Citations

Abstract Human genomic studies link reduced CUB domain-containing protein 1 (CDCP1) expression with myocardial recovery in heart failure. While CDCP1 regulates cardiac fibroblast proliferation in vitro, it’s in vivo role in cardiac fibrosis remains unclear. Using a Cdcp1 -knockout (KO) angiotensin II/phenylephrine mouse model, we show that Cdcp1 deletion reduces echocardiographic left ventricular mass, histologic cardiac fibrosis, and pro-fibrotic gene expression, along with decreased fibroblast activation and inflammatory markers. Spatial transcriptomics identified a pressure overload–expanded fibroblast subpopulation enriched for growth factor and TGF-β signaling (FB5), which was markedly attenuated in Cdcp1 -KO hearts, alongside reduction of a pro-inflammatory cardiomyocyte subtype (CM4). Complementary studies in human ventricular fibroblasts demonstrate that CDCP1 knockdown reduced extracellular matrix gene expression and collagen I deposition. These findings establish CDCP1 as a regulator of cardiac fibrotic remodeling in vivo and open avenues for its further investigation as a potential therapeutic target.

Background. Acute cellular rejection (ACR) remains a major cause of morbidity after heart transplantation despite advances in immunosuppression. Whole genome transcriptomic profiling offers a systems-based, unbiased approach to elucidate the molecular mechanisms underlying ACR. However, noninvasive, longitudinal biomarker assessments capable of capturing the temporal dynamics of rejection biology remain scarce. Methods. RNA sequencing of peripheral blood from heart transplant recipients before, during, and after ACR was compared with nonrejection controls. Pathway analysis was conducted using differentially expressed genes (DEGs), and a machine learning approach was applied to assess gene-based prediction of ACR. Results. A total of 235 rejection-specific significant DEGs and 863 postrejection DEGs (false discovery rate < 0.05) were identified. During ACR, DEGs were enriched for T-cell activation/differentiation, apoptosis, and B-cell receptor signaling pathways. By combining the 2 sets of DEGs, a panel of 71 common genes was identified that reflected the significant, longitudinal transcriptomic dynamics of ACR. In an elastic net machine learning–based classifier, DYNLL1 and SERF2 were identified as ACR predictive genes, and achieved a cross-validated area under the receiver operating characteristic curve of 0.63. Conclusions. Peripheral blood transcriptomics identify dynamic temporal responses in ACR including T- and B-cell pathways with potential ACR predictive genes that warrant further investigation.

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.

Background: CDCP1 has been associated with reverse remodeling in human dilated cardiomyopathy (DCM) mediating its effect by reducing cardiac fibrosis which has been demonstrated in-vitro using human cardiac fibroblasts (CF) and in-vivo histologically in mice. However, the role of and the molecular mechanisms by which CDCP1 attenuates cardiac fibrosis in-vivo is unknown. Methods: To characterize the transcriptomic profiles of CDCP1 in cardiac fibrosis, Cdcp1 KO FVB/NJ mice were generated, and implanted with osmotic minipumps containing angiotensin II and phenylephrine (Ang II/PE) or saline at age of 10 weeks. There were 4 experimental groups (6 mice each), Saline_WT, Saline_KO, AngII/PE_WT, and AngII/PE_KO. After 4 weeks of AngII/PE induction, mice were euthanized, RNA was extracted from their heart tissue followed by RNA-seq to explore transcriptomic profiles. Fibrosis was histologically determined using picosirius (PSR) staining and was quantified by percentage of fibrosis area. Results: Histological analysis demonstrated that Cdcp1 KO attenuated severe cardiac fibrosis by 32.7% determined by quantification of percentage of fibrosis area. When comparing the transcriptome-wide gene expression in WT mice hearts from Saline to AngII/PE induction, a total of 316 differentially expressed genes (DEGs) were identified ( Fig. 1A ). Expression of Nppb (encodes ProBNP), a marker for heart failure, was significantly upregulated. The most significantly upregulated DEG after AngII/PE induction was Crlf1 ( Fig. 1A ), a gene predominantly expressed in CF, consistent with previous findings. We next compared transcriptomic profiles of AngII/PE induction WT and Cdcp1 KO mice hearts, to explore the role of CDCP1 in cardiac fibrosis. A total of 163 DEGs were identified ( Fig. 1B ). Notably, Cdcp1 -mediated DEGs enriched GO Pathways associated with extracellular matrix organization (Biological Process) and collagen-containing extracellular matrix (Cellular Component) ( Figs. 1C, 1D ), pivotal processes in cardiac fibrosis. In addition, Cdcp1 KO resulted in several “top” DEGs (including Rnase1, Ccl7, Ccl12 Il21r , and Il6 ) which have known function in inflammation, suggesting that CDCP1 might attenuate cardiac fibrosis through immune regulation . Conclusion: Our findings underscore the pivotal role of CDCP1 in modulating cardiac fibrosis in-vivo, potentially through immune regulation. Targeting CDCP1 may offer promising therapeutic avenues for mitigating myocardial fibrosis.

