Single-Cell RNA Sequencing Deconstructs the Distribution of Immune Cells Within Abdominal Aortic Aneurysms in Mice.

BACKGROUND: Inflammation is a key component in the development of abdominal aortic aneurysm (AAA), yet insights into the roles of immune cells and their interactions in this process are limited. METHODS: Using single-cell RNA transcriptomic analysis, we deconstructed the CD45+ cell population in elastase-induced murine AAA at the single-cell level. We isolated each group of immune cells from murine AAA tissue at different time points and divided them into several subtypes, listed the remarkable differentially expressed genes, explored the developmental trajectories of immune cells, and demonstrated the interactions among them. RESULTS: Our findings reveal significant differences in several immune cell subsets, including macrophages, dendritic cells, and T cells, within the AAA microenvironment compared with the normal aorta. Especially, conventional dendritic cell type 1 exclusively existed in the AAA tissue rather than the normal aortas. Via CellChat analysis, we identified several intercellular communication pathways like visfatin, which targets monocyte differentiation and neutrophil extracellular trap-mediated interaction between neutrophils and dendritic cells, which might contribute to AAA development. Some of these pathways were validated in human AAA. CONCLUSIONS: Despite the absence of external pathogenic stimuli, AAA tissues develop a complex inflammatory microenvironment involving numerous immune cells. In-depth studies of the inflammatory network shall provide new strategies for patients with AAA.

Characterization and acceleration of genome shuffling and ploidy reduction in synthetic allopolyploids by genome sequencing and editing.

Polyploidy and the subsequent ploidy reduction and genome shuffling are the major driving forces of genome evolution. Here, we revealed short-term allopolyploid genome evolution by sequencing a synthetic intergeneric hybrid (Raphanobrassica, RRCC). In this allotetraploid, the genome deletion was quick, while rearrangement was slow. The core and high-frequency genes tended to be retained while the specific and low-frequency genes tended to be deleted in the hybrid. The large-fragment deletions were enriched in the heterochromatin region and probably derived from chromosome breaks. The intergeneric translocations were primarily of short fragments dependent on homoeology, indicating a gene conversion origin. To accelerate genome shuffling, we developed an efficient genome editing platform for Raphanobrassica. By editing Fanconi Anemia Complementation Group M (FANCM) genes, homoeologous recombination, chromosome deletion and secondary meiosis with additional ploidy reduction were accelerated. FANCM was shown to be a checkpoint of meiosis and controller of ploidy stability. By simultaneously editing FLIP genes, gene conversion was precisely introduced, and mosaic genes were produced around the target site. This intergeneric hybrid and genome editing platform not only provides models that facilitate experimental evolution research by speeding up genome shuffling and conversion but also accelerates plant breeding by enhancing intergeneric genetic exchange and creating new genes.

Profiling cardiomyocytes at single cell resolution reveals COX7B could be a potential target for attenuating heart failure in cardiac hypertrophy.

Cardiac hypertrophy can develop to end-stage heart failure (HF), which inevitably leading to heart transplantation or death. Preserving cardiac function in cardiomyocytes (CMs) is essential for improving prognosis in hypertrophic cardiomyopathy (HCM) patients. Therefore, understanding transcriptomic heterogeneity of CMs in HCM would be indispensable to aid potential therapeutic targets investigation. We isolated primary CM from HCM patients who had extended septal myectomy, and obtained transcriptomes in 338 human primary CM with single-cell tagged reverse transcription (STRT-seq) approach. Our results revealed that CMs could be categorized into three subsets in nonfailing HCM heart: high energy synthesis cluster, high cellular metabolism cluster and intermediate cluster. The expression of electron transport chain (ETC) was up-regulated in larger-sized CMs from high energy synthesis cluster. Of note, we found the expression of Cytochrome c oxidase subunit 7B (COX7B), a subunit of Complex IV in ETC had trends of positively correlation with CMs size. Further, by assessing COX7B expression in HCM patients, we speculated that COX7B was compensatory up-regulated at early-stage but down-regulated in failing HCM heart. To test the hypothesis that COX7B might participate both in hypertrophy and HF progression, we used adeno associated virus 9 (AAV9) to mediate the expression of Cox7b in pressure overload-induced mice. Mice in vivo data supported that knockdown of Cox7b would accelerate HF and Cox7b overexpression could restore partial cardiac function in hypertrophy. Our result highlights targeting COX7B and preserving energy synthesis in hypertrophic CMs could be a promising translational direction for HF therapeutic strategy.

