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International Journal of Molecular... Sep 2023Our previous studies revealed the protection of stachydrine hydrochloride (STA) against cardiopathological remodeling. One of the underlying mechanisms involves the...
Our previous studies revealed the protection of stachydrine hydrochloride (STA) against cardiopathological remodeling. One of the underlying mechanisms involves the calcium/calmodulin-dependent protein kinase Ⅱ (CaMKII). However, the way STA influences CaMKII needs to be further investigated. The nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-coupled reactive oxygen species (ROS) overproduction putatively induces the oxidative activation of CaMKII, resulting in the occurrence of pathological cardiac remodeling and dysfunction in experimental models of mice. Thus, in this study, we assessed the role of the NOX2-ROS signal axis in STA cardioprotection. The transverse aortic constriction (TAC)-induced heart failure model of mice, the phenylephrine-induced hypertrophic model of neonatal rat primary cardiomyocytes, and the HO-induced oxidative stress models of adult mouse primary cardiomyocytes and H9c2 cells were employed. The echocardiography and histological staining were applied to assess the cardiac effect of STA (6 mg/kg/d or 12 mg/kg/d), which was given by gavage. NOX2, ROS, and excitation-contraction (EC) coupling were detected by Western blotting, immunofluorescence, and calcium transient-contraction synchronous recordings. ROS and ROS-dependent cardiac fibrosis were alleviated in STA-treated TAC mice, demonstrating improved left ventricular ejection fraction and hypertrophy. In the heart failure model of mice and the hypertrophic model of cardiomyocytes, STA depressed NOX2 protein expression and activation, as shown by inhibited translocation of its phosphorylation, p67phox and p47phox, from the cytoplasm to the cell membrane. Furthermore, in cardiomyocytes under oxidative stress, STA suppressed NOX2-related cytosolic Ca overload, enhanced cell contractility, and decreased Ca-dependent regulatory protein expression, including CaMKⅡ and Ryanodine receptor calcium release channels. Cardioprotection of STA against pressure overload-induced pathological cardiac remodeling correlates with the NOX2-coupled ROS signaling cascade.
Topics: Animals; Rats; Reactive Oxygen Species; Calcium; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Hydrogen Peroxide; Stroke Volume; Ventricular Remodeling; Ventricular Function, Left; Heart Failure; Hypertrophy; Myocytes, Cardiac; Aortic Valve Stenosis; Calcium, Dietary
PubMed: 37762672
DOI: 10.3390/ijms241814369 -
European Heart Journal. Cardiovascular... Dec 2023Anterior mitral valve leaflet (AMVL) elongation is detectable in overt and subclinical hypertrophic cardiomyopathy (HCM). We sought to investigate the dynamic motion of...
AIMS
Anterior mitral valve leaflet (AMVL) elongation is detectable in overt and subclinical hypertrophic cardiomyopathy (HCM). We sought to investigate the dynamic motion of the aorto-mitral apparatus to understand the behaviour of the AMVL and the mechanisms of left ventricular outflow tract obstruction (LVOTO) predisposition in HCM.
METHODS AND RESULTS
Cardiovascular magnetic resonance imaging using a 1.5 Tesla scanner was performed on 36 HCM sarcomere gene mutation carriers without left ventricular hypertrophy (G+LVH-), 31 HCM patients with preserved ejection fraction carrying a pathogenic sarcomere gene mutation (G+LVH+), and 53 age-, sex-, and body surface area-matched healthy volunteers. Dynamic excursion of the aorto-mitral apparatus was assessed semi-automatically on breath-held three-chamber cine steady-state free precession images. Four pre-defined regions of interest (ROIs) were tracked: ROIPMVL: hinge point of the posterior mitral valve leaflet; ROITRIG: intertrigonal mitral annulus; ROIAMVL: AMVL tip; and ROIAAO: anterior aortic annulus. Compared with controls, normalized two-dimensional displacement-vs.-time plots in G+LVH- revealed subtle but significant systolic anterior motion (SAM) of the AMVL (P < 0.0001) and reduced longitudinal excursion of ROIAAO (P = 0.014) and ROIPMVL (P = 0.048). In overt and subclinical HCM, excursion of the ROITRIG/AMVL/PMVL was positively associated with the burden of left ventricular fibrosis (P < 0.028). As expected, SAM was observed in G+LVH+ together with reduced longitudinal excursion of ROITRIG (P = 0.049) and ROIAAO (P = 0.008).
