Selective loss of resident macrophage-derived insulin-like growth factor-1 abolishes adaptive cardiac growth to stress.

Hypertension affects one-third of the world's population, leading to cardiac dysfunction that is modulated by resident and recruited immune cells. Cardiomyocyte growth and increased cardiac mass are essential to withstand hypertensive stress; however, whether immune cells are involved in this compensatory cardioprotective process is unclear. In normotensive animals, single-cell transcriptomics of fate-mapped self-renewing cardiac resident macrophages (RMs) revealed transcriptionally diverse cell states with a core repertoire of reparative gene programs, including high expression of insulin-like growth factor-1 (Igf1). Hypertension drove selective in situ proliferation and transcriptional activation of some cardiac RM states, directly correlating with increased cardiomyocyte growth. During hypertension, inducible ablation of RMs or selective deletion of RM-derived Igf1 prevented adaptive cardiomyocyte growth, and cardiac mass failed to increase, which led to cardiac dysfunction. Single-cell transcriptomics identified a conserved IGF1-expressing macrophage subpopulation in human cardiomyopathy. Here we defined the absolute requirement of RM-produced IGF-1 in cardiac adaptation to hypertension.

Impact of ovary-intact menopause in a mouse model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) afflicts over half of all patients with heart failure and is a debilitating and fatal syndrome affecting postmenopausal women more than any other demographic. This bias toward older females calls into question the significance of menopause in the development of HFpEF, but this question has not been probed in detail. In this study, we report the first investigation into the impact of ovary-intact menopause in the context of HFpEF. To replicate the human condition as faithfully as possible, vinylcyclohexene dioxide (VCD) was used to accelerate ovarian failure (AOF) in female mice while leaving the ovaries intact. HFpEF was established with a mouse model that involves two stressors typical in humans: a high-fat diet and hypertension induced from the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME). In young female mice, AOF or HFpEF-associated stressors independently induced abnormal myocardial strain indicative of early subclinical systolic and diastolic cardiac dysfunction. HFpEF but not AOF was associated with elevations in systolic blood pressure. Increased myocyte size and reduced myocardial microvascular density were not observed in any group. Also, a broad panel of measurements that included echocardiography, invasive pressure measurements, histology, and serum hormones revealed no interaction between AOF and HFpEF. Interestingly, AOF did evoke a higher density of infiltrating cardiac immune cells in both healthy and HFpEF mice, suggestive of proinflammatory effects. In contrast to young mice, middle-aged "old" mice did not exhibit cardiac dysfunction from estrogen deprivation alone or from HFpEF-related stressors.NEW & NOTEWORTHY This is the first preclinical study to examine the impact of ovary-intact menopause [accelerated ovarian failure (AOF)] on HFpEF. Echocardiography of young female mice revealed early evidence of diastolic and systolic cardiac dysfunction apparent only on strain imaging in HFpEF only, AOF only, or the combination. Surprisingly, AOF did not exacerbate the HFpEF phenotype. Results in middle-aged "old" females also showed no interaction between HFpEF and AOF and, importantly, no cardiovascular impact from HFpEF or AOF.

Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton's Tyrosine Kinase Inhibitor Acalabrutinib.

Cardiac arrhythmias remain a significant concern with Ibrutinib (IBR), a first-generation Bruton's tyrosine kinase inhibitor (BTKi). Acalabrutinib (ABR), a next-generation BTKi, is associated with reduced atrial arrhythmia events. However, the role of ABR in ventricular arrhythmia (VA) has not been adequately evaluated. Our study aimed to investigate VA vulnerability and ventricular electrophysiology following chronic ABR therapy in male Sprague-Dawley rats utilizing epicardial optical mapping for ventricular voltage and Ca2+ dynamics and VA induction by electrical stimulation in ex-vivo perfused hearts. Ventricular tissues were snap-frozen for protein analysis for sarcoplasmic Ca2+ and metabolic regulatory proteins. The results show that both ABR and IBR treatments increased VA vulnerability, with ABR showing higher VA regularity index (RI). IBR, but not ABR, is associated with the abbreviation of action potential duration (APD) and APD alternans. Both IBR and ABR increased diastolic Ca2+ leak and Ca2+ alternans, reduced conduction velocity (CV), and increased CV dispersion. Decreased SERCA2a expression and AMPK phosphorylation were observed with both treatments. Our results suggest that ABR treatment also increases the risk of VA by inducing proarrhythmic changes in Ca2+ signaling and membrane electrophysiology, as seen with IBR. However, the different impacts of these two BTKi on ventricular electrophysiology may contribute to differences in VA vulnerability and distinct VA characteristics.

Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy.

BACKGROUND: Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart remain cryptic. The E3 ubiquitin ligase TRAF2 (TNF receptor associated factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial for nuclear factor-κB (NF-κB) activation by TNFα and survival. Here, we investigate alterations in TNFα-TRAF2-NF-κB signaling in the pathogenesis of DOX cardiotoxicity. METHODS: Using a combination of in vivo (4 weekly injections of DOX 5 mg·kg-1·wk-1) in C57/BL6J mice and in vitro approaches (rat, mouse, and human inducible pluripotent stem cell-derived cardiac myocytes), we monitored TNFα levels, lactate dehydrogenase, cardiac ultrastructure and function, mitochondrial bioenergetics, and cardiac cell viability. RESULTS: In contrast to vehicle-treated mice, ultrastructural defects, including cytoplasmic swelling, mitochondrial perturbations, and elevated TNFα levels, were observed in the hearts of mice treated with DOX. While investigating the involvement of TNFα in DOX cardiotoxicity, we discovered that NF-κB was readily activated by TNFα. However, TNFα-mediated NF-κB activation was impaired in cardiac myocytes treated with DOX. This coincided with loss of K63- linked polyubiquitination of RIPK1 from the proteasomal degradation of TRAF2. Furthermore, TRAF2 protein abundance was markedly reduced in hearts of patients with cancer treated with DOX. We further established that the reciprocal actions of the ubiquitinating and deubiquitinating enzymes cellular inhibitors of apoptosis 1 and USP19 (ubiquitin-specific peptidase 19), respectively, regulated the proteasomal degradation of TRAF2 in DOX-treated cardiac myocytes. An E3-ligase mutant of cellular inhibitors of apoptosis 1 (H588A) or gain of function of USP19 prevented proteasomal degradation of TRAF2 and DOX-induced cell death. Furthermore, wild-type TRAF2, but not a RING finger mutant defective for K63-linked polyubiquitination of RIPK1, restored NF-κB signaling and suppressed DOX-induced cardiac cell death. Last, cardiomyocyte-restricted expression of TRAF2 (cardiac troponin T-adeno-associated virus 9-TRAF2) in vivo protected against mitochondrial defects and cardiac dysfunction induced by DOX. CONCLUSIONS: Our findings reveal a novel signaling axis that functionally connects the cardiotoxic effects of DOX to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by DOX sensitizes cardiac myocytes to TNFα-mediated necrotic cell death and DOX cardiotoxicity.

Extracorporeal Membrane Oxygenation for Graft Dysfunction Early After Heart Transplantation: A Systematic Review and Meta-analysis.

INTRODUCTION: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a prevailing option for the management of severe early graft dysfunction. This systematic review and individual patient data (IPD) meta-analysis aims to evaluate (1) mortality, (2) rates of major complications, (3) prognostic factors, and (4) the effect of different VA-ECMO strategies on outcomes in adult heart transplant (HT) recipients supported with VA-ECMO. METHODS AND RESULTS: We conducted a systematic search and included studies of adults (≥18 years) who received VA-ECMO during their index hospitalization after HT and reported on mortality at any timepoint. We pooled data using random effects models. To identify prognostic factors, we analysed IPD using mixed effects logistic regression. We assessed the certainty in the evidence using the GRADE framework. We included 49 observational studies of 1477 patients who received VA-ECMO after HT, of which 15 studies provided IPD for 448 patients. There were no differences in mortality estimates between IPD and non-IPD studies. The short-term (30-day/in-hospital) mortality estimate was 33% (moderate certainty, 95% confidence interval [CI] 28%-39%) and 1-year mortality estimate 50% (moderate certainty, 95% CI 43%-57%). Recipient age (odds ratio 1.02, 95% CI 1.01-1.04) and prior sternotomy (OR 1.57, 95% CI 0.99-2.49) are associated with increased short-term mortality. There is low certainty evidence that early intraoperative cannulation and peripheral cannulation reduce the risk of short-term death. CONCLUSIONS: One-third of patients who receive VA-ECMO for early graft dysfunction do not survive 30 days or to hospital discharge, and one-half do not survive to 1 year after HT. Improving outcomes will require ongoing research focused on optimizing VA-ECMO strategies and care in the first year after HT.

Patients with fulminant myocarditis supported with veno-arterial extracorporeal membrane oxygenation: a systematic review and meta-analysis of short-term mortality and impact of risk factors.

