Retrospective study on the short-term efficacy of different doses of Spironolactone in patients with heart failure of ischemic cardiomyopath and the influence of ventricular remodeling markers.

OBJECTIVE: To evaluate the impact of varying dosages of Spironolactone on the short-term effectiveness and ventricular remodeling indicators in patients with Heart Failure of Ischemic Cardiomyopathy (HFIC). METHODS: A cohort of 141 HFIC patients, admitted to our hospital between October 2018 and February 2023, were enrolled for this study. Alongside the standard treatment for Chronic Congestive Heart Failure (CHF), these patients were randomly assigned to either a low-dose (20 mg/d, N=70) or a high-dose (60 mg/d, N=71) Spironolactone group. After four weeks, various parameters were assessed and compared within each group before and after the treatment. These parameters included echocardiographic indices (LVEF, LVESD, LVEDD, LVESV, and LVEDV), New York Heart Association (NYHA) cardiac function classification, ventricular remodeling markers (hs-CRP, TNF-α, NT-pro BNP, Gal-3, MMP-9, and TIMP-4), and the Six Minute Walk Distance (6MWD). RESULTS: Both low-dose and high-dose Spironolactone significantly improved LVEF and 6MWD in HFIC patients (P<0.05), as well as markedly reduced LVESD, LVEDD, LVESV, LVEDV, and NYHA cardiac function grades (P<0.05). The high-dose group exhibited the most pronounced improvements (P<0.05). High-dose Spironolactone was more effective in improving the clinical and total effective rate compared to the low-dose, significantly reducing treatment inefficacy (P<0.05). Both dosages significantly increased serum potassium levels within normal ranges. They also improved the expression of ventricular remodeling markers (hs-CRP, TNF-α, NT-pro BNP, Gal-3, MMP-9, and TIMP-4) in HFIC patients, with the high-dose group showing the most significant results (P<0.05). CONCLUSION: High-dose Spironolactone (60 mg/d) demonstrates superior efficacy over the low-dose (20 mg/d) in rapidly diminishing ventricular remodeling damage and enhancing cardiac function and clinical symptoms in HFIC patients over a short duration.

Impact of COVID-19 Pandemic on Mechanical Reperfusion in ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: A Multicenter Retrospective Study From a Non-epicenter Region.

Objective: The COVID-19 pandemic placed heavy burdens on emergency care and posed severe challenges to ST-segment-elevation myocardial infarction (STEMI) treatment. This study aimed to investigate the impact of COVID-19 pandemic on mechanical reperfusion characteristics in STEMI undergoing primary percutaneous coronary intervention (PPCI) in a non-epicenter region. Methods: STEMI cases undergoing PPCI from January 23 to March 29 between 2019 and 2020 were retrospectively compared. PPCI parameters mainly included total ischemic time (TIT), the period from symptom onset to first medical contact (S-to-FMC), the period from FMC to wire (FMC-to-W) and the period from door to wire (D-to-W). Furthermore, the association of COVID-19 pandemic with delayed PPCI risk was further analyzed. Results: A total of 14 PPCI centers were included, with 100 and 220 STEMI cases undergoing PPCI in 2020 and 2019, respectively. As compared to 2019, significant prolongations occurred in reperfusion procedures (P < 0.001) including TIT (420 vs. 264 min), S-to-FMC (5 vs. 3 h), FMC-to-W (113 vs. 95 min) and D-to-W (83 vs. 65 min). Consistently, delayed reperfusion surged including TIT ≥ 12 h (22.0 vs.3.6%), FMC-to-W ≥ 120 min (34.0 vs. 6.8%) and D-to-W ≥ 90 min (19.0 vs. 4.1%). During the pandemic, the patients with FMC-to-W ≥ 120 min had longer durations in FMC to ECG completed (6 vs. 5 min, P = 0.007), FMC to DAPT (24 vs. 21 min, P = 0.001), catheter arrival to wire (54 vs. 43 min, P < 0.001) and D-to-W (91 vs. 78 min, P < 0.001). The pandemic was significantly associated with high risk of delayed PPCI (OR = 7.040, 95% CI 3.610-13.729, P < 0.001). Conclusions: Even in a non-epicenter region, the risk of delayed STEMI reperfusion significantly increased due to cumulative impact of multiple procedures prolongation.

EDN1 gene potentially involved in the development of acute mountain sickness.

