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Chemico-biological Interactions Aug 2024Interrupted ER homeostasis contributes to the etiology of obesity cardiomyopathy although it remains elusive how ER stress evokes cardiac anomalies in obesity. Our study...
Interrupted ER homeostasis contributes to the etiology of obesity cardiomyopathy although it remains elusive how ER stress evokes cardiac anomalies in obesity. Our study evaluated the impact of ER stress inhibition on cardiac anomalies in obesity. Lean and ob/ob obese mice received chemical ER chaperone tauroursodeoxycholic acid (TUDCA, 50 mg/kg/d, p.o.) for 35 days prior to evaluation of glucose sensitivity, echocardiographic, myocardial geometric, cardiomyocyte mechanical and subcellular Ca property, mitochondrial integrity, oxidative stress, apoptosis, and ferroptosis. Intracellular Ca governing domains including sarco(endo)plasmic reticulum Ca-ATPase (SERCA) were monitored byCauptake and immunoblotting. Our results noted that TUDCA alleviated myocardial remodeling (fibrosis, hypertrophy, enlarged LVESD), echocardiographic anomalies (compromised fractional shortening and ejection fraction), cardiomyocyte contractile dysfunction (amplitude and velocity of cell shortening, relengthening time) and intracellular Ca anomalies (compromised subcellular Ca release, clearance and SERCA function), mitochondrial damage (collapsed membrane potential, downregulated mitochondrial elements and ultrastructural alteration), ER stress (GRP78, eIF2α and ATF4), oxidative stress, apoptosis and ferroptosis [downregulated SLC7A11, GPx4 and upregulated transferrin receptor (TFRC)] without affecting global glucose sensitivity and serum Fe in obese mice. Obesity-evoked change in HSP90, phospholamban and Na-Ca exchanger was spared by the chemical ER chaperone. Moreover, in vitro results noted that TUDCA, PERK inhibitor GSK2606414, TFRC neutralizing antibody and ferroptosis inhibitor LIP1 mitigated palmitic acid-elicited changes in lipid peroxidation and mechanical function. Our findings favored a role for ferroptosis in obesity cardiomyopathy downstream of ER stress.
Topics: Taurochenodeoxycholic Acid; Animals; Endoplasmic Reticulum Stress; Mice; Ferroptosis; Obesity; Endoplasmic Reticulum Chaperone BiP; Male; Myocytes, Cardiac; Calcium; Mice, Inbred C57BL; Ventricular Remodeling; Oxidative Stress; Myocardial Contraction; Mice, Obese
PubMed: 38906502
DOI: 10.1016/j.cbi.2024.111104 -
International Journal of Surgery... Jun 2024The modified Morrow operation for hypertrophic obstructive cardiomyopathy (HOCM) in children has a favorable outcome, but some children still have a poor prognosis after...
OBJECTIVE
The modified Morrow operation for hypertrophic obstructive cardiomyopathy (HOCM) in children has a favorable outcome, but some children still have a poor prognosis after the procedure. In this study, we aimed to investigate the application of cardiac computed tomography (CCT) to construct a three-dimensional(3D) model of the left ventricle (LV) and analyze the association between hypertrophy in different parts of the LV and poor prognosis.
METHODS
We retrospectively analyzed 57 children with HOCM from April 2015 to October 2022, among whom 16 underwent preoperative CCT examination. All children underwent the modified Morrow surgery in our center. We defined heart failure (HF), malignant ventricular arrhythmia, and recurrent left ventricular outflow tract obstruction (LVOTO) as adverse events. We performed a retrospective Cox analysis and conducted genetic testing. A 3D model of the LV was built through the standard 17-segment method and analyzing the high-risk factors.
