linc-ADAIN, a human adipose lincRNA, regulates adipogenesis by modulating KLF5 and IL-8 mRNA stability.

Adipose tissue remodeling and dysfunction, characterized by elevated inflammation and insulin resistance, play a central role in obesity-related development of type 2 diabetes (T2D) and cardiovascular diseases. Long intergenic non-coding RNAs (lincRNAs) are important regulators of cellular functions. Here, we describe the functions of linc-ADAIN (adipose anti-inflammatory), an adipose lincRNA that is downregulated in white adipose tissue of obese humans. We demonstrate that linc-ADAIN knockdown (KD) increases KLF5 and interleukin-8 (IL-8) mRNA stability and translation by interacting with IGF2BP2. Upregulation of KLF5 and IL-8, via linc-ADAIN KD, leads to an enhanced adipogenic program and adipose tissue inflammation, mirroring the obese state, in vitro and in vivo. KD of linc-ADAIN in human adipose stromal cell (ASC) hTERT adipocytes implanted into mice increases adipocyte size and macrophage infiltration compared to implanted control adipocytes, mimicking hallmark features of obesity-induced adipose tissue remodeling. linc-ADAIN is an anti-inflammatory lincRNA that limits adipose tissue expansion and lipid storage.

Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease.

BACKGROUND: Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell-like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis. METHODS: We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis. RESULTS: SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell-like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant KrasG12D in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. CONCLUSIONS: Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease.

Mortality After Alcohol Septal Ablation vs. Septal Myectomy in Patients With Obstructive Hypertrophic Cardiomyopathy.

Background: Alcohol septal ablation (ASA) and septal myectomy (SM) are 2 options for septal reduction therapy (SRT) to treat medication-resistant symptomatic obstructive hypertrophic cardiomyopathy (HCM). Because differences in mortality rates after these different SRT methods have not been extensively investigated in real-world settings, in this study compared the 1-year mortality rates after ASA and SM using population-based database. Methods and Results: Utilizing New York Statewide Planning and Research Cooperative System (SPARCS) data from 2005 to 2016, we performed a comparative effectiveness study of ASA vs. SM in patients with HCM. The outcome was all-cause death up to 360 days after SRT. We constructed a multivariable logistic regression model and performed sensitivity analysis with propensity score (PS)-matching and inverse probability of treatment weighting (IPTW) methods. We identified 755 patients with HCM who underwent SRT: 348 with ASA and 407 with SM. The multivariable analysis showed that all-cause deaths were significantly fewer in the ASA group at 360 days after SRT (adjusted odds ratio=0.34; 95% confidence interval [CI] 0.13-0.84; P=0.02). The PS-matching and IPTW methods also supported a lower mortality rate in the ASA group at 360 days post-SRT. Conclusions: In this population-based study of patients with HCM who underwent SRT in a real-world setting, the 1-year all-cause mortality rate was significantly lower in patients who underwent ASA compared with SM.

Prediction of cardiac death in patients with hypertrophic cardiomyopathy using plasma adipokine levels.

BACKGROUNDS AND AIMS: Hypertrophic cardiomyopathy (HCM) causes cardiac death through both sudden cardiac death (SCD) and death due to heart failure (HF). Although adipokines lead to adverse cardiac remodeling in HCM, the prognostic value of plasma adipokines in HCM remains unknown. We aimed to predict cardiac death in patients with HCM using plasma adipokines. METHODS AND RESULTS: We performed a multicenter prospective cohort study of patients with HCM. The outcome was cardiac death including heart transplant, death due to HF, and SCD. With data from 1 institution (training set), a prediction model was developed using random forest classification algorithm based on 10 plasma adipokines. The performance of the prediction model adjusted for 8 clinical parameters was examined in samples from another institution (test set). Time-to-event analysis was performed in the test set to compare the rate of outcome events between the low-risk and high-risk groups determined by the prediction model. In total, 389 (267 in the training set; 122 in the test set) patients with HCM were included. During the median follow-up of 2.7 years, 21 patients experienced the outcome event. The area under the covariates-adjusted receiver-operating characteristics curve was 0.89 (95 % confidence interval [CI] 0.71-0.99) in the test set. revealed the high-risk group had a significantly higher risk of cardiac death (hazard ratio 17.8, 95 % CI 2.1-148.3, P = 0.008). CONCLUSION: The present multicenter prospective study demonstrated that a panel of plasma adipokines predicts cardiac death in patients with HCM.

