Keeping immune checkpoint inhibitor myocarditis in check: advanced circulatory mechanical support as a bridge to recovery.

Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare, potentially life-threatening complication of immunotherapy. We report a case of a 60-year-old female with a history of colorectal cancer treated with nivolumab immunotherapy who presented with new cardiomyopathy complicated by cardiogenic shock and ventricular arrhythmias. Treatment of ICI-associated myocarditis requires aggressive immunosuppression and supportive therapy. In this case, the patient required advanced mechanical circulatory support as a bridge to recovery. This case highlights the complexity of diagnosis, haemodynamic management, and treatment of fulminant ICI myocarditis.

Heart transplantation in the early phase of the COVID-19 pandemic: A single-center case series.

The infectious disease coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization in March 2020. The impact of COVID-19 on solid organ transplantations, including heart transplantation, is currently unclear. Many transplant programs have been forced to swiftly re-evaluate and adapt their practices, leading to a marked decrease in transplants performed. This trend has been due to various factors, including increased donor COVID-19 screening scrutiny and recipient waiting list management in anticipation of COVID-19 critical care surge capacity planning. In the face of these unknown variables, determining when and how to proceed with transplantation in our population of patients with end-stage cardiomyopathies is challenging. Here, we describe our center's experience with orthotopic heart transplantation (OHT) in one of the country's pandemic epicenters, where we performed eight OHTs in the first 2 months after community spread began in late February 2020.

Discovery of non-HLA antibodies associated with cardiac allograft rejection and development and validation of a non-HLA antigen multiplex panel: From bench to bedside.

We analyzed humoral immune responses to nonhuman leukocyte antigen (HLA) after cardiac transplantation to identify antibodies associated with allograft rejection. Protein microarray identified 366 non-HLA antibodies (>1.5 fold, P < .5) from a discovery cohort of HLA antibody-negative, endothelial cell crossmatch-positive sera obtained from 12 cardiac allograft recipients at the time of biopsy-proven rejection. From these, 19 plasma membrane proteins and 10 autoantigens identified from gene ontology analysis were combined with 48 proteins identified through literature search to generate a multiplex bead array. Longitudinal sera from a multicenter cohort of adult cardiac allograft recipients (samples: n = 477 no rejection; n = 69 rejection) identified 18 non-HLA antibodies associated with rejection (P < .1) including 4 newly identified non-HLA antigenic targets (DEXI, EMCN, LPHN1, and SSB). CART analysis showed 5/18 non-HLA antibodies distinguished rejection vs nonrejection. Antibodies to 4/18 non-HLA antigens synergize with HLA donor-specific antibodies and significantly increase the odds of rejection (P < .1). The non-HLA panel was validated using an independent adult cardiac transplant cohort (n = 21 no rejection; n = 42 rejection, >1R) with an area under the curve of 0.87 (P < .05) with 92.86% sensitivity and 66.67% specificity. We conclude that multiplex bead array assessment of non-HLA antibodies identifies cardiac transplant recipients at risk of rejection.

Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients.

BACKGROUND: Donor-specific HLA antibodies (DSA) are associated with increased rates of rejection and of graft failure in cardiac transplantation. The goal of this study was to determine the association of preformed and posttransplant development of newly detected DSA (ndDSA) with antibody-mediated rejection (AMR) and characterize the clinical relevance of complement-activating DSA in heart allograft recipients. METHODS: The study included 128 adult and 48 pediatric heart transplant patients transplanted between 2010 and 2013. Routine posttransplant HLA antibody testing was performed by IgG single-antigen bead test. The C3d single-antigen bead assay was used to identify complement-activating antibodies. Rejection was diagnosed using International Society for Heart and Lung Transplantation criteria. RESULTS: In this study, 22 patients were transplanted with preexisting DSA, and 43 patients developed ndDSA posttransplant. Pretransplant (P < 0.05) and posttransplant (P < 0.001) ndDSA were associated with higher incidence of AMR. Patients with C3d + DSA had significantly higher incidence of AMR compared with patients with no DSA (P < 0.001) or patients with C3d-DSA (P = 0.02). Nine (36%) of 25 patients with AMR developed transplant coronary artery disease compared with 17 (15.9%) of 107 patients without AMR (P < 0.05). Among the 47 patients who received ventricular assistant device (VAD), 7 of 9 VAD+ patients with preformed DSA experienced AMR compared with 7 of 38 VAD+ patients without preformed DSA, indicating presensitization to donor HLA significantly increased the risk of AMR (P < 0.01). CONCLUSIONS: Preformed and posttransplant ndDSA were associated with AMR. C3d + DSA correlates with complement deposition on the graft and higher risk of AMR which may permit the application of personalized immunotherapy targeting the complement pathway.

