Randomized Trial of a Selective Aldose Reductase Inhibitor in Patients With Diabetic Cardiomyopathy.

BACKGROUND: Progression to symptomatic heart failure is a complication of type 2 diabetes; heart failure onset in this setting is commonly preceded by deterioration in exercise capacity. OBJECTIVES: The study sought to determine whether AT-001, a highly selective aldose reductase inhibitor, can stabilize exercise capacity among individuals with diabetic cardiomyopathy (DbCM) and reduced peak oxygen uptake (Vo2). METHODS: A total of 691 individuals with DbCM meeting inclusion and exclusion criteria were randomized to receive placebo or ascending doses of AT-001 twice daily. Stratification at inclusion included region of enrollment, cardiopulmonary exercise test results, and use of sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists. The primary endpoint was proportional change in peak Vo2 from baseline to 15 months. Subgroup analyses included measures of disease severity and stratification variables. RESULTS: The mean age was 67.5 ± 7.2 years, and 50.4% of participants were women. By 15 months, peak Vo2 fell in the placebo-treated patients by -0.31 mL/kg/min (P = 0.005 compared to baseline), whereas in those receiving high-dose AT-001, peak Vo2 fell by -0.01 mL/kg/min (P = 0.21); the difference in peak Vo2 between placebo and high-dose AT-001 was 0.30 (P = 0.19). In prespecified subgroup analyses among those not receiving sodium-glucose cotransporter 2 inhibitors or glucagon-like peptide-1 receptor agonists at baseline, the difference between peak Vo2 in placebo vs high-dose AT-001 at 15 months was 0.62 mL/kg/min (P = 0.04; interaction P = 0.10). CONCLUSIONS: Among individuals with DbCM and impaired exercise capacity, treatment with AT-001 for 15 months did not result in significantly better exercise capacity compared with placebo. (Safety and Efficacy of AT-001 in Patients With Diabetic Cardiomyopathy [ARISE-HF]; NCT04083339).

The Wallet Biopsy: Medical Crowdfunding for Heart Transplantation.

Financial considerations continue to impact access to heart transplantation. Transplant recipients face various costs, including, but not limited to, the index hospitalization, immunosuppressive medications, and lodging and travel to appointments. In this study, we sought to describe the state of crowdfunding for individuals being evaluated for heart transplantation. Using the search term heart transplant, 1000 GoFundMe campaigns were reviewed. After exclusions, 634 (63.4%) campaigns were included. Most campaigns were in support of white individuals (57.8%), males (63.1%) and adults (76.7%). Approximately 15% of campaigns had not raised any funds. The remaining campaigns fundraised a median of $53.24 dollars per day. Of the patients, 44% were admitted at the time of the fundraising. Within the campaigns in the United States, the greatest proportions were in the Southeast United States in non-Medicaid expansion states. These findings highlight the significant financial toxicities associated with heart transplantation and the need for advocacy at the governmental and payer levels to improve equitable access and coverage for all.

Implementation Science to Achieve Equity in Heart Failure Care: A Scientific Statement From the American Heart Association.

Guideline-directed medical therapies and guideline-directed nonpharmacological therapies improve quality of life and survival in patients with heart failure (HF), but eligible patients, particularly women and individuals from underrepresented racial and ethnic groups, are often not treated with these therapies. Implementation science uses evidence-based theories and frameworks to identify strategies that facilitate uptake of evidence to improve health. In this scientific statement, we provide an overview of implementation trials in HF, assess their use of conceptual frameworks and health equity principles, and provide pragmatic guidance for equity in HF. Overall, behavioral nudges, multidisciplinary care, and digital health strategies increased uptake of therapies in HF effectively but did not include equity goals. Few HF studies focused on achieving equity in HF by engaging stakeholders, quantifying barriers and facilitators to HF therapies, developing strategies for equity informed by theory or frameworks, evaluating implementation measures for equity, and titrating strategies for equity. Among these HF equity studies, feasibility was established in using various educational strategies to promote organizational change and equitable care. A couple include ongoing randomized controlled pragmatic trials for HF equity. There is great need for additional HF implementation trials designed to promote delivery of equitable guideline-directed therapy.

