Lima, João A.C.

Abstract Background There is limited data on immune checkpoint inhibitor (ICI) use in patients with non-small cell lung cancer (NSCLC) and known pericardial effusions. Methods This international multi-center observational retrospective study included patients with advanced NSCLC with or without pericardial effusions receiving ICIs. Immune-related adverse events (irAEs) were graded per CTCAE v5.0. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method. Cox proportional hazards multivariable models assessed the association between survival outcomes and clinicopathologic variables, and an inverse probability of treatment weighting (IPTW) model compared outcomes between the two groups. Results A total of 1248 patients with advanced NSCLC treated with ICIs across 13 institutions were included. Of these, 85 patients (6.8%) had pre-existing pericardial effusions. Compared to controls, patients with pericardial effusions were younger (median age 63 vs 67 years, P = .007), diagnosed more frequently with PD-L1 positive tumors (96% vs 76%, P < .001), and had a higher median number of baseline metastatic sites (3 vs 1, P < .001). IrAEs were similar between both groups (42% vs 38%), and no cardiac irAEs occurred in patients with pericardial effusions. PFS (median 5.6 vs 4.6 months, P = .3) and OS (median 10.2 vs 14.7 months, P = .50) were not statistically different between patients with pericardial effusions and the controls, respectively. In both multivariable and IPTW models, pericardial effusions were not associated with PFS or OS. Conclusions Among patients with NSCLC and pre-existing pericardial effusions, ICIs demonstrate meaningful clinical benefit similar to those without effusions, with no new cardiac or severe toxicities.

Importance Clinical trials in cardiovascular medicine aim to deliver high-quality evidence with greater efficiency, including smaller sample sizes and shorter timelines. The selection of sensitive and reliable end points is central to this goal. Right ventricular (RV) structure and function play a critical role in many cardiovascular conditions; however, RV-specific parameters remain underused and inconsistently applied in interventional clinical trials. In this article, the current and emerging role of RV-focused imaging and hemodynamic parameters as end points in clinical trials are explored and a comprehensive framework for their development, validation, and broader implementation is proposed. Observations Across multiple disease domains, RV-focused parameters derived from echocardiography, cardiac magnetic resonance imaging, computed tomography, and right-sided heart catheterization demonstrate potential value in assessing the therapeutic effects of new medicines or devices across a wide range of conditions including heart failure, cardiomyopathies, valve diseases, pulmonary hypertension, and congenital heart conditions. However, their use is inconsistent, and feasibility challenges are common, particularly in multicenter clinical trial settings. Key limitations include variability in imaging acquisition, incomplete data capture, lack of standardized protocols, and insufficient validation linking short-term RV changes to long-term clinical outcomes. Emerging tools such as artificial intelligence may improve reproducibility and efficiency, while collaborative, multidisciplinary efforts are essential for advancing end-point development. Conclusions and Relevance RV-specific end points hold substantial promise for enhancing the sensitivity and mechanistic insight of clinical trials but remain inadequately integrated into current practice. Optimal end-point selection requires balancing clinical relevance, analytical validity, and operational feasibility, with consideration of disease-specific pathophysiology and trial design. Standardization of acquisition, validation of clinically meaningful changes, and centralized data analysis are important next steps. Broader adoption of robust RV metrics supported by technological innovation and cross-sector collaboration has the potential to improve trial efficiency, accelerate therapeutic development, and ultimately enhance patient outcomes.

BACKGROUND: Although chronic obstructive pulmonary disease (COPD) and heart failure with preserved ejection fraction often coexist with overlapping clinical features, they are usually studied separately. The SPIROMICS HF (Subpopulations and Intermediate Outcome Measures in COPD and Heart Failure Study) is testing hypotheses that new computed tomography emphysema subtypes are associated with specific cardiovascular phenotypes (eg, cor pulmonale , cor pulmonale parvus ), common airway branch variants are associated with right heart dysfunction, and symptomatic tobacco-exposed persons with preserved spirometry have signs of increased left ventricular afterload. METHODS: SPIROMICS is a multicenter observational study of COPD with extensive pulmonary phenotyping of participants with ≥20 pack-years smoking and nonsmoking controls. COPD and COPD severity were defined by standard spirometric criteria and symptomatic tobacco-exposed persons with preserved spirometry by ≥20 pack-years, normal spirometry, and COPD Assessment Test score >10. SPIROMICS HF selected all participants in SPIROMICS visit 5 at major sites. Its comprehensive speckle-tracking echocardiography, which included physiological perturbations of leg raise and low-intensity exercise, was harmonized prospectively with the Multi-Ethnic Study of Atherosclerosis Early Heart Failure and HeartSHARE (Combining Omics, Deep Phenotyping, and Electronic Health Records for Heart Failure Subtypes and Treatment Targets) studies. The cardiopulmonary magnetic resonance imaging protocol with gadolinium administration included myocardial fibrosis sequences, pulmonary angiography, time-resolved 3-dimensional cine magnetic resonance imaging (4-dimensional flow) of venous return, and metronome-paced tachypnea to induce dynamic hyperinflation. Coronary artery calcium was assessed on computed tomography scans. The Kansas City Cardiomyopathy Questionnaire was administered. RESULTS: Of the final sample of 753 participants, 57% had COPD (15% mild, 27% moderate, and 15% severe), 18% had symptomatic tobacco-exposed persons with preserved spirometry, 16% were smoking controls, and 8% were nonsmoking controls. Reproducibility of the main measures from speckle-tracking echocardiography (intraclass correlation coefficient, 0.83–0.99), exercise echocardiography (intraclass correlation coefficient, 0.71–0.99) and magnetic resonance imaging (intraclass correlation coefficient, 0.57–0.99) were good-to-excellent, including in severe COPD. CONCLUSIONS: SPIROMICS HF aims to characterize and understand cardiopulmonary interactions in COPD and COPD-related phenotypes to inform targeted treatments for combined cardiopulmonary failure.