RESULTS
17 (29.8%) had adverse events during follow-up. Multivariate Cox analysis revealed that genetic mutation (HR:5.634, 95%CI:1.663-19.086, P=0.005), Noonan syndrome (HR:3.770, 95%CI:1.245-11.419, P=0.019), preoperational systolic anterior motion (SAM)(HR:4.596, 95%CI:1.532-13.792, P=0.007)and mid-ventricular obstruction (HR:4.763, 95%CI:1.538-14.754, P=0.007) were high-risk factors, suggesting that the degree of hypertrophy in the left ventricle is associated with poor prognosis. By analyzing the CCT with 3D model, children with poor prognosis have more hypertrophy in basal-inferior (P=0.014), mid-inferoseptal(P=0.044), mid-inferior(P=0.017). It suggests that a more hypertrophied posterior left ventricular wall portends a worse prognosis.
CONCLUSION
Even after modified Morrow surgery, the prognostic impact of genetic mutation remains significant. Moreover, the degree of hypertrophy of the posterior wall in the LV was also related to the postoperative prognosis through CCT combined with 3D technology. It provides surgeons guiding to evaluate the overall prognosis and the treatment plan before surgery.
PubMed: 38905490
DOI: 10.1097/JS9.0000000000001862 -
The International Journal of Artificial... Jun 2024To investigate the effects of different blood purification modes on left ventricular remodeling and its relationship with serum cardiac troponin I (cTnI) in patients...
OBJECTIVE
To investigate the effects of different blood purification modes on left ventricular remodeling and its relationship with serum cardiac troponin I (cTnI) in patients with end-stage renal disease (ESRD).
METHOD
A total of 108 patients with ESRD were selected, 55 cases were divided into hemodialysis combined with hemoperfusion (HD + HP) group, in which patients participants accepted routine hemodialysis for three times/week and hemoperfusion for three times/month; 53 cases in hemodialysis combined with hemodialysis filtration (HD + HDF) group, routine hemodialysis three times/week + hemodialysis filtration three times/month. The total duration of dialysis in the study was 1 year. Cardiac troponin I (cTnI) levels were measured before dialysis and 1 year after treatment, and related parameters were measured by echocardiography, including ventricular septal thickness (IVST), left ventricular posterior wall thickness (LVPWT), left ventricular end diastolic diameter (LVEDd), left ventricular end systolic diameter (LVEDs), and left ventricular myocardial mass index (LVMI). The paired test was used within the group. Correlation analysis was performed using Spearman correlation analysis.
RESULT
After treatment, the levels of cTnI, IVST, LVPWT, LVEDd, LVEDs, and LVMI in the two groups were increased, and the results were statistically significant (all < 0.05). In addition, cTnI of the two groups was significantly correlated with IVST, LVPWT, LVEDd, LVEDs, and LVMI (all < 0.05).
CONCLUSION
Left ventricular remodeling is common in patients with ESRD, HD + Hp, and HD + HDF cannot reduce the phenomenon of left ventricular remodeling, cTnI can be used as a predictor of left ventricular hypertrophy and enlargement.
PubMed: 38904358
DOI: 10.1177/03913988241259975 -
SAGE Open Medical Case Reports 2024Midventricular obstruction (MVO) is a rare form of hypertrophic cardiomyopathy (HCM). While surgical treatment for HCM is among the most technically challenging cardiac...
Midventricular obstruction (MVO) is a rare form of hypertrophic cardiomyopathy (HCM). While surgical treatment for HCM is among the most technically challenging cardiac operations for acquired disease, surgery for MVO is rarely reported. A 38-year-old man was admitted to our hospital with a cough and dyspnea. Transthoracic and transesophageal echography and computed tomography revealed extensive left ventricular hypertrophy, extending from the anteroseptal wall to the apex, and marked papillary muscle hypertrophy. We underwent septal myectomy via aortotomy (Morrow procedure) and apical surgery. Extended myectomy provides the best exposure to the hypertrophied septum and improves the functional status of patients.
