Fatal Heart Research Articles

Pathogenetic mechanisms of muscle-specific ribosomes in dilated cardiomyopathy.

The heart employs a specialized ribosome in its muscle cells to translate genetic information into proteins, a fundamental adaptation with an elusive physiological role 1-3 . Its significance is underscored by the discovery of neonatal patients suffering from often fatal heart failure caused by severe dilated cardiomyopathy when both copies of the gene RPL3L are mutated 4-9 . RPL3L is a muscle-specific paralog 1-3 of the ubiquitous ribosomal protein L3 (RPL3), which makes the closest contact of any protein to the ribosome's RNA-based catalytic center 10 . RPL3L -linked heart failure represents the only known human disease associated with tissue-specific ribosomes, yet the underlying pathogenetic mechanisms remain poorly understood. Intriguingly, disease is linked to a large number of mostly missense variants in RPL3L , and RPL3L -knockout resulted in no severe heart defect in either human or mice 3, 11-13 , challenging the prevailing view that autosomal recessive diseases are caused by loss-of-function mutations. Here, we report three new cases of RPL3L -linked severe neonatal heart failure and present a unifying pathogenetic mechanism by which a large number of variants in the muscle-specific ribosome led to disease. Specifically, affected families often carry one of two recurrent toxic gain-of-function variants alongside a family-specific putative loss-of-function variant. While the non-recurrent variants often trigger partial compensation of RPL3 similar to Rpl3l -knockout mice, both recurrent variants exhibit increased affinity for the RPL3/RPL3L chaperone GRWD1 14-16 and 60S biogenesis factors, sequester 28S rRNA in the nucleus, disrupt ribosome biogenesis, and trigger severe cellular toxicity that extends beyond the loss of ribosomes. These findings provide critical insights for genetic screening and therapeutic development of neonatal heart failure. Our results suggest that gain-of-toxicity mechanisms may be more prevalent in autosomal recessive diseases, and a combination of gain-of-toxicity and loss-of-function mechanisms could underlie many diseases involving genes with paralogs.

Clinical Outcomes in Diabetic Females Presenting with STEMI: A Cohort Study

Introduction: Although the incidence of Acute Coronary Syndrome (ACS) is lower in women, outcomes are worse, particularly in diabetic females. Despite advances in revascularisation and treatment, mortality rates among diabetic females remain higher, with poorer postpercutaneous coronary intervention outcomes. Studies have rarely addressed the differences in the course of myocardial infarction in diabetic females and this underrepresentation has influenced the formulation of guidelines. Aim: To evaluate the in-hospital composite outcomes of death, non fatal myocardial infarction, emergency revascularisation, heart failure and cerebrovascular accident in diabetic women presenting with ST Elevation Myocardial Infarction (STEMI), as well as the individual in-hospital outcomes and outcomes at one and three months follow-up. Materials and Methods: This was a prospective single-centre cohort study conducted between November 2017 and October 2018 on 204 patients with STEMI and followed-up for three months. Data were collected from patients using a semistructured questionnaire-based interview, clinical examination, laboratory investigations, echocardiography and angiography. In-hospital outcomes—death, non fatal MI, emergency revascularisation, heart failure and cerebrovascular accident—were studied. Telephonic follow-up was conducted at one and three months. The comparison of variables was carried out using the Independent Student’s t-test or Chi-square test, and regression analysis was performed to identify predictors of mortality. Results: The mean age was 64±11 years; 60.3% were hypertensive and 26% had dyslipidaemia. A total of 12.3% were newly diagnosed diabetics. The mean prehospital delay was 201.9±156.8 minutes. Primary angioplasty was performed in 77%, while thrombolysis was done in 16.7%. The composite outcome was observed in 26.3% of the patients, with heart failure occurring in 19%, cardiogenic shock in 27.9% and death in 16.2%. Cerebrovascular accidents were noted in 0.5% and renal dysfunction was present in 13.2%. At one and three months, heart failure occurred in 7.6% and 5.8%, respectively. Among those with in-hospital mortality, a higher proportion had Anterior Wall Myocardial Infarction (AWMI) (p=0.043), were in Killip class>II (p-value <0.0001), and had qRBBB (Right Bundle Branch Block) (p-value <0.0001). They presented later, with higher blood sugar (p-value <0.0001) and creatinine values (p-value=0.009) and had a lower Ejection Fraction (EF) (p-value=0.003). Killip class (OR=16.0), presence of Ventricular Septal Rupture (VSR) (OR=23.4), no-reflow phenomenon (OR=23.4) and development of renal dysfunction (OR=9.0) were identified as predictors of mortality. Conclusion: Despite a high rate of revascularisation and fewer procedure-related complications, outcomes remain grim, with a higher incidence of heart failure, cardiogenic shock, renal dysfunction and mortality. A worse clinical profile, left ventricular dysfunction and renal dysfunction were significant predictors of mortality

