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Cardiac fibrosis is mediated by the persistent activity of myofibroblasts, which differentiates from resident cardiac fibroblasts in response to tissue damage and stress signals. The signaling pathways and transcription factors regulating fibrotic transformation have been thoroughly studied. In contrast, the roles of chromastin factors in myofibroblast differentiation and their contribution to pathogenic cardiac fibrosis remain poorly understood. Here, we combined bulk and single-cell CRISPR screens to characterize the roles of chromatin factors in the fibrotic transformation of primary cardiac fibroblasts. We uncover strong regulators of fibrotic states including Srcap and Kat5 chromatin remodelers. We confirm that these factors are required for functional processes underlying fibrosis including collagen synthesis and cell contractility. Using chromatin profiling in perturbed cardiac fibroblasts, we demonstrate that pro-fibrotic chromatin complexes facilitate the activity of well-characterized pro-fibrotic transcription factors. Finally, we show that KAT5 inhibition alleviates fibrotic responses in patient-derived human fibroblasts. Cardiac fibrosis arises from persistent myofibroblast activity. This study reveals how chromatin factors control scar-forming cells in the heart and shows that inhibiting KAT5 can reduce harmful cardiac fibrosis.

In this observational and multicenter study, that included all patients who underwent a heart transplantation (HT) in Spain from 1984 to 2018, we analyzed the incidence, management, and prognosis of colorectal cancer (CRC) after HT. Of 6,244 patients with a HT and a median follow-up of 8.8 years since the procedure, 116 CRC cases (11.5% of noncutaneous solid cancers other than lymphoma registered) were diagnosed, mainly adenocarcinomas, after a mean of 9.3 years post-HT. The incidence of CRC increased with age at HT from 56.6 per 100,000 person-years among under 45 year olds to 436.4 per 100,000 person-years among over 64 year olds. The incidence rates for age-at-diagnosis groups were significantly greater than those estimated for the general Spanish population. Curative surgery, performed for 62 of 74 operable tumors, increased the probability of patient survival since a diagnosis of CRC, from 31.6% to 75.7% at 2 years, and from 15.8% to 48.6% at 5 years, compared to patients with inoperable tumors. Our results suggest that the incidence of CRC among HT patients is greater than in the general population, increasing with age at HT.

Background/Objectives: Cardiac allograft vasculopathy (CAV) remains a prevalent and serious long-term complication following orthotopic heart transplantation (OHT), contributing substantially to graft failure and patient mortality. Given the adverse prognostic impact of extensive coronary artery involvement, this study investigates whether myocardial work (MW) indices can serve as a non-invasive tool to detect OHT recipients with a high burden of coronary disease. Methods: In this prospective study, 55 OHT recipients underwent paired evaluations with coronary computed tomography angiography (CCTA) and transthoracic echocardiography (TTE) during routine follow-up. From the echocardiograms, global longitudinal strain (GLS) of the left ventricle (LV) and myocardial work (MW) indices were derived. Patients were classified into two groups according to CCTA findings: those without extensive coronary artery disease (disease affecting fewer than four coronary segments or none, OHT < 4) and those with extensive disease (disease of four or more coronary artery segments, OHT ≥ 4). Results: CCTA revealed extensive coronary disease in 38 OHT recipients, while 17 had involvement of fewer than four segments or none. Between-group comparisons showed significant differences in global wasted work (GWW, energy expended without generating forward flow) and global work efficiency (GWE, the percentage of constructive work relative to total work). Using the Youden Index, the optimal thresholds for identifying extensive disease were GWW > 88 mmHg% and GWE < 94%. Patients exceeding these thresholds had a markedly higher probability of having ≥ 4 affected segments, with ORs of 4.61 for pathological GWW and 3.68 for pathological GWE compared to those with normal values. Conclusions: GWW and GWE demonstrated the strongest performance for identifying OHT recipients with extensive coronary disease. If confirmed in larger cohorts, these indices could offer a practical, non-invasive approach for detecting extensive CAV.