Previous investigations have indicated that environmental and genetic factors collectively contribute to the development of acute mountain sickness (AMS), but whether the EDN1 gene is involved in AMS remains to be elucidated. A total of 356 healthy male soldiers who had not traveled to high altitudes in the previous 12 months were enrolled in our study. All participants were taken by plane from 500 m (Chengdu in Sichuan Province) to a 3700 m highland (Lhasa) within 2 hours. Clinical data were collected within 24 hours, and pulmonary function parameters were completed simultaneously. Genotypes were obtained by using iMLDR genotyping assays. A total of 237 soldiers (66.57%) presented AMS symptoms, including headache, dizziness, gastrointestinal upset and fatigue. Soldiers with AMS showed an increase in heart rate (HR), plasma tryptophan and serotonin, and a decrease in SaO2, FEV1, PEF, FVC, V75, V50, V25 and MMF (all P < 0.01). Notably, allele T in single nucleotide polymorphism (SNP) rs2070699 showed a positive correlation with the occurrence of AMS. A general linear regression analysis showed that rs2060799, Mean Arterial Pressure (MAP), SaO2, FVC, tryptophan and serotonin were independent predictors for the occurrence of AMS. Importantly, the area under the curve (AUC) values for tryptophan (0.998), serotonin (0.912) and FVC (0.86) had diagnostic specificity and sensitivity. Our results demonstrated that AMS is accompanied by changes in lung function parameters, increased plasma tryptophan and serotonin levels, and that the EDN1 polymorphism is a potential risk factor for AMS.

PPARA genetic variants increase the risk for cardiac pumping function reductions following acute high-altitude exposure: A self-controlled study.

BACKGROUND: Left cardiac pumping function determines the compensatory capacity of the cardiovascular system following acute high-altitude exposure. Variations in cardiac output (CO) at high altitude are inconsistent between individuals, and genetic susceptibility may play a crucial role. We sought to identify genetic causes of cardiac pumping function variations and describe the genotype-phenotype correlations. METHODS: A total of 151 young male volunteers were recruited and transferred to Lhasa (3,700 m) from Chengdu (<500 m) by plane. Genetic information related to hypoxic signaling and cardiovascular-related pathways was collected before departure. Echocardiography was performed both before departure and 24 hr after arrival at high altitude. RESULTS: Here we reported that PPARA variants were closely related to high-altitude cardiac function. The variants of rs6520015 C-allele and rs7292407 A-allele significantly increased the risk for cardiac pumping function reductions following acute high-altitude exposure. In addition, the individuals carrying haplotypes in PPARA, namely, rs135538 C-allele, rs4253623 A-allele, rs6520015 C-allele and rs7292407 A-allele (C-A-C-A), suffered a 7.27-fold risk for cardiac pumping function reduction (95% CI: 2.39-22.15, p = .0006) compared with those carrying the wild-type haplotype. CONCLUSIONS: This self-controlled study revealed that PPARA variations significantly increased the risk for cardiac pumping function reductions following acute high-altitude exposure, providing a potential predictive marker before high-altitude exposure and targets in mechanistic studies.

Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure.

Improving biological functions of endothelial progenitor cells (EPCs) is beneficial to maintaining endothelium homeostasis and promoting vascular re-endothelialization. Because macroautophagy/autophagy has been documented as a double-edged sword in cell functions, its effects on EPCs remain to be elucidated. This study was designed to explore the role and molecular mechanisms of store-operated calcium entry (SOCE)-activated autophagy in proliferation of EPCs under hypercholesterolemia. We employed oxidized low-density lipoprotein (ox-LDL) to mimic hypercholesterolemia in bone marrow-derived EPCs from rat. Ox-LDL dose-dependently activated autophagy flux, while inhibiting EPC proliferation. Importantly, inhibition of autophagy either by silencing Atg7 or by 3-methyladenine treatment, further aggravated proliferative inhibition by ox-LDL, suggesting the protective effects of autophagy against ox-LDL. Interestingly, ox-LDL increased STIM1 expression and intracellular Ca2+ concentration. Either Ca2+ chelators or deficiency in STIM1 attenuated ox-LDL-induced autophagy activation, confirming the involvement of SOCE in the process. Furthermore, CAMKK2 (calcium/calmodulin-dependent protein kinase kinase 2, ß) activation and MTOR (mechanistic target of rapamycin [serine/threonine kinase]) deactivation were associated with autophagy modulation. Together, our results reveal a novel signaling pathway of SOCE-CAMKK2 in the regulation of autophagy and offer new insights into the important roles of autophagy in maintaining proliferation and promoting the survival capability of EPCs. This may be beneficial to improving EPC transplantation efficacy and enhancing vascular re-endothelialization in patients with hypercholesterolemia.