Prognostic role of high-sensitivity cardiac troponin T in patients with cardiac sarcoidosis: insights from ILLUMINATE-CS.

The prognostic role of high-sensitivity cardiac troponin T (hs-cTnT) as a biomarker in patients with cardiac sarcoidosis (CS) has yet to be fully determined, especially when compared with B-type natriuretic peptide (BNP). In this post-hoc analysis of the ILLUMINATE-CS (ILLUstration of the Management and prognosIs of JapaNese pATiEnts with Cardiac Sarcoidosis), which is a multicentre retrospective observational study, we analysed 103 patients (62.2±10.9years old, 31.1% male) diagnosed as CS and with available data for hs-cTnT measured at the time of diagnosis. The primary outcome was the combined outcomes of all-cause death, fatal ventricular arrhythmia events and heart failure hospitalization. During a median follow-up period of 2.6 (inter-quartile range, 1.6-5.7) years, 24 primary outcomes were observed. Patients with a high hs-cTnT level, defined as a level above the median value (>0.016ng/mL), were associated with a higher incidence of adverse events than those with a low hs-cTnT level (log-rank, P=0.017). In Cox regression analysis, a high log-transformed hs-cTnT level and a high log-transformed BNP level were significant risk factors for primary outcome [hazard ratio (HR), 4.368 (95% confidence interval, CI, 1.032-18.480), P=0.045. and HR, 3.127 (95% CI, 1.029-9.499), P=0.044, respectively]. Patients with both high hs-cTnT and high BNP (>140pg/mL: above the median value) levels had a 3.49 (95% CI, 1.23-9.88)-fold increased risk of the primary outcome compared with patients with both low hs-cTnT and low BNP levels. In patients with CS, a high hs-cTnT level is a useful predictor of adverse events, and combined measurement of hs-cTnT and BNP further improves the prognostic value.

Upper normal serum magnesium is associated with a reduction in incident death from fatal Heart Failure, coronary Heart Disease, and stroke in non-dialysis patients with CKD stages 4 and 5

Upper normal serum magnesium is associated with a reduction in incident death from fatal Heart Failure, coronary Heart Disease, and stroke in non-dialysis patients with CKD stages 4 and 5

Abstract 4126463: The Relationship Between Hope and Hopelessness in Adults with an Acute Cardiac Event

Introduction: Hope has been positively associated with behavior change in individuals screened for cardiovascular risk, and negatively associated with fatal ischemic heart disease (IHD). Hopelessness is associated with increased risk of mortality or nonfatal myocardial infarction in patients with IHD, and negatively associated with physical activity outcomes. Hope and hopelessness are sometimes considered to be ends of a continuum, yet the relationship between hope and hopelessness is not commonly examined in IHD patients. Aim: To determine the relationship between the State-Trait Hopelessness Scale (STHS) and Snyder Adult State and Adult Trait Hope Scales in a sample of patients with IHD. Hypotheses: 1) There would be an inverse relationship between hopelessness and hope as measured by the scales and 2) discriminant validity of the instruments would be confirmed. Methods: A total of 156 participants were enrolled as part of a 3-group randomized controlled trial testing an intervention to promote physical activity and reduce hopelessness. Data were collected two weeks after hospital discharge. Correlations and partial correlations were computed for all combinations of scales. Principal component analysis (PCA) was conducted on hope and hopelessness scales. Results: A total of 106 participants (68%) had moderate or high trait hope, and 92 (59%) had moderate or high state. Moderate or severe hopelessness was reported by 93 participants (59.6%) for state hopelessness and 108 participants (69.2%) for trait. There were moderately strong negative correlations (r=-0.54 to -0.66, p=<0.001) between the total STHS and the Snyder Hope scales for both full and short versions of the STHS. Correlations were virtually unchanged when adjusted for age, sex, cardiac diagnosis, and marital status (r=-0.5 to -0.63, p<0.001) indicating that as hopelessness increases, hope decreases. PCA revealed 4 factors that explained 64.7% of the variance in scores while demonstrating conceptual distinctions between the STHS and Snyder Hope scales. Conclusions: As hypothesized, as hopelessness increased, hope decreased; however, we found a proportion of patients with hopelessness who still expressed hope for the future. Discriminant validity was supported by inverse correlations and factor analyses indicating conceptual distinctions between the two instruments. Interventions to reduce hopelessness for patients with IHD may be successful since hope and hopelessness are not mutually exclusive.