Estrogen Oppositely Regulates Pulmonary Hypertension via METTL3/PFKFB3 Under Normoxia and Hypoxia.

Despite extensive investigation into estrogen's role in pulmonary hypertension (PH) development, its effects-whether beneficial or detrimental-remains contentious. This study aimed to elucidate estrogen's potential role in PH under normoxic and hypoxic conditions. Utilizing norfenfluramine- and hypoxia-induced rat models of PH, the study evaluated the impact of 17ß-estradiol (E2) on PH progression. E2 promoted PH development under normoxia while providing protection under hypoxia. Mechanistically, under normoxia, E2 upregulated methyltransferase-like 3 (METTL3) gene transcription and protein via an estrogen response element-dependent pathway, which in turn elevated the m6A methylation and translational efficiency of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase isoform 3 (PFKFB3) mRNA, leading to increased PFKFB3 protein levels and enhanced proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Conversely, under hypoxia, E2 downregulated METTL3 transcription through a hypoxia response element-dependent mechanism, driven by elevated hypoxia-induced factor 1α (HIF-1α) levels, resulting in reduced PFKFB3 protein expression and diminished PASMCs proliferation and migration. Both METTL3 and PFKFB3 proteins are upregulated in the pulmonary arteries of patients with PAH. Collectively, these findings suggest that E2 exerts differential effects on PH progression via dual regulation of the METTL3/PFKFB3 protein under normoxic and hypoxic conditions, positioning the METTL3/PFKFB3 protein as a potential therapeutic target for PH treatment.

Single-cell RNA sequencing in donor and end-stage heart failure patients identifies NLRP3 as a therapeutic target for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Dilation may be the first right ventricular change and accelerates the progression of threatening ventricular tachyarrhythmias and heart failure for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), but the treatment for right ventricular dilation remains limited. METHODS: Single-cell RNA sequencing (scRNA-seq) of blood and biventricular myocardium from 8 study participants was performed, including 6 end-stage heart failure patients with ARVC and 2 normal controls. ScRNA-seq data was then deeply analyzed, including cluster annotation, cellular proportion calculation, and characterization of cellular developmental trajectories and interactions. An integrative analysis of our single-cell data and published genome-wide association study-based data provided insights into the cell-specific contributions to the cardiac arrhythmia phenotype of ARVC. Desmoglein 2 (Dsg2)mut/mut mice were used as the ARVC model to verify the therapeutic effects of pharmacological intervention on identified cellular cluster. RESULTS: Right ventricle of ARVC was enriched of CCL3+ proinflammatory macrophages and TNMD+ fibroblasts. Fibroblasts were preferentially affected in ARVC and perturbations associated with ARVC overlap with those reside in genetic variants associated with cardiac arrhythmia. Proinflammatory macrophages strongly interact with fibroblast. Pharmacological inhibition of Nod-like receptor protein 3 (NLRP3), a transcriptional factor predominantly expressed by the CCL3+ proinflammatory macrophages and several other myeloid subclusters, could significantly alleviate right ventricular dilation and dysfunction in Dsg2mut/mut mice (an ARVC mouse model). CONCLUSIONS: This study provided a comprehensive analysis of the lineage-specific changes in the blood and myocardium from ARVC patients at a single-cell resolution. Pharmacological inhibition of NLRP3 could prevent right ventricular dilation and dysfunction of mice with ARVC.

New insights gained from cellular landscape changes in myocarditis and inflammatory cardiomyopathy.

Advances in the etiological classification of myocarditis and inflammatory cardiomyopathy (ICM) have reached a consensus. However, the mechanism of myocarditis/ICM remains unclear, which affects the development of treatment and the improvement of outcome. Cellular transcription and metabolic reprogramming, and the interactions between cardiomyocytes and non-cardiomyocytes, such as the immune cells, contribute to the process of myocarditis/ICM. Recent efforts have been made by multi-omics techniques, particularly in single-cell RNA sequencing, to gain a better understanding of the cellular landscape alteration occurring in disease during the progression. This article aims to provide a comprehensive overview of the latest studies in myocarditis/ICM, particularly as revealed by single-cell sequencing.

Single-Cell RNA Sequencing of Coronary Perivascular Adipose Tissue From End-Stage Heart Failure Patients Identifies SPP1+ Macrophage Subpopulation as a Target for Alleviating Fibrosis.

