></div>

<div><h4>Prognostic Importance of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) Following High-Risk Myocardial Infarction in the PARADISE-MI Trial.</h4><i>Jering KS, Claggett BL, Pfeffer MA, Granger CB, ... von Lewinski D, Braunwald E</i><br /><b>Background</b><br />NT-proBNP (N-terminal pro-B-type natriuretic peptide) is a potent predictor of death and heart failure (HF) across multiple populations. We evaluated the prognostic importance of NT-proBNP in patients with acute myocardial infarction (MI) complicated by left ventricular systolic dysfunction, pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors enrolled in the PARADISE-MI trial (Prospective ARNI vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction).<br /><b>Methods</b><br />Patients were randomized to sacubitril/valsartan 200 mg or ramipril 5 mg twice daily within 0.5 to 7 days of a MI. Patients with prior HF were excluded. NT-proBNP and hs-cTnT (high-sensitivity troponin T) were collected at randomization in a prespecified substudy of 1129 patients. The primary end point of PARADISE-MI was a composite of cardiovascular death or incident HF (hospitalization or outpatient symptomatic HF), analyzed as time-to-first event; additional end points included all-cause death and the composite of fatal or nonfatal MI or stroke.<br /><b>Results</b><br />Median NT-proBNP was 1757 ng/L (25th-75th percentiles, 896-3462 ng/L) at randomization (4.0±1.8 days after the index MI). Patients in the highest quartile of NT-proBNP were older, more commonly women and had more hypertension, atrial fibrillation, renal dysfunction, and pulmonary congestion on presentation (all <i>P</i><0.001). NT-proBNP was strongly associated with the primary end point (adjusted hazard ratio, 1.45 per doubling of NT-proBNP; [95% CI, 1.23-1.70]), adjusted for clinical variables and baseline hs-cTnT. NT-proBNP was also independently associated with all-cause death (adjusted hazard ratio, 1.74 [95% CI, 1.38-2.21]) and fatal or nonfatal MI or stroke (adjusted hazard ratio, 1.24 [95% CI, 1.05-1.45]). NT-proBNP did not significantly modify the neutral treatment effect of sacubitril/valsartan relative to ramipril (<i>P</i> interaction=0.46).<br /><b>Conclusions</b><br />Within the first week of a high-risk MI NT-proBNP is associated with incident HF, death and atherosclerotic events. This prognostic information is independent of hs-cTnT.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT02924727.<br /><br /><br /><br /><small>Circ Heart Fail: 01 May 2023:e010259; epub ahead of print</small></div>

<div><h4>Use of a Pulmonary Artery Pressure Sensor to Manage Patients With Left Ventricular Assist Devices.</h4><i>Thohan V, Abraham J, Burdorf A, Sulemanjee N, ... Drakos SG, INTELLECT 2-HF Investigators</i><br /><AbstractText><b>Background:</b> Hemodynamic-guided management with a pulmonary artery pressure (PAP) sensor (CardioMEMS<sup>TM</sup>) is effective in reducing heart failure hospitalization (HFH) in patients with chronic heart failure (HF). This study aims to determine the feasibility and clinical utility of the CardioMEMS HF system to manage patients supported with LVADs. <br /><b>Methods:</b><br/>In this multi-center prospective study, we followed patients with HeartMate II<sup>TM</sup> (n=52) or HeartMate 3<sup>TM</sup> (n=49) LVADs and with CardioMEMS PA Sensors, and measured PAP, 6-minute walk distance (6MWD), quality of life (EQ-5D-5L scores), and HFH rates through 6 months. Patients were stratified as responders (R) and non-responders (NR) to reductions in PA diastolic pressure (PAD). <br /><b>Results:</b><br/>There were significant reductions in PAD from baseline to 6 months in R (21.5 to 16.5 mmHg, p<0.001), compared to an increase in NR (18.0 to 20.3, p=0.002). and there was a significant increase in 6MWD among R (266 vs 322 meters, p=0.025) compared to no change in NR. Patients who maintained PAD < 20 compared with PAD ≥ 20 mmHg for more than half the time throughout the study (averaging 15.6 vs 23.3 mmHg) had a statistically significant lower rate of HFH (12.0% vs 38.9%, p=0.005). <b>Conclusions:</b> LVAD patients managed with CardioMEMS with a significant reduction in PAD at 6 months showed improvements in 6MWD. Maintaining PAD < 20 mmHg was associated with fewer HF hospitalizations. Hemodynamic-guided management of LVAD patients with CardioMEMS is feasible and may result in functional and clinical benefits. Prospective evaluation of ambulatory hemodynamic management in LVAD patients is warranted. <b>Registration:</b> URL: https://clinicaltrials.gov Unique Identifier: NCT03247829.</AbstractText><br /><br /><br /><br /><small>Circ Heart Fail: 20 Apr 2023; epub ahead of print</small></div>