Venetoclax plus decitabine as a bridge to allogeneic haematopoietic stem-cell transplantation in older patients with acute myeloid leukaemia (VEN-DEC GITMO): final report of a multicentre, single-arm, phase 2 trial

Access to allogeneic haematopoietic stem-cell transplantation (HSCT) remains challenging for older patients (aged >60 years) with acute myeloid leukaemia. We aimed to evaluate the efficacy of venetoclax plus decitabine as first-line therapy and bridge to transplantation in this patient population. This multicentre, single-arm, phase 2 trial was conducted in 20 Gruppo Italiano Trapianto Midollo Osseo (GITMO) centres in Italy. Patients aged ≥60 and <75 years, with newly diagnosed acute myeloid leukaemia categorised as intermediate or high risk according to 2016 WHO and 2017 European LeukemiaNet, an ECOG performance status of less than 2, and considered fit for allogeneic HSCT were included. Patients received oral venetoclax with a 3-day ramp-up: 100 mg on day 1, 200 mg on day 2, and 400 mg once per day from day 3 of cycle one, and then every 28 days of each cycle (two to four in total). Decitabine was administered intravenously at a dose of 20 mg/m2 from days 1 to 5 every 28 days. At cycle one, patients were admitted to hospital for a minimum of 24 h, whereas subsequent cycles could be administered on an outpatient basis. Two additional cycles were allowed while waiting for allogeneic HSCT or for those with no response or partial response after cycle two. The primary endpoint was the proportion of patients who had allogeneic HSCT performed during first complete remission, assessed in all patients who received at least one dose of the study medication. This study was registered with ClinicalTrials.gov (NCT04476199, ongoing) and EudraCT (2020-002297-26). Between June 1, 2021, and Dec 30, 2022, 93 patients were enrolled and started venetoclax plus decitabine induction (44 [47%] at intermediate risk and 49 [53%] at high risk). The median age was 68·5 (IQR 60·3-74·7). All 93 participants were White, of whom 43 (46%) were female and 50 (54%) were male. The median follow-up was 236 days (IQR 121-506). 64 (69%) of 93 patients reached complete remission and 53 (57%) underwent allogeneic HSCT in complete remission. 53 (83%) of 64 with a complete remission underwent allogeneic HSCT. Five (8%) of 64 patients in complete remission relapsed before transplantation and four died as a consequence. Adverse events (grade ≥3) occurred in 49 (53%) of 93 patients. The most common adverse events were infections (including pneumonia, bacterial sepsis, and SARS-CoV-2 causing seven deaths among 28 [57%] of 49 patients), neutropenia (17 [35%]), thrombocytopenia (two [4%], including one fatal CNS bleeding), and cardiac events (four [8%], including one fatal heart failure). No treatment-related deaths were observed. Venetoclax plus decitabine induction can significantly enhance the feasibility of allogeneic HSCT in older patients with acute myeloid leukaemia who are deemed fit for transplantation. AbbVie and Johnson & Johnson.

