Increased Opportunities for Transplantation for Women in the New Heart Allocation System.

BACKGROUND: Historically, women have had less access to advanced heart failure therapies, including temporary and permanent mechanical circulatory support and heart transplantation (HT), with worse waitlist and post-transplant survival compared with men. This study evaluated for improvement in sex differences across all phases of HT in the 2018 allocation system. METHODS AND RESULTS: The United Network for Organ Sharing registry was queried to identify adult patients (≥18 years) listed for HT from October 18, 2016, to October 17, 2018 (old allocation), and from October 18, 2018, to October 18, 2020 (new allocation). The outcomes of interest included waitlist survival, pretransplant use of temporary and durable mechanical circulatory support, rates of HT, and post-transplant survival. There were 15,629 patients who were listed for HT and included in this analysis; 7745 (2039 women, 26.3%) in the new and 7875 patients (2074 women, 26.3%) in the old allocation system. When compared with men in the new allocation system, women were more likely to have lower priority United Network for Organ Sharing status at time of transplant, and less likely to be supported by an intra-aortic balloon pump (27.1% vs 32.2%, P < .001), with no difference in the use of venoarterial extracorporeal membrane oxygenation (5.5% vs 6.3%, P = .28). Despite these findings, when transplantation was viewed in the context of risk for death or delisting, the cumulative incidence of transplant within 6 months of listing was higher in women than men in the new allocation system (62.4% vs 54.9%, P < .001) with no differences in post-transplant survival. When comparing women in the old with the new allocation system, the distance traveled for organ procurement was 187.5 ± 207.0 miles vs 272.8 ± 233.7 miles (P < .001). CONCLUSIONS: Although the use of temporary mechanical circulatory support in women remains lower than in men in the new allocation system, more women are being transplanted with comparable waitlist and post-transplant outcomes as men. Broader sharing may be making its greatest impact on improving transplant opportunities for women.

Sex Differences in Advanced Heart Failure Therapies.

This in-depth review of sex differences in advanced heart failure therapy summarizes the existing literature on implantable cardioverter defibrillators, biventricular pacemakers, mechanical circulatory support, and transplantation with a focus on utilization, efficacy/clinical effectiveness, adverse events, and controversies. One will learn about the controversies regarding efficacy/clinical effectiveness of implantable cardioverter defibrillators and understand why these devices should be implanted in women even if there are sex differences in appropriate shocks. Individuals will learn about the sex differences with biventricular pacemakers with respect to ventricular remodeling and reduction in heart failure hospitalizations/mortality, as well as, possible mechanisms. We will demonstrate sex differences in heart transplantation and waitlist survival. Despite similar survival for women and men with left ventricular assist devices, there are sex differences in adverse events. These devices do successfully bridge women and men to transplant, yet women are less likely than men to have a left ventricular assist at time of listing and time of transplantation. Finally, one will learn about the concerns regarding poor outcome for men who receive female donor hearts and discover this may not be due to sex, but rather size. More research is needed to better understand sex differences and further improve advanced heart failure therapy for both women and men.

Variables of importance in the Scientific Registry of Transplant Recipients database predictive of heart transplant waitlist mortality.

The prelisting variables essential for creating an accurate heart transplant allocation score based on survival are unknown. To identify these we studied mortality of adults on the active heart transplant waiting list in the Scientific Registry of Transplant Recipients database from January 1, 2004 to August 31, 2015. There were 33 069 candidates awaiting heart transplantation: 7681 UNOS Status 1A, 13 027 Status 1B, and 12 361 Status 2. During a median waitlist follow-up of 4.3 months, 5514 candidates died. Variables of importance for waitlist mortality were identified by machine learning using Random Survival Forests. Strong correlates predicting survival were estimated glomerular filtration rate (eGFR), serum albumin, extracorporeal membrane oxygenation, ventricular assist device, mechanical ventilation, peak oxygen capacity, hemodynamics, inotrope support, and type of heart disease with less predictive variables including antiarrhythmic agents, history of stroke, vascular disease, prior malignancy, and prior tobacco use. Complex interactions were identified such as an additive risk in mortality based on renal function and serum albumin, and sex-differences in mortality when eGFR >40 mL/min/1.73 m. Most predictive variables for waitlist mortality are in the current tiered allocation system except for eGFR and serum albumin which have an additive risk and complex interactions.

