Molecular Diagnosis of Rejection in Heart Transplantation.

Despite the overall success of heart transplantation as a definitive treatment for endstage heart failure, cardiac allograft rejection remains an important cause of morbidity and mortality. Endomyocardial biopsy has been the standard of care for rejection monitoring, but is associated with several diagnostic limitations and serious procedural complications. The use of molecular diagnostics has emerged over the past decade as a tool to potentially circumvent some of these limitations. We present an update on novel molecular approaches to detecting transplant rejection, focusing on 4 categories: microarray technology, gene expression profiling, cell-free DNA and microRNA.

Association between Cardiorespiratory Fitness and Lung Health from Young Adulthood to Middle Age.

RATIONALE: Beyond the risks of smoking, there are limited data on factors associated with change in lung function over time. OBJECTIVES: To determine whether cardiorespiratory fitness was longitudinally associated with preservation of lung health. METHODS: Prospective data were collected from 3,332 participants in the Coronary Artery Risk Development in Young Adults study aged 18-30 in 1985 who underwent treadmill exercise testing at baseline visit, and 2,735 participants with a second treadmill test 20 years later. The association between cardiorespiratory fitness and covariate adjusted decline in lung function was evaluated. MEASUREMENTS AND MAIN RESULTS: Higher baseline fitness was associated with less decline in lung function. When adjusted for age, height, race-sex group, peak lung function, and years from peak lung function, each additional minute of treadmill duration was associated with 1.00 ml/yr less decline in FEV1 (P < 0.001) and 1.55 ml/yr less decline in FVC (P < 0.001). Greater decline in fitness was associated with greater annual decline in lung function. Each 1-minute decline in treadmill duration between baseline and Year 20 was associated with 2.54 ml/yr greater decline in FEV1 (P < 0.001) and 3.27 ml/yr greater decline in FVC (P < 0.001). Both sustaining higher and achieving relatively increased levels of fitness over 20 years were associated with preservation of lung health. CONCLUSIONS: Greater cardiopulmonary fitness in young adulthood, less decline in fitness from young adulthood to middle age, and achieving increased fitness from young adulthood to middle age are associated with less decline in lung health over time. Clinical trial registered with www.clinicaltrials.gov (NCT 00005130).

Diagnosis and Management of Chagas Cardiomyopathy in the United States.

PURPOSE OF REVIEW: Chagas cardiomyopathy is an emerging form of non-ischemic cardiomyopathy in the USA. This review aims to summarize current concepts in pathophysiology, disease transmission, medical therapy, and heart transplantation for patients with chronic Chagas cardiomyopathy. RECENT FINDINGS: The incidence of Chagas cardiomyopathy is increasing in the USA, driven mainly by immigration from countries where Chagas disease is endemic. Chagas cardiomyopathy is a chronic, progressive myocarditis, with hallmark features of biventricular dysfunction, ventricular arrhythmias, thromboembolic complications, and a high risk of mortality. Currently, there is no effective treatment for chronic Chagas cardiomyopathy. Heart transplantation is the only treatment for patients with end-stage Chagas cardiomyopathy, but is associated with unique challenges including risk of reactivation. As the prevalence of Chagas cardiomyopathy increases in the USA, practitioners must be aware of the unique challenges in diagnosis and management that Chagas cardiomyopathy presents.

HLA sensitization is associated with an increased risk of primary graft dysfunction after heart transplantation.