Background/Objectives: Cardiac allograft vasculopathy (CAV) is a major complication following orthotopic heart transplantation (OHT). Graft denervation results in silent ischemia, even when already established, requiring regular screening for early diagnosis. This study explores whether myocardial work (MW) can non-invasively identify OHT patients with obstructive coronary lesions (OCL). Methods: During regular follow-ups, 55 OHT recipients underwent paired, prospective coronary computed tomography angiography (CCTA) and transthoracic echocardiography (TTE) examinations. Additionally, 57 healthy volunteers (HV) provided reference TTE data. Classic echocardiographic parameters, such as left ventricle global longitudinal strain (LV-GLS) and MW indices, were obtained in all individuals. Data from three groups were analyzed: HV, OHT patients without coronary lesions or with <50% lesions on the CCTA (OHT-non-OCL), and OHT patients with ≥50% lesions on the CCTA (OHT-OCL). Results: CCTA identified seven OHT patients with OCL. Significant differences across the groups existed for LV-GLS (OHT-OCL −10.6% CI −14 to −6.8 vs. OHT-non-OCL −15.6% CI −16.5 to −13.4% vs. HV −18% CI −20 to −16, p < 0.01) and global work efficiency (GWE) (OHT-OCL 87% CI 86 to 92 vs. OHT-non-OCL 94% CI 91 to 95 vs. HV 96% CI 95 to 97, p < 0.01). The optimal cut-off values identified using the Youden Index were LV-GLS < −14.4% (AUC 0.80, sensitivity 0.86, specificity 0.71) and GWE < 89% (AUC 0.75, sensitivity 0.71, specificity 0.85). Multivariate analysis showed GWE as the best marker for detecting OCL. Conclusions: GWE is the echocardiographic parameter that best identifies OHT patients that have OCL on CCTA. If validated in larger studies, GWE could become a readily accessible tool for CAV detection.

Anthracycline-based cancer chemotherapy (ACC) causes myocardial fibrosis, a lesion contributing to left ventricular dysfunction (LVD). We investigated whether the procollagen-derived type-I C-terminal-propeptide (PICP): (1) associates with subclinical LVD (sLVD) at 3-months after ACC (3m-post-ACC); (2) predicts cardiotoxicity 1-year after ACC (12m-post-ACC) in breast cancer patients (BC-patients); and (3) associates with LVD in ACC-induced heart failure patients (ACC-HF-patients). Echocardiography, serum PICP and biomarkers of cardiomyocyte damage were assessed in two independent cohorts of BC-patients: CUN (n = 87) at baseline, post-ACC, and 3m and 12m (n = 65)-post-ACC; and HULAFE (n = 70) at baseline, 3m and 12m-post-ACC. Thirty-seven ACC-HF-patients were also studied. Global longitudinal strain (GLS)-based sLVD (3m-post-ACC) and LV ejection fraction (LVEF)-based cardiotoxicity (12m-post-ACC) were defined according to guidelines. BC-patients: all biomarkers increased at 3m-post-ACC versus baseline. PICP was particularly increased in patients with sLVD (interaction-p < 0.001) and was associated with GLS (p < 0.001). PICP increase at 3m-post-ACC predicted cardiotoxicity at 12m-post-ACC (odds-ratio ≥ 2.95 per doubling PICP, p ≤ 0.025) in both BC-cohorts, adding prognostic value to the early assessment of GLS and LVEF. ACC-HF-patients: PICP was inversely associated with LVEF (p = 0.004). In ACC-treated BC-patients, an early increase in PICP is associated with early sLVD and predicts cardiotoxicity 1 year after ACC. PICP is also associated with LVD in ACC-HF-patients.

The purpose of this study was to compare LV function and mass quantification derived from cardiac dual-source CT (DSCT) exams with those obtained by MRI in heart transplant recipients. Twelve heart transplant recipients who underwent cardiac DSCT and MRI examination were included. Double-oblique short-axis 8-mm slice thickness images were evaluated. Left ventricular ejection fraction, end-diastolic volume, end-systolic volume, stroke volume, cardiac output and myocardial mass were manually assessed for each patient by two blinded readers. A systematic overestimation of all left ventricular volumes by DSCT when compared with MRI was observed. Mean difference was 16.58 ± 18.61 ml for EDV, 4.9 4 ±  6.84 ml for ESV, 11.64 ± 13.58 ml for SV and 5.73 ± 1.14 l/min for CO. Slightly lower values for left ventricular ejection fraction with DSCT compared with MRI were observed (mean difference 0.34 ± 3.18%, p = 0.754). Correlation between DSCT and MRI for left ventricular mass was excellent ( rho   = 0.972). Bland and Altman plots and CCC indicated good agreement between DSCT and MRI left ventricular function and mass measurements. The interobserver correlation was good. In conclusion, DSCT accurately estimates left ventricular ejection fraction, volumes and mass in heart transplant recipients.