CONCLUSION
Dyskinesia of the aorto-mitral apparatus, including SAM of the elongated AMVL, is detectable in subclinical HCM before the development of LVH or left atrial enlargement. These data have the potential to improve our understanding of early phenotype development and LVOTO predisposition in HCM.
Topics: Humans; Mitral Valve; Cardiomyopathy, Hypertrophic; Hypertrophy, Left Ventricular; Magnetic Resonance Imaging; Phenotype; Ventricular Outflow Obstruction
PubMed: 37523765
DOI: 10.1093/ehjci/jead186 -
Nutrients Jul 2023Few studies have examined the sex differences in left ventricle (LV) structure and physiology from early life stages. We aimed to assess the role of sex and...
Few studies have examined the sex differences in left ventricle (LV) structure and physiology from early life stages. We aimed to assess the role of sex and overweight/obesity on left ventricular mass (LVM) and LV volume in Chinese children without preexisting cardiovascular risk factors. We selected 934 healthy children aged 6-8 years from an existing cohort in Beijing, China. Linear regression models were used to regress body mass index (BMI), fat mass, systolic blood pressure, diastolic blood pressure, waist circumference, and visceral fat area (VFA) with LVM, left ventricle end-diastolic volume (LVEDV) and end-systolic volume (LVESV). Higher BMI, fat mass, waist circumference, VFA, and stroke volume (SV) predicted higher LVM, LVEDV, and LVESV in both sexes. Multivariable analysis showed that boys with an elevated BMI had greater LV hypertrophy. LVEDV and LVESV were higher among boys than among girls and increased with higher BMI in both boys and girls. LVEDV and LVESV were associated with VFA in boys. We observed sex differences in LVM, LVESV, and LVEDV among prepubertal children, independent of obesity, with higher values observed in boys. Sex differences in cardiac structure in children may help explain the higher incidence of cardiovascular disease in male adults. Whether interventions to reduce childhood obesity can improve the trajectory of cardiac dynamics is worth investigating.
Topics: Adult; Humans; Male; Child; Female; Body Mass Index; Cross-Sectional Studies; Sex Characteristics; Pediatric Obesity; Hypertrophy, Left Ventricular; China; Ventricular Function, Left
PubMed: 37447393
DOI: 10.3390/nu15133066 -
Journal of Atherosclerosis and... Sep 2023Patients with end-stage kidney disease (ESKD) have an unparalleled risk of left ventricular hypertrophy (LVH) and vascular calcification (VC), both of which introduce...
Left Ventricular Hypertrophy Geometry and Vascular Calcification Co-Modify the Risk of Cardiovascular Mortality in Patients with End-Stage Kidney Disease: A Retrospective Cohort Study.
AIM
Patients with end-stage kidney disease (ESKD) have an unparalleled risk of left ventricular hypertrophy (LVH) and vascular calcification (VC), both of which introduce excessive cardiovascular risk. However, it remains unclear whether LVH geometry co-modulates cardiovascular outcomes with VC in this population.
METHODS
A retrospective cohort study was conducted. Patients with ESKD requiring chronic hemodialysis were identified from Shin Kong Wu Ho-Su Memorial Hospital between October and December 2018, with echocardiographic LVH geometry and aortic arch calcification (AoAC) determined. They were divided into four groups according to AoAC severity and eccentric or concentric LVH. We used Kaplan-Meier analysis and Cox proportional hazard regression to analyze their cardiovascular and all-cause mortality after multivariate adjustment.
RESULTS
Overall, 223 patients with ESKD with LVH were analyzed, among whom 29.1%, 23.3%, 25.1%, and 22.4% had non-to-mild AoAC with eccentric and concentric LVH and moderate-to-severe AoAC with eccentric and concentric LVH, respectively. After 3.5 years of follow-up, patients with ESKD with moderate-to-severe AoAC and concentric LVH had a significantly higher risk of cardiovascular mortality than those with non-to-mild AoAC and eccentric LVH (hazard ratio 3.35, p=0.002). However, those with moderate-to-severe AoAC but eccentric LVH did not have higher cardiovascular mortality. Similarly, patients with ESKD with moderate-to-severe AoAC and concentric LVH had a significantly higher all-cause mortality than those with non-to-mild AoAC and eccentric LVH, whereas the other two groups did not have higher risk.
CONCLUSION
LVH geometry could help stratify the risk of patients with ESKD when they had severe VC, and co-existing severe VC and concentric LVH aggravated cardiovascular risk.
