Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).

Effects of Empagliflozin in Women and Men With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). METHODS: The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed. RESULTS: Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; Pinteraction=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; Pinteraction=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score. CONCLUSIONS: Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03057951.

Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).

A randomized controlled trial of renin-angiotensin-aldosterone system inhibitor management in patients admitted in hospital with COVID-19.

BACKGROUND: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection coronavirus disease 2019 (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes. METHODS: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-to-treat principle. RESULTS: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); P = .60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06-2.62]; P = .027); RAASi discontinuation increased brain natriuretic peptide levels (% change from baseline: +16.7% vs -27.5%; P = .024) and the incidence of acute heart failure (33% vs 4.2%, P = .016). CONCLUSION: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased brain natriuretic peptide levels and may increase risk of acute heart failure; where possible, RAASi should be continued.

Empagliflozin and health-related quality of life outcomes in patients with heart failure with reduced ejection fraction: the EMPEROR-Reduced trial.

AIMS: In this secondary analysis of the EMPEROR-Reduced trial, we sought to evaluate whether the benefits of empagliflozin varied by baseline health status and how empagliflozin impacted patient-reported outcomes in patients with heart failure with reduced ejection fraction. METHODS AND RESULTS: Health status was assessed by the Kansas City Cardiomyopathy Questionnaires-clinical summary score (KCCQ-CSS). The influence of baseline KCCQ-CSS (analyzed by tertiles) on the effect of empagliflozin on major outcomes was examined using Cox proportional hazards models. Responder analyses were performed to assess the odds of improvement and deterioration in KCCQ scores related to treatment with empagliflozin. Empagliflozin reduced the primary outcome of cardiovascular death or heart failure hospitalization regardless of baseline KCCQ-CSS tertiles [hazard ratio (HR) 0.83 (0.68-1.02), HR 0.74 (0.58-0.94), and HR 0.61 (0.46-0.82) for <62.5, 62.6-85.4, and ≥85.4 score tertiles, respectively; P-trend = 0.10]. Empagliflozin improved KCCQ-CSS, total symptom score, and overall summary score at 3, 8, and 12 months. More patients on empagliflozin had ≥5-point [odds ratio (OR) 1.20 (1.05-1.37)], 10-point [OR 1.26 (1.10-1.44)], and 15-point [OR 1.29 (1.12-1.48)] improvement and fewer had ≥5-point [OR 0.75 (0.64-0.87)] deterioration in KCCQ-CSS at 3 months. These benefits were sustained at 8 and 12 months and were similar for other KCCQ domains. CONCLUSION: Empagliflozin improved cardiovascular death or heart failure hospitalization risk across the range of baseline health status. Empagliflozin improved health status across various domains, and this benefit was sustained during long-term follow-up. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03057977.

Prediction of heart failure outcomes in patients with type 2 diabetes mellitus: Validation of the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM ) in patients in the ACCORD trial.

AIM: To investigate the ability of the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM ) to stratify patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk for heart failure (HF) hospitalization. MATERIALS AND METHODS: We used data from the control group of the Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) trial (n = 5123; mean follow-up 4.8 years). The TRS-HFDM includes: prior HF (2 points), atrial fibrillation (1 point), coronary artery disease (1 point), estimated glomerular filtration rate <60 mL/min/1.73 m2 (1 point), and urine albumin-to-creatinine ratio (>300 mg/g: 2 points; 30-300 mg/g: 1 point). We evaluated the discrimination (Harrell's C-index) and calibration (Nam-D'Agostino calibration statistic) of the TRS-HFDM with regard to time to HF hospitalization or death due to HF. RESULTS: The mean age of the participants was 62.8 ± 6.6 years, and 38% were women. The prevalences of TRS-HFDM 0, 1, 2, 3 and ≥4 were 42.1%, 34.9%, 14.6%, 6.0% and 2.5%, respectively. Increasing TRS-HFDM corresponded to an increasing HF risk: 1.3 per 1000 person-years for a TRS-HFDM of 0 to 64.7 per 1000 person-years for TRS-HFDM of ≥4. The TRS-HFDM demonstrated robust discrimination of HF outcomes (C-index 0.78). Furthermore, the score was well calibrated for HF outcomes (calibration statistic P = 0.13). Similar results were seen in participants without baseline HF (C-index 0.75). CONCLUSION: The TRS-HFDM discriminates HF-specific risk among people with T2DM. The use of TRS-HFDM to identify those who would maximally benefit from therapies that reduce HF risk warrants evaluation.