The image quality and optimal reconstruction interval for coronary arteries in heart transplant recipients undergoing non-invasive dual-source computed tomography (DSCT) coronary angiography was evaluated. Twenty consecutive heart transplant recipients who underwent DSCT coronary angiography were included (19 male, one female; mean age 63.1 ± 10.7 years). Data sets were reconstructed in 5% steps from 30% to 80% of the R-R interval. Two blinded independent observers assessed the image quality of each coronary segments using a five-point scale (from 0 = not evaluative to 4 = excellent quality). A total of 289 coronary segments in 20 heart transplant recipients were evaluated. Mean heart rate during the scan was 89.1 ± 10.4 bpm. At the best reconstruction interval, diagnostic image quality (score ≥2) was obtained in 93.4% of the coronary segments (270/289) with a mean image quality score of 3.04 ± 0.63. Systolic reconstruction intervals provided better image quality scores than diastolic reconstruction intervals (overall mean quality scores obtained with the systolic and diastolic reconstructions 3.03 ± 1.06 and 2.73 ± 1.11, respectively; P  < 0.001). Different systolic reconstruction intervals (35%, 40%, 45% of RR interval) did not yield to significant differences in image quality scores for the coronary segments ( P  = 0.74). Reconstructions obtained at the systolic phase of the cardiac cycle allowed excellent diagnostic image quality coronary angiograms in heart transplant recipients undergoing DSCT coronary angiography.

Objectives To assess feasibility, image quality, and radiation dose of prospectively ECG-triggered coronary CT angiography (CTA) in orthotopic heart transplant (OHT) recipients. Methods 47 consecutive OHT recipients (40 men, mean age 62.1±10.9 years, mean heart rate 86.3±14.4 bpm) underwent dual-source CTA to rule out coronary allograft vasculopathy in a prospectively ECG-triggered mode with data acquisition during 35% to 45% of the cardiac cycle. Two independent observers blindly assessed image quality on a per-segment and per-vessel basis using a four-point scale (1-excellent, 4-not evaluable). Scores 1–3 were considered acceptable for diagnosis. Multivariate analysis was performed to evaluate differences between image quality scores obtained at different reconstruction intervals. Effective radiation doses were calculated. Results 671 coronary segments were evaluated. Interobserver agreement on the image quality was κ=0.75. Diagnostic image quality was observed in 93.9%, 95.5% and 93.3% of the segments at 35%, 40% and 45% reconstruction intervals. Mean image quality score was 1.5±0.7 for the entire coronary tree, 1.4±0.7 for the RCA, 1.6±0.8 for the LCA and 1.6±0.7 for the Cx at the best reconstruction interval. Estimated mean radiation dose was 4.5±1.2 mSv. Conclusion Systolic prospectively ECG-triggered CTA allows diagnostic image quality coronary angiograms in OHT recipients at low radiation doses.

Perioperative anemia is an important risk factor for cardiac surgery-associated acute kidney injury (CSA-AKI). Nonetheless, the severity of the anemia and the time in the perioperative period in which the hemoglobin level should be considered as a risk factor is conflicting. The present study introduces the concept of perioperative hemoglobin area under the curve (pHb-AUC) as a surrogate marker of the evolution of perioperative hemoglobin concentration. Through a retrospective analysis of prospectively collected data, we assessed this new variable as a risk factor for the development of acute kidney injury after cardiac surgery in 966 adult patients who underwent cardiac surgery with cardiopulmonary bypass, at twenty-three academic hospitals in Spain. Exclusion criteria were patients on renal replacement therapy, who needed a reoperation because of bleeding and/or with missing perioperative hemoglobin or creatinine values. Using a multivariate regression analysis, we found that a pHb-AUC <19 g/dL was an independent risk factor for CSA-AKI even after adjustment for intraoperative red blood cell transfusion (OR 1.41, p <0.05). It was also associated with mortality (OR 2.48, p <0.01) and prolonged hospital length of stay (4.67 ± 0.99 days, p <0.001).

Cardiac fibrosis is mediated by the persistent activity of myofibroblasts, which differentiate from resident cardiac fibroblasts in response to tissue damage and stress signals. The signaling pathways and transcription factors regulating fibrotic transformation have been thoroughly studied. In contrast, the roles of chromatin factors in myofibroblast differentiation and their contribution to pathogenic cardiac fibrosis remain poorly understood. Here, we combined bulk and single-cell CRISPR screens to characterize the roles of chromatin factors in the fibrotic transformation of primary cardiac fibroblasts. We uncover strong regulators of fibrotic states including Srcap and Kat5 chromatin remodelers. We confirm that these factors are required for functional processes underlying fibrosis including collagen synthesis and cell contractility. Using chromatin profiling in perturbed cardiac fibroblasts, we demonstrate that pro-fibrotic chromatin complexes facilitate the activity of well-characterized pro-fibrotic transcription factors. Finally, we show that KAT5 inhibition alleviates fibrotic responses in patient-derived human fibroblasts.