PubMed: 38903183
DOI: 10.1177/2050313X241263704 -
BioRxiv : the Preprint Server For... Apr 2024Hypertrophic cardiomyopathy (HCM) is associated with phenotypic variability. To gain insights into transcriptional regulation of cardiac phenotype, single-nucleus linked...
Hypertrophic cardiomyopathy (HCM) is associated with phenotypic variability. To gain insights into transcriptional regulation of cardiac phenotype, single-nucleus linked RNA-/ATAC-seq was performed in 5-week-old control mouse-hearts (WT) and two HCM-models (R92W-TnT, R403Q-MyHC) that exhibit differences in heart size/function and fibrosis; mutant data was compared to WT. Analysis of 23,304 nuclei from mutant hearts, and 17,669 nuclei from WT, revealed similar dysregulation of gene expression, activation of AP-1 TFs (FOS, JUN) and the SWI/SNF complex in both mutant ventricular-myocytes. In contrast, marked differences were observed between mutants, for gene expression/TF enrichment, in fibroblasts, macrophages, endothelial cells. Cellchat predicted activation of pro-hypertrophic IGF-signaling in both mutant ventricular-myocytes, and profibrotic TGFβ-signaling only in mutant-TnT fibroblasts. In summary, our bioinformatics analyses suggest that activation of IGF-signaling, AP-1 TFs and the SWI/SNF chromatin remodeler complex promotes myocyte hypertrophy in early-stage HCM. Selective activation of TGFβ-signaling in mutant-TnT fibroblasts contributes to genotype-specific differences in cardiac fibrosis.
PubMed: 38903075
DOI: 10.1101/2024.04.24.589078 -
Kidney International Reports Jun 2024Fluid and salt overload in patients on dialysis result in high blood pressure (BP), left ventricular hypertrophy (LVH) and hemodynamic instability, resulting in...
INTRODUCTION
Fluid and salt overload in patients on dialysis result in high blood pressure (BP), left ventricular hypertrophy (LVH) and hemodynamic instability, resulting in cardiovascular morbidity.
METHODS
Analysis of 910 pediatric patients on maintenance hemodialysis/hemodiafiltration (HD/HDF), prospectively followed-up with 2758 observations recorded every 6-months in the International Pediatric Hemodialysis Network (IPHN).
RESULTS
Uncontrolled hypertension was present in 55% of observations, with 27% of patients exhibiting persistently elevated predialysis BP. Systolic and diastolic age- and height-standardized BP (BP-SDS) were independently associated with the number of antihypertensive medications (odds ratio [OR] = 1.47, 95% confidence interval 1.39-1.56, 1.36 [1.23-1.36]) and interdialytic weight gain (IDWG; 1.19 [1.14-1.22], 1.09 [1.06-1.11]; all < 0.0001). IDWG was related to urine output (OR = 0.27 [0.23-0.32]) and dialysate sodium (dNa; 1.06 [1.01-1.10]; all < 0.0001). The prevalence of masked hypertension was 24%, and HD versus HDF use was an independent risk factor of elevated age- and height-standardized mean arterial pressure (MAP-SDS) (OR = 2.28 [1.18-4.41], = 0.01). Of the 1135 echocardiograms, 51% demonstrated LVH. Modifiable risk factors included predialysis systolic BP-SDS (OR = 1.06 [1.04-1.09], < 0.0001), blood hemoglobin (0.97 [0.95-0.99], = 0.004), HD versus HDF modality (1.09 [1.02-1.18], = 0.01), and IDWG (1.02 [1.02-1.03], = 0.04). In addition, HD modality increased the risk of LVH progression (OR = 1.23 [1.03-1.48], = 0.02). Intradialytic hypotension (IDH) was prevalent in patients progressing to LVH and independently associated with predialysis BP-SDS below 25th percentile, lower number of antihypertensives, HD versus HDF modality, ultrafiltration (UF) rate, and urine output, but not with dNa.