Heart Failure with Reduced Ejection Fraction in Women: Epidemiology, Outcomes, and Treatment.

There are millions of people affected by heart failure with reduced ejection fraction (HFrEF) as diagnosed with ejection fraction 40% or less by imaging. Established therapies have been proven through clinical trials on lifestyle interventions, medications, and devices for HFrEF to improve quality of life, heart function, and survival. Although there are more men than women suffering with HFrEF, there are no prospectively proven, sex-specific guideline therapies because women have been underrepresented in clinical trials. Current recommendations for medications in women with HFrEF are described in this article.

Infectious Myocarditis on FDG-PET Imaging Mimicking Sarcoidosis.

Cardiac positron emission tomography with fluorine-18 fluorodeoxyglucose (FDG-PET) is often used for the diagnosis of cardiac involvement in sarcoidosis. Areas of segmental perfusion defects coupled with FDG uptake are considered to represent active inflammation. However, these findings may be associated with other inflammatory myocardial diseases. We describe a case of tuberculous myocarditis with imaging findings mimicking those found in cardiac sarcoidosis.

Relationship between sex, ejection fraction, and B-type natriuretic peptide levels in patients hospitalized with heart failure and associations with inhospital outcomes: findings from the Get With The Guideline-Heart Failure Registry.

BACKGROUND: In heart failure (HF), there are known differences in plasma B-type natriuretic peptide (BNP) levels between reduced and preserved ejection fraction (EF), but few HF studies have explored sex differences. We sought to evaluate the relationship between sex, EF, and BNP in HF patients and determine prognostic significance of BNP as it relates to sex and EF. METHODS: We included hospitals in Get With The Guidelines-Heart Failure that admitted 99,930 HF patients with reduced (EF <40%), borderline (EF 40%-49%), or preserved (EF ≥50%) EF. The primary end point was inhospital mortality. Multivariate models were used to compute odds ratios while accounting for hospital clustering. RESULTS: There were 47,025 patients with reduced (37% female), 13,950 with borderline (48% female), and 38,955 with preserved (65% female) EF. Women compared with men had higher admission median BNP levels with the greatest difference among reduced EF and smallest difference among preserved EF (median BNP in women vs men: EF reduced 1,259 vs 1,113 pg/mL, borderline 821 vs 732 pg/mL, and preserved 559 vs 540 pg/mL; P < .001 all comparisons). Ejection fraction and sex were independently associated with BNP. Inhospital mortality was 2.7%, and patients above the median BNP level had higher mortality than those below. After adjusting for over 20 clinical variables, the ability of BNP to predict inhospital mortality was similar among all subgroups (P for heterogeneity = .47). CONCLUSIONS: In a large registry, we found that despite sex/EF differences in BNP values, there was no significant difference in the ability of BNP to predict inhospital mortality among these subgroups.

Value of psychosocial evaluation for left ventricular assist device candidates.