BACKGROUND: Perivascular adipose tissue (PVAT) is vital for vascular homeostasis, and PVAT dysfunction is associated with increased atherosclerotic plaque burden. But the mechanisms underlining coronary PVAT dysfunction in coronary atherosclerosis remain elusive. METHODS: We performed single-cell RNA sequencing of the stromal vascular fraction of coronary PVAT from 3 groups of heart transplant recipients with end-stage heart failure, including 3 patients with nonobstructive coronary atherosclerosis, 3 patients with obstructive coronary artery atherosclerosis, and 4 nonatherosclerosis control subjects. Bioinformatics was used to annotate the cellular populations, depict the cellular developmental trajectories and interactions, and explore the differences among 3 groups of coronary PVAT at the cellular and molecular levels. Pathological staining, quantitative real-time polymerase chain reaction, and in vitro studies were performed to validate the key findings. RESULTS: Ten cell types were identified among 67 936 cells from human coronary PVAT. Several cellular subpopulations, including SPP1+ (secreted phosphoprotein 1) macrophages and profibrotic fibroadipogenic progenitor cells, were accumulated in PVAT surrounding atherosclerotic coronary arteries compared with nonatherosclerosis coronary arteries. The fibrosis percentage was increased in PVAT surrounding atherosclerotic coronary arteries, and it was positively associated with the grade of coronary artery stenosis. Cellular interaction analysis suggested OPN (osteopontin) secreted by SPP1+ macrophages interacted with CD44 (cluster of differentiation 44)/integrin on fibroadipogenic progenitor cells. Strikingly, correlation analyses uncovered that higher level of SPP1 in PVAT correlates with a more severe fibrosis degree and a higher coronary stenosis grade. In vitro studies showed that conditioned medium from atherosclerotic coronary PVAT promoted the migration and proliferation of fibroadipogenic progenitor cells, while such effect was prevented by blocking CD44 or integrin. CONCLUSIONS: SPP1+ macrophages accumulated in the PVAT surrounding atherosclerotic coronary arteries, and they promoted the migration and proliferation of fibroadipogenic progenitor cells via OPN-CD44/integrin interaction and thus aggravated the fibrosis of coronary PVAT, which was positively correlated to the coronary stenosis burden. Therefore, SPP1+ macrophages in coronary PVAT may participate in the progression of coronary atherosclerosis.

Single-Cell Transcriptomic Analysis Reveals Myocardial Fibrosis Mechanism of Doxorubicin-Induced Cardiotoxicity.

Myocardial fibrosis is a pathological feature of doxorubicin-induced chronic cardiotoxicity that severely affects the prognosis of oncology patients. However, the specific cellular and molecular mediators driving doxorubicin-induced cardiac fibrosis, and the relative impact of different cell populations on cardiac fibrosis, remain unclear.This study aimed to explore the mechanism of doxorubicin-induced cardiotoxicity and myocardial fibrosis and to find potential therapeutic targets. Single-cell RNA sequencing was used to analyze the transcriptome of non-cardiomyocytes from normal and doxorubicin-induced chronic cardiotoxicity in mouse model heart tissue.We established a mouse model of doxorubicin-induced cardiotoxicity with a well-defined fibrotic phenotype. Analysis of single-cell sequencing results showed that fibroblasts were the major origin of extracellular matrix in doxorubicin-induced myocardial fibrosis. Further resolution of fibroblast subclusters showed that resting fibroblasts were converted to matrifibrocytes and then to myofibroblasts to participate in the myocardial remodeling process in response to doxorubicin treatment. Ctsb expression was significantly upregulated in fibroblasts after doxorubicin-induced.This study provides a comprehensive map of the non-cardiomyocyte landscape at high resolution, reveals multiple cell populations contributing to pathological remodeling of the cardiac extracellular matrix, and identifies major cellular sources of myofibroblasts and dynamic gene-expression changes in fibroblast activation. Finally, we used this strategy to detect potential therapeutic targets and identified Ctsb as a specific target for fibroblasts in doxorubicin-induced myocardial fibrosis.

Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox.

