Daily Cardiology Research Analysis

BACKGROUND AND AIMS: Acquired somatic mutations emerged as important drivers of adverse cardiovascular disease outcomes. Recently, mosaic loss of Y chromosome (LOY) in haematopoietic cells was identified to induce diffuse cardiac fibrosis in male mice. The aim of the present study was to determine the association between LOY and cardiovascular mortality in patients undergoing coronary angiography. METHODS: LOY was quantified in 1698 male participants of the LURIC study, who underwent coronary angiography, and its association with all-cause and cardiovascular mortality was determined. Furthermore, the interaction between LOY and inherited genetic susceptibility for cardiac fibrosis was assessed. RESULTS: The frequency of LOY steeply increased in male participants of LURIC at the age of 60 years. Loss of Y chromosome > 17% was associated with significantly higher all-cause [hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.09-1.82] and cardiovascular mortality (HR 1.49, 95% CI 1.09-2.03), which was driven by a higher risk for fatal myocardial infarction (HR 2.65, 95% CI 1.46-4.81). Loss of Y chromosome > 17% was associated with a profibrotic and proinflammatory plasma protein expression profile as characterized by higher plasma levels of osteoprotegerin, matrix metalloproteinase-12, growth differentiation factor 15, heparin-binding EGF-like growth factor, and resistin. Genetic predisposition for lower myocardial fibrosis attenuated the association between LOY and cardiovascular mortality. Genome-wide methylation analyses identified differential methylation in 298 genes including ACTB, RPS5, WDR1, CD151, and ARAP1. Single-cell RNA sequencing further confirmed differential gene expression of 37 of these genes in LOY in peripheral blood mononuclear cells comprising a set of fibrosis-regulating genes including RPS5. RPS5 silencing in macrophages induced a paracrine induction of collagen expression in cardiac fibroblasts documenting a functional role in vitro. CONCLUSIONS: LOY represents an important independent risk factor for cardiovascular mortality in male patients with coronary artery disease. Targeting LOY may represent a sex-specific personalized medicine approach.

BACKGROUND AND AIMS: The risk of heart failure progression or mortality in patients with peri-partum cardiomyopathy (PPCM) during subsequent pregnancies (SSPs) is a significant concern for patients, their families, and healthcare providers. However, there is limited contemporary, prospective data on SSP outcomes in PPCM patients from diverse ethnic and sociodemographic groups. This study aimed to assess maternal and neonatal outcomes in PPCM patients undergoing SSPs. METHODS: This is a sub-study on PPCM and SSPs of the global European Society of Cardiology PPCM Registry that recruited patients from 2012 to 2023. Maternal and neonatal outcomes were reported. RESULTS: From 332 patients with PPCM, there were 98 SSPs among 73 women. Of these, 25 (26%) SSPs ended prematurely due to therapeutic termination (20/25), miscarriage (4/25), and stillbirth (1/25). The median follow-up from the end of the SSP was 198 days (inter-quartile range 160-240). Left ventricular ejection fraction (LVEF) was persistently reduced to <50% prior to the SSP in 26% of patients, with only 6% having an LVEF <40%. Patient characteristics were similar, irrespective of SSP baseline LVEF. Clinical worsening [composite of all-cause death, cardiovascular rehospitalization, or decline in LVEF ≥10% (percentage points) and to <50%] occurred in 20% SSPs, with 2% all-cause maternal mortality. Signs/symptoms of heart failure and worsening of New York Heart Association class occurred in 26% and 22% of SSPs, respectively. At follow-up, the mean LVEF was 50% (±12%), and in 69% of SSPs, the LVEF was ≥50%. African women had similar outcome as the other ethnic groups. Pre-term delivery occurred in 24% of SSPs, 20% of babies were of low birth weight, and there was 3% all-cause neonatal mortality. Compared with women with SSP baseline LVEF <50%, fewer women with LVEF ≥50% were on heart failure pharmacotherapies prior to the SSP, and in this group of women, there was a significant decline in LVEF. CONCLUSIONS: Maternal morbidity and mortality rates were lower than anticipated. Baseline LVEF <50% was not associated with an increased frequency of adverse maternal outcomes, and no further decline in LVEF was observed in this group. In contrast, women with SSPs and a baseline LVEF ≥50% experienced a decline in LVEF, potentially attributable to reduced use of heart failure pharmacotherapy during pregnancy and the post-partum period. Therapeutic termination was performed in approximately a fifth of cases. The findings suggest that reclassification of a SSP with persisting mild left ventricular impairment from modified World Health Organization (mWHO) Class IV (contraindicated) to mWHO III may be considered, while remaining under the care of an experienced medical team and with appropriate pharmacological management.

IMPORTANCE: Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking. OBJECTIVE: To determine factors predictive of SCD/major ventricular arrhythmias (MVA) in carriers of FLNCtv. DESIGN, SETTING, AND PARTICIPANTS: This was an international, multicenter, retrospective cohort study conducted from February 2023 to June 2024. The Filamin C Registry Consortium included 19 referral centers for genetic cardiomyopathies worldwide. Participants included carriers of pathogenic or likely pathogenic FLNCtv. Phenotype negative was defined as the absence of any pathological findings detected by 12-lead electrocardiogram (ECG), Holter ECG monitoring, echocardiography, or cardiac magnetic resonance. EXPOSURES: Composite of SCD and MVA in carriers of FLNCtv. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of SCD and MVA, the last including aborted SCD, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator (ICD) interventions. RESULTS: Among 308 individuals (median [IQR] age, 45 [33-56] years; 160 male [52%]) with FLNCtv, 112 (36%) were probands, and 72 (23%) were phenotype negative. Median (IQR) left ventricular ejection fraction (LVEF) was 51% (38%-59%); 89 participants (34%) had LVEF less than 45%, and 50 (20%) had right ventricular dysfunction. During a median (IQR) follow-up of 34 (8-63) months, 57 individuals (19%) experienced SCD/MVA, with an annual incidence rate of 4 cases per 100 person-years (95% CI, 3-6). Incidence rates were higher in probands vs nonprobands and in phenotype-positive vs phenotype-negative individuals. A predictive model estimating SCD/MVA risk was derived from multivariable analysis, which included older age, male sex, previous syncope, nonsustained ventricular tachycardia, and LVEF with a time-dependent area under the curve (AUC) ranging between 0.76 (95% CI, 0.67-0.86) at 12 months and 0.78 (95% CI, 0.70-0.86) at 72 months. Notably, the association of LVEF with the SCD/MVA risk was not linear, showing significant lower risk for values of LVEF greater than 58%, and no increase for values less than 58%. Internal validation with bootstrapping confirmed good accuracy and calibration of the model. Results were consistent in subgroups analysis (ie, phenotype-positive carriers and phenotype-positive carriers without MVA at onset). CONCLUSIONS AND RELEVANCE: Results suggest that the risk of SCD/MVA in phenotype-positive carriers of FLNCtv was high. A 5-variable predictive model derived from this cohort allows risk estimation and could support clinicians in the shared decision for prophylactic ICD implantation. External cohort validation is warranted.