Clinical Phenotypes in Patients With Type 2 Diabetes Mellitus: Characteristics, Cardiovascular Outcomes and Treatment Strategies.

PURPOSE OF REVIEW: With recent advances in the pharmacological management of type 2 diabetes mellitus (T2DM), there is a growing need to understand which patients optimally benefit from these novel therapies. Various clinical clustering methodologies have emerged that utilise data-agnostic strategies to categorise patients that have similar clinical characteristics and outcomes; broadly, this characterisation is termed phenotyping. In patients with T2DM, we aimed to describe patient characteristics from phenotype studies, their cardiovascular risk profiles and the impact of antihyperglycemic treatment. RECENT FINDINGS: Numerous phenotypic studies have been undertaken that have utilised a combination of clinical, biochemical, imaging and genetic variables. Each of these has produced phenotypes that display a spectrum of cardiovascular risk. Studies that aimed to describe pathophysiological phenotypes generally identified five phenotypes: autoimmune phenotype, insulin-related phenotypes (including permutations of insulin deficiency and resistance), obesity phenotype, ageing phenotype, and a sex-related phenotype. Studies examining risk profiles have demonstrated that across such phenotypes there is a spectrum of risk for diabetic complications. Few studies have examined treatment effects across these phenotypes, and thus provide little insights towards making phenotype-guided treatment decisions Clustering analyses in patients with T2DM have identified distinct phenotypes with unique risk profiles. Further studies are needed that harness the use of clinical, biochemical, imaging and genetic data to explore therapeutic heterogeneity and response to antihyperglycemic treatment across the spectrum of patient phenotypes.

Pregnancy after heart transplantation: a well-thought-out decision? The Quebec provincial experience - a multi-centre cohort study.

Despite reports of successful pregnancies in heart transplant (HTx) recipients, many centers recommend their patients against maternity. We reviewed our provincial experience of pregnancy in HTx recipients by performing charts review of all known gestations following HTx in the province of Quebec (Canada), stratified between planned and unplanned pregnancies. Long-term survival was compared to HTx recipient women of childbearing age who did not become pregnant. Eighteen pregnancies, 56% unplanned, occurred in eight patients, 10.1 (2.6-27.0) years after HTx. Immunosuppression was CNI-based, with a mean dose increase of 48.3% (tacrolimus) and 26.5% (cyclosporine), without rejection. Cardiometabolic complications were high compared to the general Canadian population, including preeclampsia (15.4% vs. 5.5%), hypertension (38.5% vs. 4.6%), and diabetes (15.4% vs. 5.6%). Mean gestational age was 35.1 (23.4-39.6) weeks (72.2% live births; 53.8% prematurity). Mean birthweight was 2418 (660-3612) g. Serum creatinine increased during pregnancy, becoming significant after delivery (P = 0.0239), and returning to preconception level in all but three patients within a year. After 4.6 (1.2-17.2) years of follow-up, two rejection episodes occurred in one patient. Long-term mortality was similar to overall HTx women (Kaplan-Meier; P = 0.8071). Pregnancy in HTx carries high cardiometabolic complications and decreased kidney function, but is feasible with acceptable outcomes and no impact on mother's survival.

A qualitative study of the current state of heart failure community care in Canada: what can we learn for the future?