Clinical phenomapping and outcomes after heart transplantation.

BACKGROUND: Survival after heart transplantation (HTx) is limited by complications related to alloreactivity, immune suppression, and adverse effects of pharmacologic therapies. We hypothesize that time-dependent phenomapping of clinical and molecular data sets is a valuable approach to clinical assessments and guiding medical management to improve outcomes. METHODS: We analyzed clinical, therapeutic, biomarker, and outcome data from 94 adult HTx patients and 1,557 clinical encounters performed between January 2010 and April 2013. Multivariate analyses were used to evaluate the association between immunosuppression therapy, biomarkers, and the combined clinical end point of death, allograft loss, retransplantation, and rejection. Data were analyzed by K-means clustering (K = 2) to identify patterns of similar combined immunosuppression management, and percentile slopes were computed to examine the changes in dosages over time. Findings were correlated with clinical parameters, human leucocyte antigen antibody titers, and peripheral blood mononuclear cell gene expression of the AlloMap (CareDx, Inc., Brisbane, CA) test genes. An intragraft, heart tissue gene coexpression network analysis was performed. RESULTS: Unsupervised cluster analysis of immunosuppressive therapies identified 2 groups, 1 characterized by a steeper immunosuppression minimization, associated with a higher likelihood for the combined end point, and the other by a less pronounced change. A time-dependent phenomap suggested that patients in the group with higher event rates had increased human leukocyte antigen class I and II antibody titers, higher expression of the FLT3 AlloMap gene, and lower expression of the MARCH8 and WDR40A AlloMap genes. Intramyocardial biomarker-related coexpression network analysis of the FLT3 gene showed an immune system-related network underlying this biomarker. CONCLUSIONS: Time-dependent precision phenotyping is a mechanistically insightful, data-driven approach to characterize patterns of clinical care and identify ways to improve clinical management and outcomes.

Emerging pharmacologic and structural therapies for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is the most common inherited heart disease. Although it was first described over 50 years ago, there has been little in the way of novel disease-specific therapeutic development for these patients. Current treatment practice largely aims at symptomatic control using old drugs made for other diseases and does little to modify the disease course. Septal reduction by surgical myectomy or percutaneous alcohol septal ablation are well-established treatments for pharmacologic-refractory left ventricular outflow tract obstruction in hypertrophic cardiomyopathy patients. In recent years, there has been a relative surge in the development of innovative therapeutics, which aim to target the complex molecular pathophysiology and resulting hemodynamics that underlie hypertrophic cardiomyopathy. Herein, we review the new and emerging therapeutics for hypertrophic cardiomyopathy, which include pharmacologic attenuation of sarcomeric calcium sensitivity, allosteric inhibition of cardiac myosin, myocardial metabolic modulation, and renin-angiotensin-aldosterone system inhibition, as well as structural intervention by percutaneous mitral valve plication and endocardial radiofrequency ablation of septal hypertrophy. In conclusion, while further development of these therapeutic strategies is ongoing, they each mark a significant and promising advancement in treatment for hypertrophic cardiomyopathy patients.

Cardiac Amyloidosis: Diagnosis and Treatment Strategies.

Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective.

Heart Failure Therapies for End-Stage Chemotherapy-Induced Cardiomyopathy.