Analysis of High-altitude Syndrome and the Underlying Gene Polymorphisms Associated with Acute Mountain Sickness after a Rapid Ascent to High-altitude.

To investigated the objective indicators and potential genotypes for acute mountain sickness (AMS). 176 male subjects were evaluated for symptoms scores and physiological parameters at 3700 m. EPAS1 gene polymorphisms were explored and verified effects of potential genotypes on pulmonary function by inhaled budesonide. The incidence of AMS was 53.98% (95/176). The individuals who suffered from headache with anxiety and greater changes in heart rate (HR), the forced vital capacity (FVC), and mean flow velocity of basilar artery (Vm-BA), all of which were likely to develop AMS. The rs4953348 polymorphism of EPAS1 gene had a significant correlation with the SaO2 level and AMS, and a significant difference in the AG and GG genotype distribution between the AMS and non-AMS groups. The spirometric parameters were significantly lower, but HR (P = 0.036) and Vm-BA (P = 0.042) significantly higher in the AMS subjects with the G allele than those with the A allele. In summary, changes in HR (≥82 beats/min), FVC (≤4.2 Lt) and Vm-BA (≥43 cm/s) levels may serve as predictors for diagnosing AMS accompanied by high-altitude syndrome. The A allele of rs4953348 is a protective factor for AMS through HR and Vm-BA compensation, while the G allele may contribute to hypoxic pulmonary hypertension in AMS.

DNMT1-PPARγ pathway in macrophages regulates chronic inflammation and atherosclerosis development in mice.

The DNA methyltransferase-mediated proinflammatory activation of macrophages is causally linked to the development of atherosclerosis (AS). However, the role of DNMT1, a DNA methylation maintenance enzyme, in macrophage polarization and AS development remains obscure. Here, we established transgenic mice with macrophage-specific overexpression of DNMT1 (Tg(DNMT1)) or PPAR-γ (Tg(PPAR-γ)) to investigate their effects on AS progression in ApoE-knockout mice fed an atherogenic diet. Primary macrophages were extracted to study the role of the DNMT1/PPAR-γ pathway in regulating inflammatory cytokine production. We demonstrated that Tg(DNMT1) significantly increased proinflammatory cytokine production in macrophages and plasma, and it accelerated the progression of AS in the atherogenic diet-treated ApoE-knockout mice. Further, we found that the DNA methylation status of the proximal PPAR-γ promoter was regulated by DNMT1 in macrophages. Notably, additional Tg(PPAR-γ) or pharmacological activation of PPAR-γ effectively prevented Tg(DNMT1)-induced proinflammatory cytokine production in macrophages and AS development in the mouse model. Finally, we demonstrated that elevated DNMT1 was correlated with decreased PPAR-γ, and increased proinflammatory cytokine production in the peripheral blood monocytes isolated from the patients with AS, compared to those of healthy donors. Our findings shed light on a novel strategy for the prevention and therapy of AS.

PPARγ suppresses the proliferation of cardiac myxoma cells through downregulation of MEF2D in a miR-122-dependent manner.

Peroxisome proliferator-activated receptor gamma (PPARγ), a multiple functional transcription factor, has been reported to have anti-tumor effects through inhibition of cells proliferation. However, its effects on cardiac myxoma (CM) cells and the underlying signaling mechanism is unclear. In the present study, we demonstrated that the level of PPARγ is inversely correlated with that of myocyte enhancer factor 2D (MEF2D), a biomarker of CM. We found that activation of PPARγ inhibit MEF2D expression via upregulation of miR-122, which can target the 3'-UTR of MEF2D and inhibit MEF2D expression, by directly binding to the PPRE in the miR-122 promoter region. Functional experiments further showed that miR-122-dependent downregulation of MEF2D by PPARγ suppress the proliferation of CM cells. These results suggest that PPARγ may exert its antiproliferative effects by negatively regulating the MEF2D in CM cells, which through upregulation of miR-122, and PPARγ/miR-122/MEF2D signaling pathway may be a novel target for treatment of CM.