BACKGROUND: In North America and other industrialized countries, heart failure (HF) has become a national public health priority. Studies indicate there is significant heterogeneity in approaches to treat and manage HF and suggest targeted changes in health care delivery are needed to reduce unnecessary health care utilization and to optimize patient outcomes. Most recent published studies have reported on the care of HF patients in tertiary care hospitals and the perspective of non-specialist stakeholders on HF management, such as general practitioners and clinics or hospital administrators is rarely considered. This study explores the current state of community-based HF care in Canada as experienced by various healthcare stakeholders providing or coordinating care to HF patients. METHODS: This study employed a qualitative exploratory research design consisting of semi-structured telephone interviews conducted with health care providers and health care administrators working outside of tertiary care in the four most populous Canadian provinces. A modified thematic analysis process was used and the different data sources were triangulated. Findings were collectively interpreted by the authors. RESULTS: Twenty-eight participants were recruited in the study: eight cardiologists, five general practitioners/family physicians, eight nurse practitioners/registered nurses, four hospital pharmacists and three health care administrators/directors. Participants reported a lack of stakeholder engagement throughout the continuum of care, which hinders the implementation of a coordinated approach to quality HF care. Four substantive themes emerged that indicated challenges and gaps in the optimal treatment and management of HF in community settings: 1) challenges in the risk assessment and early diagnosis of HF, 2) challenges in ensuring efficient and consistent transition from acute care setting to the community, 3) challenges of primary care providers to optimally treat and manage HF patients, and 4) challenges in promoting a holistic approach in HF management. CONCLUSIONS: As health systems evolve from tertiary-based care to community-based outpatient services for the management of chronic diseases, this study's findings pinpoint challenges that have been observed in the Canadian context and can stimulate and orient dialogue toward solutions for a more coordinated approach to improve the care of HF patients and reduce pressure on the healthcare system.

Spontaneous coronary artery dissection: a difficult journey from emergency coronary artery bypass grafting to left ventricular assist device.

Background: Excluding spontaneous coronary artery dissection (SCAD) as an aetiology of acute coronary syndrome in young adults is imperative. Case summary: A previously healthy 39-year-old woman experienced sudden severe chest pain, ST-segment elevation on electrocardiogram, necessitating high-dose aspirin and urgent transfer to a revascularization centre. Suffering ventricular tachycardia (VT) and ventricular fibrillation (VF), she underwent two rounds of advanced life support and venoarterial extracorporeal membrane oxygenation. Diagnosed with left main coronary artery (LMCA) SCAD, she was initially started on conservative therapy for declining left ventricular ejection fraction. However, she continued to experience an escalating anginal symptoms, worsening biomarkers, and LMCA SCAD progression, which urged the need for surgical intervention with coronary artery bypass graft surgery (CABG). Following her CABG, she experienced a worsening of her functional mitral regurgitating, which she underwent transcatheter edge-to-edge repair of her severe mitral regurgitation. Despite being listed for orthotopic heart transplantation (OHTx), her low body mass index and elevated antibodies necessitated the HeartMate III left ventricular assist device (LVAD) for bridge to transplant. After treating frequent VT episodes with medications, she eventually received a LVAD as a bridge to cardiac transplantation. Within 1 year of her receiving LVAD, she underwent a successful OHTx. Discussion: The pathogenesis of SCAD involves intramural haematoma formation through intimal tears or vasa vasorum haemorrhage. Adverse outcomes that could occur in SCAD patients include cardiac arrest, cardiogenic shock, reduced left ventricle systolic function, and occasionally serious cardiac arrhythmia-such as VF-which can lead to sudden cardiac death. Although most SCAD cases heal spontaneously, revascularization can be considered in case of worsening SCAD progression. Advanced therapeutic intervention including mechanical circulatory support and OHTx should be considered in refractory cases.

Factors Impacting Physician Prognostic Accuracy in Heart Failure Patients With Reduced Left Ventricular Ejection Fraction.

