How Artificial Intelligence Can Enhance the Diagnosis of Cardiac Amyloidosis: A Review of Recent Advances and Challenges.

Cardiac amyloidosis (CA) is an underdiagnosed form of infiltrative cardiomyopathy caused by abnormal amyloid fibrils deposited extracellularly in the myocardium and cardiac structures. There can be high variability in its clinical manifestations, and diagnosing CA requires expertise and often thorough evaluation; as such, the diagnosis of CA can be challenging and is often delayed. The application of artificial intelligence (AI) to different diagnostic modalities is rapidly expanding and transforming cardiovascular medicine. Advanced AI methods such as deep-learning convolutional neural networks (CNNs) may enhance the diagnostic process for CA by identifying patients at higher risk and potentially expediting the diagnosis of CA. In this review, we summarize the current state of AI applications to different diagnostic modalities used for the evaluation of CA, including their diagnostic and prognostic potential, and current challenges and limitations.

Non-invasive detection of cardiac allograft rejection among heart transplant recipients using an electrocardiogram based deep learning model.

Aims: Current non-invasive screening methods for cardiac allograft rejection have shown limited discrimination and are yet to be broadly integrated into heart transplant care. Given electrocardiogram (ECG) changes have been reported with severe cardiac allograft rejection, this study aimed to develop a deep-learning model, a form of artificial intelligence, to detect allograft rejection using the 12-lead ECG (AI-ECG). Methods and results: Heart transplant recipients were identified across three Mayo Clinic sites between 1998 and 2021. Twelve-lead digital ECG data and endomyocardial biopsy results were extracted from medical records. Allograft rejection was defined as moderate or severe acute cellular rejection (ACR) based on International Society for Heart and Lung Transplantation guidelines. The extracted data (7590 unique ECG-biopsy pairs, belonging to 1427 patients) was partitioned into training (80%), validation (10%), and test sets (10%) such that each patient was included in only one partition. Model performance metrics were based on the test set (n = 140 patients; 758 ECG-biopsy pairs). The AI-ECG detected ACR with an area under the receiver operating curve (AUC) of 0.84 [95% confidence interval (CI): 0.78-0.90] and 95% (19/20; 95% CI: 75-100%) sensitivity. A prospective proof-of-concept screening study (n = 56; 97 ECG-biopsy pairs) showed the AI-ECG detected ACR with AUC = 0.78 (95% CI: 0.61-0.96) and 100% (2/2; 95% CI: 16-100%) sensitivity. Conclusion: An AI-ECG model is effective for detection of moderate-to-severe ACR in heart transplant recipients. Our findings could improve transplant care by providing a rapid, non-invasive, and potentially remote screening option for cardiac allograft function.

Cardiologist Evaluation and Approval Was the Primary Predictor of Kidney Transplant Candidacy and Transplantation Among Patients With Reduced Left Ventricular Ejection Fraction.

End-stage kidney disease patients with concomitant heart failure (HF) with reduced ejection fraction are often denied kidney transplantation. The aims of this study were to explore factors predictive of suitability for kidney transplant and to assess cardiovascular outcomes in patients with impaired left ventricular ejection fraction (LVEF) after transplant. Methods: We evaluated 109 consecutive adults with LVEF ≤40% at the time of initial kidney transplant evaluation between 2013 and 2018. Posttransplant cardiovascular outcomes were defined as nonfatal myocardial infarction (MI), admission for HF, cardiovascular death, and all-cause mortality. Results: A cardiologist participated in kidney transplant evaluation for 87% of patients and was present at 49% of transplant selection conferences. Twenty-four patients (22%) were denied by a cardiologist for kidney transplant' and 59 (54%) were denied by the selection committee, of whom 43 were because of cardiovascular risk. Forty-two (38%) patients were approved for kidney transplant. On univariate analysis, the variables associated with denial for kidney transplant included cardiologist denial, higher cardiac troponin T, prior coronary intervention, cardiovascular event, positive stress study, lower ejection fraction, and lower VO2 max (all P < 0.05). Cardiologist denial was the most significant predictor of denial for kidney transplant in different multivariate models. At a median follow-up of 15 mo, 5 (5%) suffered nonfatal MI, 13 (12%) were hospitalized for HF exacerbation, and 17 (16%) died. Only 22 patients, 52% of those approved, underwent kidney transplant. After kidney transplant, there was 1 death, 1 nonfatal MI, and 3 hospitalizations for HF. Median LVEF improved from 38% before listing to 55% posttransplant. Conclusions: Cardiologist denial was the primary predictor of rejection for kidney transplant. Despite careful selection, prevalence of cardiovascular events and mortality after kidney transplant was 23%. There is need for a structured multidisciplinary approach for patients with impaired LVEF.