Proposal of a workplace classification model for heart attack accidents from the field of occupational safety and health engineering

Research on occupational accidents is a key factor in improving working conditions and sustainability. Fatal accidents incur significant human and economic costs. Therefore, it is essential to examine fatal accidents to identify the factors that contribute to their occurrence. This study presents an overview of fatal heart attack accidents at work in Spain over the period 2009–2021. Descriptive analysis was conducted considering 13 variables classified into five groups. These variables were selected as predictors to determine the occurrence of this type of accident using a machine learning technique. Thirteen Naïve Bayes prediction models were developed using an unbalanced dataset of 15,616 valid samples from the Spanish Delta@database, employing a two-stage algorithm. The final model was retained using a General Performance Score index. The model selected for this study used a 70:30 distribution for the training and test datasets. A sample was classified as a fatal heart attack if its posterior probability exceeded 0.25. This model is assumed to be a compromise between the confusion matrix values of each model. Sectors with the highest number of heart attacks are ‘Health and social work’, ‘Transport and storage’, ‘Manufacturing’, and ‘Construction’. The incidence of heart attacks and fatal heart attack accidents is higher in men than in women and higher in private sector employees. The findings and model development may assist in the formulation of surveillance strategies and preventive measures to reduce the incidence of heart attacks in the workplace.

Abstract Mo015: Myeloid Specific PD-L1 Deletion Promotes Cardiac Dysfunction And Myocardial Inflammation

Background: Immunotherapy, particularly PD-1/PD-L1 blockers, is effective in cancer treatment but can cause rare, but potentially fatal heart issues. Despite the significant impact of these adverse events, there is limited research into the underlying mechanisms of immune checkpoint inhibitor (ICI)-mediated cardiotoxicity. PD-L1, which is abundantly expressed in cardiac tissue, particularly exhibits high expression levels over myeloid cells. However, the precise role of myeloid-specific PD-L1 signaling in mediating autoimmune cardiac disease pathology remains unclear. Methods and Results: To study the role of myeloid cell-specific PD-L1 (myeloid-PD-L1) in cardiac pathophysiology, we generated myeloid-specific PD-L1 KO mice, using Lyz2tm1(Cre) Ifo systems. As expected, PD-L1 expression was significantly down-regulated in Mφs from myeloid-PD-L1 KOs. The cardiac function was followed by echocardiography. Controls and myeloid-PD-L1-KO hearts had comparable ventricular function at 1 month of age. Interestingly, as early as 2 months of age, myeloid-PD-L1-KOs displayed marked cardiac dysfunction as reflected by reduced LVEF, LVFS, and HF markers. Immune profiling was conducted whether chronic inflammation contributes to cardiac dysfunction and remodeling at a later age as observed at 2 and 3 months of age. Interestingly, excessive systemic inflammation and substantial immune infiltration (innate and adoptive), activation, and a pro-inflammatory cytokine storm were detected in the KO hearts. Furthermore, myeloid-PD-L1 KO hearts showed increased recruitment of pro-inflammatory CCR2+ monocytes and macrophages. Conclusion: Our data with myeloid-PD-L1 KOs suggest that deleting PD-L1 in myeloid lineage promotes myocardial and systemic inflammation through innate and adaptive immune cell activation and recruitment of CCR2+ MΦs. Subsequently, this leads to impaired cardiac pathophysiology. Thus, these translational studies will directly evaluate the potential of targeting myeloid-PD-L1 signaling to alleviate cardiac damage.

Machine Learning-Based Cardiovascular Disease Prediction System to reduce the incidence of occurrence

Health is a paramount factor when considering any nation's sustainable growth and development. The concentration of the larger population of Nigerians is in the rural areas where public health infrastructures are either inadequate or not available. This has affected the larger labor force, leaving society vulnerable to high health. In recent times, one of the major health challenges facing rural and urban dwellers is heart disease occasioned by the non-existence of proper medical diagnosis. This study develops a machine learning model to predict the onset of heart disease to minimize onset cases of occurrence. The health prediction system is integrated with a prediction module to help in providing public healthcare services to rural dwellers. The developed system was comparatively achieved using hybrid machine learning techniques, which include a support vector machine and random forest in the design of the predictive module. The system integrates rural dwellers' health records with the global health database to form part of the Big Data for global access and considerations. The performance evaluation was achieved with the help of Random Forest. The system developed shows an average accuracy of 98% using machine learning algorithms. It also provides a convenient means for rural dwellers to access public health and enables them to receive health predictions to guide against fatal heart disease.