BACKGROUND: A recent study showed that the accuracy of heart failure (HF) cardiologists and family doctors to predict mortality in outpatients with HF proved suboptimal, performing less well than models. OBJECTIVES: The authors sought to evaluate patient and physician factors associated with physician accuracy. METHODS: The authors included outpatients with HF from 11 HF clinics. Family doctors and HF cardiologists estimated patient 1-year mortality. They calculated predicted mortality using the Seattle HF Model and followed patients for 1 year to record mortality (or urgent heart transplant or ventricular assist device implant as mortality-equivalent events). Using multivariable logistic regression, the authors evaluated associations among physician experience and confidence in estimates, duration of patient-physician relationship, patient-physician sex concordance, patient race, and predicted risk, with concordant results between physician and model predictions. RESULTS: Among 1,643 patients, 1-year event rate was 10% (95% CI: 8%-12%). One-half of the estimates showed discrepant results between model and physician predictions, mainly owing to physician risk overestimation. Discrepancies were more frequent with increasing patient risk from 38% in low-risk to ∼75% in high-risk patients. When making predictions on male patients, female HF cardiologists were 26% more likely to have discrepant predictions (OR: 0.74; 95% CI: 0.58-0.94). HF cardiologist estimates in Black patients were 33% more likely to be discrepant (OR: 0.67; 95% CI: 0.45-0.99). Low confidence in predictions was associated with discrepancy. Analyses restricted to high-confidence estimates showed inferior calibration to the model, with risk overestimation across risk groups. CONCLUSIONS: Discrepant physician and model predictions were more frequent in cases with perceived increased risk. Model predictions outperform physicians even when they are confident in their predictions. (Predicted Prognosis in Heart Failure [INTUITION]; NCT04009798).

Access to heart failure care post emergency department visit: do we meet established benchmarks and does it matter?

BACKGROUND: The Canadian Cardiology Society recommends that patients should be seen within 2 weeks after an emergency department (ED) visit for heart failure (HF). We sought to investigate whether patients who had an ED visit for HF subsequently consult a physician within the current established benchmark, to explore factors related to physician consultation, and to examine whether delay in consultation is associated with adverse events (AEs) (death, hospitalization, or repeat ED visit). METHODS: Patients were recruited by nurses at 8 hospital EDs in Québec, Canada, and interviewed by telephone within 6 weeks of discharge and subsequently at 3 and 6 months. Clinical variables were extracted from medical charts by nurses. We used Cox regression in the analysis. RESULTS: We enrolled 410 patients (mean age 74.9 ± 11.1 years, 53% males) with a confirmed primary diagnosis of HF. Only 30% consulted with a physician within 2 weeks post-ED visit. By 4 weeks, 51% consulted a physician. Over the 6-month follow-up, 26% returned to the ED, 25% were hospitalized, and 9% died. Patients who were followed up within 4 weeks were more likely to be older and have higher education and a worse quality of life. Patients who consulted a physician within 4 weeks of ED discharge had a lower risk of AEs (hazard ratio 0.59, 95% CI 0.35-0.99). CONCLUSION: Prompt follow-up post-ED visit for HF is associated with lower risk for major AEs. Therefore, adherence to current HF guideline benchmarks for timely follow-up post-ED visit is crucial.

Recurrent giant cell myocarditis following orthotopic heart transplant resulting in urgent redo orthotopic heart transplantation: a case report.

Background: Giant cell myocarditis (GCM) is a severe and rapidly progressing condition that can lead to end-stage heart failure. We present a case of a 51-year-old male with a history of orthotopic heart transplantation (OHTx) for GCM, who experienced recurrent GCM in the allograft, leading to progressive heart failure and the need for a second heart transplant. Case summary: A 51-year-old male with a history of OHTx for GCM presented with rapidly worsening heart failure symptoms. Despite initial stability, he deteriorated to cardiogenic shock and required intensive support. His clinical course was complicated by recurrent COVID-19 infections, worsened left ventricular ejection fraction, and withdrawal of guideline-directed medical therapy. Imaging showed extensive scar burden, and subsequent investigations ruled out coronary artery disease. With declining functional status and worsening cardiogenic shock, he was re-listed for OHTx and successfully underwent a second heart transplant. Discussion: Giant cell myocarditis poses challenges due to its aggressive nature. Early, aggressive immunosuppression and mechanical circulatory support are crucial. The recurrence rate of GCM post-OHTx is notable, often within the first year, and the optimal immunosuppressive regimen remains uncertain. In this case, GCM recurrence following OHTx led to continued deterioration despite treatment, necessitating a second heart transplant. This unique case emphasizes the complexity of managing recurrent GCM post-OHTx.