<div><h4>Propensity-Matched Study of Early Cardiac Rehabilitation in Patients With Acute Decompensated Heart Failure.</h4><i>Enzan N, Matsushima S, Kaku H, Tohyama T, ... Ide T, Tsutsui H</i><br /><b>Background</b><br />The impact of early implementation of cardiac rehabilitation (CR) in heart failure (HF) patients remains to be elucidated. This study sought to determine whether CR during HF hospitalization could improve prognostic outcomes in patients with acute decompensated HF.<br /><b>Methods</b><br />We analyzed patients with HF enrolled in the JROADHF (Japanese Registry of Acute Decompensated Heart Failure) registry, a retrospective, multicenter, nationwide registry of patients hospitalized for acute decompensated HF. Eligible patients were divided into 2 groups according to CR during hospitalization. The primary outcome was a composite of cardiovascular death or rehospitalization due to cardiovascular event after discharge. The secondary outcomes were cardiovascular death and cardiovascular event rehospitalization.<br /><b>Results</b><br />Out of 10 473 eligible patients, 3210 patients underwent CR. Propensity score matching yielded 2804 pairs. Mean age was 77±12 years and 3127 (55.8%) were male. During a mean follow-up of 2.8 years, the CR group had lower incidence rates of the composite outcome (291 versus 327 events per 1000 patient-years; rate ratio, 0.890 [95% CI, 0.830-0.954]; <i>P</i>=0.001) and rehospitalization due to cardiovascular event (262 versus 295 events per 1000 patient-years; rate ratio, 0.888 [95% CI, 0.825-0.956]; <i>P</i>=0.002) than the no CR group. In-hospital CR was associated with an improvement in Barthel index for activities of daily living (<i>P</i>=0.002). Patients with very low Barthel index at admission were benefited by CR in comparison with patients with independent Barthel index (very low; hazard ratio, 0.834 [95% CI, 0.742-0.938]: independent; hazard ratio, 0.985 [95% CI, 0.891-1.088]; <i>P</i> for interaction=0.035).<br /><b>Conclusions</b><br />CR implementation during hospitalization was associated with better long-term outcomes in patients with acute decompensated HF. These data support the need for a randomized, controlled, adequately powered trial to definitively test the role of early physical rehabilitation in hospitalized patients with HF.<br /><br /><br /><br /><small>Circ Heart Fail: 07 Apr 2023:e010320; epub ahead of print</small></div>

