Cumulative non-high-density lipoprotein cholesterol burden and risk of atherosclerotic cardiovascular disease: a prospective community-based study.

Background: The relationship between cumulative non-high-density lipoprotein cholesterol (non-HDL-C) burden and atherosclerotic cardiovascular disease (ASCVD) remains unclear. Objective: To prospectively examine the association between cumulative non-HDL-C burden and ASCVD risk in the Kailuan cohort of China. Methods: A total of 49,679 subjects who were free of ASCVD participated in three consecutive examinations in 2006, 2008 and 2010 were enrolled. Duration and concentration of cumulative exposure to non-HDL-C (cumNon-HDL-C) were respectively used to estimate the extent of cumulative non-HDL-C burden. The participants were divided into four groups according to durations of cumNon-HDL-C (0, 2, 4 and 6 years) and five groups according to the quintiles of cumNon-HDL-C concentration (<10.93, 10.93-12.68, 12.69-14.32, 14.33-16.72 and ≥16.73 mmol/L). Cox regression models were used to analyze the influence of cumulative non-HDL-C burden on ASCVD risk. Results: We identified 1,134 incident ASCVD cases during a mean of 4.89 years of follow-up. Multivariable adjusted analysis revealed that compared with no exposure, cumNon-HDL-C duration 2, 4 and 6 years increased ASCVD risk by 26% (HR: 1.26, 95% CI: 1.07-1.47), 56% (HR: 1.56, 95% CI: 1.31-1.86) and 91% (HR: 1.91, 95% CI: 1.59-2.31) respectively; The hazard ratios (HRs) for the fourth and fifth versus lowest quintile of cumNon-HDL-C concentration were 1.25 and 1.72 for ASCVD. Each standard deviation increment in cumNon-HDL-C concentration was associated with a 10% increased risk of ASCVD. Conclusion: Long-term and higher cumNon-HDL-C were all significantly associated with an increased risk of ASCVD independent of single non-HDL-C level.

Short QRS Duration After His-Purkinje Conduction System Pacing Predicts Left Ventricular Complete Reverse Remodeling in Patients With True Left Bundle Branch Block and Heart Failure.

Objective: This study aimed to explore the outcomes of His-Purkinje conduction system pacing (HPCSP) and to screen the predictors of left ventricular (LV) complete reverse remodeling in patients with true left bundle branch block (LBBB) and heart failure with reduced ejection fraction (HFrEF). Methods: Patients who underwent HPCSP for true LBBB and HFrEF from April 2018 to August 2020 were consecutively enrolled. All participants were followed up for at least 1 year. Thrombosis, infection, lead dislodgement, perforation, and other complications were observed after HPCSP. Clinical data, including echocardiographic parameters, electrocardiogram measurements, and cardiac function, were assessed before and after the procedure. Results: A total of 46 patients were enrolled. HPCSP was successfully deployed in 42 cases (91.30%), which included 37 cases with His bundle pacing (HBP) and 5 cases with left bundle branch pacing (LBBP). The QRS duration decreased significantly (169.88 ± 19.17 ms vs. 113.67 ± 20.68 ms, P < 0.001). Left ventricular end-systolic volume (LVESV) (167.67 ± 73.20 ml vs. 85.97 ± 62.24 ml, P < 0.001), left ventricular end-diastolic diameter (LVEDD) (63.57 ± 8.19 mm vs. 55.46 ± 9.63 mm, P = 0.003) and left ventricular ejection fraction (LVEF) (26.52 ± 5.60% vs. 41.86 ± 11.56%, P < 0.001) improved dramatically. Complete reverse remodeling of the LV with normalized LVEF and LVEDD was found in nearly half of the patients (45.24%). A short QRS duration after HPCSP was a strong predictor of normalized LVEF and LVEDD (P < 0.001). The thresholds increased markedly in two patients approximately 6 months after HBP. No patients died during the total follow-up period of 20.07 ± 6.45 months. Conclusion: Complete reverse remodeling of the LV could be found in nearly half of the patients with HFrEF and true LBBB after HPCSP, and the short QRS duration after HPCSP was a strong predictor.

CXCL1-CXCR2 axis mediates angiotensin II-induced cardiac hypertrophy and remodelling through regulation of monocyte infiltration.