Sirolimus-Based Immunosuppression Is Associated with Decreased Incidence of Post-Transplant Lymphoproliferative Disorder after Heart Transplantation: A Double-Center Study.

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein-Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8-26.6; p < 0.001), and conversion to SRL was found to be protective against development of PTLD (HR 0.19, 95% CI: 0.04-0.80; p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03-0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk.

Epidemiology, risk factors, and association of antifungal prophylaxis on early invasive fungal infection in heart transplant recipients.

BACKGROUND: Invasive fungal infection (IFI) in heart transplant recipients is associated with poor outcomes. Estimated risk of 1-year IFI in heart transplant recipients is 3.4-8.6% with risk factors inconsistently identified in previous studies. The role of antifungal prophylaxis is unclear. The transplant program at Mayo Clinic provides 6 months of universal azole prophylaxis for those heart transplant recipients in Arizona. We sought to define risk factors for 1-year IFI and determine the effect of antifungal prophylaxis. METHODS: We conducted a retrospective cohort study of patients undergoing heart transplantation at Mayo Clinic from January 2000 to March 2019. We analyzed demographics, details of transplant hospitalization, antifungal prophylaxis, and fungal infection. Multivariable Cox analyses were performed to identify risk factors of 1-year IFI and impact of IFI on posttransplant mortality. RESULTS: A total of 966 heart transplant recipients were identified with a median age of 56 years (IQR 47, 62). A total of 444 patients received antifungal prophylaxis. Over 1-year follow-up, 62 patients developed IFI with a cumulative incidence of 6.4%. In multivariable analysis, factors associated with IFI were renal replacement therapy (RRT) (HR 3.24, 95% CI 1.65-6.39), allograft rejection (HR 2.33, 95% CI 1.25-4.34), and antifungal prophylaxis (HR 0.32, 95% CI 0.11-0.96). RRT was also associated with invasive mold infection (HR 3.00, 95% CI 1.29-6.97). CONCLUSIONS: RRT and allograft rejection after transplantation are associated with 1-year IFI, and RRT is also associated with invasive mold infection. Antifungal prophylaxis appears to be protective and further study is needed in the heart transplant population.

Cardiac Transplantation and Consecutive Minimally Invasive Pectus Excavatum Repair.

Pectus excavatum is a common chest wall deformity with inward deviation of sternum and accompanying ribs. The depression can cause symptomatic cardiac compression, although the cardiopulmonary impact remains controversial. We present 2 cases of cardiac transplantation followed by modified minimally invasive pectus excavatum repair due to the hemodynamic consequences of the pectus deformity.

Edge-to-edge tricuspid valve repair for severe tricuspid regurgitation 20 years after cardiac transplantation.

Tricuspid valve regurgitation in orthotopic heart transplant recipients is common. Surgical corrections have been the mainstay of the treatment for diuretic-refractory heart failure due to severe tricuspid regurgitation. However, post-transplant patients inherently carry higher surgical risk owing to previous sternotomy and immunocompromised state. We report a case of successful percutaneous edge-to-edge tricuspid valve repair for severe tricuspid regurgitation after cardiac transplantation. A 27-year-old man with a history of idiopathic restrictive cardiomyopathy status after orthotopic heart transplant presented with severe right-sided heart failure symptoms. A transthoracic echocardiogram showed bi-atrial enlargement and moderate-to-severe tricuspid regurgitation, and an increase to the severe range with exercise. Percutaneous edge-to-edge tricuspid valve repair was performed. The patient's symptoms improved, and follow-up echocardiogram showed mild tricuspid regurgitation. Percutaneous tricuspid valve repair can be considered as an alternative option to conventional surgery for symptomatic severe tricuspid regurgitation in orthotopic heart transplant recipients with suitable anatomy.

Successful Use of Intragastric Balloon Therapy as a Bridge to Heart Transplantation.

