A change of heart: Characteristics and outcomes of multiple cardiac retransplant recipients.

BACKGROUND: Among heart transplant (HT) recipients who develop advanced graft dysfunction, cardiac re-transplantation may be considered. A smaller subset of patients will experience failure of their second allograft and undergo repeat re-transplantation. Outcomes among these individuals are not well-described. METHODS: Adult and pediatric patients in the United Network for Organ Sharing (UNOS) registry who received HT between January 1, 1990 and December 31, 2020 were included. RESULTS: Between 1990 and 2020, 90 individuals received a third HT and three underwent a fourth HT. Recipients were younger than those undergoing primary HT (mean age 32 years). Third HT was associated with significantly higher unadjusted rates of 1-year mortality (18% for third HT vs. 13% for second HT vs. 9% for primary HT, p < .001) and 10-year mortality (59% for third HT vs. 42% for second HT vs. 37% for primary HT, p < .001). Mortality was highest amongst recipients aged >60 years and those re-transplanted for acute graft failure. Long-term rates of CAV, rejection, chronic dialysis, and hospitalization for infection were also higher. CONCLUSIONS: Third HT is associated with higher morbidity and mortality than primary HT. Further consensus is needed regarding appropriate organ stewardship for this unique subgroup.

Cardio-Renal-Metabolic Outcomes Associated With the Use of GLP-1 Receptor Agonists After Heart Transplantation.

BACKGROUND: The use of glucagon-like-peptide 1 receptor agonists (GLP1-RA) has dramatically increased over the past 5 years for diabetes mellitus type 2 (T2DM) and obesity. These comorbidities are prevalent in adult heart transplant (HT) recipients. However, there are limited data evaluating the efficacy of this drug class in this population. The aim of the current study was to describe cardiometabolic changes in HT recipients prescribed GLP1-RA at a large-volume transplant center. METHODS: We retrospectively reviewed all adult HT recipients who received GLP1-RA after HT for a minimum of 1-month. Cardiometabolic parameters including body mass index (BMI), lipid panel, hemoglobin A1C, estimated glomerular filtration rate (eGFR), and NT-proBNP were compared prior to initiation of the drug and at most recent follow-up. We also evaluated for significant dose adjustments to immunosuppression after drug initiation and adverse effects leading to drug discontinuation. RESULTS: Seventy-four patients were included (28% female, 53% White, 20% Hispanic) and followed for a median of 383 days [IQR 209, 613] on a GLP1-RA. The majority of patients (n = 56, 76%) were prescribed semaglutide. The most common indication for prescription was T2DM alone (n = 33, 45%), followed by combined T2DM and obesity (n = 26, 35%). At most recent follow-up, mean BMI decreased from 33.3 to 31.5 kg/m2 (p < 0.0001), HbA1C from 7.3% to 6.7% (p = 0.005), LDL from 78.6 to 70.3 mg/dL (p = 0.018) and basal insulin daily dose from 32.6 to 24.8 units (p = 0.0002). CONCLUSION: HT recipients prescribed GLP1-RA therapy showed improved glycemic control, weight loss, and cholesterol levels during the study follow-up period. GLP1-RA were well tolerated and were rarely associated with changes in immunosuppression dosing.

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

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

Early post-transplant leukopenia in heart transplant recipients and its impact on outcomes.

BACKGROUND: Leukopenia in the early period following heart transplantation (HT) is not well-studied. The aim of this study was to evaluate risk factors for the development of post-transplant leukopenia and its consequences for HT recipients. METHODS: Adult patients at a large-volume transplant center who received HT between January 1, 2010 and December 31, 2020 were included. The incidence of leukopenia (WBC ≤3 × 103 /µL) in the first 90-days following HT, individual risk factors, and its effect on 1-year outcomes were evaluated. RESULTS: Of 506 HT recipients, 184 (36%) developed leukopenia within 90-days. Median duration of the first leukopenia episode was 15.5 days (IQR 8-42.5 days). Individuals who developed leukopenia had lower pre-transplant WBC counts compared to those who did not (6.1 × 103 /µL vs. 6.9 × 103 /µL, p = .02). Initial immunosuppressive and infectious chemoprophylactic regimens were not significantly different between groups. Early leukopenia was associated with a higher mortality at 1-year (6.6% vs. 2.1%, p = .008; adjusted HR 3.0) and an increased risk of recurrent episodes. Rates of infection and rejection were not significantly different between the two groups. CONCLUSIONS: Leukopenia in the early period following HT is common and associated with an increased risk of mortality. Further study is needed to identify individuals at highest risk for leukopenia prior to transplant and optimize immunosuppressive and infectious chemoprophylactic regimens for this subgroup.