Fulminant myocarditis (FM) may lead to cardiogenic shock requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Results of effectiveness studies of VA-ECMO have been contradictory. We evaluated the aggregate short-term mortality after VA-ECMO and predictive factors in patients with FM. We systematically searched in electronic databases (February 2022) to identify studies evaluating short-term mortality (defined as mortality at 30 days or in-hospital) after VA-ECMO support for FM. We included studies with 5 or more patients published after 2009. We assessed the quality of the evidence using the QUIPS and GRADE tools. Mortality was pooled using random effect models. We performed meta-regression to explore heterogeneity based on a priori defined factors. We included 54 observational studies encompassing 2388 FM patients supported with VA-ECMO. Median age was 41 years (25th to 75th percentile 37-47), and 50% were female. The pooled short-term mortality was 35% (95% CI 29-40%, I2 = 69%; moderate certainty). By meta-regression, studies with younger populations showed lower mortality. Female sex, receiving a biopsy, cardiac arrest, left ventricular unloading, and earlier recruitment time frame, did not explain heterogeneity. These results remained consistent regardless of continent and the risk of bias category. In individual studies, low pH value, high lactate, absence of functional cardiac recovery on ECMO, increased burden of malignant arrhythmia, high peak coronary markers, and IVIG use were identified as independent predictors of mortality. When conventional therapies have failed, especially in younger patients, cardiopulmonary support with VA-ECMO should be considered in the treatment of severe FM.

Towards Allograft Longevity: Leveraging Omics Technologies to Improve Heart Transplant Outcomes.

PURPOSE OF REVIEW: Heart transplantation (HT) remains the optimal therapy for patients living with end-stage heart disease. Despite recent improvements in peri-transplant management, the median survival after HT has remained relatively static, and complications of HT, including infection, rejection, and allograft dysfunction, continue to impact quality of life and long-term survival. RECENT FINDINGS: Omics technologies are becoming increasingly accessible and can identify novel biomarkers for, and reveal the underlying biology of, several disease states. While some technologies, such as gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA), are routinely used in the clinical care of HT recipients, a number of emerging platforms, including pharmacogenomics, proteomics, and metabolomics, hold great potential for identifying biomarkers to aid in the diagnosis and management of post-transplant complications. Omics-based assays can improve patient and allograft longevity by facilitating a personalized and precision approach to post-HT care. The following article is a contemporary review of the current and future opportunities to leverage omics technologies, including genomics, transcriptomics, proteomics, and metabolomics in the field of HT.

Acute complication posttransplant: primary allograft dysfunction.

PURPOSE OF REVIEW: Heart transplant is the gold standard treatment for patients with end-stage heart failure, improving both quality of life and survival. Despite advances in donor and recipient management, primary graft dysfunction (PGD) remains the most common cause of morbidity and mortality in the early posttransplant period. This review summarizes recent discoveries in the underlying pathophysiology, risk prediction and management of PGD. RECENT FINDINGS: The incidence of PGD appears to be rising and it is not clear whether this is due to better recognition or secular changes in transplant practice. The utilization of donation after circulatory death organs for transplant is a further consideration for the development of PGD. Organ transport systems and preservation techniques may help to prevent PGD. As some of the risk factors for developing PGD remain modifiable, we summarize the current evidence for prevention and management of PGD. SUMMARY: A better understanding will allow us to appropriately manage donors and recipients to reduce the complex interactions that lead to PGD. The development of an international consortium provides the opportunity for deep phenotyping and development of contemporary risk prediction models for PGD, which may reduce the incidence and consequent early mortality associated with heart transplantation.

Clonal hematopoiesis confers an increased mortality risk in orthotopic heart transplant recipients.

Novel risk stratification and non-invasive surveillance methods are needed in orthotopic heart transplant (OHT) to reduce morbidity and mortality post-transplant. Clonal hematopoiesis (CH) refers to the acquisition of specific gene mutations in hematopoietic stem cells linked to enhanced inflammation and worse cardiovascular outcomes. The purpose of this study was to investigate the association between CH and OHT. Blood samples were collected from 127 OHT recipients. Error-corrected sequencing was used to detect CH-associated mutations. We evaluated the association between CH and acute cellular rejection, CMV infection, cardiac allograft vasculopathy (CAV), malignancies, and survival. CH mutations were detected in 26 (20.5%) patients, mostly in DNMT3A, ASXL1, and TET2. Patients with CH showed a higher frequency of CAV grade 2 or 3 (0% vs. 18%, p < .001). Moreover, a higher mortality rate was observed in patients with CH (11 [42%] vs. 15 [15%], p = .008) with an adjusted hazard ratio of 2.9 (95% CI, 1.4-6.3; p = .003). CH was not associated with acute cellular rejection, CMV infection or malignancies. The prevalence of CH in OHT recipients is higher than previously reported for the general population of the same age group, with an associated higher prevalence of CAV and mortality.