Characterizing diabetic cardiomyopathy: baseline results from the ARISE-HF trial.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM. METHODS: Among study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified. RESULTS: Among 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [6, 12] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy. CONCLUSIONS: Baseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM. TRIAL REGISTRATION: ARISE-HF, NCT04083339.

Left Ventricular Ejection Fraction and the Future of Heart Failure Phenotyping.

Heart failure (HF) is a complex syndrome traditionally classified by left ventricular ejection fraction (LVEF) cutpoints. Although LVEF is prognostic for risk of events and predictive of response to some HF therapies, LVEF is a continuous variable and cutpoints are arbitrary, often based on historical clinical trial enrichment decisions rather than physiology. Holistic evaluation of the treatment effects for therapies throughout the LVEF range suggests the standard categorization paradigm for HF merits modification. The multidisciplinary Heart Failure Collaboratory reviewed data from large-scale HF clinical trials and found that many HF therapies have demonstrated therapeutic benefit across a large range of LVEF, but specific treatment effects vary across that range. Therefore, HF should practically be classified by association with an LVEF that is reduced or not reduced, while acknowledging uncertainty around the precise LVEF cutpoint, and future research should evaluate new therapies across the continuum of LVEF.

Achieving Health Equity in the Care of Patients with Heart Failure.

PURPOSE OF REVIEW: To discuss the prevailing racial and ethnic disparities in heart failure (HF) care by identifying barriers to equitable care and proposing solutions for achieving equitable outcomes. RECENT FINDINGS: Throughout the entire spectrum of HF care, from prevention to implementation of guideline-directed medical therapy and advanced interventions, racial and ethnic disparities exist. Factors such as differential distribution of risk factors, poor access to care, inadequate representation in clinical trials, and discrimination from healthcare clinicians, among others, contribute to these disparities. Recent data suggests that despite improvements, disparities prevail in several aspects of HF care, hindering our progress towards equity in HF care. This review highlights the urgent need to address racial and ethnic disparities in HF care, emphasizing the importance of a multifaceted approach involving policy changes, quality improvement strategies, targeted interventions, and intentional community engagement. Our proposed framework was derived from existing research and emphasizes integrating equity into routine quality improvement efforts, tailoring interventions to specific populations, and advocating for policy transformation. By acknowledging these disparities, implementing evidence-based strategies, and fostering collaborative efforts, the HF community can strive to reduce disparities and achieve equity in HF care.

Temporal Changes in Racial and Ethnic Disparities in the Utilization of Left Atrial Appendage Occlusion in the United States.

Racial and ethnic disparities in the access to left atrial appendage occlusion (LAAO) have been previously described. However, it remains unclear if there have been any changes in these disparities over the years and if the disparities include other racial and ethnic groups not previously studied. We aimed to determine the temporal evolution of the racial and ethnic disparities in the utilization of LAAO from 2016 to 2019. We conducted a retrospective cohort study using the National Inpatient Sample from 2016 to 2019. International Classification of Diseases, 10th edition codes were used to identify all adult admissions with atrial fibrillation (AF) and those who underwent LAAO. The sample was divided into Asian American and Pacific Islander, Black, Hispanic, White, and other races/ethnicities. Our primary outcome was the utilization of LAAO in patients admitted with a diagnosis of AF. The Cochran-Armitage test was conducted to evaluate the yearly trend in LAAO utilization stratified by race/ethnicity. Multivariable regression analysis was conducted to assess the association of race/ethnicity with multiple end points. A total of 59,415 patients underwent LAAO. The highest yearly increase in LAAO utilization was seen in White patients (trend: 0.16%, p <0.001). Furthermore, compared with White patients, the yearly increase in LAAO utilization was lower in all other racial/ethnic groups. Black patients had the lowest odds of who underwent LAAO (odds ratio = 0.45, 95% confidence interval 0.40 to 0.50, p <0.001). In conclusion, significant gaps exist in the utilization of LAAO between racial and ethnic groups, and they appear to continue worsening from 2016 to 2019.

Race-Based Differences in ST-Segment-Elevation Myocardial Infarction Process Metrics and Mortality From 2015 Through 2021: An Analysis of 178 062 Patients From the American Heart Association Get With The Guidelines-Coronary Artery Disease Registry.