Racial Differences in Val122Ile-Associated Transthyretin Cardiac Amyloidosis.

BACKGROUND: The valine-to-isoleucine substitution (Val122Ile) is the most common variant of transthyretin (TTR) amyloidosis in the United States, affecting primarily individuals of African descent. This variant has been identified recently in a cluster of white individuals in Italy. METHODS AND RESULTS: Clinical phenotype and chamber performance of Black and white individuals with Val122Ile TTR cardiac amyloidosis (ATTR-CA) were compared. Compared to white patients (n = 17), Black individuals (n = 53) had lower systolic blood pressures (110 vs 131 mmHg, <0.001), reduced pulse pressures (41 vs 58 mmHg; P < 0.001), and impaired renal function (eGFR 46 vs 67 mL/min/1.73m2; P < 0.001) at presentation. Systolic properties and arterial elastance were similar. Black patients had end-diastolic pressure-volume relationships that were shifted upward and leftward relative to those of white patients, indicating reduced left ventricular chamber capacitance. Pressure-volume area at a left ventricular end-diastolic pressure of 30 mmHg was lower in Black than in white individuals (8055 mmHg/mL vs 11,538 mmHg/mL; P = 0.008). CONCLUSION: Despite presenting at ages similar to those of white patients, Black individuals with Val122Ile-associated ATTR-CA had a greater degree of cardiac chamber dysfunction at the time of diagnosis due to impaired ventricular capacitance. Whether these differences are attributable to amyloidosis or other cardiovascular disease requires further study.

Letermovir for cytomegalovirus prophylaxis in high-risk heart transplant recipients.

Letermovir is a novel agent for the prevention of cytomegalovirus (CMV) infection and disease that, unlike traditional CMV DNA polymerase inhibitors, does not carry the risk of myelosuppression. The purpose of this study was to evaluate the safety, efficacy, and clinical application of letermovir for CMV prophylaxis in heart transplant (HT) recipients. Between November 1, 2019, and October 1, 2021, at a single, tertiary care hospital, 17 HT recipients were initiated on letermovir due to leukopenia while on valganciclovir. Fifteen (88%) had high-risk mismatch (CMV D+/R-). Median time on letermovir was 5 months (interquartile range, 2-8 months.) At the end of the study period, nine of 17 patients (52.9%) were still on letermovir and four of the 17 (23.5%) had successfully completed the prophylaxis window on letermovir and been switched to the pre-emptive strategy. One patient developed clinically significant CMV viremia in the setting of being unable to obtain medication due to insurance barriers but was later successfully restarted on letermovir. One patient was unable to tolerate letermovir due to symptoms of headache and myalgias. Two patients developed low-level non-clinically significant CMV viremia and were switched back to valacyclovir. All patients had tacrolimus dosages reduced at time of letermovir initiation to minimize the risk of supratherapeutic tacrolimus concentration. One patient required hospitalization due to symptomatic tacrolimus toxicity. For HT recipients who cannot tolerate valganciclovir, letermovir presents an alternative for CMV prophylaxis. Close monitoring for breakthrough CMV and calcineurin inhibitor levels is necessary. Larger studies are required to further delineate its use and help provide further evidence of its safety and efficacy.

