Kushwaha, Sudhir S.

Background: While implantation of left ventricular assist devices (LVAD) improves survival and quality of life in patients with advanced heart failure, very little is known about healthcare resource utilization, including hospital readmissions, post-LVAD. Methods: Administrative claims data from a large, national US health plan were used to identify privately insured and Medicare Advantage patients that received an LVAD (ICD-9-CM code 37.66) and survived to hospital discharge from January 1, 2006 through 31 August 31, 2013, and had at least six months coverage pre-LVAD. The individuals covered by this health plan, about 88 million in years 2003 to 2013, are geographically dispersed across the United States, with greatest representation in the South and Midwest census regions. Reasons for subsequent readmissions were categorized according to the AHRQ Clinical Classifications Software and risk factors for readmission analyzed using multiple failure Cox regression analysis. Patients were censored at the time of heart transplantation or end of coverage through November 30, 2013. Results: In total, 857 patients received an LVAD, of whom 693 (81%) survived to hospital discharge without undergoing heart transplantation (mean age 56 years, 77% male). After a median follow-up of 0.69 (interquartile range [IQR]: 0.31, 1.50) years, 1,659 readmissions occurred among 509 patients. Over this period, patients spent a median of 10.5 days (IQR: 0 -40 days) per followup year hospitalized. The number of readmissions per patient varied widely (0 to 20 per person), with 184 (26.6%) patients experiencing no readmissions, while 112 (16.2%) had 5 or more readmissions during follow-up. The most common reasons for readmission were device complications (291 readmissions in 155 patients), heart failure (246 readmissions in 135 patients), gastrointestinal bleeding (90 readmissions in 52 patients), and arrhythmia (88 readmissions in 55 patients). Readmission risk was higher in patients who had longer initial length of stay and more comorbid conditions. Discussion: There is tremendous variability in the readmission burden experienced post-LVAD, with some patients experiencing no readmissions while others are repeatedly hospitalized. LVAD therapy introduces a unique set of problems that often prompt readmission including device complications and gastrointestinal bleeding.

Introduction: The number of patients with sarcoidosis requiring heart transplantation (HT) is on the rise. Hypothesis: The aim of this study was to evaluate outcomes of isolated HT in patients with sarcoid cardiomyopathy. Methods: Adult HT recipients were identified in the UNOS Registry between 1990 and 2020. Patients were grouped according to diagnosis. The cumulative incidences for the all-cause mortality and rejection were compared using Fine and Gray model analysis, accounting for re-transplantation as a competing risk. Moreover, we reviewed characteristics and outcomes of all HT recipients with previous diagnosis of sarcoid cardiomyopathy from a single-center. Results: A total of 30,874 HT recipients were included in the present study (n=240 sarcoidosis, n=1,431 non-ischemic restrictive cardiomyopathy, and n=29,203 non-ischemic dilated cardiomyopathy). During a total of 196,985 patient-years, all-cause mortality at the latest follow-up was not significantly different when comparing sarcoidosis to non-ischemic dilated cardiomyopathy (adjusted subhazard ratio [aSHR] 1.4, 95% confidence intervals [CI]: 0.88-2.3, p=0.15) or restrictive cardiomyopathy (aSHR 1.12, 95% CI: 0.65-1.95, p=0.67). Accordingly, multivariable analysis suggested that 1-year mortality was not significantly different between sarcoidosis and non-ischemic dilated cardiomyopathy (aSHR 1.56, 95% CI: 0.9-2.7, p=0.12) or restrictive (aSHR 1.15, 95% CI: 0.61-2.18, p=0.66) cardiomyopathy. Additionally, no differences were observed regarding 30-day mortality after HT. Data from the single-center case review showed excellent long-term outcomes with sirolimus-based immunosuppression. Conclusions: Short- and long-term outcomes after isolated HT do not seem to be inferior in sarcoid cardiomyopathy when compared to common types of non-ischemic cardiomyopathy.

