Pereira, Naveen L.

ABSTRACT Ischemic events after contemporary percutaneous coronary intervention (PCI) are uncommon but carry high morbidity/mortality. Identifying patients at highest risk is critical to guide dual antiplatelet therapy (DAPT) intensity while minimizing bleeding. Current machine learning (ML) model‐developed risk scores do not incorporate pharmacogenetic data. To develop and externally validate ML models that integrate clinical, demographic, and CYP2C19 genetic information to predict 1‐year ischemic outcomes post‐PCI to refine clinical decision making. We analyzed 8317 patients from TAILOR‐PCI trial ( n = 4572) and the Precision PCI registry ( n = 3745). The outcome was a composite of cardiovascular death, myocardial infarction, stroke, and stent thrombosis at 1 year. Boruta feature selection identified 11 predictors. Multiple ML algorithms were trained in TAILOR‐PCI and validated in Precision PCI using cross‐validation and synthetic minority oversampling (SMOTE). Model performance was assessed by area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. The best external performance was achieved with a support vector machine (SVM, polynomial kernel) (AUC 0.667; sensitivity 0.871; specificity 0.282), while XGBoost provided a more balanced profile (AUC 0.619; sensitivity 0.442; specificity 0.688). Variable importance for the SVM polynomial model demonstrated that all 11 included Boruta feature selected predictors had relatively high importance (> 75). ML models trained on large clinical trial and real‐world registry datasets can help identify the small subset of patients at high ischemic risk after PCI. This distinction is of relevance because ischemic events are rare, and most patients may safely de‐escalate DAPT to reduce bleeding risk while maintaining ischemic protection through a multimodal approach to risk stratification. Trial Registration: TAILOR‐PCI URL: https://clinicaltrials.gov/ct2/show/NCT01742117

Abstract Background Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM) in case-control studies. However, the phenotypic profile and biological mechanisms by which genetic background may predispose individuals to DCM and outcomes in the general population remain unclear. Aim The primary objectives of this study were twofold: (1) to validate a DCM polygenic score (PRS-1) based on a prior meta-analysis of case–control genetic association studies [Tadros R et al. Nat Genet (2021)]; and (2) To apply this PRS, along with two recently developed PRSs for DCM [PRS-2 from Zheng SL et al. Nat Genet (2024) and PRS-3 from Jurgens SJ et al. Nat Genet (2024)] to a general population that underwent comprehensive longitudinal phenotypic assessments and had long-term outcomes available. Methods While the PRS-1 was derived from only 13 SNPs, PRS-2 and PRS-3 were generated from 709,534 and 1,072,247 SNPs, respectively with significant overlap between them. These DCM-PRSs were applied to an unselected community-based cohort (n=1897) aged >45 years, who underwent a physical examination, echocardiogram, and blood sample at baseline. Subsequent clinical outcomes were collected over a median 16 year follow-up (IQR: 15-17). Results No significant differences between the quartiles were present in terms of age, sex (48% male), and cardiovascular risk factors (CV-RF) (such as hypertension, diabetes, and coronary artery disease). However, linear regression models demonstrated a significant correlation between all DCM-PRSs and left ventricular (LV) parameters, including LV ejection fraction, LV end-systolic diameter, and LV end-diastolic diameter (Table). Multivariable regression analysis confirmed that these correlations were independent of age, sex, CV-RF, and population stratification (adjusted for the first 10 principal components [PCs]). During follow-up, 47 individuals developed DCM. A logistic regression analysis, using a 3:1 matched cohort of non-DCM vs. DCM individuals based on age and sex and adjusted for the same 10 PCs, found a significant correlation between DCM development and both PRS-1 [OR=2.27 (1.06–4.85), p=0.03] and PRS-3 [OR=2.63 (1.20–5.75), p=0.02], while PRS-2 did not show a significant association [OR=1.85 (0.84–4.06), p=0.12]. No association was found between the DCM-PRSs and heart failure (HF) biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3) or HF outcomes (all-cause mortality/HF hospitalization). Conclusion PRS-1 for DCM despite being derived from only 13 risk alleles, performs at least as well as the newer and more extensive PRSs, in its correlation with LV function, dimensions, and DCM development (except for PRS-2) in a general population. The absence of correlation between these DCM-PRSs and the renin-angiotensin-aldosterone system or natriuretic peptides suggests that genetic background influences LV traits through mechanisms independent of these biological pathways.