Obesity is an important limiting factor for heart transplantation (HT) in patients with congestive heart failure (CHF). Achieving substantial weight loss is challenging in this population due to activity limitations and fluid retention. Endoscopic bariatric therapies (EBTs) including intragastric balloons (IGB) are effective primary weight loss therapies. IGBs have also been successfully utilized as a bridge therapy prior to liver transplantation and, in one case report, prior to HT. Potential advantages of IGBs in this population include low bleeding risk and less invasiveness as compared to other EBTs and surgery. We report the successful use of IGB as a bridge therapy in two patients with class II obesity and end-stage CHF requiring left ventricular assist devices (LVAD), anticoagulation, antiplatelet, and inotrope therapy.

Early Postoperative Aortic Root Thrombus After Heartmate 3.

As a bridge to heart transplantation or destination treatment, implantation of the Heartmate 3 (HM3) left ventricular assist device is a viable option for patients with end-stage congestive heart failure. The recent Momentum 3 trial has shown favorable outcomes compared with Heartmate 2. We report the first case of aortic root thrombus occurring early after HM3 implantation as a bridge to heart transplantation. Our case suggests that bridging with an Impella 5.0 preceding HM3 implantation could potentially predispose patients to aortic root thrombus after HM3 implantation, due to Impella-related injury to the aortic valve and aortic root stasis after durable LVAD support.

Identifying Patterns of Adverse Events of Solid Organ Transplantation Through Departmental Case Reviews.

The best approach to adverse-event review in solid organ transplantation is unknown. We initiated a departmental case review (DCR) method based on root-cause analysis methods in a high-volume multiorgan transplant center. We aimed to describe this process and its contributions to process improvement. METHODS: Using our prospectively maintained transplant center quality portfolio, we performed a retrospective review of a 30-month period (October 26, 2015, to May 14, 2018) after DCR-process initiation at our center. We used univariate statistics to identify counts of adverse events, DCRs, death and graft-loss events, and quality improvement action-plan items identified during case review. We evaluated variation among organ groups in action-plan items, associated phase of transplant care, and quality improvement theme. RESULTS: Over 30 months, we performed 1449 transplant and living donor procedures with a total of 45 deaths and 31 graft losses; 91 DCRs were performed (kidney transplant n=43; liver transplant n=24; pancreas transplant n=10; heart transplant n=6; lung transplant n=3; living donor n=5). Seventy-nine action-plan items were identified across improvement domains, including errors in clinical decision making, communication, compliance, documentation, selection, waitlist management, and administrative processes. Median time to review was 83 days and varied significantly by program. Median time to action-plan item completion was 9 weeks. Clinical decision making in the pretransplant phase was identified as an improvement opportunity in all programs. CONCLUSIONS: DCRs provide a robust approach to transplant adverse-event review. Quality improvement targets and domains may vary based on adverse-event profiles.

Factors associated with adverse outcomes from cardiovascular events in the kidney transplant population: an analysis of national discharge data, hospital characteristics, and process measures.

BACKGROUND: Kidney transplant (KT) patients presenting with cardiovascular (CVD) events are being managed increasingly in non-transplant facilities. We aimed to identify drivers of mortality and costs, including transplant hospital status. METHODS: Data from the 2009-2011 Nationwide Inpatient Sample, the American Hospital Association, and Hospital Compare were used to evaluate post-KT patients hospitalized for MI, CHF, stroke, cardiac arrest, dysrhythmia, and malignant hypertension. We used generalized estimating equations to identify clinical, structural, and process factors associated with risk-adjusted mortality and high cost hospitalization (HCH). RESULTS: Data on 7803 admissions were abstracted from 275 hospitals. Transplant hospitals had lower crude mortality (3.0% vs. 3.8%, p = 0.06), and higher un-adjusted total episodic costs (Median $33,271 vs. $28,022, p < 0.0001). After risk-adjusting for clinical, structural, and process factors, mortality predictors included: age, CVD burden, CV destination hospital, diagnostic cardiac catheterization without intervention (all, p < 0.001). Female sex, race, documented co-morbidities, and hospital teaching status were protective (all, p < 0.05). Transplant and non-transplant hospitals had similar risk-adjusted mortality. HCH was associated with: age, CVD burden, CV procedures, and staffing patterns. Hospitalizations at transplant facilities had 37% lower risk-adjusted odds of HCH. Cardiovascular process measures were not associated with adverse outcomes. CONCLUSION: KT patients presenting with CVD events had similar risk-adjusted mortality at transplant and non-transplant hospitals, but high cost care was less likely in transplant hospitals. Transplant hospitals may provide better value in cardiovascular care for transplant patients. These data have significant implications for patients, transplant and non-transplant providers, and payers.