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.

High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis.

BACKGROUND: Atherosclerotic plaques are complex tissues composed of a heterogeneous mixture of cells. However, our understanding of the comprehensive transcriptional and phenotypic landscape of the cells within these lesions is limited. METHODS: To characterize the landscape of human carotid atherosclerosis in greater detail, we combined cellular indexing of transcriptomes and epitopes by sequencing and single-cell RNA sequencing to classify all cell types within lesions (n=21; 13 symptomatic) to achieve a comprehensive multimodal understanding of the cellular identities of atherosclerosis and their association with clinical pathophysiology. RESULTS: We identified 25 cell populations, each with a unique multiomic signature, including macrophages, T cells, NK (natural killer) cells, mast cells, B cells, plasma cells, neutrophils, dendritic cells, endothelial cells, fibroblasts, and smooth muscle cells (SMCs). Among the macrophages, we identified 2 proinflammatory subsets enriched in IL-1B (interleukin-1B) or C1Q expression, 2 TREM2-positive foam cells (1 expressing inflammatory genes), and subpopulations with a proliferative gene signature and SMC-specific gene signature with fibrotic pathways upregulated. Further characterization revealed various subsets of SMCs and fibroblasts, including SMC-derived foam cells. These foamy SMCs were localized in the deep intima of coronary atherosclerotic lesions. Utilizing cellular indexing of transcriptomes and epitopes by sequencing data, we developed a flow cytometry panel, using cell surface proteins CD29, CD142, and CD90, to isolate SMC-derived cells from lesions. Lastly, we observed reduced proportions of efferocytotic macrophages, classically activated endothelial cells, and contractile and modulated SMC-derived cells, while inflammatory SMCs were enriched in plaques of clinically symptomatic versus asymptomatic patients. CONCLUSIONS: Our multimodal atlas of cell populations within atherosclerosis provides novel insights into the diversity, phenotype, location, isolation, and clinical relevance of the unique cellular composition of human carotid atherosclerosis. These findings facilitate both the mapping of cardiovascular disease susceptibility loci to specific cell types and the identification of novel molecular and cellular therapeutic targets for the treatment of the disease.

Signaling Pathways Associated With Prior Cardiovascular Events in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. A subset of patients experience major adverse cardiovascular events (MACEs), including arrhythmias, strokes and heart failure. However, the molecular mechanisms underlying MACEs in HCM are still not well understood. Therefore, we conducted a multicenter case-control study of patients with HCM, comparing those with and without prior histories of MACEs to identify dysregulated signaling pathways through plasma proteomics profiling. METHODS: We performed plasma proteomics profiling of 4986 proteins. We developed a proteomics-based discrimination model in patients enrolled at 1 institution (training set) and externally validated the model in patients enrolled at another institution (test set). We performed pathway analysis of proteins dysregulated in patients with prior MACEs. RESULTS: A total of 402 patients were included, with 278 in the training set and 124 in the test set. In this cohort, 257 (64%) patients had prior MACEs (172 in the training set and 85 in the test set). Using the proteomics-based model from the training set, the area under the receiver operating characteristic curve was 0.82 (95% confidence interval, 0.75-0.90) in the test set. Patients with prior MACEs demonstrated dysregulation in pathways known to be associated with MACEs (eg, TGF-ß) and novel pathways (eg, Ras-MAPK and associated pathways). CONCLUSIONS: In this multicenter study of 402 patients with HCM, we identified both known and novel pathways dysregulated in a subset of patients with more advanced disease.

Patient experiences in receiving telegenetics care for inherited cardiovascular diseases.

