Cardiac Allograft Vasculopathy: Challenges and Advances in Invasive and Non-Invasive Diagnostic Modalities.

Cardiac allograft vasculopathy (CAV) is a distinct form of coronary artery disease that represents a major cause of death beyond the first year after heart transplantation. The pathophysiology of CAV is still not completely elucidated; it involves progressive circumferential wall thickening of both the epicardial and intramyocardial coronary arteries. Coronary angiography is still considered the gold-standard test for the diagnosis of CAV, and intravascular ultrasound (IVUS) can detect early intimal thickening with improved sensitivity. However, these tests are invasive and are unable to visualize and evaluate coronary microcirculation. Increasing evidence for non-invasive surveillance techniques assessing both epicardial and microvascular components of CAV may help improve early detection. These include computed tomography coronary angiography (CTCA), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and vasodilator stress myocardial contrast echocardiography perfusion imaging. This review summarizes the current state of diagnostic modalities and their utility and prognostic value for CAV and also evaluates emerging tools that may improve the early detection of this complex disease.

Suppression of IL-1ß promotes beneficial accumulation of fibroblast-like cells in atherosclerotic plaques in clonal hematopoiesis.

Clonal hematopoiesis (CH) is an independent risk factor for atherosclerotic cardiovascular disease. Murine models of CH suggest a central role of inflammasomes and IL-1ß in accelerated atherosclerosis and plaque destabilization. Here we show using single-cell RNA sequencing in human carotid plaques that inflammasome components are enriched in macrophages, while the receptor for IL-1ß is enriched in fibroblasts and smooth muscle cells (SMCs). To address the role of inflammatory crosstalk in features of plaque destabilization, we conducted SMC fate mapping in Ldlr-/- mice modeling Jak2VF or Tet2 CH treated with IL-1ß antibodies. Unexpectedly, this treatment minimally affected SMC differentiation, leading instead to a prominent expansion of fibroblast-like cells. Depletion of fibroblasts from mice treated with IL-1ß antibody resulted in thinner fibrous caps. Conversely, genetic inactivation of Jak2VF during plaque regression promoted fibroblast accumulation and fibrous cap thickening. Our studies suggest that suppression of inflammasomes promotes plaque stabilization by recruiting fibroblast-like cells to the fibrous cap.

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.

Oxidized Phospholipids Promote NETosis and Arterial Thrombosis in LNK(SH2B3) Deficiency.

BACKGROUND: LNK/SH2B3 inhibits Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling by hematopoietic cytokine receptors. Genome-wide association studies have shown association of a common single nucleotide polymorphism in LNK (R262W, T allele) with neutrophilia, thrombocytosis, and coronary artery disease. We have shown that LNK(TT) reduces LNK function and that LNK-deficient mice display prominent platelet-neutrophil aggregates, accelerated atherosclerosis, and thrombosis. Platelet-neutrophil interactions can promote neutrophil extracellular trap (NET) formation. The goals of this study were to assess the role of NETs in atherosclerosis and thrombosis in mice with hematopoietic Lnk deficiency. METHODS: We bred mice with combined deficiency of Lnk and the NETosis-essential enzyme PAD4 (peptidyl arginine deiminase 4) and transplanted their bone marrow into Ldlr-/- mice. We evaluated the role of LNK in atherothrombosis in humans and mice bearing a gain of function variant in JAK2 (JAK2V617F). RESULTS: Lnk-deficient mice displayed accelerated carotid artery thrombosis with prominent NETosis that was completely reversed by PAD4 deficiency. Thrombin-activated Lnk-/- platelets promoted increased NETosis when incubated with Lnk-/- neutrophils compared with wild-type platelets or wild-type neutrophils. This involved increased surface exposure and release of oxidized phospholipids (OxPL) from Lnk-/- platelets, as well as increased priming and response of Lnk-/- neutrophils to OxPL. To counteract the effects of OxPL, we introduced a transgene expressing the single-chain variable fragment of E06 (E06-scFv). E06-scFv reversed accelerated NETosis, atherosclerosis, and thrombosis in Lnk-/- mice. We also showed increased NETosis when human induced pluripotent stem cell-derived LNK(TT) neutrophils were incubated with LNK(TT) platelet/megakaryocytes, but not in isogenic LNK(CC) controls, confirming human relevance. Using data from the UK Biobank, we found that individuals with the JAK2VF mutation only showed increased risk of coronary artery disease when also carrying the LNK R262W allele. Mice with hematopoietic Lnk+/- and Jak2VF clonal hematopoiesis showed accelerated arterial thrombosis but not atherosclerosis compared with Jak2VFLnk+/+ controls. CONCLUSIONS: Hematopoietic Lnk deficiency promotes NETosis and arterial thrombosis in an OxPL-dependent fashion. LNK(R262W) reduces LNK function in human platelets and neutrophils, promoting NETosis, and increases coronary artery disease risk in humans carrying Jak2VF mutations. Therapies targeting OxPL may be beneficial for coronary artery disease in genetically defined human populations.