BACKGROUND: The nuclear receptor Rev-erbα/ß, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear. METHODS: We generated mouse lines with cardiac-specific Rev-erbα/ß knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) analyses, and performed dietary and pharmacological rescue experiments to assess the time-of-the-day effects. We compared the temporal pattern of cardiac clock gene expression with the cardiac dilation severity in failing human hearts. RESULTS: KO mice display progressive dilated cardiomyopathy and lethal heart failure. Inducible ablation of Rev-erbα/ß in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, in particular, in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, in particular, in the dark cycle. Increasing dietary lipid or sugar supply in the dark cycle does not affect cardiac dysfunctions in KO mice. However, obesity coupled with systemic insulin resistance paradoxically ameliorates cardiac dysfunctions in KO mice, associated with rescued expression of lipid oxidation genes only in the light cycle in phase with increased fatty acid availability from adipose lipolysis. Inhibition of glycolysis in the light cycle and lipid oxidation in the dark cycle, but not vice versa, ameliorate cardiac dysfunctions in KO mice. Altered temporal patterns of cardiac Rev-erb gene expression correlate with the cardiac dilation severity in human hearts with dilated cardiomyopathy. CONCLUSIONS: The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipid supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human dilated cardiomyopathy. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and dilated cardiomyopathy.

Ruxolitinib attenuates acute rejection and can serve as an immune induction therapy in heart transplantation.

The benefits of IL2RA antagonists in heart transplant patients are controversial. We aimed to elucidate the effects of IL2RA antagonists and identify targets that could be better than IL2RA antagonists. By using single-cell RNA sequencing of immune cells at different time points in patients receiving IL2RA antagonists, we identified nineteen types of cells. We revealed higher IL2RA expression in regulatory T cells (Tregs), suggesting that IL2RA antagonists attenuated IL-2-induced Treg activation. CD4_C04_IFNGR1 and CD8_C05_IFITM2 which had more cytotoxic effects, remained elevated at later time points. IFNGR1 was upregulated in these two subtypes, but was not expressed in Treg. Ruxolitinib targeted the pathways of IFNGR1 (JAK1/2) while not affecting the pathway of IL-2-induced Tregs activation (JAK3). Ruxolitinib showed prolonged survival compared to IL2RA mAb-treated mice. Our study provided dynamic changes of immune cells after IL2RA antagonists treatment at single-cell resolution. Ruxolitinib has potential as a new immunoinduction therapy without affecting Treg.

Tomo-seq identifies NINJ1 as a potential target for anti-inflammatory strategy in thoracic aortic dissection.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening disease caused by an intimal tear in the aorta. The histological characteristics differ significantly between the tear area (TA) and the distant area. Previous studies have emphasized that certain specific genes tend to cluster at the TA. Obtaining a thorough understanding of the precise molecular signatures near the TA will assist in discovering therapeutic strategies for TAD. METHODS: We performed a paired comparison of the pathological patterns in the TA with that in the remote area (RA). We used Tomo-seq, genome-wide transcriptional profiling with spatial resolution, to obtain gene expression signatures spanning from the TA to the RA. Samples from multiple sporadic TAD patients and animal models were used to validate our findings. RESULTS: Pathological examination revealed that the TA of TAD exhibited more pronounced intimal hyperplasia, media degeneration, and inflammatory infiltration compared to the RA. The TA also had more apoptotic cells and CD31+α-SMA+ cells. Tomo-seq revealed four distinct gene expression patterns from the TA to the RA, which were inflammation, collagen catabolism, extracellular matrix remodeling, and cell stress, respectively. The spatial distribution of genes allowed us to identify genes that were potentially relevant with TAD. NINJ1 encoded the protein-mediated cytoplasmic membrane rupture, regulated tissue remodeling, showed high expression levels in the tear area, and co-expressed within the inflammatory pattern. The use of short hairpin RNA to reduce NINJ1 expression in the beta-aminopropionitrile-induced TAD model led to a significant decrease in TAD formation. Additionally, it resulted in reduced infiltration of inflammatory cells and a decrease in the number of CD31+α-SMA+ cells. The NINJ1-neutralizing antibody also demonstrated comparable therapeutic effects and can effectively impede the formation of TAD. CONCLUSIONS: Our study showed that Tomo-seq had the advantage of obtaining spatial expression information of TAD across the TA and the RA. We pointed out that NINJ1 may be involved in inflammation and tissue remodeling, which played an important role in the formation of TAD. NINJ1 may serve as a potential therapeutic target for TAD.

Single-cell RNA sequencing to identify cellular heterogeneity and targets in cardiovascular diseases: from bench to bedside.