Telegenetics played an important role in providing genetic services to patients during the COVID-19 pandemic. In particular, at our institution, it enabled us to expand our genetic counseling and testing services to non-local family members of patients outside of our prior catchment area. However, as telegenetics continues to be utilized even as social distancing is no longer required, further information is needed regarding the impact of this modality on patient experience within cardiogenetics. This study qualitatively explored the experiences of 12 genotype positive individuals who underwent genetic counseling and testing via telegenetics during the first 22 months of the COVID-19 pandemic and compared the experiences of local vs. non-local patients. Both local and non-local participants discussed similar benefits and drawbacks to the use of technology in telegenetics and overall found the use of telegenetics and at-home genetic testing to be convenient. Both groups also noted having to make changes in their daily lives and future planning as a consequence of the positive genetic testing results. However, access to follow-up care differed between local and non-local participants, with more local participants having scheduled and attended appointments with the appropriate medical providers compared to non-local participants. Supplying non-local patients access to remote cardiogenetic testing may therefore require careful consideration in how to ensure proper follow-up care for genotype positive patients and may necessitate the involvement of national professional or patient-centered organizations to help streamline the referral process.

Leveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials.

Importance: Multicenter clinical trials play a critical role in the translational processes that enable new treatments to reach all people and improve public health. However, conducting multicenter randomized clinical trials (mRCT) presents challenges. The Trial Innovation Network (TIN), established in 2016 to partner with the Clinical and Translational Science Award (CTSA) Consortium of academic medical institutions in the implementation of mRCTs, consists of 3 Trial Innovation Centers (TICs) and 1 Recruitment Innovation Center (RIC). This unique partnership has aimed to address critical roadblocks that impede the design and conduct of mRCTs, in expectation of accelerating the translation of novel interventions to clinical practice. The TIN's challenges and achievements are described in this article, along with examples of innovative resources and processes that may serve as useful models for other clinical trial networks providing operational and recruitment support. Observations: The TIN has successfully integrated more than 60 CTSA institution program hubs into a functional network for mRCT implementation and optimization. A unique support system for investigators has been created that includes the development and deployment of novel tools, operational and recruitment services, consultation models, and rapid communication pathways designed to reduce delays in trial start-up, enhance recruitment, improve engagement of diverse research participants and communities, and streamline processes that improve the quality, efficiency, and conduct of mRCTs. These resources and processes span the clinical trial spectrum and enable the TICs and RIC to serve as coordinating centers, data centers, and recruitment specialists to assist trials across the National Institutes of Health and other agencies. The TIN's impact has been demonstrated through its response to both historical operational challenges and emerging public health emergencies, including the national opioid public health crisis and the COVID-19 pandemic. Conclusions and Relevance: The TIN has worked to reduce barriers to implementing mRCTs and to improve mRCT processes and operations by providing needed clinical trial infrastructure and resources to CTSA investigators. These resources have been instrumental in more quickly and efficiently translating research discoveries into beneficial patient treatments.

High-Dimensional Single-Cell Multimodal Landscape of Human Carotid Atherosclerosis.

Background: Atherosclerotic plaques are complex tissues composed of a heterogeneous mixture of cells. However, we have limited understanding of the comprehensive transcriptional and phenotypical landscape of the cells within these lesions. Methods: To characterize the landscape of human carotid atherosclerosis in greater detail, we combined cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and single-cell RNA sequencing (scRNA-seq) to classify all cell types within lesions (n=21; 13 symptomatic) to achieve a comprehensive multimodal understanding of the cellular identities of atherosclerosis and their association with clinical pathophysiology. Results: We identified 25 distinct cell populations each having a unique multi-omic signature, including macrophages, T cells, NK cells, mast cells, B cells, plasma cells, neutrophils, dendritic cells, endothelial cells, fibroblasts, and smooth muscle cells (SMCs). Within the macrophage populations, we identified 2 proinflammatory subsets that were enriched in IL1B or C1Q expression, 2 distinct TREM2 positive foam cell subsets, one of which also expressed inflammatory genes, as well as subpopulations displaying a proliferative gene expression signature and one expressing SMC-specific genes and upregulation of fibrotic pathways. An in-depth characterization uncovered several subsets of SMCs and fibroblasts, including a SMC-derived foam cell. We localized this foamy SMC to the deep intima of coronary atherosclerotic lesions. Using CITE-seq data, we also developed the first flow cytometry panel, using cell surface proteins CD29, CD142, and CD90, to isolate SMC-derived cells from lesions. Last, we found that the proportion of efferocytotic macrophages, classically activated endothelial cells, contractile and modulated SMC-derived cell types were reduced, and inflammatory SMCs were enriched in plaques of clinically symptomatic vs. asymptomatic patients. Conclusions: Our multimodal atlas of cell populations within atherosclerosis provides novel insights into the diversity, phenotype, location, isolation, and clinical relevance of the unique cellular composition of human carotid atherosclerosis. This facilitates both the mapping of cardiovascular disease susceptibility loci to specific cell types as well as the identification of novel molecular and cellular therapeutic targets for treatment of the disease.