Background: We have previously demonstrated by performing a genome-wide association study that a genetic locus resulting in ↓CDCP1 expression was associated with myocardial recovery in patients with dilated cardiomyopathy (DCM). We have subsequently shown that ↓CDCP1 decreases human cardiac fibroblast proliferation in vitro , however, its potential role in modulating cardiac fibrosis and function in vivo is unknown. Methods: A Cdcp1 knock-out (KO) mouse was generated on FVB/NJ background. Angiotensin II/Phenylephrine (AngII/PE) or saline was infused by an osmotic pump into mice ( Cdcp1 KO n=20; wild type/wt n=18) for 4 weeks. Echocardiography was performed at 0 and 4 weeks. Picrosirius red (PSR) staining was performed on cross-sectional heart tissue to identify cardiac fibrosis, which was quantified, using ImageJ software, as a percentage of left ventricular (LV) area stained by PSR. Results: LV mass index (LVMI) significantly increased in AngII/PE wt mice as compared to saline wt (figure a. 3.65±0.15 mg/g vs 3.05±0.17mg/g, p=0.01), however, AngII/PE Cdcp1 KO mice had significantly decreased LVMI as compared to AngII/PE wt mice (figure a. 3.17±0.09 mg/g vs 3.65±0.15 mg/g, p=0.01). In addition, fractional shortening trended higher in AngII/PE Cdcp1 KO mice as compared to AngII/PE wt mice (figure b. 50.36±2.06% vs 45.48±1.43%, p=0.07). Extent of cardiac fibrosis was significantly higher in AngII/PE wt mice as compared to saline wt (figure c. 15.79±0.49% vs 7.93±0.39%, p<0.0001), however AngII/PE Cdcp1 KO mice had significantly reduced cardiac fibrosis as compared to AngII/PE wt mice (figure c. 9.41±0.43%, p<0.0001). Conclusions: CDCP1 KO significantly reduces pressure over-load induced LV hypertrophy and cardiac fibrosis. Its role as a novel therapeutic target in attenuating fibrosis and improving cardiac function in DCM needs to be further explored.