Destination Therapy: Standardizing the Role of Palliative Medicine and Delineating the DT-LVAD Journey.

CONTEXT: Destination therapy (DT) patients face significant challenges as they transition from chronic left ventricular assist device (LVAD) support to comfort-oriented care. Integration of palliative medicine (PM) into the multidisciplinary team is important to facilitate advanced care planning (ACP) and improve quality of life (QoL). OBJECTIVES: We evaluated the impact of a structured programmatic approach to the end-of-life (EOL) process in DT patients as measured by QoL surveys and the utilization of ACP. METHODS: We instituted a four prong intervention approach: 1) delineated the path from implant to EOL by defining specific stages, including a transitional phase where care limits were agreed upon, 2) standardized the role of PM, 3) held transitional care meetings to support shared decision-making, and 4) held multidisciplinary team debriefings to facilitate communication. Preintervention and postintervention outcomes were measured for patients/caregivers by using the QUAL-E/QUAL-E (family) QoL instrument. Wilcoxon signed-ranks test compared nonparametric variables. RESULTS: All patients (n = 41)/caregivers (n = 28) reported improved QoL measures (patient P = 0.035/caregiver P = 0.046). Preparedness plans increased from 52% to 73% after implementation and advance directives increased from 71% to 83%. Fifty-nine percent of the patients completed an outpatient PM clinic visit; 51% completed/scheduled a second visit. Clinician outcomes improved including satisfaction with multidisciplinary team communication/expectations, ACP processes, and EOL management. CONCLUSION: A programmatic approach that standardizes the role of PM and delineates the patient's path from implant to EOL improved quality outcomes and increased implementation of ACP. A defined communication process allowed the multidisciplinary team to have a clear patient management approach.

Myocardial Contraction Fraction by M-Mode Echocardiography Is Superior to Ejection Fraction in Predicting Mortality in Transthyretin Amyloidosis.

BACKGROUND: Transthyretin amyloidosis (ATTR) is often associated with cardiac involvement manifesting as conduction disease as well as restrictive cardiomyopathy causing heart failure and death. Myocardial contraction fraction (MCF), the ratio of left ventricular stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening that is superior to ejection fraction (EF) in predicting mortality in patients with primary amyloid light chain cardiac amyloidosis. We hypothesized that MCF would be an independent predictor of survival in TTR-CA. METHODS AND RESULTS: MCF was derived from 2-dimensional echocardiography-guided M-mode data for 530 subjects in the Transthyretin Amyloidosis Outcomes Survey (THAOS) database: age 61 ± 16years, 74% male, 158 wild-type (ATTRwt) and 372 mutant (ATTRm), follow-up 1.5 ± 1.7years. Using multivariate Cox proportional hazard regression models, MCF <25% was highly associated with survival (hazard ratio [HR] 8.5, 95% confidence interval [CI] 4.8-14.9,-P < .0001), which was stronger than the association of EF dichotomized at 50% (HR 2.8, 95% CI 1.8-4.4; P < .0001). MCF <25% remained significantly predictive of survival in a multivariate model that included systolic blood pressure, estimated glomerular filtration rate <65 mL·min-1·m-2, New York Heart Association (NYHA) functional class, and health status based on the EuroQol-5D-3L questionnaire (area under the receiver operating characteristic curve [AUC] = 0.83, 95% CI 0.78-0.89). CONCLUSIONS: MCF was superior to EF in predicting mortality in patients with ATTR. A predictive model combining MCF with systolic blood pressure, renal function, NYHA functional class, and health status was strongly associated with survival in patients with ATTR. CLINICALTRIALS. GOV IDENTIFIER: NCT00628745.

Cardiorespiratory Fitness (Peak Oxygen Uptake): Safe and Effective Measure for Cardiovascular Screening Before Kidney Transplant.