OBJECTIVE: Left ventricular assist devices require a psychosocial assessment to determine candidacy despite limited data correlating with outcome. Our objective is to determine whether the Stanford Integrated Psychosocial Assessment for Transplant, a tool validated for transplant and widely used by left ventricular assist device programs, predicts left ventricular assist device program hospital readmissions and death. METHODS: We performed a retrospective analysis of adults at the Cleveland Clinic with Stanford Integrated Psychosocial Assessment for Transplant scores before primary left ventricular assist device program implantation from April 1, 2013, to December 31, 2018. The primary outcome was unplanned hospital readmissions censored at death, transplantation, and transfer of care. The secondary outcome was death. RESULTS: There were 263 patients in the left ventricular assist device program with a median (Q1, Q3) Stanford Integrated Psychosocial Assessment for Transplant score of 16 (8, 28). During a median follow-up 1.2 years, 56 died, 65 underwent transplantation, and 21 had transferred care. There were 640 unplanned hospital readmissions among 250 patients with at least 1 outpatient visit at our center. In a multivariable analysis, Stanford Integrated Psychosocial Assessment for Transplant components but not total Stanford Integrated Psychosocial Assessment for Transplant score was associated with readmissions. Psychopathology (Stanford Integrated Psychosocial Assessment for Transplant C-IX) was associated with hemocompatibility (coefficient 0.21 ± standard error 0.11, P = .040) and cardiac (0.15 ± 0.065, P = .02) readmissions. Patient readiness was associated with noncardiac (Stanford Integrated Psychosocial Assessment for Transplant A-III, 0.24 ± 0.099, P = .016) and cardiac (Stanford Integrated Psychosocial Assessment for Transplant A-low total, 0.037 ± 0.014, P = .007) readmissions. Poor living environment (Stanford Integrated Psychosocial Assessment for Transplant B-VIII) was associated with device-related readmissions (0.83 ± 0.34, P = .014). Death was associated with organic psychopathology or neurocognitive impairment (Stanford Integrated Psychosocial Assessment for Transplant C-X, 0.59 ± 0.21, P = .006). CONCLUSIONS: Total Stanford Integrated Psychosocial Assessment for Transplant score was not associated with left ventricular assist device program readmission or mortality. However, we identified certain Stanford Integrated Psychosocial Assessment for Transplant components that were associated with outcome and could be used to create a left ventricular assist device program specific psychosocial tool.

Effects of Body Mass Index on Presentation and Outcomes of COVID-19 among Heart Transplant and Left Ventricular Assist Device Patients: A Multi-Institutional Study.

The coronavirus disease 2019 (COVID-19) pandemic continues to pose a significant threat to patients receiving advanced heart failure therapies. The current study was undertaken to better understand the relationship between obesity and outcomes of SARS-CoV-2 infection in patients with a left ventricular assist device (LVAD) or heart transplant. We performed a retrospective review of patients with a heart transplant or LVAD who presented to one of the participating 11 institutions between April 1 and November 30, 2020. Patients were grouped by body mass index (BMI) into obese (BMI ≥ 30 k/m2) and nonobese cohorts (BMI < 30 kg/m2). Multivariable logistic regression models were used to estimate effects of obesity on outcomes of interest. Across all centers, 162 heart transplant and 81 LVAD patients were identified; 54 (33%) and 38 (47%) were obese, respectively. Obese patients tended to have more symptoms at presentation. No differences in rates of hospitalization or ICU admission were noted. Obese patients with LVADs were more likely to require mechanical ventilation (39% vs. 8%, p < 0.05). No differences in renal failure or secondary infection were noted. Mortality was similar among heart transplant patients (11% [obese] vs. 16% [nonobese], p = 0.628) and LVAD patients (12% vs. 15%, p = 1.0). BMI was not associated with increased adjusted odds of mortality, ICU admission, or mechanical ventilation (all p > 0.10). In summary, acute presentations of SARS-CoV-2 among heart transplant and LVAD recipients carry a significantly higher mortality than the general population, although BMI does not appear to impact this. Further studies on the longer-term effects of COVID-19 on this population are warranted.

Sex differences in in-hospital mortality in acute decompensated heart failure with reduced and preserved ejection fraction.

BACKGROUND: There are no sex-specific survival comparisons between patients with heart failure (HF) with reduced and those with preserved ejection fraction. Large registries noting women have better survival than men combined HF patients with reduced and preserved EF. Other registries that compared patients with reduced and preserved EF did not analyze their data by sex. We sought to evaluate sex/EF differences in mortality and risk factors for survival in hospitalized patients with HF. METHODS: We included hospitals fully participating in Get With The Guidelines-Heart Failure that admitted HF patients with reduced (EF <40%) or preserved (EF ≥50%) EF. The primary end point was in-hospital mortality. Multivariate generalized estimating equation logistic models were used to compute odds ratios accounting for hospital clustering. RESULTS: The study cohort consisted of 51,428 patients with EF <40% (36% women, 64% men) and 37,699 patients with EF ≥50% (65% women, 35% men). Women compared with men with reduced and preserved EF were older and more likely to have hypertension, depression, or valvular heart disease and less likely to have coronary artery disease or peripheral vascular disease. There were no sex differences in in-hospital mortality (EF <40%, 2.69% women vs 2.89% men, P = .20; EF ≥50%, 2.61% women vs 2.62% men, P = .96), and risk factors such as age, systolic blood pressure, heart rate, and history of renal failure/dialysis were highly predictive of death for each sex/EF subgroup. CONCLUSIONS: In a large, multicenter registry, we found that despite differences in baseline characteristics, women and men with reduced and preserved EF have similar in-hospital mortality and risk factors predicting death.