Defining the molecular underpinnings controlling cardiomyocyte proliferation.

Shortly after birth, mammalian cardiomyocytes (CM) exit the cell cycle and cease to proliferate. The inability of adult CM to replicate renders the heart particularly vulnerable to injury. Restoration of CM proliferation would be an attractive clinical target for regenerative therapies that can preserve contractile function and thus prevent the development of heart failure. Our review focuses on recent progress in understanding the tight regulation of signaling pathways and their downstream molecular mechanisms that underly the inability of CM to proliferate in vivo. In this review, we describe the temporal expression of cell cycle activators e.g., cyclin/Cdk complexes and their inhibitors including p16, p21, p27 and members of the retinoblastoma gene family during gestation and postnatal life. The differential impact of members of the E2f transcription factor family and microRNAs on the regulation of positive and negative cell cycle factors is discussed. This review also highlights seminal studies that identified the coordination of signaling mechanisms that can potently activate CM cell cycle re-entry including the Wnt/Ctnnb1, Hippo, Pi3K-Akt and Nrg1-Erbb2/4 pathways. We also present an up-to-date account of landmark studies analyzing the effect of various genes such as Argin, Dystrophin, Fstl1, Meis1, Pitx2 and Pkm2 that are responsible for either inhibition or activation of CM cell division. All these reports describe bona fide therapeutically targets that could guide future clinical studies toward cardiac repair.

Impact of serial measurements of tricuspid annular plane systolic excursion on mortality and morbidity after heart transplantation.

The impact of right ventricular (RV) dysfunction on long-term post-HTx outcomes remains uncertain. We assessed the impact of serial measurements of Tricuspid Annular Plane Systolic Excursion (TAPSE) on post-HTx mortality and morbidity. This two-center retrospective cohort study included consecutive adult HTx recipients (2000-2017). We used multivariable extended hazard regression models to evaluate the association between TAPSE and left ventricular ejection fraction (LVEF), entered as time-dependent variables, and all-cause mortality, cardiac allograft vasculopathy (CAV), acute cellular rejection (ACR), and chronic kidney disease (CKD). TAPSE was modelled using cubic splines. We included 485 HTx recipients (9461 TAPSE measurements), median (25th- 75th percentile) 19 (10-27) mm; median age was 52 (41-59) years, and 71.3% were male. During a follow-up of 6.7 (3.0-10.8) years, 92 patients died, 225 had ACR >2R, 234 CAV, and 91 CKD. By multivariable analysis, for each 1-mm decrease in patients with a TAPSE value <15mm, mortality increased by 22% (P<.001). For the average HTx recipient with a TAPSE of 15mm, 10mm, and 6mm, 1-year mortality was 3%, 7%, and 17%, and 5-year mortality was 8%, 20%, and 43%, respectively. Reduced TAPSE was significantly associated with increased CAV but notACR and CKD. A decrease in TAPSE below 15mm represents clinically significant graft dysfunction, warranting close monitoring.

Association between continuous-flow left ventricular assist device infections requiring long-term antibiotic use and post-heart transplant morbidity and mortality.

BACKGROUND AND AIM OF STUDY: There exists controversy regarding the impact of infection in patients with a left ventricular assist device (LVAD) on post-heart transplant outcomes. This study evaluated the association between infections during LVAD support and the risk of early and late post-heart transplant infection, rejection, and mortality in transplant recipients bridged with an LVAD. METHODS: This is a single-center retrospective observational cohort study of consecutive adults supported with a continuous flow LVAD undergoing heart transplant between 2006 and 2019 at the Toronto General Hospital. The grade of LVAD infection was classified as per International Society of Heart and Lung Transplantation guidelines. Patients were divided into three groups: (1) patients with LVAD-specific infection confirmed with positive cultures requiring long-term antibiotic use until the time of transplant; (2) patients with any type of infection in whom antibiotics were stopped at least 1 month before transplant; (3) patients without any infections between LVAD implant and transplant. Logistic regression and Cox proportional hazard models were used to evaluate early- and late-post transplant outcomes, respectively. RESULTS: We included 75 LVAD recipients: 16 (21%) patients had a chronic LVAD-related infection on suppressive antibiotics, 30 (40%) had a resolved infection, and 29 (39%) had no infections. During a median post-transplant follow-up time of 4 (2 to 7) years, 65 (87%) patients developed infections, 43 (64%) rejections, and 17 (23%) deaths. Both short- and long-term risks of infection, rejection, and mortality did not differ significantly among the groups. CONCLUSION: LVAD patients with infections did not have a significantly higher risk of infection, rejection, or mortality at any time point after transplant.