BACKGROUND: Significant heterogeneity exists in practice patterns and algorithms used for cardiac screening before kidney transplant. Cardiorespiratory fitness, as measured by peak oxygen uptake (VO2peak), is an established validated predictor of future cardiovascular morbidity and mortality in both healthy and diseased populations. The literature supports its use among asymptomatic patients in abrogating the need for further cardiac testing. METHODS AND RESULTS: We outlined a pre-renal transplant screening algorithm to incorporate VO2peak testing among a population of asymptomatic high-risk patients (with diabetes mellitus and/or >50 years of age). Only those with VO2peak <17 mL/kg per minute (equivalent to <5 metabolic equivalents) underwent further noninvasive cardiac screening tests. We conducted a retrospective study of the a priori dichotomization of the VO2peak <17 versus ≥17 mL/kg per minute to determine negative and positive predictive value of future cardiac events and all-cause mortality. We report a high (>90%) negative predictive value, indicating that VO2peak ≥17 mL/kg per minute is effective to rule out future cardiac events and all-cause mortality. However, lower VO2peak had low positive predictive value and should not be used as a reliable metric to predict future cardiac events and/or mortality. In addition, a simple mathematical calculation documented a cost savings of ≈$272 600 in the cardiac screening among our study cohort of 637 patients undergoing evaluation for kidney and/or pancreas transplant. CONCLUSIONS: We conclude that incorporating an objective measure of cardiorespiratory fitness with VO2peak is safe and allows for a cost savings in the cardiovascular screening protocol among higher-risk phenotype (with diabetes mellitus and >50 years of age) being evaluated for kidney transplant.

Single-center experience of antifungal prophylaxis for coccidioidomycosis in heart transplant recipients within an endemic area.

In endemic regions, coccidioidomycosis causes substantial morbidity and mortality for patients receiving solid organ transplants. We aimed to demonstrate the effect of antifungal coccidioidal prophylaxis in heart transplant (HT) recipients. We retrospectively reviewed the electronic health records of all patients who received HTs between October 19, 2005, and December 13, 2014. We collected information regarding antifungal regimens and determined whether patients subsequently developed infections. Our 174-person cohort all received antifungal prophylaxis for at least 6 months (mean follow-up, 53.8 months). One proven and one probable coccidioidal infection (each, 0.6%) occurred during the study period. The incidence of coccidioidomycosis was 0.6% at 1 year and 2.3% at 5 years. No cases of proven coccidioidomycosis occurred within 2 years after transplantation. No patients developed disseminated disease, and no sentinel events were attributed to coccidioidomycosis. Both fluconazole and voriconazole were well tolerated. In the absence of intolerance or contraindication, we suggest continuing a universal antifungal prophylactic regimen with fluconazole for at least 6-12 months in HT recipients residing in a coccidioidomycosis-endemic area.

Soluble ST2 does not change cardiovascular risk prediction compared to cardiac troponin T in kidney transplant candidates.

BACKGROUND: Solubility of Tumorigenicity 2 (sST2) is a novel biomarker that better stratifies risk of cardiovascular events (CVE) compared to cardiac troponin T(cTnT) in heart failure. We assessed the association of sST2 with the composite outcome of CVE and/or mortality compared to cTnT in kidney transplant candidates. METHODS: 200 kidney transplant candidates between 2010 and 2013 were included. Elevated sST2 was defined as ≥30ng/ml, cTnT≥0.01 ng/ml. RESULTS: Median age 53 (interquartile range (IQR) 42-61) years, 59.7% male and 82.0% white. 33.5% had history of CVE, 42.5% left ventricular hypertrophy (LVH) and 15.6% positive cardiac stress test. Elevated sST2 correlated with male gender, history of prior-transplants, CVE, positive stress test, LVH, elevated cTnT, anemia, hyperphosphatemia, increased CRP and non-transplanted status. Male gender, history of CVE and LVH were independent determinants of sST2. During 28 months (IQR 25.3-30), 7.5% died, 13.0% developed CVE and 19.0% developed the composite outcome. Elevated sST2 was associated with the composite outcome (hazard ratio = 1.76, CI 1.06-2.73, p = 0.029) on univariate analysis but not after adjusting for age, diabetes and cTnT (p = 0.068). sST2 did not change the risk prediction model for composite outcome after including age, diabetes, prior history of CVE and elevated cTnT. CONCLUSIONS: Increased sST2 level is significantly associated with variables associated with CVE in kidney transplant candidates. sST2 was associated with increased risk of the composite outcome of CVE and/or death but not independent of cTnT. Larger studies are needed to confirm these findings and determine whether sST2 has added value in CV risk stratification in this cohort of patients.

Patterns of Care and Outcomes in Cardiovascular Disease After Kidney Transplantation in the United States.