Background Although VCAM‐1 (vascular cell adhesion molecule‐1) and ICAM‐1 (intercellular adhesion molecule‐1) have been associated with incident heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF), the associations of VCAM‐1 and ICAM‐1 with sensitive measures of cardiac structure/function are unclear. The objective of this study is to evaluate associations between VCAM‐1, ICAM‐1, and measures of cardiac structure and function as potential pathways through which cellular adhesion molecules promote HFpEF and AF risk. Methods and Results In MESA (Multi‐Ethnic Study of Atherosclerosis), we evaluated the associations of circulating VCAM‐1 and ICAM‐1 at examination 2 (2002–2004) with measures of cardiac structure/function on cardiac magnetic resonance imaging at examination 5 (2010–2011) after multivariable adjustment. Mediation analysis of left atrial (LA) strain on the association between VCAM‐1 or ICAM‐1 and AF or HFpEF was also performed. Overall, 2304 individuals (63±10 years; 47% men) with VCAM‐1 or ICAM‐1, cardiac magnetic resonance imaging, and covariate data were included in analysis. Higher VCAM‐1 and ICAM‐1 were associated with lower LA peak longitudinal strain and worse global circumferential left ventricular strain but were not associated with left ventricular myocardial scar or interstitial fibrosis. Lower LA peak longitudinal strain mediated 8% (95% CI, 2–30) of the relationship between VCAM‐1 and HFpEF and 9% (95% CI, 2–21) of the relationship between VCAM‐1 and AF. Conclusions Higher VCAM‐1 and ICAM‐1 were associated with lower LA function and left ventricular systolic function but were not associated with myocardial scar or interstitial fibrosis. VCAM‐1 and ICAM‐1 may promote HFpEF and AF risk through impaired LA reservoir function.

BACKGROUND: Common genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown. METHODS: Multi-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts. RESULTS: The SMARCB1 rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume ( P= 0.0002) after adjusting for confounding clinical variables. The SMARCB1 rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume ( P= 0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of SMARCB1 ( P= 7.3×10 -22 ). SMARCB1 knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-β1–mediated α-smooth muscle actin and collagen expression. CONCLUSIONS: Common genetic variation in SMARCB1 previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging–based myocardial fibrosis and increased TGF-β1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven.

Introduction: Genome-wide association studies have identified common genetic variants associated with hypertrophic (HCM) and dilated cardiomyopathy (DCM) and left ventricular (LV) characteristics. However, the association of these variants with myocardial fibrosis (MF), an important pathophysiological mediator of cardiomyopathy, is unknown. Hypothesis: We used the Multi-Ethnic Study of Atherosclerosis (MESA), to evaluate the association of these loci with interstitial MF measured by cardiac MRI (CMR). Methods: Unrelated MESA participants with T1-mapping CMR and no history of MI or heart failure were included (n=1,235). We used the extracellular volume (ECV) fraction as a well-established surrogate of interstitial MF. Genotyping was performed by Affymetrix Human SNP array 6.0, and imputation was performed using the TOPMED reference panel. Log ECV(%) was regressed on 50 candidate SNPs, in each ethnicity/race group, adjusting for age, sex, and population stratification principal component. The race-specific results were pooled by fixed-effect meta-analyses using METASOFT. Results: The SMARCB1 rs2186370 intronic variant, previously identified as a risk variant for DCM and HCM, was associated with ECV (p=0.0004). The rs2186370 A allele (frequency: 0.18 in Whites, and 0.50 in African Americans) was associated with a 1.6% increase in ECV. The rs2070458 A allele (another SMARCB1 intronic variant), in complete linkage disequilibrium with rs2186370, was known previously to be associated with increased LV wall thickness, mass, and concentricity. The direction of effect was similar in all four ancestry groups, but the effect was strongest in African Americans. These variants are strong expression quantitative loci (eQTLs) in human LV tissue and are associated with genotype-dependent expression of SMARCB1 ( p =7.3х10 -22 ) and MMP11 ( p =2.5х10 -24 ). Conclusions: In conclusion, variants in two linked SMARCB1 loci previously associated with HCM, DCM and LV traits, are associated with CMR-based interstitial MF. These loci are eQTL not only for SMARCB1 but also for MMP11 an important mediator of MF . These findings underscore the important link between MF and CM, and potentially provide novel mechanistic targets in understanding the development of CM.