<div><h4>Adverse Outcomes Associated With Interleukin-6 in Patients Recently Hospitalized for Heart Failure With Preserved Ejection Fraction.</h4><i>Mooney L, Jackson CE, Adamson C, McConnachie A, ... Petrie MC, Lang NN</i><br /><b>Background</b><br />Inflammation may play a role in the pathophysiology of heart failure with preserved ejection fraction. We examined whether circulating levels of interleukin-6 identify patients at greater risk of adverse outcomes following hospitalization with heart failure with preserved ejection fraction.<br /><b>Methods</b><br />We assessed relationships between interleukin-6 (IL-6) tertiles (T1-3) and all-cause death, cardiovascular death, and subsequent heart failure hospitalization (sHFH) in 286 patients recently hospitalized with heart failure with preserved ejection fraction. Associations between IL (interleukin)-6 and outcomes were examined in a Cox-regression model adjusted for risk factors including BNP (B-type natriuretic peptide). Biomarkers including hsCRP (high-sensitivity C-reactive protein) were assessed.<br /><b>Results</b><br />The range of IL-6 (pg/mL) in each tertile was T1 (0.71-4.16), T2 (4.20-7.84), and T3 (7.9-236.32). Compared with T1, patients in the highest IL-6 tertile were more commonly male (56% versus 35%) and had higher creatinine (117±45 versus 101±36 μmol/L), hsCRP (11.6 [4.9-26.6]mg/L versus 2.3[1.1-4.2] mg/L). In univariable analysis, rates of all-cause death, cardiovascular death, and sHFH were higher in T3 versus T1. All-cause and cardiovascular death rates remained higher in T3 versus T1 after adjustment (<i>P</i><0.001). One log unit increase in IL-6 was associated with higher risk of all-cause death (hazard ratio, 1.46 [1.17-1.81]), cardiovascular death (hazard ratio, 1.40 [1.10-1.77]), and sHFH (hazard ratio, 1.24 [1.01-1.51]) after adjustment. One log unit increase in hsCRP was associated with a higher risk of cardiovascular death and all-cause death before and after adjustment for other factors but was not associated with risk of sHFH before or after adjustment.<br /><b>Conclusions</b><br />In patients recently hospitalized with heart failure with preserved ejection fraction, IL-6 is an independent predictor of all-cause mortality, cardiovascular death, and sHFH after adjustment for risk factors including BNP. These findings are of particular relevance in the context of current anti-IL-6 drug development.<br /><br /><br /><br /><small>Circ Heart Fail: 10 Mar 2023:e010051; epub ahead of print</small></div>

<div><h4>In-Hospital Observation on Oral Diuretics After Treatment for Acute Decompensated Heart Failure: Evaluating the Utility.</h4><i>Ivey-Miranda JB, Rao VS, Cox ZL, Moreno-Villagomez J, ... Krumholz HM, Testani JM</i><br /><b>Background</b><br />Following treatment for acute decompensated heart failure, in-hospital observation on oral diuretics (OOD) is recommended, assuming it provides actionable information on discharge diuretic dosing and thus reduces readmissions.<br /><b>Methods</b><br />In the Mechanisms of Diuretic Resistance (MDR) cohort, we analyzed in-hospital measures of diuretic response, provider\'s decisions, and diuretic response ≈30 days postdischarge. In a Yale multicenter cohort, we assessed if in-hospital OOD was associated with 30-day readmission risk. The main objective of this study was to evaluate the utility of in-hospital OOD.<br /><b>Results</b><br />Of the 468 patients in the MDR cohort, 57% (N=265) underwent in-hospital OOD. During the OOD, weight change and net fluid balance correlated poorly with each other (<i>r</i>=0.36). Discharge diuretic dosing was similar between patients who had increased, stable, or decreased weight (decreased discharge dose from OOD dose in 77% versus 72% versus 70%, respectively), net fluid status (decreased discharge dose from OOD dose in 100% versus 69% versus 74%, respectively), and urine output (decreased discharge dose from OOD dose in 69% versus 79% versus 72%, respectively) during the 24-hour OOD period (<i>P</i>>0.27 for all). In participants returning at 30 days for formal quantification of outpatient diuretic response (n=98), outpatient and inpatient OOD natriuresis was poorly correlated (<i>r</i>=0.26). In the Yale multicenter cohort (n=18 454 hospitalizations), OOD occurred in 55% and was not associated with 30-day hospital readmission (hazard ratio, 0.98 [95% CI, 0.93-1.05]; <i>P</i>=0.51).<br /><b>Conclusions</b><br />In-hospital OOD did not provide actionable information on diuretic response, was not associated with outpatient dose selection, did not predict subsequent outpatient diuretic response, and was not associated with lower readmission rate. Additional research is needed to replicate these findings and understand if these resources could be better allocated elsewhere.<br /><b>Registration</b><br />URL: https://www.<br /><b>Clinicaltrials</b><br />gov; Unique identifier: NCT02546583.<br /><br /><br /><br /><small>Circ Heart Fail: 10 Mar 2023:e010206; epub ahead of print</small></div>