The mechanisms of cardiovascular diseases (CVDs) remain incompletely elucidated. Single-cell RNA sequencing (scRNA-seq) has enabled the profiling of single-cell transcriptomes at unprecedented resolution and throughput, which is critical for deciphering cardiovascular cellular heterogeneity and underlying disease mechanisms, thereby facilitating the development of therapeutic strategies. In this review, we summarize cellular heterogeneity in cardiovascular homeostasis and diseases as well as the discovery of potential disease targets based on scRNA-seq, and yield new insights into the promise of scRNA-seq technology in precision medicine and clinical application.

Advances in novel devices for the treatment of heart failure.

Heart failure (HF) is one of the leading causes of global health impairment. Current drugs are still limited in their effectiveness in the treatment and reversal of HF: for example, drugs for acute HF (AHF) help to reduce congestion and relieve symptoms, but they do little to improve survival; most conventional drugs for HF with preserved ejection fraction (HFpEF) do not improve the prognosis; and drugs have extremely limited effects on advanced HF. In recent years, progress in device therapies has bridged this gap to a certain extent. For example, the availability of the left ventricular assist device has brought new options to numerous advanced HF patients. In addition to this recognizable device, a range of promising novel devices with preclinical or clinical trial results are emerging that seek to treat or reverse HF by providing circulatory support, repairing structural abnormalities in the heart, or providing electrical stimulation. These devices may be useful for the treatment of HF. In this review, we summarized recent advances in novel devices for AHF, HFpEF, and HF with reduced ejection fraction (HFrEF) with the aim of providing a reference for clinical treatment and inspiration for novel device development.

PRMT5 Prevents Dilated Cardiomyopathy via Suppression of Protein O-GlcNAcylation.

[Figure: see text].

Cellular Landscapes of Nondiseased Human Cardiac Valves From End-Stage Heart Failure-Explanted Heart.

BACKGROUND: Exploring the mechanisms of valvular heart disease at the cellular level may be useful to identify new therapeutic targets; however, the comprehensive cellular landscape of nondiseased human cardiac valve leaflets remains unclear. METHODS: The cellular landscapes of nondiseased human cardiac valve leaflets (5 aortic valves, 5 pulmonary valves, 5 tricuspid valves, and 3 mitral valves) from end-stage heart failure patients undergoing heart transplantation were explored using single-cell RNA sequencing. Bioinformatics was used to identify the cell types, describe the cell functions, and investigate cellular developmental trajectories and interactions. Differences among the 4 types of cardiac valves at the cellular level were summarized. Pathological staining was performed to validate the key findings of single-cell RNA sequencing. An integrative analysis of our single-cell data and published genome-wide association study-based and bulk RNA sequencing-based data provided insights into the cell-specific contributions to calcific aortic valve diseases. RESULTS: Six cell types were identified among 128 412 cells from nondiseased human cardiac valve leaflets. Valvular interstitial cells were the largest population, followed by myeloid cells, lymphocytes, valvular endothelial cells, mast cells, and myofibroblasts. The 4 types of cardiac valve had distinct cellular compositions. The intercellular communication analysis revealed that valvular interstitial cells were at the center of the communication network. The integrative analysis of our single-cell RNA sequencing data revealed key cellular subpopulations involved in the pathogenesis of calcific aortic valve diseases. CONCLUSIONS: The cellular landscape differed among the 4 types of nondiseased cardiac valve, which might explain their differences in susceptibility to pathological remodeling and valvular heart disease.

Single-Cell Transcriptome Sequencing Reveals Molecular Mechanisms of Renal Injury in Essential Hypertension.

INTRODUCTION: Hypertensive nephropathy is characterized by glomerular and tubulointerstitial damage, but we know little about changes in cell-specific gene expression in the early stages of hypertensive kidney injury, which usually has no obvious pathological changes. METHODS: We performed unbiased single-cell RNA sequencing of rat kidney samples from hypertensive kidney injury to generate 10,602 single-cell transcriptomes from 2 control and 2 early stage hypertensive kidney injury samples. RESULTS: All major cell types of the kidney were represented in the final dataset. Side-by-side comparisons showed that cell type-specific changes in gene expression are critical for functional impairment of glomeruli and tubules and activation of immune cells. In particular, we found a significantly reduced gene expression profile of maintaining vascular integrity in glomerular cells of hypertensive kidney injury. Meanwhile, the expression of genes associated with oxidative stress injury and fibrosis in the renal tubules and collecting ducts was elevated, but the degree of tubular cells response to injury differed between parts. We also found a signature of immune cell infiltration in hypertensive kidney injury. CONCLUSION: Exploring the changes of gene expression in hypertension-injured kidneys may be helpful to identify the early biomarkers and signal pathways of this disease. Our data provide rich resources for understanding the pathogenesis of hypertensive renal injury and formulating effective treatment strategies.