Sex Differences in the Phenotype of Transthyretin Cardiac Amyloidosis Due to Val122Ile Mutation: Insights from Noninvasive Pressure-Volume Analysis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CA) is an under-recognized cause of heart failure with preserved ejection fraction. In the United States, the valine-to-isoleucine substitution (Val122Ile) is the most common inherited variant. Data on sex differences in presentation and outcomes of Val122Ile associated ATTR-CA are lacking. METHODS AND RESULTS: In a retrospective, single-center study of 73 patients diagnosed with Val122Ile associated ATTR-CA between 2001 and 2018, sex differences in clinical and echocardiographic data at the time of diagnosis were evaluated. Pressure-volume analysis using noninvasive single beat techniques was used to compare chamber performance. Compared with men (n = 46), women (n = 27) were significantly older at diagnosis, 76 years vs 69 years; P < .001. The end-systolic pressure-volume relationship, 5.1 mm Hg*m2/mL vs 4.3 mm Hg*m2/mL; P = .27, arterial elastance, 5.5 mm Hg*m2/mL vs 5.7 mm Hg*m2/mL; P = .62, and left ventricular capacitance were similar between sexes as was pressure-volume areas indexed to a left ventricular end-diastolic pressure of 30 mm Hg, a measure of overall pump function. The 3-year mortality rates were also similar, 34% vs 43%; P = .64. CONCLUSIONS: Despite being significantly older at time of diagnosis with Val122Ile associated ATTR-CA, women have similar overall cardiac chamber function and rates of mortality to men, suggesting a less aggressive disease trajectory. These findings should be confirmed with longitudinal studies.

Case report of pregnancy complicated by severe pulmonary hypertension from mitral stenosis and placenta accreta spectrum disorder: management of two life-threatening conditions.

Background: Antenatal cardiovascular disease is a major cause of maternal morbidity and mortality. Severe rheumatic mitral stenosis is especially poorly tolerated during pregnancy. Case Summary: We present a young woman with severe pulmonary hypertension secondary to rheumatic mitral stenosis. She presented at 25 weeks 4 days gestation for evaluation of a pregnancy complicated by placenta accreta spectrum disorder. Invasive hemodynamic testing was carried out to delineate her hemodynamics, and a multidisciplinary cardio-obstetrics team collaborated closely with the patient and her partner to create a management plan. Ultimately, the patient was initiated on veno-arterial extracorporeal membrane oxygenation and underwent caesarean section delivery followed by hysterectomy and subsequent valve replacement surgery. Discussion: This case describes the treatment options considered to balance the risk of decompensation in the setting of severe pulmonary hypertension with hemorrhage associated with placenta accreta spectrum disorder. It highlights the importance of a multidisciplinary, team-based approach to the management of high-risk cardiac conditions throughout pregnancy.

Case Report: Rare Presentation of Nodular Fasciitis over Dorsum of Wrist.

Introduction: Nodular fasciitis is a benign, reactive fibroblastic tumor that usually presents as a rapidly growing lesion with occasional involvement of the deep fascia and muscle. We present a case of nodular fasciitis over the dorsum of the wrist. In our knowledge, this is the first reported case of nodular fasciitis at this location in the literature. Case Report: A 33-year-old South Asian male with a desk job, presented with a rapidly growing lesion over the dorsum of the left wrist over 5 months, associated with pain and restriction of dorsiflexion of wrist. The X-ray, ultrasound, and magnetic resonance imaging images were inconclusive and excisional biopsy was done for definitive diagnosis. Conclusion: Nodular fasciitis is a relatively uncommon but important differential diagnosis for any rapid soft-tissue growth. It is a self-limiting proliferative fibroblastic lesion, with excisional biopsy as the gold standard for diagnosis of this condition.

A Case of a Cardiac Hamartoma in Pregnancy: Preconception Through Delivery.

A 32-year-old woman with a large cardiac hamartoma was referred to our institution's cardio-obstetrics group for preconception counseling. Results of hemodynamic testing revealed restrictive physiology. This case highlights the role of multimodality testing in predicting the hemodynamic consequences of pregnancy in the setting of high-risk cardiovascular conditions.

Long-Term Outcomes of Permanent Pacemaker Implantation in Bicaval Heart Transplant Recipients.

BACKGROUND: Permanent pacemakers (PPMs) may be necessary in up to 10% of patients after heart transplantation (HT). OBJECTIVES: The purpose of this study was to evaluate long-term outcomes and clinical courses of heart transplant recipients who received PPM. METHODS: All patients who required PPM after bicaval HT at Columbia University between January 2005 and December 2021 were included. Cases were compared to matched heart transplant recipients by age, sex, and year of transplantation. Patient and device characteristics including complications and device interrogations were reviewed. Outcomes of re-transplantation or graft failure/death were compared between groups. RESULTS: Of 1,082 heart transplant recipients, 41 (3.8%) received PPMs. The median time from transplantation to PPM was 118 days (IQR: 18-920 days). The most common indications were sinus node dysfunction (60%, n = 25) and atrioventricular (AV) nodal disease (41.5%, n = 17). Post-implantation complications included pocket hematoma (n = 3), lead under-sensing (n = 2), and pocket infection requiring explant (n = 1). Rates of death and re-transplantation at 10 years post-HT were similar between groups. In multivariable analysis, after adjustment for mechanical circulatory support, pretransplantation amiodarone use, donor ischemic time and age, only older donor age was associated with increased risk of PPM implantation (P = 0.03). There was a significant decrease in PPM placement after 2018 (1.2% vs 4.4%, P = 0.02), largely driven by a decline in early PPM placement. There were no differences in mortality or need for re-transplantation between groups. CONCLUSIONS: PPMs are implanted after HT for sinus and atrioventricular node dysfunctions with low incidence of device-related complications. Our study shows a decrease in PPM implantation after 2018, likely attributable to expectant management in the early postoperative period.