A new variant in the heterotaxy polysplenia syndrome

Heterotaxy is a low incidence genetic disorder of multifactorial inheritance characterized by various abnormalities in the position of organs and vessels relative to the midline of the body. It is most often associated with fatal congenital heart defects at birth. As a result, only a small percentage of patients survive into adulthood. The following clinical case presents a female adult patient with abdominal pain secondary to choledocholithiasis. During the diagnostic workup, she was diagnosed with intestinal malrotation complicated by portal vein thrombosis, which later developed into portal hypertension. In addition to several anomalies (agenesis of the inferior vena cava with direct communication of the suprahepatic veins to the right atrium, polysplenia and shortening of the pancreas), a possible variant of heterotaxy syndrome was diagnosed.

Effectiveness of polypill for primary and secondary prevention of cardiovascular disease: a pragmatic cluster-randomised controlled trial (PolyPars)

BackgroundWe aimed to investigate the effectiveness of fixed-dose combination therapy (polypill) for primary and secondary prevention of major cardiovascular diseases in a typical rural setting.MethodsThe PolyPars Study is a two-arm...

Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression

AbstractThe regulation of red blood cell (RBC) homeostasis by erythropoietin (EPO) is critical for O2 transport and maintaining the adequate number of RBCs in vertebrates. Therefore, dysregulation in EPO synthesis results in disease conditions such as polycythemia in the case of excessive EPO production and anemia, which occurs when EPO is inadequately produced. EPO plays a crucial role in treating anemic patients; however, its overproduction can increase blood viscosity, potentially leading to fatal heart failure. Consequently, the identification of druggable transcription factors and their associated ligands capable of regulating EPO offers a promising therapeutic approach to address EPO-related disorders. This study unveils a novel regulatory mechanism involving 2 pivotal nuclear receptors (NRs), Rev-ERBA (Rev-erbα, is a truncation of reverse c-erbAa) and RAR-related orphan receptor A (RORα), in the control of EPO gene expression. Rev-erbα acts as a cell-intrinsic negative regulator, playing a vital role in maintaining erythropoiesis at the correct level. It accomplishes this by directly binding to newly identified response elements within the human and mouse EPO gene promoter, thereby repressing EPO production. These findings are further supported by the discovery that a Rev-erbα agonist (SR9011) effectively suppresses hypoxia-induced EPO expression in mice. In contrast, RORα functions as a positive regulator of EPO gene expression, also binding to the same response elements in the promoter to induce EPO production. Finally, the results of this study revealed that the 2 NRs, Rev-erbα and RORα, influence EPO synthesis in a negative and positive manner, respectively, suggesting that the modulating activity of these 2 NRs could provide a method to target disorders linked with EPO dysregulation.

The biased apelin receptor agonist, MM07, reverses Sugen/hypoxia-induced pulmonary arterial hypertension as effectively as the endothelin antagonist macitentan.

Introduction: Pulmonary arterial hypertension (PAH) is characterised by endothelial dysfunction and pathological vascular remodelling, resulting in the occlusion of pulmonary arteries and arterioles, right ventricular hypertrophy, and eventually fatal heart failure. Targeting the apelin receptor with the novel, G protein-biased peptide agonist, MM07, is hypothesised to reverse the developed symptoms of elevated right ventricular systolic pressure and right ventricular hypertrophy. Here, the effects of MM07 were compared with the clinical standard-of-care endothelin receptor antagonist macitentan. Methods: Male Sprague-Dawley rats were randomised and treated with either normoxia/saline, or Sugen/hypoxia (SuHx) to induce an established model of PAH, before subsequent treatment with either saline, macitentan (30mg/kg), or MM07 (10mg/kg). Rats were then anaesthetised and catheterised for haemodynamic measurements, and tissues collected for histopathological assessment. Results: The SuHx/saline group presented with significant increases in right ventricular hypertrophy, right ventricular systolic pressure, and muscularization of pulmonary arteries compared to normoxic/saline controls. Critically, MM07 was as at least as effective as macitentan in significantly reversing detrimental structural and haemodynamic changes after 4weeks of treatment. Discussion: These results support the development of G protein-biased apelin receptor agonists with improved pharmacokinetic profiles for use in human disease.