Abstract Background The number of patients with sarcoidosis requiring heart transplantation (HT) is increasing. The aim of this study was to evaluate outcomes of isolated HT in patients with sarcoid cardiomyopathy and compare them to recipients with non-ischaemic restrictive or dilated cardiomyopathy. Methods and results Adult HT recipients were identified in the UNOS Registry between 1990 and 2020. Patients were grouped according to diagnosis. The cumulative incidences for the all-cause mortality and rejection were compared using Fine and Gray model analysis, accounting for re-transplantation as a competing risk. Rejection was evaluated using logistic regression analysis. We also reviewed characteristics and outcomes of all HT recipients with previous diagnosis of sarcoid cardiomyopathy from a single centre. A total of 30 160 HT recipients were included in the present study (n = 239 sarcoidosis, n = 1411 non-ischaemic restrictive cardiomyopathy, and n = 28 510 non-ischaemic dilated cardiomyopathy). During a total of 194 733 patient-years, all-cause mortality at the latest follow-up was not significantly different when comparing sarcoidosis to non-ischaemic dilated cardiomyopathy [adjusted subhazard ratio (aSHR) 1.46, 95% confidence intervals (CIs): 0.9–2.4, P = 0.12] or restrictive cardiomyopathy (aSHR 1.12, 95% CI: 0.65–1.95, P = 0.67). Accordingly, multivariable analysis suggested that 1 year mortality was not significantly different between sarcoidosis and non-ischaemic dilated cardiomyopathy (aSHR 1.56, 95% CI: 0.9–2.7, P = 0.12) or restrictive cardiomyopathy (aSHR 1.15, 95% CI: 0.61–2.18, P = 0.66). No differences were observed regarding 30 day mortality, treated and hospitalized acute rejection, and 30 day death from graft failure after HT. Thirty-day mortality did not improve significantly in more recent HT eras whereas there was a trend towards improved 1 year mortality in the latest HT era (P = 0.06). Data from the single-centre case review showed excellent long-term outcomes with sirolimus-based immunosuppression. Conclusions Short-term and long-term post HT outcomes among patients with sarcoid cardiomyopathy are similar to those with common types of non-ischaemic cardiomyopathy.

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.

Abstract Background A higher serum phosphorus level, although within the normal range has been linked to coronary artery and aortic calcification in the non-transplant population. Coronary calcification is mostly associated with donor-derived lesions, and is uncommon within the first years after heart transplantation. Purpose We aimed to investigate the association of phosphorus levels with plaque calcification after heart transplantation. Methods A total of 156 patients who underwent virtual histology intravascular ultrasound (VH-IVUS) studies for cardiac allograft vasculopathy (CAV) surveillance and had fasting serum phosphorus levels &lt;4.5 mg/dL, were included in the analyses. IVUS analyses were performed in the proximal left anterior descending artery, and plaque composition of dense calcium (DC) was evaluated using VH-IVUS, and presented as percent DC of total plaque volume. The patients were separated into 3 groups according to tertiles of serum phosphorus levels. Results Mean recipient and donor ages were 54±13 and 31±14 years, respectively. Mean serum phosphorus in recipients was 3.5±0.6 mg/dL, with median time after transplantation at the IVUS studies of 6 (3,10) years. There were no significant differences in %DC between phosphorus tertiles in patients who underwent IVUS within 6 years after transplantation (p=0.11, Fig. 1A). However, beyond 6 years after transplantation, we observed an incremental association between phosphorus levels and the extent of calcification (p=0.02, Fig. 1B). In this group, serum phosphorus levels significantly correlated with %DC (standardized β=0.29, P=0.008), and this correlation remained significant after adjustment for donor age, recipient age, and eGFR (standardized β=0.26, P=0.001). Conclusion Higher serum phosphorus levels were associated with a level-dependent increase in calcified coronary artery plaque in patients starting 6 years post heart transplant. Long-term exposure to higher serum phosphorus, even within the normal range, might promote plaque calcification after heart transplantation. Funding Acknowledgement Type of funding sources: None.