Electromagnetic interference from left ventricular assist device in patients with transvenous implantable cardioverter-defibrillator.

BACKGROUND: Many advanced heart failure patients have both a left ventricular assist device (LVAD) and an implantable cardioverter-defibrillator (ICD). This study examines incidence, clinical impact, and management of LVAD-related EMI. METHODS: We performed a three-center retrospective analysis of transvenous ICD implanted patients with LVAD implanted between January 1, 2005 and December 31, 2020. The primary outcome was EMI after LVAD implantation, categorized as LVAD-related noise or telemetry interference. RESULTS: The rate of LVAD-related EMI among the 737 patients (mean age 58.6 ± 12.8 years) studied was 5.0%. Telemetry interference (1.5%) compromised ICD interrogation in all patients. This was resolved successfully with use of a metal shield, encased wand, radiofrequency tower, different ICD programmer or by increasing distance between ICD programmer and LVAD (n = 6). ICD replacement was required to reestablish successful communication in three patients. LVAD-related noise (3.5%) led to oversensing (n = 4), inappropriate mode switches (n = 4), noise reversion (n = 3), inhibition of pacing (n = 2), inappropriate detection as atrial fibrillation (AF) (n = 2) and inappropriate detection as ventricular tachycardia (VT) and/or ventricular fibrillation (VF) (n = 2). This noise interference persisted (n = 3), resolved spontaneously (n = 16), resolved with programming change (n = 6) or required lead revision (n = 1). CONCLUSIONS: EMI from LVAD impacts ICD function, although, the incidence rate is low. Physicians implanting both, LVAD in patients with ICD (more common) or ICD in patients with LVAD, should be aware of possible interferences. Telemetry failure not resolved by metal shielding was overcome by ICD generator replacement to a different manufacturer. In most cases, LVAD-related noise resolves spontaneously.

Successful Treatment of Steroid-Refractory Checkpoint Inhibitor Myocarditis with Globulin Derived-Therapy: A Case Report and Literature Review.

Immune checkpoint inhibitor (ICI) monoclonal antibody drugs are an important interface of immunology and cancer biology with the intended goal to create cancer specific treatments with less systemic toxicity. Recognition of immune-related adverse events is critical and these include significant cardiovascular toxicity and myocarditis. Compared with other immune-related events, ICI associated myocarditis is rare but is associated with high mortality. The majority of cases present early in the course of therapy and patients can rapidly progress to fulminant myocarditis. Initially, the mainstay of treatment in patients with ICI-associated myocarditis is immunosuppressive therapy with glucocorticoids. For those who do not respond to steroids, the optimal treatment is unclear. This review summarizes the potential adjunctive treatment options for patients with steroid-refractory myocarditis by illustrating a case of myocarditis that was treated with Thymoglobulin and immunoglobulin.

The AIM2 inflammasome exacerbates atherosclerosis in clonal haematopoiesis.

Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors1. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2V617F (JAK2VF) mutation, which increases JAK-STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease1,2. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1ß reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1ß or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.

Machine learning helps predict long-term mortality and graft failure in patients undergoing heart transplant.

OBJECTIVE: We aimed to develop a risk prediction model using a machine learning to predict survival and graft failure (GF) 5 years after orthotopic heart transplant (OHT). METHODS: Using the International Society of Heart and Lung Transplant (ISHLT) registry data, we analyzed 15,236 patients who underwent OHT from January 2005 to December 2009. 342 variables were extracted and used to develop a risk prediction model utilizing a gradient-boosted machine (GBM) model to predict the risk of GF and mortality 5 years after hospital discharge. After excluding variables missing at least 50% of the observations and variables with near zero variance, 87 variables were included in the GBM model. Ten fold cross-validation repeated 5 times was used to estimate the model's external performance and optimize the hyperparameters simultaneously. Area under the receiver operator characteristic curve (AUC) for the GBM model was calculated for survival and GF 5 years post-OHT. RESULTS: The median duration of follow-up was 5 years. The mortality and GF 5 years post-OHT were 27.3% (n = 4161) and 28.1% (n = 4276), respectively. The AUC to predict 5-year mortality and GF is 0.717 (95% CI 0.696-0.737) and 0.716 (95% CI 0.696-0.736), respectively. Length of stay, recipient and donor age, recipient and donor body mass index, and ischemic time had the highest relative influence in predicting 5-year mortality and graft failure. CONCLUSION: The GBM model has a good accuracy to predict 5-year mortality and graft failure post-OHT.

Incidence, Risk Factors, and Trends for Postheart Transplantation Diabetes Mellitus.