With ongoing advancements in cancer-related treatments, the number of cancer survivors continues to grow globally, with numbers in the United States predicted to reach 18 million by 2020. As a result, it is expected that a greater number of patients will present with chemotherapy-related side effects. One entity in particular, chemotherapy-related cardiomyopathy (CCMP), is a known cardiotoxic manifestation associated with agents such as anthracyclines, trastuzumab, and tyrosine kinase inhibitors. Although such effects have been described in the medical literature for decades, concrete strategies for screening, prevention, and management of CCMP continue to be elusive owing to limited studies. Late recognition of CCMP is associated with a poorer prognosis, including a lack of clinical response to pharmacologic therapy, and end-stage heart failure. A number of advanced cardiac therapies, including cardiac resynchronization therapy, ventricular assist devices, and orthotopic cardiac transplantation, are available to for end-stage heart failure; however, the role of these therapies in CCMP is unclear. In this review, management of end-stage CCMP with the use of advanced therapies and their respective effectiveness are discussed, as well as clinical characteristics of patients undergoing these treatments. The relative paucity of data in this field highlights the importance and need for larger-scale longitudinal studies and long-term registries tracking the outcomes of cancer survivors who have received cardiotoxic cancer therapy to determine the overall incidence of end-stage CCMP, as well as prognostic factors that will ultimately guide such patients toward receiving appropriate end-stage care.

Outcomes of biventricular mechanical support patients discharged to home to await heart transplantation.

BACKGROUND: The use of left ventricular assist devices has grown rapidly in recent years for patients with end-stage heart failure. A significant proportion of patients require both left- and right-sided support with biventricular assist devices (BiVADs) as a bridge to transplantation. Traditionally, these patients have waited in the hospital until they receive a transplant. PURPOSE: The aim of this study was to characterize the clinical course of BiVAD patients discharged to home to await heart transplantation. METHODS: Between November 2009 and July 2011, 24 adult patients underwent Thoratec paracorporeal BiVAD placement at the University of California Los Angeles, all with an Interagency Registry for Mechanically Assisted Circulatory Support score 1 or 2. The disposition, complications, and rehospitalizations of these subjects were retrospectively reviewed. RESULTS: Fourteen of the 24 patients were successfully discharged to home, with a mean time of 60 ± 27 days from BiVAD implantation to discharge. Ninety-three percent (13/14) of the patients sent home went on to be transplanted. Eleven of the 14 (79%) came in from home to receive their transplant. The mean time from BiVAD implantation to transplantation was 100 ± 65 days. Of the 14 patients discharged to home, there were 18 readmissions in 8 patients. CONCLUSION: In this small single-center review, we found that complex medical patients with BiVADs can be discharged to home and can await a heart transplant from home under the close management of multidisciplinary acute care and outpatient teams.

Free fatty acid impairment of nitric oxide production in endothelial cells is mediated by IKKbeta.

OBJECTIVE: Free fatty acids (FFA) are commonly elevated in diabetes and obesity and have been shown to impair nitric oxide (NO) production by endothelial cells. However, the signaling pathways responsible for FFA impairment of NO production in endothelial cells have not been characterized. Insulin receptor substrate-1 (IRS-1) regulation is critical for activation of endothelial nitric oxide synthase (eNOS) in response to stimulation by insulin or fluid shear stress. METHODS AND RESULTS: We demonstrate that insulin-mediated tyrosine phosphorylation of IRS-1 and serine phosphorylation of Akt, eNOS, and NO production are significantly inhibited by treatment of bovine aortic endothelial cells with 100 micromol/L FFA composed of palmitic acid for 3 hours before stimulation with 100 nM insulin. This FFA preparation also increases, in a dose-dependent manner, IKKbeta activity, which regulates activation of NF- kappaB, a transcriptional factor associated with inflammation. Similarly, elevation of other common FFA such as oleic and linoleic acid also induce IKKbeta activation and inhibit insulin-mediated eNOS activation. Overexpression of a kinase inactive form of IKKbeta blocks the ability of FFA to inhibit insulin-dependent NO production, whereas overexpression of wild-type IKKbeta recapitulates the effect of FFA on insulin-dependent NO production. CONCLUSIONS: Elevated levels of common FFA found in human serum activate IKKbeta in endothelial cells leading to reduced NO production, and thus may serve to link pathways involved in inflammation and endothelial dysfunction.