Abstract Background An artificial intelligence (AI) algorithm detecting age from 12-lead ECG has been suggested to signal “physiological age” of the individual. Importantly, increased physiological age gauged by an increased difference between ECG-age and chronological age has been associated with higher risk of cardiac events in non-transplant population. Purpose We sought to investigate the validity of the AI-derived ECG-age algorithm in patients who underwent heart transplantation and its relationship to major adverse cardiovascular events (MACE). Methods A total of 489 consecutive patients who had undergone heart transplantation in our institution between 1994 and 2018 were studied. AI-ECG age was calculated by a previously-trained artificial intelligence (AI) algorithm using a 12-lead ECG per patient. ECGs used in the training process of the algorithm were excluded. The average of the ECG-ages within one year before and one year after heart transplantation was used to represent pre- and post-transplant ECG-ages. MACE was defined as any incidence of revascularization, re-transplantation, and death. Results Pre-transplant ECG-age (mean 63±10 years) correlated significantly with recipient chronological age (mean 50±13 years, r=0.57, p&lt;0.0001), but this correlation between recipient and ECG-ages was weakened after transplantation (mean post-transplant ECG age of 55±10 years, r=0.34, p&lt;0.0001). Interestingly, post-transplant ECG-age correlated significantly with donor age (mean ECG age of 55±10 years vs. mean donor age of 32±13 years, r=0.42, p&lt;0.0001). During a median (IQR) follow-up of 9 (5, 14) years, 251 patients had MACE. Mean change in ECG age after transplantation compared to before was −8.8±12.7 years. Patients who had an increase in ECG-age after compared to before transplantation showed increased risk of MACE (HR: 1.53 [1.16, 2.01], p=0.002), independent of recipient and donor ages (adjusted HR: 1.68 [1.26, 2.25], p=0.001); whereas there were no significant differences in risk of MACE in patients who were transplanted with an older donor heart (HR: 1.07 [0.77, 1.50], p=0.66). In a Kaplan Meier survival analysis, those with increased ECG-age after transplantation had significantly lower MACE-free survival compared to those with decreased ECG-age. (Log-rank P=0.002; Wilcoxon P=0.001) (Figure) Conclusion Post-transplant ECG-age correlates more faithfully with the donor's than the recipient's chronological age, suggesting that ECG-age more closely reflects cardiac age than the patient age. Furthermore, ECG-age derived cardiac aging after transplantation is associated with higher risk of MACE. Funding Acknowledgement Type of funding sources: None.

Abstract Aims Cardiac allograft vasculopathy (CAV) is the major cause of increased morbidity and mortality after heart transplantation. Peripheral endothelial dysfunction (PED) is associated with early atherosclerosis and future risk of major adverse cardiovascular events (MACE) in non-heart transplant population. We aimed to investigate the association of PED with future MACE, and plaque progression assessed by intravascular ultrasound (IVUS) after heart transplantation. Methods and results We included 66 transplant patients who underwent serial IVUS surveillance for CAV and baseline assessment of peripheral endothelial function using reactive hyperaemia peripheral arterial tonometry. PED was defined as reactive hyperaemia index &lt; 2. The primary endpoint of the study was to investigate the association of PED with CAV progression assessed by intravascular ultrasound (IVUS). CAV progression was assessed as the change (Δ) in plaque volume divided by segment length, and Δ plaque index (plaque volume/vessel volume), adjusted for the time between IVUS measurements (median 3.0 [2.2, 3.1] years). The secondary endpoint was to investigate the association between PED and future MACE, which was defined as any incident of revascularization, heart failure hospitalization, stroke, myocardial infarction, re-transplantation, and death. Patients with PED (n = 27) had more yearly plaque progression (0.50 ± 0.66 vs. 0.15 ± 0.50 mm3/mm/year, P = 0.02) and a higher Δ plaque index (2.41 ± 2.53% vs. 0.69 ± 2.22%, P = 0.01). Patients with PED were more likely to experience MACE during a median follow-up of 8.2 years (interquartile range [7.6, 8.4]), after adjustment for potential cofounders such as age, high-density lipoprotein cholesterol levels, total rejection score, baseline International Society for Heart & Lung Transplantation CAV grade, and indication of transplantation. (hazard ratio 2.15, 95% confidence interval [1.09, 4.23], P = 0.03). Conclusions Peripheral endothelial dysfunction is associated with increased plaque progression and adverse long-term cardiovascular outcomes in transplant patients. PED assessment might be a useful clinical tool for risk stratification after heart transplantation.