This retrospective study analyzed glycemic trends, incidence of post-transplant diabetes mellitus (PTDM) incidence and associated risk factors in a cohort of patients who underwent first-time heart transplantation (HT). Univariate analyses compared patient with and without pretransplant diabetes mellitus (DM). Multivariate regression analyses were conducted to determine association between PTDM and different risk factors. Finally, trends in glucometrics and other outcomes are described across follow-up time points. There were 152 patients who underwent HT between 2010 and 2015, 109 of whom had no pretransplant history of DM. PTDM incidence was 38% by the 1-year follow-up. Pretransplant body mass index (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.01 to 1.23, p = 0.03), insulin use during the final 24 hours of inpatient stay (OR 4.26, 95% CI 1.72 to 10.56, p <0.01), mean inpatient glucose (OR 2.21, 95% CI 1.33 to 3.69, p <0.01), and mean glucose in the final 24 hours before discharge (OR 1.29, 95% CI 1.03 to 1.60, p = 0.03) were associated with increased odds of PTDM at 1 year. In patients on insulin before discharge, blood glucose values were significantly higher compared with those who were not (136 mg/dl vs 114 mg/dl at 1 to 3 months, 112 vs 100 at 4 to 6 months, 109 vs 98 at 8 to 12 months, all p <0.01). This analysis improves understanding of PTDM incidence, glucometric trends, and risk differences by DM status in the HT population. Similar to liver and kidney patients, inpatient glucometrics may be informative of PTDM risk in HT patients. Guidelines for this population should be developed to account for risk heterogeneity and need for differential management.

Adriamycin-associated cardiomyopathy: where are we now? updates in pathophysiology, dose recommendations, prognosis, and outcomes.

PURPOSE OF REVIEW: Advances in cancer treatments have resulted in significant improvements in survival. Anthracycline chemotherapeutics play a major role in the treatment of hematologic malignancies and solid tumors; however, there is a risk of anthracycline cardiomyopathy in survivors. This focused review will provide a historical context on anthracycline cardiomyopathy and will also review pathophysiologic mechanisms of cardiotoxicity, dosage recommendations, prognosis, and outcomes. RECENT FINDINGS: Anthracycline inhibition of topoisomerase 2ß in cardiomyocytes is believed to be the dominant mechanism of anthracycline-related cardiotoxicity. Emerging data suggest that downregulation of the RNA-binding protein quaking 5 may also be contributing. There is continued lack of agreement regarding what dosage of anthracycline is associated with the highest risk of cardiotoxicity. SUMMARY: Ongoing research into the mechanisms of anthracycline cardiotoxicity is warranted to allow for the development of targeted preventive therapies. A consensus definition of anthracycline cardiomyopathy will facilitate analyses of existing data and allow for the conduction of prospective clinical trials in this area.

Chylopericardium following orthotopic lung transplantation.

Chylopericardium is an uncommon condition, reported to occur following routine cardiac surgery, orthotopic heart transplantation, cardiac trauma, intrathoracic tumors, or infection. It has not, to date, been reported following uncomplicated orthotopic lung transplantation. This article describes chylopericardium following bilateral orthotopic lung transplantation.

Characteristics and survival of patients with chemotherapy-induced cardiomyopathy undergoing heart transplantation.

BACKGROUND: New anti-neoplastic drugs have improved survival of cancer patients but have also been associated with chemotherapy-induced cardiomyopathy (CCMP), ultimately requiring orthotopic heart transplantation (OHT). We conducted this study to describe the clinical characteristics and outcomes of patients with CCMP treated with OHT and compare them with outcomes of patients with other forms of non-ischemic cardiomyopathy (NICMP). METHODS: We retrospectively identified 232 CCMP patients and 8,890 NICMP patients from the International Society of Heart and Lung Transplantation Registry who underwent OHT between January 2000 and December 2008. Survival rates were calculated using the Kaplan-Meier method. Categoric characteristics and outcomes groups were compared using the χ(2) and Fisher exact test. Comparisons for continuous variables were made using Wilcoxon-Mann-Whitney test. Multivariable analyses of predictors of survival were performed using Cox proportional hazard regression analysis. RESULTS: Short-term and long-term post-transplant survival of the 232 CCMP patients was similar to the 8,890 NICMP patients (p = 0.19). Survival (95% confidence interval) at 1, 3, and 5 years was, respectively, 86% (0.81-0.91), 79% (0.76-0.87), and 71% 0.73-0.85) in the CCMP patients and 87% (0.86-0.88), 81% (0.82-0.84), and 74% (0.80-0.81) in the NICMP patients (p = 0.19). Compared with NICMP patients, CCMP patients had higher rates of post-OHT infection (22% vs 14%, p = 004) and malignancies (5% vs 2%, p = 0.006), but neither affected survival. There was only 1 malignancy recurrence in the CCMP patients and no differences in post-OHT death due to malignancies between the groups. Importantly, CCMP patients were twice as likely as NICMP patients to require right ventricular assist devices before OHT (5.6% vs 2.3%, p = 0.0021). CONCLUSIONS: Patients with CCMP selected for OHT are younger, have less comorbidity, and are more likely to require biventricular mechanical support pre-OHT than other NICMP patients who receive allografts. Despite the higher incidence of malignancy and infection in CCMP patients who have received a heart transplant, their survival is comparable to those who receive allografts for other cardiomyopathies.