Measuring Single-Cell Calcium Dynamics Using a Myofilament-Localized Optical Biosensor in hiPSC-CMs Derived from DCM Patients.

Synchronized contractions of cardiomyocytes within the heart are tightly coupled to electrical stimulation known as excitation-contraction coupling. Calcium plays a key role in this process and dysregulated calcium handling can significantly impair cardiac function and lead to the development of cardiomyopathies and heart failure. Here, we describe a method and analytical technique to study myofilament-localized calcium signaling using the intensity-based fluorescent biosensor, RGECO-TnT. Dilated cardiomyopathy is a heart muscle disease that negatively impacts the heart's contractile function following dilatation of the left ventricle. We demonstrate how this biosensor can be used to characterize 2D hiPSC-CMs monolayers generated from a healthy control subject compared to two patients diagnosed with dilated cardiomyopathy. Lastly, we provide a step-by-step guide for single-cell data analysis and describe a custom Transient Analysis application, specifically designed to quantify features of calcium transients. All in all, we explain how this analytical approach can be applied to phenotype hiPSC-CM behaviours and stratify patient responses to identify perturbations in calcium signaling.

Comparison of Questionnaire and Performance-Based Physical Frailty Scales to Predict Survival and Health-Related Quality of Life in Patients With Heart Failure.

Background Frailty is prevalent in older adults with heart failure and is associated with poor outcomes; however, there remains uncertainty on how to measure frailty in clinical practice. Methods and Results A multicentric prospective cohort study was assembled at 4 heart failure clinics to compare the prognostic value of 3 physical frailty scales in ambulatory patients with heart failure. Outcomes were all-cause death or hospitalization and health-related quality of life using the 36-Item Short Form survey questionnaire (SF-36) at 3 months. Multivariable regression was adjusted for age, sex, Meta-Analysis Global Group in Chronic Heart Failure score, and baseline SF-36 score. The cohort included 215 patients (mean age 77.6 years). All 3 frailty scales were independently associated with death or hospitalization at 3 months; the adjusted odds ratios standardized per 1 SD worsening of the Short Physical Performance Battery; Fried, and strength, assistance with walking, rising from a chair, climbing stairs, and falls scales were 1.67 (95% CI, 1.09-2.55), 1.60 (95% CI, 1.04-2.46), and 1.55 (95% CI, 1.03-2.35), respectively, with C statistics of 0.77 to 0.78. All 3 frailty scales were independently associated with worsening SF-36 scores, especially the Short Physical Performance Battery, for which 1 SD worsening of frailty translated to a decrement of -5.86 (-8.55 to -3.17) and -5.51 (-7.82 to -3.21) points in the Physical Component Score and Mental Component Score. Conclusions All 3 physical frailty scales were associated with death, hospitalization, and reduced health-related quality of life in ambulatory patients with heart failure. Questionnaire or performance-based physical frailty scales can be used to offer prognostic value and a therapeutic target in this vulnerable population. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03887351.

Mobile Health Fitness Interventions: Impact of Features on Routine Use and Data Sharing Acceptability.