Prediction of worsening heart failure in hypertrophic cardiomyopathy using plasma proteomics.

OBJECTIVE: Heart failure (HF) is one of the most common and lifestyle-limiting complications of hypertrophic cardiomyopathy (HCM). Prediction of worsening HF using clinical measures alone remains limited. Moreover, the mechanisms by which patients with HCM develop worsening HF have not been elucidated. Therefore, the aim of this study was to develop a plasma proteomics-based model to predict worsening HF among patients with HCM and to identify signalling pathways that are differentially regulated in those who subsequently develop worsening HF. METHODS: In this multi-centre, prospective cohort study of 389 patients with HCM, plasma proteomics profiling of 4986 proteins was performed at enrolment. A proteomics-based random forest model was developed to predict worsening HF using data from one institution (training set, n=268). This model was externally validated in patients from a different institution (test set, n=121). Pathway analysis of proteins significantly dysregulated in patients who subsequently developed worsening HF compared with those who did not was executed, using a false discovery rate (FDR) threshold of <0.001. RESULTS: Using the 11-protein proteomics-based model derived from the training set, the area under the receiver-operating characteristic curve to predict worsening HF was 0.87 (95% CI: 0.76 to 0.98) in the test set. Pathway analysis revealed that the Ras-MAPK pathway (FDR<0.00001) and related pathways were dysregulated in patients who subsequently developed worsening HF. CONCLUSIONS: The present study with comprehensive plasma proteomics profiling demonstrated a high accuracy to predict worsening HF in patients with HCM and identified the Ras-MAPK and related signalling pathways as potential underlying mechanisms.

Comprehensive Transcriptomics Profiling of MicroRNA Reveals Plasma Circulating Biomarkers of Hypertrophic Cardiomyopathy and Dysregulated Signaling Pathways.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes coding for proteins essential for myocardial contraction. However, it remains unclear through which signaling pathways these gene mutations mediate HCM pathogenesis. Growing evidence indicates that microRNAs (miRNAs) play an important role in the regulation of gene expression. We hypothesized that transcriptomics profiling of plasma miRNAs would reveal circulating biomarkers and dysregulated signaling pathways in HCM. METHODS: We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma transcriptomics profiling of miRNAs using RNA sequencing. We developed a transcriptomics-based discrimination model using samples retrieved during the first two-thirds of the study period at one institution (training set). We prospectively tested its discriminative ability in samples collected thereafter from the same institution (prospective test set). We also externally validated the model by applying it to samples collected from the other institutions (external test set). We executed pathway analysis of dysregulated miRNAs with univariable P<0.05. RESULTS: This study included 555 patients (392 cases and 163 controls). One thousand one hundred forty-one miRNAs passed our quality control filters. The area under the receiver operating characteristic curve of the transcriptomics-based model derived from the training set was 0.86 (95% CI, 0.79-0.93) in the prospective test set and 0.94 (95% CI, 0.90-0.97) in the external test set. Pathway analysis revealed dysregulation of the Ras-MAPK (mitogen-activated protein kinase) pathway and pathways related to inflammation in HCM. CONCLUSIONS: This study utilized comprehensive transcriptomics profiling with RNA sequencing in HCM, revealing circulating miRNA biomarkers and dysregulated pathways.

Effects of bariatric surgery on cardiovascular-related acute care use in patients with hypertrophic cardiomyopathy.