Outcomes Associated With COVID-19 Hospitalization in Heart Transplantation Patients.

BACKGROUND: Heart transplantation (HT) recipients infected with COVID-19 may be at an increased risk of severe illness due to chronic immunosuppression. MATERIALS AND METHODS: Adult HT patients hospitalized with COVID-19 at the Cleveland Clinic between March 2020 and March 2021 were included in this retrospective cohort analysis. Twenty-four HT cases were matched to 96 non-HT controls, similarly hospitalized with COVID-19, out of 11,481 patients based on different baseline characteristics. Primary outcome was all-cause mortality; secondary outcomes included mechanical ventilation, intensive care unit admission, vasopressor need, dialysis, pneumonia, and 90-day readmission. Subgroup analysis was performed based on the time from transplantation (within 1 year of transplantation and greater than 1 year since transplantation). RESULTS: Both primary and secondary outcomes were not significant. Subgroup analysis did not show a significant difference in mortality (P = .355) or 30-day readmission (P = .841) between patients who were within 1 year of transplantation and remote transplantation beyond 1 year. Univariable analysis of immunosuppressant continuation, dose-reduction, or discontinuation did not significantly affect HT mortality. CONCLUSIONS: Despite limited sample size, our results suggest that HT patients do not show worse outcomes after acquiring COVID-19, whether in the first year of transplantation or after a remote transplantation procedure. Future studies with multicenter data that incorporate the subsequent COVID-19 variants (eg, Delta and Omicron), the impact of long COVID-19, and assessing full vs reduced immunosuppression regimens would add insights to this patient population.

Special Considerations in the Care of Women With Advanced Heart Failure.

Advanced heart failure (AHF) is associated with increased morbidity and mortality, and greater healthcare utilization. Recognition requires a thorough clinical assessment and appropriate risk stratification. There are persisting inequities in the allocation of AHF therapies. Women are less likely to be referred for evaluation of candidacy for heart transplantation or left ventricular assist device despite facing a higher risk of AHF-related mortality. Sex-specific risk factors influence progression to advanced disease and should be considered when evaluating women for advanced therapies. The purpose of this review is to discuss the role of sex hormones on the pathophysiology of AHF, describe the clinical presentation, diagnostic evaluation and definitive therapies of AHF in women with special attention to pregnancy, lactation, contraception and menopause. Future studies are needed to address areas of equipoise in the care of women with AHF.

The growing dilemma of legalized cannabis and heart transplantation.

This in-depth review discusses cannabis as it relates to heart transplantation and the growing dilemma of legalization around the world creating disparities in transplant candidacy. One will learn about two of the most common cannabinoids: Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids are metabolized by cytochrome P-450 and P glycoprotein, which are essential for the metabolism of drugs for transplantation, such as calcineurin inhibitors. Addiction, withdrawal, and cannabis use disorder will be reviewed as well as hyperemesis syndrome. Maintaining adequate immunosuppression will depend on a variety of factors, including drug-drug interactions, pharmacokinetics of cannabinoids and chronicity of cannabis usage. These drug interactions are further confounded by varying concentrations of cannabis products available at medical dispensaries. One will also learn about the outcomes of transplant recipients using cannabis such as graft failure and the risk of infections. Although more research is needed to establish transplant guidelines, the available data is concerning and fairness in organ distribution should not vary by transplant program or institution.

Kinetics of generic tacrolimus in heart transplantation: A cautionary note.