Background: Cardiac fibrosis is a critical and independent driver of heart failure (HF), characterized by excessive extracellular matrix (ECM) deposition. Decreased CDCP1 (CUB domain-containing protein 1) expression has been associated with myocardial recovery in human genome wide association studies by attenuating PDGF-BB driven cardiac fibroblast proliferation with no effect on canonical TGF-beta mediated transdifferentiation in-vitro. In-vivo, Cdcp1 deletion significantly reduced cardiac fibrosis and dysfunction in an angiotensin II/phenylephrine-induced pressure overload mouse model. However, its upstream regulators and its downstream effects on molecular signaling pathways that modulate ECM remodeling are unknown. Hypothesis: CDCP1 promotes human cardiac fibroblast mediated ECM remodeling in the HF microenvironment. Methods: Human ventricular fibroblasts (HVF) were treated with PDGF-BB (20 ng/ml), TGF-β (10 ng/ml), or Angiotensin II (100 ng/ml) for 48 hours. CDCP1 knockdown (KD) was achieved through siRNA transfection. Gene expression analysis was performed using qRT-PCR and protein quantification by Western blot. Both intact HVF and decellularized ECM were immunostained for collagen 1 to evaluate for ECM compositional changes. Results: Individual and combination treatments with fibrotic stimuli significantly increased CDCP1 expression (Figure 1A-1B). CDCP1 KD resulted in reduction of key ECM markers COL1A1, CTGF, and LOX (Figure 1C) across all fibrotic stimuli . Immunostaining of HVF after treatment with fibrotic stimuli showed reduced collagen 1 production with CDCP1 KD (Figure 1D). Western blot analysis showed increased phosphorylation of Src (tyr416) with 6h of treatment with fibrotic stimuli which was nullified by silencing of CDCP1 (Figure 1E). Conclusion: Our findings demonstrate that CDCP1 is necessary for ECM synthesis and Src signaling across multiple profibrotic pathways. Selective targeting of CDCP1 to modulate Src signaling pathways could provide novel therapeutic avenues for HF and fibrosis treatment.

Background: Cardiac fibrosis is a central pathological process that leads to worse outcomes in various cardiomyopathies. Recent evidence shows that CDCP1 (CUB domain-containing protein 1) modulates myocardial recovery by attenuating human cardiac fibroblast (HCF) proliferation. This study investigates the hypothesis that selective targeting of the CDCP1 cleavage domain can mitigate fibroblast proliferation, thereby offering a novel therapeutic approach to reducing cardiac fibrosis. Methods: A high-throughput in silico screening was performed using the Enamine compound library, focusing on structural regions that include the cleavage and adjacent sites of CDCP1 . A total of 147 candidate compounds were prioritized based on docking scores and binding stability profiles. Selected compounds were subsequently evaluated in vitro using HCF cultures seeded at 3,000 cells/well in 96-well plates. Each compound was administered at 10 μM concentration, and cell proliferation and viability were assessed by time-lapse imaging in the Incucyte® system at 24 and 96 hours. All experiments were done in triplicate with appropriate DMSO vehicle controls. Results: Compound C3 significantly reduced HCF proliferation (Fig B) to 27.3±2.4% relative to DMSO controls (99.9±0.5%, P <0.001) at 96 hours. Detailed structural modeling indicated that C3 binds to the CDCP1 cleavage site (Fig C) with a favorable Glide XP docking score of -7.66 kcal/mol. The interaction is stabilized by hydrogen bonds with Lys365 and Cys374 (Fig D), and supplementary hydrophobic interactions between aromatic rings and aliphatic groups, which contribute to a strong inhibitory effect. Conclusion: Targeting the CDCP1 cleavage domain with compound C3 effectively diminishes HCF proliferation in vitro. Therefore, these results substantiate the therapeutic potential of CDCP1 inhibition in cardiac fibrosis. Ongoing in vivo studies will explore the translational relevance of these findings.

Background Disease‐causative variants in LMNA ‐encoded lamin A/C cause a genetic cardiomyopathy characterized by atrioventricular block, atrial fibrillation, ventricular arrhythmias, and systolic dysfunction. The influence of LMNA variant type/localization on late gadolinium enhancement (LGE) patterns and clinical outcomes remains unclear. Methods Retrospective analysis of 822 genotype‐positive patients with arrhythmogenic/dilated cardiomyopathy was used to identify those with disease‐causative variants in LMNA . Data on LGE distribution and prevalence of advanced heart failure, thromboembolic and sudden cardiac death/major ventricular arrhythmia events were extracted from the electronic record and analyzed by variant type/localization. Results Among the 72/116 (62%) LMNA variant‐positive patients with cardiac magnetic resonance imaging data, LGE was observed in 40/72 (56%) cases. Most exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and 6/40 (15%) showed a unique “pseudo‐infarct” transmural pattern, predominantly affecting the apical segments. All 6 patients with this distinct LGE pattern harbored C‐terminal IgD (immunoglobulin‐like domain) variants (p.Arg471His or p.Arg541His). In patients with clinically manifest disease (76/116), those with IgD‐localizing variants had a lower prevalence of atrioventricular block (25% versus 72%, P =0.002) and atrial fibrillation (50% versus 81%, P =0.019) but higher rates of thromboembolic events (42% versus 16%, P =0.038). During a median follow‐up of 37 months, IgD variant presence independently predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio, 2.391 [95% CI, 1.046–5.464]; P =0.039). Conclusions LMNA missense variants localizing to IgD present a distinct apical pseudo‐infarct LGE pattern associated with increased risk of ventricular arrhythmias and thromboembolic events but reduced atrioventricular block and atrial fibrillation. Multicenter studies are warranted to develop variant‐specific risk‐stratification strategies in cardiac laminopathy.