Sex related differences in exercise performance in patients with hypertrophic cardiomyopathy: Hemodynamic insights through non-invasive pressure volume analysis.

BACKGROUND: Women with HCM have worse cardiopulmonary exercise performance compared to men. We used non-invasive pressure-volume (PV) analysis to delineate sex related hemodynamic differences in HCM. METHODS: PV loops were constructed from echocardiograms using left ventricular (LV) volumes indexed to body surface area, Doppler estimates of LV end-diastolic pressure and blood pressure. The end-systolic PV relationship (ESPVR) and end-diastolic PV relationship (EDPVR) were derived from validated single-beat techniques. The area between the ESPVR and EDPVR (isovolumetric PV area), was indexed to an LV end-diastolic pressure of 30 mmHg (PVAiso30), as the integrated metric of LV function. LV volume at an end-diastolic pressure of 30 mmHg (V30) indexed ventricular capacity. RESULTS: 202 patients were included, 56 women. Women were older (51 vs 44 years, p = 0.012) and had reduced exercise capacity (5.6 vs 6.9 METs, p < 0.001). Only 32 patients (16%) had a peak gradient >30 mmHg at rest with no sex differences. Women had significantly lower indexed PVAiso30 (9094 vs 10,255 mmHg*mL/m2, p = 0.02) driven by reduced ventricular capacitance (V30 54 vs 62 mL/m2, p < 0.001). In multivariable linear regression indexed V30 was an independent predictor of exercise capacity. CONCLUSION: Impaired exercise capacity in women with HCM appears associated with abnormalities in passive diastolic properties, suggesting a unique pathophysiology compared to men, and a potential difference in viable therapeutic molecular targets.

Impact of Pretransplant Malignancy on Heart Transplantation Outcomes: Contemporary United Network for Organ Sharing Analysis Amidst Evolving Cancer Therapies.

BACKGROUND: An aging population and improved cancer survivorship have increased the number of individuals with treated malignancy who develop advanced heart failure. The benefits of heart transplantation (HT) in patients with a pretransplant malignancy (PTM) must be balanced against risks of posttransplant malignancy in the setting of immunosuppression. METHODS: Adult patients in the United Network for Organ Sharing registry who received HT between January 1, 2010, and December 31, 2020 were included. Trends, patient characteristics, and posttransplant outcomes in HT recipients with PTM were evaluated. RESULTS: From 2000 to 2020, the proportion of HT recipients with PTM increased from 3.2% to 8.2%. From 2010 to 2020, 2113 (7.7%) of 27 344 HT recipients had PTM. PTM was associated with higher rates of 1-year mortality after HT (11.9% versus 9.2%; adjusted hazard ratio, 1.25 [95% CI, 1.09-1.44], P=0.001), driven by increased mortality in patients with hematologic PTM (adjusted hazard ratio, 2.00 [95% CI, 1.61-2.48]; P<0.001). For recipients who survived the first year, 5-year survival was similar between patients with and without PTM. Rates of malignancy at 5-years posttransplant were higher in the PTM group (20.4% versus 13.1%; adjusted hazard ratio, 1.57 [95% CI, 1.38-1.79], P<0.001). CONCLUSIONS: Prevalence of PTM in HT recipients nearly tripled over the past 2 decades. Patients with hematologic PTM were at increased risk of early mortality after HT. Patients with PTM were also at higher risk for posttransplant malignancy. Guidelines that reflect contemporary oncological care are needed to inform care of this heterogenous and expanding group of individuals.

C-Reactive Protein Levels Predict Outcomes in Continuous-Flow Left Ventricular Assist Device Patients: An INTERMACS Analysis.