BACKGROUND: Cardiovascular disease (CVD) is an important driver of mortality after kidney transplantation. Its broader impact on posttransplant health care utilization in US hospitals is unknown. METHODS: We used administrative claims data from the Nationwide Inpatient Sample and the American Hospital Association Annual Survey to identify hospitalizations for kidney transplant patients with a cardiovascular diagnosis from 2005 to 2011. CVD hospitalizations were stratified by transplant hospital status to characterize patterns in inpatient health care utilization and outcomes. Based on these analyses, the domestic burden of treatment for posttransplant CVD (myocardial infarction, stroke, congestive heart failure, dysrhythmia, cardiac arrest, malignant hypertension) was estimated. RESULTS: The total domestic burden of post-kidney transplant hospitalization between 2005 and 2011 is estimated at 389 138 of which 26.5% of episodes were related to CVD (n = 103 118). CVD was responsible for a growing proportion of post-transplant hospitalizations over time (24.4%-30.4%, P < 0.001). Compared with nontransplant hospitals, transplant hospitals had similar length of stay (median length of stay, 3.7 days), higher median costs per hospitalization (US $10 364 vs US $8606, overall US $9324), and lower adjusted mortality (3.2% vs 3.9%, overall 3.6%; P = 0.003). CONCLUSIONS: Inpatient CVD care is increasing over time for kidney transplant patients, accounting for 30% of all post-transplant hospitalizations. Variation exists in the inpatient care, outcomes, and costs between by hospital type. Further studies are needed to better understand the mechanisms behind these phenomena.

Calculated panel-reactive antibody predicts outcomes on the heart transplant waiting list.

BACKGROUND: Sensitized heart transplant candidates spend more time and have higher mortality on the waiting list. Although the calculated panel-reactive antibody (CPRA) value is used to assign allocation priority to kidney transplant candidates in the United States, the relationship between CPRA and outcomes on the heart transplant waiting list is unknown. METHODS: A data set of patients listed for heart transplant with unacceptable human leukocyte antigens (HLA) entered was obtained from the United Network for Organ Sharing. The study cohort was composed of 3,855 adult candidates listed for heart transplant between 2006 and 2013 with active waiting time. The cohort was divided into 5 groups by increasing CPRA. Outcomes were assessed using competing risks and sub-hazard regression analyses. RESULTS: In each group of successively higher CPRA, the percentage of candidates who received a transplant decreased, whereas the percentage of those who were still waiting for a transplant increased, as did the percentage of those removed from the waiting list or had died. The group of candidates with a CPRA >80% displayed a markedly decreased incidence of transplantation (hazard ratio 0.37) and an increased risk of removal from the waiting list or death (hazard ratio 2.18) as compared to those with CPRA of ≤10%. CONCLUSIONS: Sensitized heart transplant candidates are at high risk of adverse outcomes on the heart transplant waiting list. Clinicians should strive to minimize the CPRA by maximizing specificity in the selection of HLA antigens to exclude. The optimal clinical approach for candidates with high CPRA requires further study.

Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey).

BACKGROUND: Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis. OBJECTIVES: The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry. METHODS: Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189). RESULTS: U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival. CONCLUSIONS: In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

Pathology of Chronic Chagas Cardiomyopathy in the United States: A Detailed Review of 13 Cardiectomy Cases.

OBJECTIVES: The pathologic features of chronic Chagas cardiomyopathy may not be widely appreciated in the United States. We sought to describe the gross, microscopic, immunohistochemical, and molecular pathology features useful to diagnose chronic Chagas cardiomyopathy. METHODS: The features from a case series of cardiectomy specimens of patients undergoing heart transplantation (12 patients) or mechanical circulatory support device implantation (one patient) for chronic Chagas cardiomyopathy at three institutions in the United States are reported and analyzed. RESULTS: Gross findings included enlarged and dilated ventricles (100% of cases), mural thrombi (54%), epicardial plaques (42%), and left ventricular aneurysm (36%). Microscopic evaluation revealed myocarditis (100% of cases) characterized by mononuclear cell infiltration, fibrosis (100%), nonnecrotizing granulomas (62%), and giant cells (38%). Two specimens (15%) showed rare intracellular amastigotes. Immunohistochemical assays for Trypanosoma cruzi organisms were negative in all cardiectomy specimens, whereas tissue polymerase chain reaction was positive in six (54%) of 11 cases. CONCLUSIONS: The gross and microscopic features of chronic Chagas cardiomyopathy in the United States appear similar to those reported in endemic countries. Importantly, tissue polymerase chain reaction may be useful to confirm the diagnosis.