Aims: Chemokine-mediated monocyte infiltration into the damaged heart represents an initial step in inflammation during cardiac remodelling. Our recent study demonstrates a central role for chemokine receptor CXCR2 in monocyte recruitment and hypertension; however, the role of chemokine CXCL1 and its receptor CXCR2 in angiotensin II (Ang II)-induced cardiac remodelling remain unknown. Methods and results: Angiotensin II (1000 ng kg-1 min-1) was administrated to wild-type (WT) mice treated with CXCL1 neutralizing antibody or CXCR2 inhibitor SB265610, knockout (CXCR2 KO) or bone marrow (BM) reconstituted chimeric mice for 14 days. Microarray revealed that CXCL1 was the most highly upregulated chemokine in the WT heart at Day 1 after Ang II infusion. The CXCR2 expression and the CXCR2+ immune cells were time-dependently increased in Ang II-infused hearts. Moreover, administration of CXCL1 neutralizing antibody markedly prevented Ang II-induced hypertension, cardiac dysfunction, hypertrophy, fibrosis, and macrophage accumulation compared with Immunoglobulin G (IgG) control. Furthermore, Ang II-induced cardiac remodelling and inflammatory response were also significantly attenuated in CXCR2 KO mice and in WT mice treated with SB265610 or transplanted with CXCR2-deficienct BM cells. Co-culture experiments in vitro further confirmed that CXCR2 deficiency inhibited macrophage migration and activation, and attenuated Ang II-induced cardiomyocyte hypertrophy and fibroblast differentiation through multiple signalling pathways. Notably, circulating CXCL1 level and CXCR2+ monocytes were higher in patients with heart failure compared with normotensive individuals. Conclusions: Angiotensin II-induced infiltration of monocytes in the heart is largely mediated by CXCL1-CXCR2 signalling which initiates and aggravates cardiac remodelling. Inhibition of CXCL1 and/or CXCR2 may represent new therapeutic targets for treating hypertensive heart diseases.

Association of total cholesterol, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol with atherosclerotic cardiovascular disease and cancer in a Chinese male population.

This prospective study included 68,759 Chinese male adults from Kailuan cohort of China who had a standardized medical examination between 2006 and 2007 and were followed up for approximately 8 years until occurrence of ASCVD, cancer or death or until December 31, 2014. Subjects were divided into four categories based on the quartiles of TC, LDL-C and non-HDL-C. Cox regression models were used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs). During follow-up, 2,916 males developed ASCVD and 1,884 developed cancer. Compared with the lowest quartile, the upper-most quartiles of TC, LDL-C and non-HDL-C were all associated with increased ASCVD risk (HR 1.53; HR 1.16; HR 1.55); however, the upper-most quartiles of TC, LDL-C and non-HDL-C were all negatively associated with cancer (HR0.84; HR 0.82; HR 0.80) and these associations were present after exclusion of incident cancers during the first 4 years of follow-up. In a word, we report that high TC, LDL-C and non-HDL-C concentrations increased ASCVD incidence in a male population and that these lipid profiles were inversely associated with total cancer and several individual cancers.

Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein.

Carboxyl terminus of Hsp70-interacting protein (CHIP) is a critical ubiquitin ligase/cochaperone to reduce cardiac oxidative stress, inflammation, cardiomyocyte apoptosis and autophage etc. However, it is unclear whether overexpression of CHIP in the heart would exert protective effects against DOX-induced cardiomyopathy. Cardiac-specific CHIP transgenic (CHIP-TG) mice and the wild-type (WT) littermates were treated with DOX or saline. DOX-induced cardiac atrophy, dysfunction, inflammation, oxidative stress and cardiomyocyte apoptosis were significantly attenuated in CHIP-TG mice. CHIP-TG mice also showed higher survival rate than that of WT mice (40% versus 10%) after 10-day administration of DOX. In contrast, knockdown of CHIP by siRNA in vitro further enhanced DOX-induced cardiotoxic effects. Global gene microarray assay revealed that after DOX-treatment, differentially expressed genes between WT and CHIP-TG mice were mainly involved in apoptosis, atrophy, immune/inflammation and oxidative stress. Mechanistically, CHIP directly promotes ubiquitin-mediated degradation of p53 and SHP-1, which results in activation of ERK1/2 and STAT3 pathways thereby ameliorating DOX-induced cardiac toxicity.