AIMS: Prior studies have suggested causal relationships between obesity and acute cardiovascular events. It has been also known that the risk of acute cardiovascular events is reduced by bariatric surgery. However, little is known about whether bariatric surgery lowers the risk of acute cardiovascular events in patients with obesity and hypertrophic cardiomyopathy (HCM). In this context, we aimed to investigate whether bariatric surgery is associated with a reduced risk of cardiovascular-related acute care use in patients with HCM. METHODS AND RESULTS: In this population-based study, the bariatric surgery group consisted of patients with HCM who underwent bariatric surgery from January 2004 to December 2014. The control group included those who have obesity and HCM and received non-bariatric elective intra-abdominal surgery during the same period. The outcome was cardiovascular-related acute care use (i.e. emergency department (ED) visits or unplanned hospitalizations for cardiovascular disease) during a 1-year post-surgery period. We used the SPARCS database, a population-based ED and inpatient database in New York State. We constructed logistic regression models with generalized estimating equations to compare the risk of the outcome events during sequential 6-month post-surgery periods. We adjusted for age, sex, number of ED visits and hospitalizations for cardiovascular disease within 2 years before the index surgery, and the Elixhauser co-morbidity measures. We also performed propensity score (PS)-matching and inverse probability treatment weighting analyses using these variables. The analytic cohort consisted of 207 adults with obesity and HCM, including 147 patients who underwent bariatric surgery and 60 in the control group. The risk was not significantly different in the 1-6 months post-surgery period. By contrast, in the 7-12 months post-surgery period, the risk of cardiovascular-related acute care use was significantly lower in the bariatric surgery group (adjusted odds ratio 0.23; 95% CI 0.068-0.71; P = 0.01) compared with the control group. In the PS-matched cohort, there were no significant differences in the baseline characteristics. The PS-matched analysis demonstrated lower risk of the outcome event in the bariatric surgery group in the 7-12 months post-surgery period. The inverse probability treatment weighting analysis replicated the findings. CONCLUSIONS: Bariatric surgery was associated with a lower risk of cardiovascular-related acute care use in the 7-12 months post-surgery period in this population-based study.

ADAMTS7: a Novel Therapeutic Target in Atherosclerosis.

PURPOSE OF REVIEW: Genome-wide association studies have repeatedly linked the metalloproteinase ADAMTS7 to coronary artery disease. Here we aim to highlight recent findings surrounding the human genetics of ADAMTS7, novel mouse models that investigate ADAMTS7 function, and potential substrates of ADAMTS7 cleavage. RECENT FINDINGS: Recent genome-wide association studies in coronary artery disease have replicated the GWAS signal for ADAMTS7 and shown that the signal holds true even across different ethnic groups. However, the direction of effect in humans remains unclear. A recent novel mouse model revealed that the proatherogenicity of ADAMTS7 is derived from its catalytic functions, while at the translational level, vaccinating mice against ADAMTS7 reduced atherosclerosis. Finally, in vitro proteomics approaches have identified extracellular matrix proteins as candidate substrates that may be causal for the proatherogenicity of ADAMTS7. ADAMTS7 represents an enticing target for therapeutic intervention. The recent studies highlighted here have replicated prior findings, confirming the genetic link between ADAMTS7 and atherosclerosis, while providing further evidence in mice that ADAMTS7 is a targetable proatherogenic enzyme.

Addressing the underdiagnosis of familial hypercholesterolemia: A mixed methods study exploring the knowledge and practice behaviors of cardiology healthcare providers.

Background: Familial hypercholesterolemia (FH) is vastly underdiagnosed and causes an increased risk for sudden cardiac death. Cardiology providers (CHCPs) are in an ideal position to care for FH patients. This research aimed to understand the practice behaviors of CHCPs in the screening, diagnosis, and management of FH. Methods: Adaptation of an existing FH knowledge tool guided survey development. The results of the quantitative survey guided development of the interview protocol. CHCPs were recruited in the Division of Cardiology at Columbia University Irving Medical Center (CUIMC). A review of the educational materials offered by the Division of Cardiology was conducted to identify FH knowledge domains presented. Results: CHCPs with MDs, at CUIMC for 6-10 years, in clinical practice for 1-5 years, and in inpatient services had the highest average total knowledge scores. CHCPs with RNs, at CUIMC for less than 1 year, in clinical practice for 6-10 years, and in Cath Lab had the lowest average knowledge scores. Four themes emerged - variability in FH care; issues related to addressing FH at institutional, practice setting, and individual levels; importance of identifying FH early; and intervention approaches to overcome barriers to caring for FH patients in cardiology. CHCPs with MDs or with experiential FH knowledge described FH care beyond screening. The document review revealed that only MDs were provided lectures pertaining to FH. Conclusions: Future interventions should increase didactic and experiential FH knowledge incorporating institutional, local, and national FH resources. Improving FH care can reduce FH-related morbidity and mortality, as well as improve FH health outcomes.