Accurate Classification of Non-ischemic Cardiomyopathy.

PURPOSE OF REVIEW: This article aims to review the accurate classification of non-ischemic cardiomyopathy, including the methods, basis, subtype characteristics, and prognosis, especially the similarities and differences between different classifications. RECENT FINDINGS: Non-ischemic cardiomyopathy refers to a myocardial disease that excludes coronary artery disease or ischemic injury and has a variety of etiologies and high incidence. Recent studies suggest that traditional classification methods based on primary/mixed/acquired or genetic/non-genetic cannot meet the precise needs of contemporary clinical management. This article systematically describes the history of classifications of cardiomyopathy and presents etiological and genetic differences between cardiomyopathies. The accurate classification is described from the perspective of morphology, function, and genomics in hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, left ventricular noncompaction, and partially acquired cardiomyopathy. The different clinical characteristics and treatment needs of these cardiomyopathies are elaborated. Some single-gene mutant cardiomyopathies have unique phenotypes, and some cardiomyopathies have mixed phenotypes. These special classifications require personalized precision treatment, which is worthy of independent research. This article describes recent advances in the accurate classification of non-ischemic cardiomyopathy from clinical phenotypes and causative genes, discusses the advantages and usage scenarios of each classification, compares the differences in prognosis and patient management needs of different subtypes, and summarizes common methods and new exploration directions for accurate classification.

Cardio-oncology: Shared Genetic, Metabolic, and Pharmacologic Mechanism.

PURPOSE OF REVIEW: The article aims to investigate the complex relationship between cancer and cardiovascular disease (CVD), with a focus on the effects of cancer treatment on cardiac health. RECENT FINDINGS: Advances in cancer treatment have improved long-term survival rates, but CVD has emerged as a leading cause of morbidity and mortality in cancer patients. The interplay between cancer itself, treatment methods, homeostatic changes, and lifestyle modifications contributes to this comorbidity. Recent research in the field of cardio-oncology has revealed common genetic mutations, risk factors, and metabolic features associated with the co-occurrence of cancer and CVD. This article provides a comprehensive review of the latest research in cardio-oncology, including common genetic mutations, risk factors, and metabolic features, and explores the interactions between cancer treatment and CVD drugs, proposing novel approaches for the management of cancer and CVD.

Phenotypic Expression, Natural History, and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants.

BACKGROUND: Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. METHODS: FLNCtv carriers were identified from 10 tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP-related arrhythmogenic cardiomyopathies were used for prognostic comparison. RESULTS: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD. CONCLUSIONS: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.

Novel plasma biomarkers predicting biventricular involvement in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease characterized by fibrofatty replacement of the myocardium and ventricular arrhythmias. Biventricular involvement in ARVC may lead to heart failure. This study aimed to investigate the role of plasma biomarkers soluble (s)ST2, Galectin-3 (Gal-3) and GDF-15 in predicting biventricular involvement and adverse outcomes in ARVC. METHODS AND RESULTS: ARVC patients from 2 independent cohorts, were studied. The Bejing (Chinese) cohort (n = 108) was the discovery cohort, whereas the Zurich (Swiss) cohort (n = 47) served as validation. All patients had a definite ARVC diagnosis at time of blood withdrawal. Biomarkers were independently correlated with NT-proBNP and left ventricular (LV)-function. ARVC patients with LV involvement had higher levels of sST2 and GDF-15 as compared to controls and patients with isolated right ventricle (RV) involvement. sST2 and GDF-15 were significantly correlated with late gadolinium enhancement in CMR and with adverse heart failure outcomes. Gal-3 was elevated in ARVC patients with and without LV involvement. The combined use of the three biomarkers (sST2, GDF-15 and NT-proBNP) showed the best performance in predicting LV involvement in both cohorts. Plasma drawn from the coronary arteries and coronary sinus indicated a transmyocardial elevation of sST2, but no transmyocardial gradient of GDF-15. After heart transplantation, both sST2 and GDF-15 returned to near-normal levels. CONCLUSION: Our study showed that sST2 and GDF-15 may predict biventricular involvement in ARVC. The combined use of sST2, GDF-15 and NT-proBNP showed the best prediction of biventricular involvement in ARVC.