BACKGROUND: Systems of care have been developed across the United States to standardize care processes and improve outcomes in patients with ST-segment-elevation myocardial infarction (STEMI). The effect of contemporary STEMI systems of care on racial and ethnic disparities in achievement of time-to-treatment goals and mortality in STEMI is uncertain. METHODS: We analyzed 178 062 patients with STEMI (52 293 women and 125 769 men) enrolled in the American Heart Association Get With The Guidelines-Coronary Artery Disease registry between January 1, 2015, and December 31, 2021. Patients were stratified into and outcomes compared among 3 racial and ethnic groups: non-Hispanic White, Hispanic White, and Black. The primary outcomes were the proportions of patients achieving the following STEMI process metrics: prehospital ECG obtained by emergency medical services; hospital arrival to ECG obtained within 10 minutes for patients not transported by emergency medical services; arrival-to-percutaneous coronary intervention time within 90 minutes; and first medical contact-to-device time within 90 minutes. A secondary outcome was in-hospital mortality. Analyses were performed separately in women and men, and all outcomes were adjusted for age, comorbidities, acuity of presentation, insurance status, and socioeconomic status measured by social vulnerability index based on patients' county of residence. RESULTS: Compared with non-Hispanic White patients with STEMI, Hispanic White patients and Black patients had lower odds of receiving a prehospital ECG and achieving targets for door-to-ECG, door-to-device, and first medical contact-to-device times. These racial disparities in treatment goals were observed in both women and men, and persisted in most cases after multivariable adjustment. Compared with non-Hispanic White women, Hispanic White women had higher adjusted in-hospital mortality (odds ratio, 1.39 [95% CI, 1.12-1.72]), whereas Black women did not (odds ratio, 0.88 [95% CI, 0.74-1.03]). Compared with non-Hispanic White men, adjusted in-hospital mortality was similar in Hispanic White men (odds ratio, 0.99 [95% CI, 0.82-1.18]) and Black men (odds ratio, 0.96 [95% CI, 0.85-1.09]). CONCLUSIONS: Race- or ethnicity-based disparities persist in STEMI process metrics in both women and men, and mortality differences are observed in Hispanic White compared with non-Hispanic White women. Further research is essential to evolve systems of care to mitigate racial differences in STEMI outcomes.

Organ Donation and Transplantation among Non-US Citizens: Opportunities to Improve Global Equity in Heart Transplantation.

BACKGROUND: Non-US citizens/non-US residents (NCNR) are a unique and growing population. Patterns of heart donation and heart transplantation (HT) within this subgroup have not been described fully. The purpose of this study was to evaluate the use of organs from NCNR donors and the characteristics and outcomes of NCNR HT recipients. METHODS: All adult donors whose hearts were recovered for HT and all primary adult HT recipients from 2013 to 2020 were identified using the United Network for Organ Sharing. Donors and recipients were categorized as citizens, residents, or NCNR. NCNR were further categorized by reason for travel to the United States. Outcomes included mortality, infection, and rejection at 1-year after transplantation. RESULTS: NCNR accounted for 0.4% (n = 77) of heart donors. Most NCNR donors identified as Hispanic (61%), were predominately recovered from the South and Southwest United States, and were less likely to express written documentation to be a donor compared with citizens and residents. NCNR accounted for 0.7% (n = 147) of all HT recipients. The majority identified as non-Hispanic White individuals (57.1%). Compared with citizens and residents, NCNR recipients seemed to be sicker, as evidenced by higher intra-aortic balloon pump use before HT and higher priority United Network for Organ Sharing status. Of NCNR recipients, 63% traveled to the United States for HT, predominately from Kuwait (29.9%) and Saudi Arabia (20%). At 1-year after transplant, there were no differences in mortality, infection, or rejection between the groups. CONCLUSIONS: A growing subgroup of NCNR travel from countries with low HT rates to the United States for HT. This finding highlights the need for strategies to improve equitable access to HT domestically and abroad.