(1041) - Fatal Right Heart Failure Due to Pulmonary Tumor Emboli Syndrome in a Patient with Undiagnosed Colon Cancer

(1041) - Fatal Right Heart Failure Due to Pulmonary Tumor Emboli Syndrome in a Patient with Undiagnosed Colon Cancer

PREVALENCE OF METABOLIC SYNDROME AMONG PATIENTS WITH SCHIZOPHRENIA FROM LONG CARE UNIT IN FORENSIC PSYCHIATRY PROGRAM: AN OBSERVATIONAL STUDY

Introduction – Metabolic syndrome is a leading health concern among schizophrenia patients treated with antipsychotics. The morbidity and mortality rates of these patients can increase when they already have cardiovascular disease and other risk factors. This study aimed to examine the prevalence of metabolic syndrome and its relationship to various clinical parameters such as blood pressure, fasting blood glucose, triglycerides, high-density lipoprotein, and waist circumference. Methods – This disease-oriented observational study was carried out in the forensic psychiatric rehabilitation ward at the Erada &amp; Mental Health Complex - Taif, Saudi Arabia. Patients admitted to the inpatient ward between 2018 and 2023 participated in the study (N = 71). The relationship between metabolic syndrome and psychotropic medications was also examined. Schizophrenia was defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR) criteria. Metabolic syndrome was assessed based on the international criteria National Cholesterol Education Program’s Adult Treatment Panel III report (ATPIII) criteria and AHA/NHLB. Results – In this study, 71 volunteer schizophrenic patients were included, and an observational study over five years was conducted. We found the total number of metabolic syndrome patients was 40 (56.34%) compared with 31 (43.66%) patients without metabolic syndrome. The majority of metabolic syndrome patients (57.50%) were aged 41 to 50. The highest number of patients suffering from metabolic syndrome are those taking atypical antipsychotic medications. Among antipsychotic medications, aripiprazole was found the maximum number of 10 (25%) followed by olanzapine 7 (17.5%). Maximum number of metabolic syndrome parameters increased fasting blood sugar 26 (65%) followed by increased body mass index 21 (52.5%). Discuss – This research can contribute to the study of the prevalence of metabolic syndrome among patients with schizophrenia. In the present study, the prevalence of metabolic syndrome was 56.34 percent in schizophrenia. There are several metabolic side effects associated with second-generation antipsychotics and if these aren't treated properly, they can lead to serious health complications, such as diabetes, dyslipidemia, and fatal heart disease. Conclusion - In our study, metabolic syndrome was most prevalent among patients between 41 - 50 years of age. Therefore, clinicians are encouraged to screen and monitor metabolic syndrome and treat cardio-metabolic risk factors for optimum long-term management. Keywords: schizophrenia, metabolic syndrome, antipsychotics.

A comparative study of cardiovascular risk stratification methods in type 1 diabetes mellitus patients

The Steno Diabetes Center Copenhagen developed the Steno T1 Risk Engine (ST1RE) to predict cardiovascular events, encompassing fatal and nonfatal ischemic heart disease, ischemic stroke, heart failure, and peripheral arterial disease in type 1 diabetes mellitus(T1DM).The current study investigated the agreement between ST1RE and the Brazilian Society for Endocrinology and Metabology (SBEM) classification. Participants were included in the study if diagnosed with T1DM and had at least one outpatient visit in 2021. Patients with established cardiovascular disease and chronic kidney disease on dialysis were excluded. Clinical parameters were obtained from medical records, such as age, body mass index (BMI), blood pressure, physical activity, current smoking, microvascular target organ damage, levels of low-density lipoprotein cholesterol, creatinine, glycated hemoglobin (HbA1c), and albuminuria.Overall, 92 patients (38 males and 53 females) with an age median (P25; P75) of 33 years (25.5;42.5), BMI of 24.8 + 4.1 kg/m2, and duration of diabetes (mean ± SD) of 23.4 + 9.5 years were evaluated. There were no differences considering the gender for most analyzed variables, but a higher proportion of women exhibited microvascular complications such as microalbuminuria, macroalbuminuria, and retinopathy. Our results show a weak agreement in the 10-year cardiovascular risk estimation between SBEM and ST1RE classifications. According to SBEM criteria, 72.8% of patients were considered high-risk, while only 15.2% of patients received the same classification using ST1RE. The dissimilarities between these two classifications were also evident when age and gender factors were compared. While 60% of patients under 35 years were classified as high risk according to SBEM criteria, only 1.8% received this stratification risk in the ST1RE classification.The results indicate a low agreement between the 10-year cardiovascular event risk classification by SBEM and the classification by ST1RE for type 1 diabetes patients without established cardiovascular disease.