Tacrolimus is a core component of immunosuppressive regimens. This study compared active pharmaceutical ingredient (API) and dissolution kinetics of branded tacrolimus and formulations from three generic manufacturers (Mylan, Dr. Reddy's, Intas) including samples from patients who suffered acute cardiac allograft rejection. Generic samples showed similar API content compared to branded samples with no major impurities. Capsules that underwent uniformity testing had consistent capsule-to-capsule API. Dissolution testing showed similar profiles between branded tacrolimus and Mylan, but notable differences with Dr. Reddy's and Intas. The approximate maximal inhibitory concentration (IC50) was highest in branded tacrolimus (29 minutes), followed by Mylan (26 minutes), Dr. Reddy's (19 minutes), and Intas (14 minutes) (Student-Newman-Keuls Multiple Comparisons Test; overall ANOVA: p = 0.0199, F = 6.469). This study suggests that the bioavailability of certain generic tacrolimus formulations peak significantly earlier than branded tacrolimus. Further study is needed to determine whether these differences are clinically relevant.

Heart Transplantation: An In-Depth Survival Analysis.

OBJECTIVES: This study aims to understand the complex factors affecting heart transplant survival and to determine the importance of possible sex-specific risk factors. BACKGROUND: Heart transplant allocation is primarily focused on preventing waitlist mortality. To prevent organ wastage, future allocation must balance risk of waitlist mortality with post-transplantation mortality. However, more information regarding risk factors after heart transplantation is needed. METHODS: We included all adults (30,606) in the Scientific Registry of Transplant Recipients database who underwent isolated heart transplantation from January 1, 2004, to July 1, 2018. Mortality (8,278 deaths) was verified with the complete Social Security Death Index with a median follow-up of 3.9 years. Temporal decomposition was used to identify phases of survival and phase-specific risk factors. The random survival forests method was used to determine importance of mortality risk factors and their interactions. RESULTS: We identified 3 phases of mortality risk: early post-transplantation, constant, and late. Sex was not a significant risk factor. There were several interactions predicting early mortality such as pretransplantation mechanical ventilation with presence of end-organ function (bilirubin, renal function) and interactions predicting later mortality such as diabetes and older age (donor and recipient). More complex interactions predicting early-, mid-, and late-mortality existed and were identified with machine learning (i.e., elevated bilirubin, mechanical ventilation, and dialysis). CONCLUSIONS: Post-heart transplant mortality risk is complex and dynamic, changing with time and events. Sex is not an important mortality risk factor. To prevent organ wastage, end-organ dysfunction should be resolved before transplantation as much as possible.

Continuously Updated Estimation of Heart Transplant Waitlist Mortality.

BACKGROUND: Heart transplant allocation in the United States is made on the basis of coarse tiers, defined by mechanical circulatory devices and therapy for advanced heart failure, updated infrequently as a patient's condition deteriorates. Thus, many patients die awaiting heart transplantation. What is needed is a tool that continuously updates risk of mortality as a patient's condition changes to inform clinical decision making. OBJECTIVES: This study sought to develop a decision aid that aggregates adverse events and measures of end-organ function into a continuously updated waitlist mortality estimate. METHODS: From 2008 to 2013, 414 patients were listed for heart transplantation at Cleveland Clinic, Cleveland, Ohio. The endpoint was waitlist death. Pre-listing patient characteristics and events and laboratory results during listing were analyzed. At each event or measurement change, mortality was recomputed from the resulting model. RESULTS: There were 77 waitlist deaths, with 1- and 4-year survival of 85% and 57%, respectively. When time-varying events and measurements were incorporated into a mortality model, pre-listing patient characteristics became nonsignificant. Neurological events (hazard ratio [HR]: 13.5; 95% confidence interval [CI]: 7.63 to 23.8), new requirement for dialysis (HR: 3.67; 95% CI: 1.88 to 7.14), more respiratory complications (HR: 1.79 per episode; 95% CI: 1.23 to 2.59), and higher serum bilirubin (p < 0.0001) and creatinine (p < 0.0001) yielded continuously updated estimates of patient-specific mortality across the waitlist period. CONCLUSIONS: Mortality risk for patients with advanced heart failure who are listed for transplantation is related to adverse events and end-organ dysfunction that change over time. A continuously updated mortality estimate, combined with clinical evaluation, may inform status changes that could reduce mortality on the heart transplant waiting list.

Verification of Heart Disease: Implications for a New Heart Transplantation Allocation System.