Abstract Background and Aims Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (&lt;30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

ABSTRACTPlatelets are small, anucleate particles derived from bone marrow megakaryocytes that circulate in the blood and are central to hemostasis, atherothrombosis, and post‐angioplasty coronary restenosis. Initially thought to involve a simple process of platelet adhesion, activation, and aggregation, recent insights reveal an important interplay with genetics and other organ systems, especially in the setting of antiplatelet drug therapy. Interaction involving the hepatic cytochrome P450 enzymes, which regulate drug metabolism, and genetic variation in those enzymes affecting drug response, underscores the liver's role in modulating platelet function by attenuating circulating active drug metabolites with eventual cardiovascular implications. Circulating adhesive proteins such as von Willebrand Factor and fibronectin also significantly regulate platelet aggregation, a process that is further influenced by varying shear conditions within the vascular system. The efficacy of antiplatelet therapies can be attenuated by such individual genetic variation, which can affect multiple cellular pathways involved not only in drug metabolism and clearance but also the drug target itself. Identifying these genetic differences allows for tailored therapy, enhancing treatment outcomes and minimizing adverse effects. Genetic variation, particularly in the CYP2C19 gene, influences individual responses to the most commonly used antiplatelet drug other than aspirin, clopidogrel, with certain variants leading to reduced drug metabolism and antiplatelet effects. Therefore, genotype‐guided antiplatelet therapy has emerged as a promising approach to reduce ischemic events and minimize bleeding events. This personalized strategy requires an understanding of genetic variation, drug‐gene interaction, and the liver's role in impacting platelet function, the coagulation system, and cardiovascular systems.

ABSTRACT Aims Common genetic variants have been linked to an increased risk of non-ischaemic cardiomyopathy (NICM). The primary objective of this study was to evaluate the significance of these variants in a general population. Methods and results Thirteen NICM risk alleles, previously validated by meta-analyses of case-control genetic association studies, were used to determine genetic risk (GR) in a large, unselected cohort (n = 1897) of Olmsted County residents aged &gt;45 years. Clinical and echocardiographic data, with biomarkers, were correlated with this NICM-GR over a median of 16 years of follow-up (interquartile range [IQR] 15–17). There were no significant differences between the study population quartiles, based on NICM-GR, in terms of age (median 61.6 [IQR 53.6–70.4]), sex (48% male), and cardiovascular risk factors. A significant correlation was detected by specific linear-regression models between NICM-GR and left ventricular (LV) ejection-fraction (beta [standard error]: −2.68 [0.68], p &lt; 0.001), LV end-systolic-diameter (0.22 [0.06], p &lt; 0.001), and LV end-diastolic-diameter (0.14 [0.06], p = 0.01). During follow-up, 46 subjects developed NICM. Using a 3:1 matched-cohort of non-NICM versus NICM patients, linear-regression analysis found a significant correlation between NICM-GR and NICM development (odds ratio 2.27, 95% confidence interval 1.06–4.85, p = 0.03). There was no significant association between these variants and heart failure biomarkers (aldosterone, natriuretic peptides, ST2, galectin-3). Conclusions The NICM-GR correlates with LV function and dimension, and subsequent development of NICM in the general population. The lack of correlation of these variants with cardiovascular risk factors and the renin–angiotensin–aldosterone axis or natriuretic peptides suggest different biological mechanisms involved. These findings support the need to explore newer pathophysiologic pathways in the development of NICM.

Acute right ventricular failure (ARVF) is commonly seen in the intensive care unit and constitutes a significant clinical challenge, with associated high in-hospital mortality. Recently, the treatment of ARVF has significantly changed, with the progressive implementation of mechanical circulatory support devices that now represent important tools for clinicians in treating this condition. However, despite recent advancements, the optimal approach for ARVF remains elusive, and precise treatment algorithms and comprehensive management protocols are still lacking. In the present review, we explore the pathophysiology of ARVF, highlighting the different mechanisms that may lead to this clinical entity and emphasizing the left and right heart’s complex interplay. We analyze the different therapeutic options that are now available for short- and long-term management of ARVF, with a particular focus on the advantages and disadvantages of the mechanical circulatory support devices actually used. Furthermore, we propose future directions in the field and a possible flowchart for the treatment of this condition.