Association between time to therapeutic INR and length of stay following mechanical heart valve surgery.

BACKGROUND: Warfarin is the only oral anticoagulant approved for use following mechanical valve surgery (MeVS). Patients may experience prolonged hospital length of stay (LOS) following MeVS awaiting an appropriate warfarin effect. We aimed to determine whether an association exists between time to achieve the first therapeutic international normalized ratio (INR) and LOS following MeVS. MATERIALS AND METHODS: Retrospective single center cohort study. We included consecutive adult patients undergoing elective MeVS from 2013 to 2018. Landmark analyses and multivariable regression with time-updated INR were used to estimate the association between time to therapeutic INR (TTI) and LOS. RESULTS: Among 384 patients (median age: 51 years, interquartile range [IQR]: 41-57; 58.3% male), the median TTI was 4 days (IQR: 2-5). Thirty seven percent of patients were discharged with a subtherapeutic INR, many on bridging anticoagulation or with an INR close to target. Those achieving therapeutic INR had an increased rate of hospital discharge (adjusted hazard ratio: 2.17; 95% confidence interval: 1.71-2.76; p < .0001). Attainment of a therapeutic INR anytime between postoperative Days 4 and 13 was significantly associated with a shorter LOS. CONCLUSIONS: Prolonged time to achieve a therapeutic INR was independently associated with prolonged LOS. Future strategies aimed at improving attainment of therapeutic INR following MeVS may reduce hospital LOS.

Heart Failure and Drug Therapies: A Metabolic Review.

Cardiovascular disease is the leading cause of mortality globally with at least 26 million people worldwide living with heart failure (HF). Metabolism has been an active area of investigation in the setting of HF since the heart demands a high rate of ATP turnover to maintain homeostasis. With the advent of -omic technologies, specifically metabolomics and lipidomics, HF pathologies have been better characterized with unbiased and holistic approaches. These techniques have identified novel pathways in our understanding of progression of HF and potential points of intervention. Furthermore, sodium-glucose transport protein 2 inhibitors, a drug that has changed the dogma of HF treatment, has one of the strongest types of evidence for a potential metabolic mechanism of action. This review will highlight cardiac metabolism in both the healthy and failing heart and then discuss the metabolic effects of heart failure drugs.

Protective role of Nrf2 against ischemia reperfusion injury and cardiac allograft vasculopathy.

Ischemia-reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post-heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species-mediated NF-κB activation. We hypothesized that Nrf2 inhibits NF-κB activation post-Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild-type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline-treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2-KO showed significantly less SOD1/2 activity compared with WT. Nrf2-KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF-κB-mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase-3 activity were significantly higher in Nrf2-KO. In the allograft studies, graft beating score was significantly weaker in Nrf2-KO compared with WT. Nrf2-KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF-κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.

Neurohormones, inflammatory mediators, and cardiovascular injury in the setting of heart failure.

Neurohormones and inflammatory mediators have effects in both the heart and the peripheral vasculature. In patients with heart failure (HF), neurohormonal activation and increased levels of inflammatory mediators promote ventricular remodeling and development of HF, as well as vascular dysfunction and arterial stiffness. These processes may lead to a vicious cycle, whereby arterial stiffness perpetuates further ventricular remodeling leading to exacerbation of symptoms. Although significant advances have been made in the treatment of HF, currently available treatment strategies slow, but do not halt, this cycle. The current treatment for HF patients involves the inhibition of neurohormonal activation, which can reduce morbidity and mortality related to this condition. Beyond benefits associated with neurohormonal blockade, other strategies have focused on inhibition of inflammatory pathways implicated in the pathogenesis of HF. Unfortunately, attempts to target inflammation have not yet been successful to improve prognosis of HF. Further work is required to interrupt key maladaptive mechanisms involved in disease progression.

Anthracycline-induced cardiomyopathy: cellular and molecular mechanisms.