The World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO 2017) included updated criteria for diagnosis and classification of post-transplant lymphoproliferative disorders (PTLDs). This study evaluated the clinicopathologic spectrum using WHO 2017 criteria and adult PTLD patients’ outcomes over 30 years between 1987 and 2017 at Mayo Clinic (Rochester, MN). Patients were retrospectively reviewed for clinical features, outcomes, and diagnostic pathology material and classified based on WHO 2017 criteria. A total of 227 patients were diagnosed with PTLD, with a median time from transplant to PTLD of 45 months. PTLD occurred >1 year after transplant in 149 (66%) patients. Monomorphic PTLD was the most common subtype (173, 76%), with diffuse large B cell lymphoma as the commonest morphology (n = 137). Epstein-Barr virus was positive in 61% of total cases and 90% of PTLD that developed within 1 year from transplant. The median event-free survival (EFS) and overall survival for the entire cohort were 21 months (95% confidence interval [CI]: 9–35) and 82 months (95% CI: 39–115), respectively. The EFS or overall survival was not impacted by Epstein-Barr virus status but differed based on WHO subtypes and year of diagnosis. Management changed over time with increased use of rituximab or chemotherapy + immunosuppression reduction as initial therapy. When compared to the matched general population and de novo diffuse large B cell lymphoma, patients not achieving EFS 24 status (no progression/treatment or death within 24 mo of diagnosis) had a worse standardized mortality ratio 16.75 (95% CI: 13.91–20) versus SMR 1.72 (95% CI: 1.26–2.28) in those who achieved EFS24. Cause of death was mostly attributed to non-lymphoma–related causes in those achieving EFS 24.

Background and Purpose: Less is known about the risk factors and outcomes associated with stroke in the current era of increasing heart transplantation (HT) being performed in older patients. The impact of immunosuppression on risk of stroke has not yet been previously studied. We aimed to determine the incidence, risk factors and outcomes of stroke after HT. Methods: We retrospectively analyzed the incidence of ischemic and hemorrhagic strokes and associated outcomes in all consecutive HT recipients transplanted between 1994 and 2016 at a single institution. Results: Of 529 patients who underwent HT, 57 (10.7%) developed stroke, 8.1% had an ischemic events and (2.6%) had a hemorrhagic stroke. Age at HT (adjusted hazard ratio [HR] 1.33; P =0.03) and diabetes (HR, 2.60; P =0.02) were associated with increased risk of ischemic events. Patients with stroke (any type) were more likely to have worse kidney function (HR, 1.81; P =0.02) whereas patients with ischemic events were more likely to undergo combined organ transplantation (HR, 2.01; P =0.05). Cytomegalovirus infection was found to be associated with increased risk of any stroke (HR, 2.09; P =0.02).Conversion from calcineurin inhibitor to sirolimus-based immunosuppression was not found to be associated with a significant change in stroke risk (HR, 1.39; P =0. 45) compared with calcineurin inhibitor maintenance therapy. Stroke of any type and ischemic events were independently associated with increased risk of death (HR, 1.90; P =0.001 and HR, 2.14; P <0.001, respectively). Conclusions: Stroke after HT is associated with increased mortality. Older age at HT, diabetes, renal dysfunction, and CMV infection were associated with greater risk of stroke.

Abstract 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.