CONCLUSION
Uncontrolled hypertension and LVH are common in pediatric HD, despite intense pharmacologic therapy. The outcome may improve with use of HDF, and superior anemia and IDWG control; the latter via lowering dNa, without increasing the risk of IDH.
PubMed: 38899176
DOI: 10.1016/j.ekir.2024.03.016 -
Zhen Ci Yan Jiu = Acupuncture Research Jun 2024To observe the effect of electroacupuncture (EA) at "Neiguan"(PC6) on cardiac function, cardiac morphology and transient receptor potential channel (TRPC) protein...
OBJECTIVES
To observe the effect of electroacupuncture (EA) at "Neiguan"(PC6) on cardiac function, cardiac morphology and transient receptor potential channel (TRPC) protein expressions in myocardial tissue of mice with myocardial hypertrophy, so as to explore its mechanisms underlying improvement of myocardial hypertrophy.
METHODS
Forty-five male C57BL/6 mice were randomly divided into control, model and EA groups (15 mice/group). The myocardial hypertrophy model was established by subcutaneous injection of isoproterenol hydrochloride (15 mg·kg·d) for 14 days. The mice of the control group received subcutaneous injection of same amount of normal saline. The mice of the EA group received EA stimulation (frequency of 2 Hz, intensity of 1 mA) of bilateral PC6 for 20 min each time, once a day for 14 consecutive days. After the intervention, the body weight, tibia length and heart weight were measured. The left ventricular ejection fraction (EF), fractional shortening index (FS), left ventricular end-systolic volume (LVEV), left ventricular end-systolic internal diameter (LVID) and left ventricular posterior wall thickness (LVPW) were measured by using echocardiography for evaluating the cardiac function. The mean number and surface area of myocardial cells was detected by wheat germ agglutinin (WGA) staining, and changes of the cardiac morphology were observed under light microscopy after HE staining. The expression levels of TRPC1, TRPC3, TRPC4 and TRPC6 (TRPC1/3/4/6) in the myocardial tissue were detected by real-time quantitative PCR (qPCR) and Western blot, separately.
RESULTS
Compared with the control group, the heart-body weight ratio(<0.05) and heart-weight-to-tibia-length ratio (<0.01), LVEV and LVID levels, the relative surface area, left ventricular area ratio, and the expression levels of cardiac TRPC1/3/4/6 were significantly increased (<0.01, <0.05), while the EF, FS, LVPW, number of cardiomyocytes, and the left ventricular posterior wall ratio were obviously decreased (<0.01, <0.05) in the model group. In comparison with the model group, the heart/body weight ratio, heart-weight-to-tibia-length ratio, LVEV and LVID levels, relative surface area, left ventricular area ratio, and the expression levels of cardiac TRPC1/3/4/6 were significantly decreased (<0.01, <0.05), while the EF, FS, LVPW, number of cardiomyocytes and left ventricular posterior wall ratio were significantly increased (<0.01, <0.05) in the EA group. H.E. staining showed disordered arrangement of cardiomyocytes and obvious myocardial interstitial inflammatory cell infiltration in the model group, and evident reduction of degree of cardiac fibrosis and interstitial edema in the EA group.
CONCLUSIONS
EA of PC6 can improve the cardiac function and cardiac morphology in mice with myocardial hypertrophy, which may be related to its functions in down-regulating the expression of transient receptor potential channels.
Topics: Animals; Electroacupuncture; Mice; Mice, Inbred C57BL; Male; Humans; Myocardium; Transient Receptor Potential Channels; Cardiomegaly; Acupuncture Points; TRPC Cation Channels
PubMed: 38897799
DOI: 10.13702/j.1000-0607.20221393 -
ASAIO Journal (American Society For... Jun 2024The development of new right ventricular (RV) dysfunction after cannulation to venovenous (VV) extracorporeal membrane oxygenation (ECMO) and its association with worse...