Topics: Humans; Hypertrophy, Left Ventricular; Retrospective Studies; Kidney Failure, Chronic; Heart Ventricles; Vascular Calcification; Ventricular Remodeling
PubMed: 36567124
DOI: 10.5551/jat.63870 -
Cellular and Molecular Life Sciences :... Jan 2024Prolonged stimulation of β-adrenergic receptor (β-AR) can lead to sympathetic overactivity that causes pathologic cardiac hypertrophy and fibrosis, ultimately...
Prolonged stimulation of β-adrenergic receptor (β-AR) can lead to sympathetic overactivity that causes pathologic cardiac hypertrophy and fibrosis, ultimately resulting in heart failure. Recent studies suggest that abnormal protein ubiquitylation may contribute to the pathogenesis of cardiac hypertrophy and remodeling. In this study, we demonstrated that deficiency of a deubiquitinase, Josephin domain-containing protein 2 (JOSD2), ameliorated isoprenaline (ISO)- and myocardial infarction (MI)-induced cardiac hypertrophy, fibrosis, and dysfunction both in vitro and in vivo. Conversely, JOSD2 overexpression aggravated ISO-induced cardiac pathology. Through comprehensive mass spectrometry analysis, we identified that JOSD2 interacts with Calcium-calmodulin-dependent protein kinase II (CaMKIIδ). JOSD2 directly hydrolyzes the K63-linked polyubiquitin chains on CaMKIIδ, thereby increasing the phosphorylation of CaMKIIδ and resulting in calcium mishandling, hypertrophy, and fibrosis in cardiomyocytes. In vivo experiments showed that the cardiac remodeling induced by JOSD2 overexpression could be reversed by the CaMKIIδ inhibitor KN-93. In conclusion, our study highlights the role of JOSD2 in mediating ISO-induced cardiac remodeling through the regulation of CaMKIIδ ubiquitination, and suggests its potential as a therapeutic target for combating the disease. Please check and confirm that the authors and their respective affiliations have been correctly identified and amend if necessary. All have been checked.
Topics: Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cardiomegaly; Fibrosis; Heart Failure; Isoproterenol; Myocytes, Cardiac; Ventricular Remodeling
PubMed: 38195959
DOI: 10.1007/s00018-023-05037-7 -
ESC Heart Failure Feb 2024Observational studies have suggested that anaemia is associated with an increased risk of heart failure (HF). But the potential causal association is not clear. We aimed...
AIMS
Observational studies have suggested that anaemia is associated with an increased risk of heart failure (HF). But the potential causal association is not clear. We aimed to investigate the association between anaemia and HF risk.
METHODS AND RESULTS
A Mendelian randomization (MR) analysis was performed to confirm the causal association of anaemia with the risk of HF and left ventricular structure and function. Furthermore, a reverse-direction MR analyses was conducted to assess the causal effect of HF on anaemia. The MR analysis indicated that genetically predicted anaemia is associated with the increased risk of HF (meta: odd ratio (OR) = 1.12; 95% confidence interval (CI) [1.04, 1.20]; P = 0.002), and left ventricular mass index (β = 1.051; 95% CI [0.384, 1.718]; P = 0.002), left ventricular mass (β = 2.063; 95% CI [0.578, 3.547]; P = 0.006), left atrial minimum volume (β = 0.076; 95% CI [0.008, 0.143]; P = 0.028), and left atrial maximum volume (β = 0.090; 95% CI [0.023, 0.157]; P = 0.009). In the reverse-direction MR analyses, we found that genetic susceptibility to HF was significantly associated with the increased risk of anaemia (meta: OR = 1.40; 95% CI [1.24, 1.59]; P = 1.79 × 10 ).
CONCLUSIONS
This MR study supports the genetic evidence that there is bidirectional causality between anaemia and the risk of HF as well as anaemia may cause left ventricular hypertrophy and enlargement of the left atrium. Considering the adverse causal effects between the two diseases, more attention should be paid to the prevention and treatment of anaemia in patients with HF.
Topics: Humans; Ventricular Function, Left; Mendelian Randomization Analysis; Heart Failure; Hypertrophy, Left Ventricular; Anemia
PubMed: 37984882
DOI: 10.1002/ehf2.14579 -
Nature Communications Jun 2024Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In...