Background: Mobile health (mHealth) interventions are increasingly being used for cardiovascular research and physical activity promotion. Objectives: As a result, the authors aimed to evaluate which features facilitate and impede routine engagement with mobile fitness applications. Methods: We distributed a pan-Canadian online questionnaire via the behavioral research platform Prolific.co to evaluate what features are associated with the use and routine engagement (ie, daily or weekly use) of mHealth fitness applications and attitudes about data sharing. Binary logistic regression was used to quantify the association between these endpoints and exploratory factors such as the perceived utility of various mHealth application features. Results: The survey received 694 responses. Most people were women (62%), the median age was 28 years (range: 18-78 years), and most people reported current use of an mHealth fitness application (48%). The perceived importance of personal health (OR: 2.40; 95% CI: 1.34-4.50) was the factor most associated with the current use of an mHealth fitness application. The feature most associated with routine engagement was the ability to track progress toward a goal (OR: 5.10; 95% CI: 2.73-9.61) while the most significant barrier was the absence of goal customization features (OR: 0.44; 95% CI: 0.25-0.81). The acceptance of sharing health data for research was high (56%), and privacy concerns did not significantly affect routine engagement (OR: 0.81; 95% CI: 0.40-1.77). Results were consistent across race and gender. Conclusions: mHealth interventions have the potential to be scaled across populations. Optimizing applications to improve self-monitoring and personalization could increase routine engagement and, thus, user retention and intervention effectiveness.

Predicting 1-Year Mortality in Outpatients With Heart Failure With Reduced Left Ventricular Ejection Fraction: Do Empiric Models Outperform Physician Intuitive Estimates? A Multicenter Cohort Study.

BACKGROUND: Many studies have demonstrated that physicians often err in estimating patient prognosis. No studies have directly compared physician to model predictive performance in heart failure (HF). We aimed to compare the accuracy of physician versus model predictions of 1-year mortality. METHODS: This multicenter prospective cohort study on 11 HF clinics in 5 provinces in Canada included consecutive consented outpatients with HF with reduced left ventricular ejection fraction (<40%). By collecting clinical data, we calculated predicted 1-year mortality using the Seattle HF Model (SHFM), the Meta-Analysis Global Group in Chronic HF score, and the HF Meta-Score. HF cardiologists and family doctors, blinded to model predictions, estimated patient 1-year mortality. During 1-year follow-up, we recorded the composite end point of mortality, urgent ventricular assist device implant, or heart transplant. We compared physicians and model discrimination (C statistic), calibration (observed versus predicted event rate), and risk reclassification. RESULTS: The study included 1643 patients with ambulatory HF with a mean age of 65 years, 24% female, and mean left ventricular ejection fraction of 28%. Over 1-year follow-up, 9% had an event. The SHFM had the best discrimination (SHFM C statistic 0.76; HF Meta-Score 0.73; Meta-Analysis Global Group in Chronic Heart Failure 0.70) and calibration. Physicians' discrimination differed little (0.75 for HF cardiologists and 0.73 for family doctors) but both physician groups substantially overestimated risk by >10% in both low- and high-risk patients (poor calibration). In risk reclassification analysis, among patients without events, the SHFM better classified 51% in comparison to HF cardiologists and 43% in comparison to family doctors. In patients with events, the SHFM erroneously assigned lower risk to 44% in comparison to HF cardiologists and 34% in comparison to family doctors. CONCLUSIONS: Family doctors and HF cardiologists showed adequate risk discrimination, with however substantial overestimation of absolute risk. Predictive models showed higher accuracy. Incorporating models in family and HF cardiology practices may improve patient care and resource use in HF with reduced left ventricular ejection fraction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04009798.

Insights Into Myocardial Oxygenation and Cardiovascular Magnetic Resonance Tissue Biomarkers in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The pathophysiology of heart failure with preserved ejection fraction is not well understood, but evidence strongly suggests involvement of microvascular dysfunction. We studied the myocardial oxygenation reserve as a direct marker of coronary vascular function and its relation to myocardial deformation and tissue characteristics by cardiovascular magnetic resonance (CMR). METHODS: In a dual-center case-control study, patients with heart failure and preserved ejection fraction (>50%) and healthy controls older than 50 years underwent quantitative CMR for ventricular volumes and functional assessment with feature tracking, as well as tissue characterization (T1, T2, extracellular volume). Coronary vascular function was measured by oxygenation-sensitive (OS)-CMR of the myocardial oxygenation response to a vasoactive breathing maneuver. RESULTS: Twenty-nine patients completed the CMR exam. Compared with cutoffs derived from 12 control subjects, circumferential peak strain was attenuated in 97% of patients. Native T1 was elevated in 93%, extracellular volume was elevated in 83%. Sixty-six percent of patients revealed either regional or global myocardial edema, defined by an increased myocardial T2. An attenuated global myocardial oxygenation reserve (<4.4%) was observed in 96% of the patients (1.7±3.9% versus 9.1±5.3% in controls, P<0.001). This was correlated with septal wall thickness (r=-0.54, P=0.003), edema (myocardial T2; ß=-0.26% oxygenation-sensitive/ms [95% CI, -0.49 to -0.03], P=0.029), and reduced diastolic strain rate (ß=1.50% oxygenation-sensitive/s-1 [95% CI, 0.06-2.90], P=0.042). CONCLUSIONS: In patients with clinical heart failure with preserved ejection fraction, vascular dysfunction as measured by an attenuated myocardial oxygenation reserve is associated with myocardial edema, a thicker septum, and diastolic dysfunction. A quantitative comprehensive CMR exam including oxygenation-sensitive-CMR allows for comprehensive imaging-based phenotyping of heart failure with preserved ejection fraction.