The development of new right ventricular (RV) dysfunction after cannulation to venovenous (VV) extracorporeal membrane oxygenation (ECMO) and its association with worse outcomes is increasingly recognized in adult patients, however, no studies have evaluated this phenomenon in pediatric patients. We report results of a single-center retrospective cohort study at a large academic children's hospital. New RV systolic dysfunction was present in 48% (12/25) of pediatric patients on VV ECMO for acute respiratory distress syndrome (ARDS). There was no statistically significant difference in survival, duration of mechanical ventilation, or hospital length of stay between those with and without RV dysfunction. Over half (5/9, 56%) of survivors with RV dysfunction on ECMO had RV dilation or RV hypertrophy on post-ECMO echocardiograms, and in two patients the RV dysfunction persisted for months following decannulation. Cardiac catheterization and autopsy reports suggested that echocardiographic assessment of RV systolic function alone may not be sufficient to diagnose clinically relevant RV injury. This is the first study to report the prevalence of RV dysfunction on VV ECMO for pediatric ARDS. Future multicenter collaboration is needed to create a clinically relevant definition of pediatric "RV injury" and to further evaluate risk factors and outcomes of RV dysfunction.
PubMed: 38896850
DOI: 10.1097/MAT.0000000000002257 -
Current Protocols Jun 2024Fabry disease (FD) is a lysosomal storage disorder caused by variants in the GLA gene encoding α-galactosidase A, an enzyme required for catabolism of...
Fabry disease (FD) is a lysosomal storage disorder caused by variants in the GLA gene encoding α-galactosidase A, an enzyme required for catabolism of globotriaosylceramide (Gb). Accumulation of Gb in patients' cells, tissues, and biological fluids causes clinical manifestations including ventricular hypertrophy, renal insufficiency, and strokes. This protocol describes a methodology to analyze urinary Gb and creatinine. Samples are diluted with an internal standard solution containing Gb(C17:0) and creatinine-D, centrifuged, and directly analyzed by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) using an 8.7-min method. Eight Gb isoforms [C16:0, C18:0, C20:0, C22:1, C22:0, C24:1, C24:0, and (C24:0)OH] are analyzed and the total is normalized to creatinine. Confirmation ions are monitored to detect potential interferences. The Gb limit of quantification is 0.023 µg/ml. Its interday coefficients of variation (3 concentrations measured) are ≤15.4%. This method minimizes matrix effects (≤6.5%) and prevents adsorption or precipitation of Gb. Urine samples are stable (bias <15%) for 2 days at 21°C, 7 days at 4°C, and 4 freeze/thaw cycles, whereas prepared samples are stable for 5 days at 21°C, and 14 days at 4°C. The Gb/creatinine age-related upper reference limits (mean + 2 standard deviations) are 29 mg/mol creatinine (<7 years) and 14 mg/mol creatinine (≥7 years). This simple, robust protocol has been fully validated (ISO 15189) and provides a valuable tool for diagnosis and monitoring of FD patients. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Analysis of urinary globotriaosylceramide (Gb) and creatinine by UHPLC-MS/MS Support Protocol 1: Preparation of the urinary quality controls Support Protocol 2: Preparation of the urine matrix used for the Gb calibration curve Support Protocol 3: Preparation of the Gb calibrators Support Protocol 4: Preparation of the working solution containing the internal standards Support Protocol 5: Preparation of the creatinine calibrators Support Protocol 6: Preparation of the UHPLC solutions and mobile phases.
Topics: Humans; Tandem Mass Spectrometry; Trihexosylceramides; Chromatography, High Pressure Liquid; Fabry Disease; Creatinine
PubMed: 38896100
DOI: 10.1002/cpz1.1087 -
BioRxiv : the Preprint Server For... Jun 2024Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic...
UNLABELLED
Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse . Control mice, HFD only, Renin only and HFD-Renin (aka "HFpEF") littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e', IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions.
NEW & NOTEWORTHY
Heart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.
PubMed: 38895483
DOI: 10.1101/2024.06.06.597821