OBJECTIVES: This study sought to determine the accuracy of the pre-transplantation clinical diagnosis of heart disease in the United Network for Organ Sharing (UNOS) database. BACKGROUND: Because survival on the heart transplantation waitlist depends on underlying heart disease, a new allocation system will include the type of heart disease. Accuracy of the pre-transplantation clinical diagnosis and the effect of misclassification are unknown. METHODS: We included all adults who received transplants at our center between January 2009 to December 2015. We compared the pre-transplantation clinical diagnosis at listing with pathology of the explanted heart and determined the potential effect of misclassification with the proposed allocation system. RESULTS: A total of 334 patients had the following clinical cardiac diagnoses at listing: 148 had dilated cardiomyopathy, 19 had restrictive cardiomyopathy, 103 had ischemic cardiomyopathy, 24 had hypertrophic cardiomyopathy, 11 had valvular disease, 16 had congenital heart disease (CHD), and 13 patients had a diagnosis of "other." Pathology of the explanted hearts revealed 82% concordance and 18% discordance (10% coding errors and 8% incorrect diagnosis). The most common incorrect diagnoses were sarcoidosis (66%), arrhythmogenic right ventricular dysplasia (60%), and other causes of predominately right-sided heart failure (33%). Among the misclassified diagnoses, 40% were listed as UNOS status 2, 8% remained at status 2 at transplantation, and only sarcoidosis and CHD were potentially at a disadvantage with the new allocation. CONCLUSIONS: There is high concordance between clinical and pathologic diagnosis, except for sarcoidosis and genetic diseases. Few misclassifications result in disadvantages to patients based on the new allocation system, but rare diseases like sarcoidosis remain problematic. To improve the UNOS database and enhance outcome research, pathology of the explanted hearts should be required post-transplantation.

Sex Differences in Mortality Based on United Network for Organ Sharing Status While Awaiting Heart Transplantation.

BACKGROUND: There are sex differences in mortality while awaiting heart transplantation, and the reason remains unclear. METHODS AND RESULTS: We included all adults in the Scientific Registry of Transplant Recipients placed on the heart transplant active waitlist from 2004 to 2015. The primary end point was all-cause mortality. Multivariable Cox proportional hazards models were performed to evaluate survival by United Network for Organ Sharing (UNOS) status at the time of listing. Random survival forest was used to identify sex interactions for the competing risk of death and transplantation. There were 33 069 patients (25% women) awaiting heart transplantation. This cohort included 7681 UNOS status 1A (26% women), 13 027 UNOS status 1B (25% women), and 12 361 UNOS status 2 (26% women). During a median follow-up of 4.3 months, 1351 women and 4052 men died. After adjusting for >20 risk factors, female sex was associated with a significant risk of death among UNOS status 1A (adjusted hazard ratio, 1.14; 95% confidence interval, 1.01-1.29) and UNOS status 1B (adjusted hazard ratio, 1.17; 95% confidence interval, 1.05-1.30). In contrast, female sex was significantly protective for time to death among UNOS status 2 (adjusted hazard ratio, 0.85; 95% confidence interval, 0.76-0.95). Sex differences in probability of transplantation were present for every UNOS status, and >20 sex interactions were identified for mortality and transplantation. CONCLUSIONS: When stratified by initial UNOS status, women had a higher mortality than men as UNOS status 1 and a lower mortality as UNOS status 2. With >20 sex interactions for mortality and transplantation, further evaluation is warranted to form a more equitable allocation system.

Matching the Market for Heart Transplantation.

Heart transplantation is the most effective therapy for patients with Stage D heart failure with a median life expectancy of ≈10 to 15 years. Unfortunately, many patients die on the waiting list hoping for a chance of survival. The life boat cannot rescue everyone. Over a decade, the donor pool has remained relatively stable, whereas the number of heart transplant candidates has risen. Potential recipients often have many comorbidities and are older because the criteria for heart transplantation has few absolute contraindications. Women, Hispanics, and patients with restrictive heart disease and congenital heart disease are more likely to die while awaiting heart transplantation than men, white patients, and those with either ischemic or dilated cardiomyopathy. To better match the market, we need to (1) increase the donor pool, (2) reduce the waitlist, and (3) improve the allocation system. This review article addresses all 3 options and compares strategies in the United States to those in other countries.