Rationale and design of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure Trial (ARISE-HF) in patients with high-risk diabetic cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is a specific form of heart muscle disease that may result in substantial morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). Hyperactivation of the polyol pathway is one of the primary mechanisms in the pathogenesis of diabetic complications, including development of DbCM. There is an unmet need for therapies targeting the underlying metabolic abnormalities that drive this form of Stage B heart failure (HF). METHODS: Aldose reductase (AR) catalyzes the first and rate-limiting step in the polyol pathway, and AR inhibition has been shown to reduce diabetic complications, including DbCM in animal models and in patients with DbCM. Previous AR inhibitors (ARIs) were limited by poor specificity resulting in unacceptable tolerability and safety profile. AT-001 is a novel investigational highly specific ARI with higher binding affinity and greater selectivity than previously studied ARIs. ARISE-HF (NCT04083339) is an ongoing Phase 3 randomized, placebo-controlled, double blind, global clinical study to investigate the efficacy of AT-001 (1000 mg twice daily [BID] and 1500 mg BID) in 675 T2DM patients with DbCM at high risk of progression to overt HF. ARISE-HF assesses the ability of AT-001 to improve or prevent decline in exercise capacity as measured by functional capacity (changes in peak oxygen uptake [peak VO2]) over 15 (and possibly 27) months of treatment. Additional endpoints include percentage of patients progressing to overt HF, health status metrics, echocardiographic measurements, and changes in cardiacbiomarkers. RESULTS: The ARISE-HF Trial is fully enrolled. CONCLUSIONS: This report describes the rationale and study design of ARISE-HF.

Sex-Related Differences in Patient Characteristics, Hemodynamics, and Outcomes of Cardiogenic Shock: INOVA-SHOCK Registry.

Background: Little is known about sex-related differences in outcomes of patients with cardiogenic shock (CS) treated within a standardized team-based approach (STBA). Methods: We evaluated 520 consecutive patients (151 women and 369 men) with CS due to acute myocardial infarction (AMI) and heart failure (HF) in a single-center registry (January 2017-December 2019) and examined outcomes according to sex and CS phenotype. The primary outcome was in-hospital mortality. Secondary outcomes included major adverse cardiac events, 30-day mortality, major bleeding, vascular complications, and stroke. Results: Women with AMI-CS had higher baseline acuity (CardShock score: female [F]: 5.5 vs male [M]: 4.0; P = .04). Women with HF-CS more often presented with cardiac arrest (F: 12.4% vs M: 2.4%; P< .01) and had higher rates of vasopressor use (F: 70.8% vs M: 58.0%; P = .04) and mechanical circulatory support (F: 46.1% vs M: 32.5%; P = .04). There were no sex-related differences in in-hospital mortality for AMI-CS (F: 45.2% vs M: 36.9%; P = .28) and HF-CS (F: 28.1% vs M: 24.5%; P = .56). Women with HF-CS experienced higher rates of major bleeding (F: 25.8% vs M: 13.7%; P = .02) and vascular complications (F: 15.7% vs M: 6.1%; P = .01). However, female sex was not an independent predictor of these complications. No sex differences in survival were noted at 1 year. Conclusions: Within an STBA, although women with AMI-CS and HF-CS presented with higher acuity, they experienced similar in-hospital mortality, major adverse cardiac events, 30-day mortality, stroke, and 30-day readmissions as men. Further research is needed to better understand the extent to which historical differences in CS outcomes can be mitigated by an STBA.

Physicians' Considerations and Practice Recommendations Regarding the Use of Sodium-Glucose Cotransporter-2 Inhibitors.

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin), although initially developed as glucose-lowering drugs, provide significant beneficial effects on cardiorenal outcomes, including heart failure, regardless of type 2 diabetes status. Integration of SGLT-2is into clinical practice requires practical guidance for physicians about their use. To overcome physicians' clinical inertia for SGLT-2i use, including addressing safety, potentially a barrier to their use, a roundtable discussion with physicians from three specialties (cardiology, endocrinology, and nephrology) was conducted. This review summarizes the physicians' clinical experience and recommendations about SGLT-2i use across different patient populations, taking into consideration the beneficial effects of SGLT-2is and their safety. The key aspects discussed regarding SGLT-2i safety include acute effects on kidney function (estimated glomerular filtration rate acute dip upon SGLT-2i initiation and acute kidney injury), volume depletion, diabetic ketoacidosis, genitourinary infections, hyperkalemia, and hypoglycemia. To mitigate any potential risks related to SGLT-2i safety, physicians can make minor adjustments to an individual patient's treatment plan, while retaining the SGLT-2i cardiorenal benefits for effective disease management. Recognition by physicians that the benefits of SGLT-2i use on clinical outcomes outweigh the risks will result in the integration of SGLT-2is into clinical practice and lead to improved patient care and outcomes.