Primary graft dysfunction (PGD) is a leading cause of early morbidity and mortality following heart transplantation (HT). We sought to determine the association between pretransplant human leukocyte antigen (HLA) sensitization, as measured using the calculated panel reactive antibody (cPRA) value, and the risk of PGD. METHODS: Consecutive adult HT recipients (n = 596) from 1/2015 to 12/2019 at 2 US centers were included. Severity of PGD was based on the 2014 International Society for Heart and Lung Transplantation consensus statement. For each recipient, unacceptable HLA antigens were obtained and locus-specific cPRA (cPRA-LS) and pre-HT donor-specific antibodies (DSA) were assessed. RESULTS: Univariable logistic modeling showed that peak cPRA-LS for all loci and HLA-A was associated with increased severity of PGD as an ordinal variable (all loci: OR 1.78, 95% CI: 1.01-1.14, p = 0.025, HLA-A: OR 1.14, 95% CI: 1.03-1.26, p = 0.011). Multivariable analysis showed peak cPRA-LS for HLA-A, recipient beta-blocker use, total ischemic time, donor age, prior cardiac surgery, and United Network for Organ Sharing status 1 or 2 were associated with increased severity of PGD. The presence of DSA to HLA-B was associated with trend toward increased risk of mild-to-moderate PGD (OR 2.56, 95% CI: 0.99-6.63, p = 0.053), but DSA to other HLA loci was not associated with PGD. CONCLUSIONS: Sensitization for all HLA loci, and specifically HLA-A, is associated with an increased severity of PGD. These factors should be included in pre-HT risk stratification to minimize the risk of PGD.

Donor hyperoxia is a novel risk factor for severe cardiac primary graft dysfunction.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). Donor risk factors for the development of PGD are incompletely characterized. Donor management goals (DMG) are predefined critical care endpoints used to optimize donors. We evaluated the relationship between DMGs as well as non-DMG parameters, and the development of PGD after HT. METHODS: A cohort of HT recipients from 2 transplant centers between 1/1/12 and 12/31/19 was linked to their respective donors in the United Network for Organ Sharing (UNOS) DMG Registry (n = 1,079). PGD was defined according to modified ISHLT criteria. Variables were subject to univariate and multivariable multinomial modeling with development of mild/moderate or severe PGD as the outcome variable. A second multicenter cohort of 4,010 donors from the DMG Registry was used for validation. RESULTS: Mild/moderate and severe PGD occurred in 15% and 6% of the cohort. Multivariable modeling revealed 6 variables independently associated with mild/moderate and 6 associated with severe PGD, respectively. Recipient use of amiodarone plus beta-blocker, recipient mechanical circulatory support, donor age, donor fraction of inspired oxygen (FiO2), and donor creatinine increased risk whereas predicted heart mass ratio decreased risk of severe PGD. We found that donor age and FiO2 ≥ 40% were associated with an increased risk of death within 90 days post-transplant in a multicenter cohort. CONCLUSIONS: Donor hyperoxia at heart recovery is a novel risk factor for severe primary graft dysfunction and early recipient death. These results suggest that excessive oxygen supplementation should be minimized during donor management.

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

BACKGROUND: Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD. METHODS: We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression. RESULTS: PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD. CONCLUSIONS: Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.

Takayasu's Arteritis Presenting as Heart Failure in a 19-Year-Old Female.

This report presents the case of this atypical presentation of a rare disease in a 19-year-old female with cardiomyopathy and hypertension. Investigation revealed renovascular stenosis, infarcts, and active vasculitis pathognomonic for Takayasu arteritis (TA). Cardiac magnetic resonance imaging demonstrated mild pericardial inflammation and epicardial edema. Vasculitis-induced renovascular secondary hypertension resulted in myocardial dysfunction, which recovered with treatment of hypertension and TA. (Level of Difficulty: Beginner.).

Predicted heart mass is the optimal metric for size match in heart transplantation.