<div><h4>Circulating MicroRNAs Identify Early Phenotypic Changes in Sarcomeric Hypertrophic Cardiomyopathy.</h4><i>Sucharov CC, Neltner B, Pietra AE, Karimpour-Fard A, ... Ho CY, Miyamoto SD</i><br /><b>Background</b><br />Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. Pathogenic germline variation in genes encoding the sarcomere is the predominant cause of disease. However diagnostic features, including unexplained left ventricular hypertrophy, typically do not develop until late adolescence or after. The early stages of disease pathogenesis and the mechanisms underlying the transition to a clinically overt phenotype are not well understood. In this study, we investigated if circulating microRNAs (miRNAs) could stratify disease stage in sarcomeric HCM.<br /><b>Methods</b><br />We performed arrays for 381 miRNAs using serum from HCM sarcomere variant carriers with and without a diagnosis of HCM and healthy controls. To identify differentially expressed circulating miRNAs between groups, multiple approaches were used including random forest, Wilcoxon rank sum test, and logistic regression. The abundance of all miRNAs was normalized to miRNA-320.<br /><b>Results</b><br />Of 57 sarcomere variant carriers, 25 had clinical HCM and 32 had subclinical HCM with normal left ventricular wall thickness (21 with early phenotypic manifestations and 11 with no discernible phenotypic manifestations). Circulating miRNA profile differentiated healthy controls from sarcomere variant carriers with subclinical and clinical disease. Additionally, circulating miRNAs differentiated clinical HCM from subclinical HCM without early phenotypic changes; and subclinical HCM with and without early phenotypic changes. Circulating miRNA profiles did not differentiate clinical HCM from subclinical HCM with early phenotypic changes, suggesting biologic similarity between these groups.<br /><b>Conclusions</b><br />Circulating miRNAs may augment the clinical stratification of HCM and improve understanding of the transition from health to disease in sarcomere gene variant carriers.<br /><br /><br /><br /><small>Circ Heart Fail: 07 Mar 2023:e010291; epub ahead of print</small></div>

<div><h4>Exposure to Arterial Hyperoxia During Extracorporeal Membrane Oxygenator Support and Mortality in Patients with Cardiogenic Shock.</h4><i>Jentzer JC, Miller PE, Alviar C, Yalamuri S, Bohman JK, Tonna JE</i><br /><AbstractText><b>Background:</b> Exposure to hyperoxia, a high arterial partial pressure of oxygen (PaO2), may be associated with worse outcomes in patients receiving extracorporeal membrane oxygenator (ECMO) support. We examined hyperoxia in the Extracorporeal Life Support Organization (ELSO) Registry among patients receiving venoarterial (VA) ECMO for cardiogenic shock (CS). <br /><b>Methods:</b><br/>We included ELSO Registry patients from 2010 to 2020 who received VA ECMO for CS, excluding extracorporeal CPR. Patients were grouped based on PaO2 after 24 hours of ECMO: normoxia (PaO2 60-150 mmHg), mild hyperoxia (PaO2 151-300 mmHg), and severe hyperoxia (PaO2 >300 mmHg). In-hospital mortality was evaluated using multivariable logistic regression. <br /><b>Results:</b><br/>Among 9959 patients, 3005 (30.2%) patients had mild hyperoxia and 1972 (19.8%) had severe hyperoxia. In-hospital mortality increased across groups: normoxia, 47.8%; mild hyperoxia, 55.6% (adjusted OR 1.37, 95% CI 1.23-1.53, p <0.001); severe hyperoxia, 65.4% (adjusted OR 2.20, 95% CI 1.92-2.52, p <0.001). A higher PaO2 was incrementally associated with increased in-hospital mortality (adjusted OR 1.14 per 50 mmHg higher, 95% CI 1.12-1.16, p <0.001). Patients with a higher PaO2 had increased in-hospital mortality in each subgroup and when stratified by ventilator settings, airway pressures, acid-base status, and other clinical variables. Higher PaO2 was the second strongest predictor of in-hospital mortality, after older age. <b>Conclusions:</b> Exposure to hyperoxia during VA ECMO support for CS is strongly associated with increased in-hospital mortality, independent from hemodynamic and ventilatory status. Until clinical trial data are available, we suggest targeting a normal PaO2 and avoiding hyperoxia in CS patients receiving VA ECMO.</AbstractText><br /><br /><br /><br /><small>Circ Heart Fail: 05 Mar 2023; epub ahead of print</small></div>