A Standardized and Regionalized Network of Care for Cardiogenic Shock.

BACKGROUND: The benefits of standardized care for cardiogenic shock (CS) across regional care networks are poorly understood. OBJECTIVES: The authors compared the management and outcomes of CS patients initially presenting to hub versus spoke hospitals within a regional care network. METHODS: The authors stratified consecutive patients enrolled in their CS registry (January 2017 to December 2019) by presentation to a spoke versus the hub hospital. The primary endpoint was 30-day mortality. Secondary endpoints included bleeding, stroke, or major adverse cardiovascular and cerebrovascular events. RESULTS: Of 520 CS patients, 286 (55%) initially presented to 34 spoke hospitals. No difference in mean age (62 years vs 61 years; P = 0.38), sex (25% vs 32% women; P = 0.10), and race (54% vs 52% white; P = 0.82) between spoke and hub patients was noted. Spoke patients more often presented with acute myocardial infarction (50% vs 32%; P < 0.01), received vasopressors (74% vs 66%; P = 0.04), and intra-aortic balloon pumps (88% vs 37%; P < 0.01). Hub patients were more often supported with percutaneous ventricular assist devices (44% vs 11%; P < 0.01) and veno-arterial extracorporeal membrane oxygenation (13% vs 0%; P < 0.01). Initial presentation to a spoke was not associated with increased risk-adjusted 30-day mortality (adjusted OR: 0.87 [95% CI: 0.49-1.55]; P = 0.64), bleeding (adjusted OR: 0.89 [95% CI: 0.49-1.62]; P = 0.70), stroke (adjusted OR: 0.74 [95% CI: 0.31-1.75]; P = 0.49), or major adverse cardiovascular and cerebrovascular events (adjusted OR 0.83 [95% CI: 0.50-1.35]; P = 0.44). CONCLUSIONS: Spoke and hub patients experienced similar short-term outcomes within a regionalized CS network. The optimal strategy to promote standardized care and improved outcomes across regional CS networks merits further investigation.

Cardiovascular Disease Projections in the United States Based on the 2020 Census Estimates.

BACKGROUND: Understanding trends in cardiovascular (CV) risk factors and CV disease according to age, sex, race, and ethnicity is important for policy planning and public health interventions. OBJECTIVES: The goal of this study was to project the number of people with CV risk factors and disease and further explore sex, race, and ethnical disparities. METHODS: The prevalence of CV risk factors (diabetes mellitus, hypertension, dyslipidemia, and obesity) and CV disease (ischemic heart disease, heart failure, myocardial infarction, and stroke) according to age, sex, race, and ethnicity was estimated by using logistic regression models based on 2013-2018 National Health and Nutrition Examination Survey data and further combining them with 2020 U.S. Census projection counts for years 2025-2060. RESULTS: By the year 2060, compared with the year 2025, the number of people with diabetes mellitus will increase by 39.3% (39.2 million [M] to 54.6M), hypertension by 27.2% (127.8M to 162.5M), dyslipidemia by 27.5% (98.6M to 125.7M), and obesity by 18.3% (106.3M to 125.7M). Concurrently, projected prevalence will similarly increase compared with 2025 for ischemic heart disease by 31.1% (21.9M to 28.7M), heart failure by 33.0% (9.7M to 12.9M), myocardial infarction by 30.1% (12.3M to 16.0M), and stroke by 34.3% (10.8M to 14.5M). Among White individuals, the prevalence of CV risk factors and disease is projected to decrease, whereas significant increases are projected in racial and ethnic minorities. CONCLUSIONS: Large future increases in CV risk factors and CV disease prevalence are projected, disproportionately affecting racial and ethnic minorities. Future health policies and public health efforts should take these results into account to provide quality, affordable, and accessible health care.