BACKGROUND: Donor-recipient size match is traditionally assessed by body weight. We assessed the ability of 5 size match metrics-predicted heart mass (PHM), weight, height, body mass index (BMI) and body surface area (BSA)-to predict 1-year mortality after heart transplant and to assess the effect of size match on donor heart turn down for size. METHODS: The study cohort comprised 19,168 adult heart transplant recipients in the United Network for Organ Sharing registry between 2007 and 2016. Each size match metric was divided into 7 equally sized groups using the donor-recipient ratio for each metric. Single and multivariable Cox proportional hazard models for mortality 1 year after transplant were constructed. RESULTS: Recipients in the severely (donor-recipient PHM ratio 0.54-0.86) undersized group for PHM experienced increased mortality, with a hazard ratio of 1.34 (95% confidence interval, 1.13-1.59; p < 0.001). There was no increased risk of death at 1 year if donors were undersized for weight, height, BMI, or BSA. We found that 32% of heart offers turned down for donor size would be acceptable using a PHM threshold of 0.86 or greater and that 14% of offers accepted (most of which are female donor to male recipient) were below this threshold. CONCLUSIONS: PHM is the optimal donor-recipient size match metric for prediction of mortality after heart transplant. Many offers turned down for donor size were above the threshold for adequacy of size match by PHM identified, and thus, the use of PHM could improve donor heart utilization and post-transplant survival.

Relation of Intensity of Statin Therapy and Outcomes After Transcatheter Aortic Valve Replacement.

Statin therapy is associated with improved survival in patients at high risk for cardiovascular mortality, but the impact of statin therapy in patients treated with transcatheter aortic valve replacement (TAVR) is unknown. We reviewed 294 consecutive cases of TAVR performed at a single tertiary care medical center. We defined high-intensity statin therapy as atorvastatin 40 to 80 mg/day or rosuvastatin 20 to 40 mg/day. Study outcomes included post-TAVR adverse events, 30-day mortality, and overall survival. At the time of TAVR, 14% (n = 41) were on high-intensity statin therapy, 59% (n = 173) were on low- or moderate-intensity statin therapy, and 27% (n = 80) were not on statin therapy. There was no association between statin therapy and the rate of post-TAVR stroke, myocardial infarction, acute kidney injury, in-hospital mortality, or 30-day mortality. At 2 years, 83% of patients in the high-intensity statin group were alive, 70% in the low/moderate-intensity statin group were alive, and 57% in the no statin group were alive (log-rank p = 0.016). In a risk-adjusted model, high-intensity statin therapy was associated with a 64% reduction in all-cause mortality (hazard ratio 0.36, 95% CI 0.14 to 0.90, p = 0.029) compared with no statin therapy. In conclusion, statin therapy is associated with improved overall survival after TAVR in a dose-dependent manner.

Frailty Status and Outcomes After Transcatheter Aortic Valve Implantation.

Frailty is a syndrome of older adults associated with increased morbidity and mortality. We aimed to assess the impact of frailty status on outcomes after transcatheter aortic valve implantation (TAVI). We reviewed all 191 patients who underwent a modified Fried frailty assessment before TAVI between February 2012 and September 2015 at a single academic medical center, and we assessed the impact of preoperative frailty status on morbidity, mortality, and health care utilization after TAVI. Frailty, pre-frailty, and nonfrailty were present in 33% (n = 64), 37% (n = 70), and 30% (n = 57) of patients, respectively. Slowness (75% vs 54%, p = 0.003) and low physical activity (55% vs 31%, p = 0.001) were more common in women than men. With increasing frailty status, the proportion of women increased (35% nonfrail, 44% pre-frail, and 66% frail, p = 0.002) and stature decreased (1.68 ± 0.11 m nonfrail, 1.66 ± 0.11 m pre-frail, 1.62 ± 0.12 m frail, p = 0.028). There was no difference in post-TAVI 30-day mortality, stroke, major vascular injury, major or life-threatening bleeding, respiratory failure, mean hospital length of stay, 30-day hospital re-admission, or overall survival between groups. The rate of discharge to a rehabilitation facility increased with increasing frailty status (14% nonfrail, 22% pre-frail, and 39% frail, p = 0.005). Frailty was independently associated with discharge to a rehabilitation facility (odds ratio 4.80, 95% confidence interval 1.66 to 13.85, p = 0.004). In conclusion, the safety of TAVI is not affected by frailty status, but patients with frailty are less likely to be discharged directly home after TAVI.