Clonal hematopoiesis of indeterminate potential and outcomes after heart transplantation: A multicenter study.

Cardiac allograft vasculopathy (CAV) is a leading cause of late graft failure and mortality after heart transplantation (HT). Sharing some features with atherosclerosis, CAV results in diffuse narrowing of the epicardial coronaries and microvasculature, with consequent graft ischemia. Recently, clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a risk factor for cardiovascular disease and mortality. We aimed to investigate the relationship between CHIP and posttransplant outcomes, including CAV. We analyzed 479 HT recipients with stored DNA samples at 2 high-volume transplant centers, Vanderbilt University Medical Center and Columbia University Irving Medical Center. We explored the association between the presence of CHIP mutations with CAV and mortality after HT. In this case-control analysis, carriers of CHIP mutations were not at increased risk of CAV or mortality after HT. In a large multicenter genomics study of the heart transplant population, the presence of CHIP mutations was not associated with an increased risk of CAV or posttransplant mortality.

Atherosclerosis is a smooth muscle cell-driven tumor-like disease.

Atherosclerosis, the leading cause of cardiovascular disease, is a chronic inflammatory disease involving pathological activation of multiple cell types, such as immunocytes (e.g., macrophage, T cells), smooth muscle cells (SMCs), and endothelial cells. Multiple lines of evidence have suggested that SMC "phenotypic switching" plays a central role in atherosclerosis development and complications. Yet, SMC roles and mechanisms underlying the disease pathogenesis are poorly understood. Here, employing SMC lineage tracing mice, comprehensive molecular, cellular, histological, and computational profiling, coupled to genetic and pharmacological studies, we reveal that atherosclerosis, in terms of SMC behaviors, share extensive commonalities with tumors. SMC-derived cells in the disease show multiple characteristics of tumor cell biology, including genomic instability, replicative immortality, malignant proliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. SMC-specific expression of oncogenic KrasG12D accelerates SMC phenotypic switching and exacerbates atherosclerosis. Moreover, we present a proof of concept showing that niraparib, an anti-cancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our work provides systematic evidence that atherosclerosis is a tumor-like disease, deepening the understanding of its pathogenesis and opening prospects for novel precision molecular strategies to prevent and treat atherosclerotic cardiovascular disease.

Effect of mechanical unloading on genome-wide DNA methylation profile of the failing human heart.

Heart failure (HF) is characterized by global alterations in myocardial DNA methylation, yet little is known about the epigenetic regulation of the noncoding genome and potential reversibility of DNA methylation with left ventricular assist device (LVAD) therapy. Genome-wide mapping of myocardial DNA methylation in 36 patients with HF at LVAD implantation, 8 patients at LVAD explantation, and 7 nonfailing (NF) donors using a high-density bead array platform identified 2,079 differentially methylated positions (DMPs) in ischemic cardiomyopathy (ICM) and 261 DMPs in nonischemic cardiomyopathy (NICM). LVAD support resulted in normalization of 3.2% of HF-associated DMPs. Methylation-expression correlation analysis yielded several protein-coding genes that are hypomethylated and upregulated (HTRA1, FBXO16, EFCAB13, and AKAP13) or hypermethylated and downregulated (TBX3) in HF. A potentially novel cardiac-specific super-enhancer long noncoding RNA (lncRNA) (LINC00881) is hypermethylated and downregulated in human HF. LINC00881 is an upstream regulator of sarcomere and calcium channel gene expression including MYH6, CACNA1C, and RYR2. LINC00881 knockdown reduces peak calcium amplitude in the beating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). These data suggest that HF-associated changes in myocardial DNA methylation within coding and noncoding genomes are minimally reversible with mechanical unloading. Epigenetic reprogramming strategies may be necessary to achieve sustained clinical recovery from heart failure.