Clinical Prediction Models for Heart Failure Hospitalization in Type 2 Diabetes: A Systematic Review and Meta-Analysis.

Background Clinical prediction models have been developed for hospitalization for heart failure in type 2 diabetes. However, a systematic evaluation of these models' performance, applicability, and clinical impact is absent. Methods and Results We searched Embase, MEDLINE, Web of Science, Google Scholar, and Tufts' clinical prediction registry through February 2021. Studies needed to report the development, validation, clinical impact, or update of a prediction model for hospitalization for heart failure in type 2 diabetes with measures of model performance and sufficient information for clinical use. Model assessment was done with the Prediction Model Risk of Bias Assessment Tool, and meta-analyses of model discrimination were performed. We included 15 model development and 3 external validation studies with data from 999 167 people with type 2 diabetes. Of the 15 models, 6 had undergone external validation and only 1 had low concern for risk of bias and applicability (Risk Equations for Complications of Type 2 Diabetes). Seven models were presented in a clinically useful manner (eg, risk score, online calculator) and 2 models were classified as the most suitable for clinical use based on study design, external validity, and point-of-care usability. These were Risk Equations for Complications of Type 2 Diabetes (meta-analyzed c-statistic, 0.76) and the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (meta-analyzed c-statistic, 0.78), which was the simplest model with only 5 variables. No studies reported clinical impact. Conclusions Most prediction models for hospitalization for heart failure in patients with type 2 diabetes have potential concerns with risk of bias or applicability, and uncertain external validity and clinical impact. Future research is needed to address these knowledge gaps.

Efficacy of empagliflozin in heart failure with preserved versus mid-range ejection fraction: a pre-specified analysis of EMPEROR-Preserved.

The EMPEROR-Preserved trial showed that the sodium-glucose co-transporter 2 inhibitor empagliflozin significantly reduces the risk of cardiovascular death or hospitalization for heart failure (HHF) in heart failure patients with left ventricular ejection fraction (LVEF) > 40%. Here, we report the results of a pre-specified analysis that separately evaluates these patients stratified by LVEF: preserved (≥ 50%) (n = 4,005; 66.9%) or mid-range (41-49%). In patients with LVEF ≥ 50%, empagliflozin reduced the risk of cardiovascular death or HHF (the primary endpoint) by 17% versus placebo (hazard ratio (HR) 0.83; 95% confidence interval (CI): 0.71-0.98, P = 0.024). For the key secondary endpoint, the HR for total HHF was 0.83 (95%CI: 0.66-1.04, P = 0.11). For patients with an LVEF of 41-49%, the HR for empagliflozin versus placebo was 0.71 (95%CI: 0.57-0.88, P = 0.002) for the primary outcome (Pinteraction = 0.27), and 0.57 (95%CI: 0.42-0.79, P < 0.001) for total HHF (Pinteraction = 0.06). These results, together with those from the EMPEROR-Reduced trial in patients with LVEF < 40%, support the use of empagliflozin across the full spectrum of LVEF in heart failure.