Semaglutide, a glucagon-like peptide-1 receptor agonist, is clinically used as a glucose-lowering and weight loss medication due to its effects on energy metabolism. In heart failure, energy production is impaired due to altered mitochondrial function and increased glycolysis. However, the impact of semaglutide on cardiomyocyte metabolism under pressure overload remains unclear. Here we demonstrate that semaglutide improves cardiac function and reduces hypertrophy and fibrosis in a mouse model of pressure overload-induced heart failure. Semaglutide preserves mitochondrial structure and function under chronic stress. Metabolomics reveals that semaglutide reduces mitochondrial damage, lipid accumulation, and ATP deficiency by promoting pyruvate entry into the tricarboxylic acid cycle and increasing fatty acid oxidation. Transcriptional analysis shows that semaglutide regulates myocardial energy metabolism through the Creb5/NR4a1 axis in the PI3K/AKT pathway, reducing NR4a1 expression and its translocation to mitochondria. NR4a1 knockdown ameliorates mitochondrial dysfunction and abnormal glucose and lipid metabolism in the heart. These findings suggest that semaglutide may be a therapeutic agent for improving cardiac remodeling by modulating energy metabolism.
Topics: Animals; Male; Nuclear Receptor Subfamily 4, Group A, Member 1; Energy Metabolism; Mice; Glucagon-Like Peptides; Heart Failure; Mice, Inbred C57BL; Ventricular Remodeling; Lipid Metabolism; Myocytes, Cardiac; Cyclic AMP Response Element-Binding Protein; Disease Models, Animal; Myocardium; Signal Transduction; Mitochondria; Cardiomegaly
PubMed: 38834564
DOI: 10.1038/s41467-024-48970-2 -
Biomolecules Nov 2023Currently, the symptomatic status and left ventricular ejection fraction (LVEF) play a crucial role in aortic stenosis (AS) assessment. However, the symptoms are often... (Review)
Review
Currently, the symptomatic status and left ventricular ejection fraction (LVEF) play a crucial role in aortic stenosis (AS) assessment. However, the symptoms are often subjective, and LVEF is not a sensitive marker of left ventricle (LV) decompensation. Over the past years, the cardiac structure and function research on AS has increased due to advanced imaging modalities and potential therapies. New imaging parameters emerged as predictors of disease progression in AS. LV global longitudinal strain has proved useful for risk stratification in asymptomatic severe AS patients with preserved LVEF. The assessment of myocardial fibrosis by cardiac magnetic resonance is the most studied application and offers prognostic information on AS. Moreover, the usage of biomarkers in AS as objective measures of LV decompensation has recently gained more interest. The present review focuses on the transition from compensatory LV hypertrophy (H) to LV dysfunction and the biomarkers associated with myocardial wall stress, fibrosis, and myocyte death. Moreover, we discuss the potential impact of non-invasive imaging parameters for optimizing the timing of aortic valve replacement and provide insight into novel biomarkers for possible prognostic use in AS. However, data from randomized clinical trials are necessary to define their utility in daily practice.
Topics: Humans; Ventricular Function, Left; Stroke Volume; Aortic Valve Stenosis; Aortic Valve; Cardiomyopathies; Fibrosis; Biomarkers
PubMed: 38002343
DOI: 10.3390/biom13111661 -
Transplantation Direct Jun 2024Left ventricular hypertrophy (LVH) in patients with end stage renal disease undergoing renal replacement is linked to an increased risk for cardiovascular diseases....
BACKGROUND
Left ventricular hypertrophy (LVH) in patients with end stage renal disease undergoing renal replacement is linked to an increased risk for cardiovascular diseases. Dialysis does not completely prevent or correct this abnormality, and the evidence for kidney transplantation (KT) varies. This analysis aims to explore the relationship between KT and LVH.
METHODS
MEDLINE and Scopus were systematically searched in October 2023. All cross-sectional and longitudinal studies that fulfilled our inclusion criteria were included. Outcome was left ventricular mass index (LVMI) changes. We conducted a meta-analysis using a random effects model. Meta-regression was applied to examine the LVMI changes dependent on various covariates. Sensitivity analysis was used to handle outlying or influential studies and address publication bias.
RESULTS
From 7416 records, 46 studies met the inclusion criteria with 4122 included participants in total. Longitudinal studies demonstrated an improvement of LVMI after KT -0.44 g/m (-0.60 to -0.28). Blood pressure was identified as a predictor of LVMI change. A younger age at the time of KT and well-controlled anemia were also associated with regression of LVH. In studies longitudinally comparing patients on dialysis and renal transplant recipients, no difference was detected -0.09 g/m (-0.33 to 0.16). Meta-regression using changes of systolic blood pressure as a covariate showed an association between higher blood pressure and an increase in LVMI, regardless of the modality of renal replacement treatment.
CONCLUSIONS
In conclusion, our results indicated a potential cardiovascular benefit, defined as the regression of LVH, after KT. This benefit was primarily attributed to improved blood pressure control rather than the transplantation itself.
PubMed: 38769973
DOI: 10.1097/TXD.0000000000001647