Introduction: Common genetic variation has been linked to an increased risk of developing dilated cardiomyopathy (DCM). However, the phenotypic profile, outcomes, and biological mechanisms by which such genetic background may predispose individuals to DCM are still unknown. Hypothesis: The primary objectives of this study were to develop a DCM polygenic risk score (PRS) based on prior case control-DCM GWAS and to apply this PRS to a well clinical characterized general population. Methods: The DCM-PRS was derived from 13 DCM risk alleles that were assayed in an unselected cohort (n=1897) of unrelated Olmsted County residents age >45 years who did not have a history of heart failure (HF) or CM and underwent physical examination, echocardiography, and blood analyses. Results: The entire population was equally divided into quartiles based on the DCM-PRS. No significant differences were present in terms of age (median 62 years) and sex (48% male). However, a significant correlation was detected between the DCM-PRS and left ventricle ejection fraction (LVEF) (Beta: -2.68, p<0.001), LV end-systolic diameter (Beta: 0.22, p<0.001), and LV end-diastolic diameter (Beta: 0.14, p=0.01). During a follow-up of 16 years (IQR: 15-17), 47 subjects developed DCM. Using a 3:1 non-DCM vs DCM matched cohort, a logistic regression analysis, found a significant correlation between median DCM-PRS and DCM development [OR=2.27 (1.06, 4.85), p=0.03]. However, there was no association between the DCM-PRS and HF biomarkers (aldosterone, natriuretic peptides, ST2, Galectin-3). Conclusions: DCM-PRS correlates with decreased LVEF, increased LV dimensions, and DCM development in a general population without significant differences in baseline clinical features. The absence of correlation between the DCM-PRS and available HF biomarkers suggests that this genetic background affects LV traits and DCM development independent of these biological mechanisms.

BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure and carries a high mortality rate. Myocardial recovery in DCM-related heart failure patients is highly variable, with some patients having little or no response to standard drug therapy. A genome-wide association study may agnostically identify biomarkers and provide novel insight into the biology of myocardial recovery in DCM. METHODS: A genome-wide association study for change in left ventricular ejection fraction was performed in 686 White subjects with recent-onset DCM who received standard pharmacotherapy. Genome-wide association study signals were subsequently functionally validated and studied in relevant cellular models to understand molecular mechanisms that may have contributed to the change in left ventricular ejection fraction. RESULTS: The genome-wide association study identified a highly suggestive locus that mapped to the 5′-flanking region of the CDCP1 (CUB [complement C1r/C1s, Uegf, and Bmp1] domain containing protein 1) gene (rs6773435; P =7.12×10 −7 ). The variant allele was associated with improved cardiac function and decreased CDCP1 transcription. CDCP1 expression was significantly upregulated in human cardiac fibroblasts (HCFs) in response to the PDGF (platelet-derived growth factor) signaling, and knockdown of CDCP1 significantly repressed HCF proliferation and decreased AKT (protein kinase B) phosphorylation. Transcriptomic profiling after CDCP1 knockdown in HCFs supported the conclusion that CDCP1 regulates HCF proliferation and mitosis. In addition, CDCP1 knockdown in HCFs resulted in significantly decreased expression of soluble ST2 (suppression of tumorigenicity-2), a prognostic biomarker for heart failure and inductor of cardiac fibrosis. CONCLUSIONS: CDCP1 may play an important role in myocardial recovery in recent-onset DCM and mediates its effect primarily by attenuating cardiac fibrosis.

Objectives: Patients with schizophrenia have shortened life expectancy due to greater cardiovascular disease (CVD) risk. Due to sparse data, index study was planned to assess the CVD risk factors, vascular age (VA), and hematological parameters in patients with schizophrenia and the concordance between Framingham Risk Score (FRS) for lipids and body mass index (BMI) (FRSLIPIDS and FRSBMI). Materials and Methods: Patients with schizophrenia (n = 53) were evaluated for the presence of metabolic syndrome (MS) using the modified NCEP ATP III criteria, along with their functionality, illness severity, physical activity and nutritional score, FRSLIPIDS and FRSBMI, and hematological parameters. Results: Prevalence of MS was 39.6%; in addition, 47% of patients were at risk for developing MS as they fulfilled one or two components of MS criteria and 56% of patients were obese. BMI, obesity, and RBC count were found as significant correlates for MS. CVD risk (FRS) median score (3.10) was comparable for BMI and lipid criteria along with significant correlation for FRSLIPIDS and FRSBMI (r = 0.555, P < 0.001). Conclusion: VA and 10-year CVD risk (FRS for BMI and lipid criteria) represent easier way to communicate with the patients and caregivers and also to guide for comprehensive treatment plan, appropriate nutrition, physical activity, and cardiometabolic screening.