CRP is an established inflammatory biomarker with prognostic value in patients with chronic heart failure, yet its role in continuous-flow left ventricular assist device (LVAD) patients is largely unknown. 5,183 patients from the INTERMACS registry who underwent durable LVAD between 2008 and 2017 and had preimplant CRP levels were included. The sample was stratified into two groups based on preimplant CRP levels: CRP of 0-10 mg/L (low) and >10 mg/L (high). Kaplan-Meier survival estimates were used to assess outcomes at 2 years after LVAD implantation, with log-rank testing used to compare groups. Cox proportional hazard models were used for multivariable adjustment. Patients with high preimplant CRP were younger, more likely to be INTERMACS class I, and had a higher need for temporary mechanical circulatory support before LVAD implant compared to those with lower CRP levels (all P < 0.001). The high CRP group had higher WBC counts and BNP levels (all P < 0.001). After adjustment, higher CRP (>10 mg/L) was associated with greater risk of mortality, RV failure, and stroke postimplant (P < 0.001). In addition, elevated postimplant CRP level at 3 months was associated with increased mortality and stroke on LVAD support (P < 0.001). CRP is a predictor of death and complications on LVAD support. Future studies are necessary to explore the mechanisms underlying this finding and the potential role of antiinflammatory therapies in this population.

Difference in Metabolomic Response to Exercise between Patients with and without Hypertrophic Cardiomyopathy.

It is unclear how hypertrophic cardiomyopathy (HCM) affects cardiac metabolic pathways at rest and with exercise. This case-control study compared 15 cases with HCM to 2 control groups without HCM. Metabolomic profiling of 210 metabolites was carried out at rest and at peak exercise. The 50 most discriminant metabolites differentially regulated during exercise were selected using partial least squares discriminant analysis. Pathway enrichment analysis was also performed. At rest, no significant difference was observed in metabolomic profiling of HCM cases as compared to controls. By contrast, there were significant differences in metabolomic profiling in response to exercise (p < 0.05) in the following metabolic pathways: the aminoacyl-tRNA biosynthesis pathway; the nitrogen metabolism pathway; the glycine, serine, and threonine metabolism pathway; and the arginine and proline metabolism pathway. The present study demonstrates differential regulation of several metabolic pathways in patients with HCM in the setting of exercise stress.

Impact of Induction Immunosuppression on Post-Transplant Outcomes of Patients Bridged with Contemporary Left Ventricular Assist Devices.

For patients bridged to transplant (BTT) with left ventricular assist devices (LVAD), data regarding the use of induction immunosuppressive therapy remain limited. The objectives of the current study were to describe the current trends and clinical consequences of IT in patients BTT with LVAD. The United Network of Organ Sharing database was queried to identify adult, single-organ heart transplant recipients who were BTT with LVAD between 2008 and 2018. Propensity score matching was then used to balance clinical covariates between those patient who did and did not receive IT. The primary outcomes of interest were graft survival, hospitalization for rejection and infection, and freedom from transplant coronary artery disease (TCAD). In the overall cohort, 49.1% (n = 3,978) received IT, with basiliximab being the most commonly used agent followed by antithymocyte globulin. After propensity score matching, 4,388 patients (2,194 without induction and 2,194 with induction) were identified. Between those who did and did not receive IT, there was no significant difference in graft survival, freedom from hospitalization for rejection, and freedom from hospitalization for infection. Patients who received IT experienced increased freedom from TCAD (p = 0.004) with unadjusted hazard ratio of 0.81 (95% Cardiac Index: 0.70-0.93). For freedom from TCAD, antithymocyte globulin was associated with better outcomes than basiliximab (80.2% vs. 73.1% at 5 years, log rank p value = 0.004). In a sensitivity analysis, there was no significant increase in hospitalization for infection in those patients with an infected LVAD before transplant. Use of induction therapy in patients BTT with LVAD appears to be safe and feasible, without a significant increase in the risk of infection or rejection, even in those patients with pretransplant device-related infections. IT, particularly antithymocyte globulin, was associated with increased time to development of TCAD. Routine use of IT in patients BTT with LVAD may be considered, and further randomized control trials are warranted to further support these data.

Pharmacological Agents Targeting Thromboinflammation in COVID-19: Review and Implications for Future Research.

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.