Introduction: It has been previously demonstrated that cardiomyopathy predisposing common genetic variation in SMARCB1 is associated with interstitial myocardial fibrosis (MF) as determined by cardiac MRI (CMR) linking the development of cardiomyopathy with MF. SMARCB1 is known to be a tumor suppressor, but it’s role in the pathophysiology of MF and fibroblast physiology has not been functionally validated. Hypothesis: SMARCB1 plays an important role in regulating human cardiac fibroblast (HCF) differentiation/activation and collagen deposition, which are the critical steps in the development of MF. Methods: Cultured HCFs were treated with TGF-β1 (10ng/ml) for 48hrs to transdifferentiate into myofibroblasts, which are characterized by increased expression of α-smooth muscle actin (α-SMA, ACTA2) and collagen I (COL1A1). HCFs were transfected by siRNA using Lipofectamine™ RNAiMAX Transfection Reagent to knock-down (KD) the expression of SMARCB1 . Total RNA and protein were extracted from cell lysate followed by qPCR and Western blot (WB) to quantify the expression level of SMARCB1, ACTA2 and COL1A1. Triplicate experiments were performed using biologically independent samples. For statistical analysis, a paired two-tail t-test was used. Results: HCFs treatment with TGF-β1, resulted in a significant decrease in expression of SMARCB1 (p=0.031) with accompanying significant increase in expression of ACTA2 (p=0.025) and COL1A1 (p=0.0015) as compared to control by qPCR and WB. SMARCB1 KD resulted in a further significant increase in expression of ACTA2 (p=0.018) and COL1A1 (p=0.028) as compared to non-target siRNA control group at both the transcript and protein level. Conclusion: We demonstrate for the first time that a gene associated with the development of cardiomyopathy SMARCB1 mediates TGF-β1 induced cardiac fibrosis. These findings suggest SMARCB1 as a potential therapeutic target to attenuate MF in cardiomyopathy.

Data on the characteristics and outcomes of hospitalized patients with aortic aneurysms (AA) and HIV remain scarce. This is a cohort study of hospitalized adult patients with a diagnosis of AA from 2013 to 2019 using the US National Inpatient Readmission Database. Patients with a diagnosis of HIV were identified. Our outcomes included trends in hospitalizations and comparison of clinical characteristics, complications, and mortality in patients with AA and HIV compared to those without HIV. Among 1,905,837 hospitalized patients with AA, 4416 (0.23%) were living with HIV. There was an overall age-adjusted increase in the rate of HIV among patients hospitalized with AA over the years (14–29 per 10,000 person-years; age-adjusted p-trend < 0.001). Patients with AA and HIV were younger than those without HIV (median age: 60 vs 76 years, p < 0.001) and were less likely to have a history of smoking, hypertension, dyslipidemia, diabetes mellitus, and obesity. Thoracic aortic aneurysms were more prevalent in those with HIV (37.5% vs 26.7%, p < 0.001). On multivariable logistic regression, HIV was not associated with increased risk of aortic rupture (OR: 0.79; 95% CI: 0.61–1.01, p = 0.06), acute aortic dissection (OR: 0.73; 95% CI: 0.51–1.06, p = 0.3), readmissions (OR: 1.04; 95% CI: 0.95–1.13, p = 0.4), or aortic repair (OR: 0.89; 95% CI: 0.79–1.00, p = 0.05). Hospitalized patients with AA and HIV had a lower crude mortality rate compared to those without HIV (OR: 0.75 (0.63–0.91), p = 0.003). Hospitalized patients with AA and HIV likely constitute a distinct group of patients with AA; they are younger, have fewer traditional cardiovascular risk factors, and a higher rate of thoracic aorta involvement. Differences in clinical features may account for the lower mortality rate observed in patients with AA and HIV compared to those without HIV.