Despite the known risk of cardiotoxicity, anthracyclines are widely prescribed chemotherapeutic agents. They are broadly characterized as being a robust effector of cellular apoptosis in rapidly proliferating cells through its actions in the nucleus and formation of reactive oxygen species (ROS). And, despite the early use of dexrazoxane, no effective treatment strategy has emerged to prevent the development of cardiomyopathy, despite decades of study, suggesting that much more insight into the underlying mechanism of the development of cardiomyopathy is needed. In this review, we detail the specific intracellular activities of anthracyclines, from the cell membrane to the sarcoplasmic reticulum, and highlight potential therapeutic windows that represent the forefront of research into the underlying causes of anthracycline-induced cardiomyopathy.

Utility of the INTERMACS profile at the time of assessment for heart transplant.

The Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS) profiles are associated with mortality in heart failure patients undergoing ventricular assist device (VAD) implantation and heart transplantation (HTx). We assessed the prognostic value of the INTERMACS profile at the time of assessment for HTx or durable VAD implantation as bridge to candidacy (BTC). A total of 503 consecutive patients considered for HTx or VAD between 2006 and 2016 were included. The associations between INTERMACS profile and (a) waitlist mortality or delisting, (b) probability of HTx, and (c) overall mortality or delisting were evaluated using multivariable analysis. Median follow-up time was 2.9 years (IQR: 0.9-5.5) during which 184 received VAD, 347 received HTx, and 73 died (27 waitlist, 46 post-transplant). INTERMACS I-II profile was associated with higher waitlist mortality or delisting (HR: 3.83, 95% CI: 1.22-12.03), and this risk was reversed by VAD implantation (HR: 0.12, 95% CI: 0.03-0.50). INTERMACS III-IV profile was associated with a higher probability of HTx (HR: 1.82, 95% CI: 1.37-2.40). INTERMACS profile was not associated with the composite outcome of overall mortality or delisting. These results emphasize the prognostic utility of INTERMACS at time of decision for advanced therapies and its potential value in selecting patients for different interventions.

p53 regulates the cardiac transcriptome.

The tumor suppressor Trp53 (p53) inhibits cell growth after acute stress by regulating gene transcription. The mammalian genome contains hundreds of p53-binding sites. However, whether p53 participates in the regulation of cardiac tissue homeostasis under normal conditions is not known. To examine the physiologic role of p53 in adult cardiomyocytes in vivo, Cre-loxP-mediated conditional gene targeting in adult mice was used. Genome-wide transcriptome analyses of conditional heart-specific p53 knockout mice were performed. Genome-wide annotation and pathway analyses of >5,000 differentially expressed transcripts identified many p53-regulated gene clusters. Correlative analyses identified >20 gene sets containing more than 1,000 genes relevant to cardiac architecture and function. These transcriptomic changes orchestrate cardiac architecture, excitation-contraction coupling, mitochondrial biogenesis, and oxidative phosphorylation capacity. Interestingly, the gene expression signature in p53-deficient hearts confers resistance to acute biomechanical stress. The data presented here demonstrate a role for p53, a previously unrecognized master regulator of the cardiac transcriptome. The complex contributions of p53 define a biological paradigm for the p53 regulator network in the heart under physiological conditions.

Increases in Serum Autoantibodies After Left Ventricular Assist Device Implantation.

BACKGROUND: Left ventricular assist devices (LVADs) can serve as a bridge to transplant or destination therapy for patients with advanced heart failure. Implantation of LVADs is known to be associated with increases in anti-HLA antibodies, but less is known about how autoantibody levels change with the use of these devices. METHODS AND RESULTS: Autoantibody levels were quantified with the use of customized antigen microarrays in 22 patients both before and after LVAD. We observed an increase (1.5- to 2-fold) in 14 IgG autoantibodies in the serum of patients after LVAD, including autoantibodies against cardiac proteins (myosin, troponin I, tropomyosin), DNA, and structural proteins (collagen, laminin). There was also a small but significant rise in total serum IgG after LVAD. Increases in autoantibodies after LVAD were positively associated with increases in calculated panel-reactive antibody class II (P = .05) and negatively correlated with age (r = -0.45; P < .05). Cytokines were evaluated to gain insights into the mechanism of antibody generation, and we observed a positive correlation between total IgG levels after LVAD and the level of monocyte chemoattractant protein 1 (r = 0.60; P < .05). CONCLUSIONS: LVAD implantation is associated with increases in IgG autoantibodies, anti-HLA antibodies, and total IgG. Increases in IgG after LVAD implantation may relate to an inflammatory response triggered by these devices.