Sodium butyrate alleviates right ventricular hypertrophy in pulmonary arterial hypertension by inhibiting H19 and affecting the activation of let-7g-5p/IGF1 receptor/ERK

Pulmonary arterial hypertension (PAH) is a complex and fatal cardio-pulmonary vascular disease. Decompensated right ventricular hypertrophy (RVH) caused by cardiomyocyte hypertrophy often leads to fatal heart failure, the leading cause of mortality among patients. Sodium butyrate (SB), a compound known to reduce cardiac hypertrophy, was examined for its potential effect and the underlying mechanism of SB on PAH-RVH. The in vivo study showed that SB alleviated RVH and cardiac dysfunction, as well as improved life span and survival rate in MCT-PAH rats. The in vivo and in vitro experiments showed that SB could attenuate cardiomyocyte hypertrophy by reversing the expressions of H19, let-7g-5p, insulin-like growth factor 1 receptor (IGF1 receptor), and pERK. H19 inhibition restored the level of let-7g-5p and prevented the overexpression of IGF1 receptor and pERK in hypertrophic cardiomyocytes. In addition, dual luciferase assay revealed that H19 demonstrated significant binding with let-7g-5p, acting as its endogenous RNA. Briefly, SB attenuated PAH-RVH by inhibiting the H19 overexpression, restoring the level of let-7g-5p, and hindering IGF1 receptor/ERK activation.

Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses

Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95-1·01), stroke (1·01, [0·97-1·05]), or all-cause mortality (0·99, 0·95-1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations. Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status. British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

Plakophilin 2 gene therapy prevents and rescues arrhythmogenic right ventricular cardiomyopathy in a mouse model harboring patient genetics

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a fatal genetic heart disease characterized by cardiac arrhythmias, in which fibrofatty deposition leads to heart failure, with no effective treatments. Plakophilin 2 (PKP2) is the most frequently mutated gene in ARVC, and although altered RNA splicing has been implicated, there are no models to study its effect and therapeutics. Here, we generate a mouse model harboring a PKP2 mutation (IVS10-1G>C) affecting RNA splicing, recapitulating ARVC features and sudden death starting at 4 weeks. Administering AAV-PKP2 gene therapy (adeno-associated viral therapy to drive cardiac expression of PKP2) to neonatal mice restored PKP2 protein levels, completely preventing cardiac desmosomal and pathological deficits associated with ARVC, ensuring 100% survival of mice up to 6 months. Late-stage AAV-PKP2 administration rescued desmosomal protein deficits and reduced pathological deficits including improved cardiac function in adult mice, resulting in 100% survival up to 4 months. We suggest that AAV-PKP2 gene therapy holds promise for circumventing ARVC associated with PKP2 mutations, including splice site mutations.

Heart Disease Mortality in Cancer Survivors: A Population-Based Study in Japan.

Data on the risk of cardiovascular-related mortality in patients with cancer are limited. This retrospective cohort study used data from the Osaka Cancer Registry and vital statistics in Japan between 1985 and 2013. The causes of death were investigated, and the risk of fatal heart disease was analyzed. Standardized mortality ratios were calculated to compare the risk of fatal heart disease between patients with cancer and the general population. Fine and Gray competing risk regression models were used to assess the risk of fatal heart disease among patients with cancer. In total, 682 886 patients with cancer were included in the analysis, and 335 635 patients died during the study period. Heart disease was the leading cause of noncancer deaths, with 10 686 deaths. Among the patients who died of heart disease, 5017 had ischemic heart disease, 3598 had heart failure, 356 had hypertensive disease, and 1715 had other heart diseases. The standardized mortality ratio for heart disease was 2.80 (95% CI, 2.74-2.85). The standardized mortality ratio for ischemic heart disease, heart failure, and hypertensive disease were 3.26 (95% CI, 3.17-3.35), 2.69 (95% CI, 2.60-2.78), and 5.97 (95% CI, 5.38-6.63), respectively. The risk of fatal heart disease increased over time after cancer diagnosis. Men were more likely to die of heart disease than women (subdistribution hazard ratio, 1.08 [95% CI, 1.02-1.16]). The risk of fatal heart disease among cancer survivors has decreased in recent years. Cancer survivors have a higher risk of fatal heart disease than the general population.