Risultati per: CA-antagonisti (Nifedipina)

Stroke, Volume 56, Issue Suppl_1, Page AWP379-AWP379, February 1, 2025. Background:Ischemic stroke is a leading cause of high mortality and long-term disability. The current therapies for acute ischemic stroke remain limited to thrombolysis or thrombectomy, for which many patients are ineligible. Therefore, developing new treatments for stroke is a significant clinical need. Dysregulated calcium (Ca2+) homeostasis induces endoplasmic reticulum (ER) stress, mitochondrial dysfunction, microglial activation, inflammation, oxidative stress, and synaptic deficits implicated in stroke. Our recently developed molecular allosteric activator (CDN1163) of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA2) plays a vital role in calcium homeostasis, alleviates ER stress and has emerged as a potential therapeutic approach for metabolic disorder and brain protection. Thus, this study aimed to investigate the protective role of CDN1163 against ischemic stroke in mice.Methods:Ischemic stroke was induced in adult male mice using the Rose Bengal photothrombosis method. CDN1163 (50mg/kg) was administered intraperitoneally at specific time points following the stroke. After 72 hours, the Catwalk test was performed to assess gait impairments. The mice were then euthanized, and their brain tissues were harvested for further analysis, including the measurement of infarct volume, brain edema, and molecular analysis. Neuronal apoptosis was determined using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeled (TUNEL) staining.Results:CDN1163-treated mice showed a significant improvement in gait impairments and reduction in infarct volume and brain edema compared to the vehicle group. CDN1163 treatment also attenuated vascular damage by reducing immunoglobulin extravasation and restoring tight junction protein. In addition, CDN1163 treatment attenuated oxidative damage by reducing 4-hydroxynonenal and nitrotyrosine protein expression levels. Furthermore, the expression levels of apoptotic proteins and numbers of TUNEL-positive cells were significantly decreased in the CDN1163-treated group compared to the vehicle group (Table 1).Conclusion:Our results indicate that CDN1163 reveals neuroprotection through attenuating vascular damage, oxidative stress, and neuronal loss against stroke pathogenesis. Further investigations into the therapeutic effects of CDN1163 are needed to determine whether it can be an effective therapeutic agent for stroke.

Stroke, Volume 56, Issue Suppl_1, Page ATP266-ATP266, February 1, 2025. Background:Stroke is the 5thleading cause of death in the U.S. contributing to ≥$56 billion in annual healthcare costs. Effective blood pressure (BP) management is crucial for reducing stroke and CVD risk, yet controlled hypertension remains suboptimal especially among minority populations. Technological advancements such as remote blood pressure monitoring (RPBM) devices are promising tools to enhance BP management and reduce risk of primary and secondary stroke/CVD. This study aims to examine the association between RBPM adherence and vascular disease risk plus other demographic factors in Latino and Vietnamese individuals living in Southern California.Methods:Baseline data from the Skills Based Education strategies for Reduction of Vascular Events in Orange County (SERVE OC) RCT were used (Grant: P50MD017366). The SERVE OC intervention compares the efficacy of a community health worker led, family-based health management approach focused on skill-building, risk perception, and goal setting versus self-management in reducing BP and enhancing AHA Life’s Essential 8 scores. All households with adult participants ≥18 years were trained and given a RBPM device with instructions to take their BP remotely at least 1x/week. ANOVA and t-tests were conducted to assess the association between RBPM adherence and vascular risk, demographic factors and intervention exposure.Results:Among the 322 randomized adults in the study, 151 adults had 2+ RBPM readings indicating at least one RBPM reading was taken at home in addition to the in-clinic baseline training session, a primary factor for inclusion (Figure 1). Of the 151 adults included (Table 1), the average age was 48.9 (SD=15.8); 63.8% were female, 76.2% identified as Latino and 81.2% had access to healthcare. Risk factors included history of hypertension (37.1%), heart disease (5.6%), stroke (2.1%), and diabetes (29.1%). 44.1% of adults had elevated risk (44.1%) and 7.0% were high risk. Vascular risk (VR) levels and having high VR were significantly associated with higher adherence to RBPM (Mean % of weeks: Low VR: 15.53 weeks; Elevated VR: 15.90 weeks High VR: 29.59 weeks).Conclusion:Our findings suggest that RBPM in at-risk adults may be a feasible and important prevention strategy for stroke and CVD prevention. Further research is needed to better understand barriers and facilitators of using RBPM devices, especially among minority populations who are at higher risk for vascular disease.

Circulation, Volume 150, Issue Suppl_1, Page ASa604-ASa604, November 12, 2024. Background:Nowadays, cardiopulmonary resuscitation (CPR) instruments used worldwide utilize sinusoidal wave for chest compression. The instrument independently invented by our research group performs chest compression through trapezoidal wave, which can achieve higher carotid blood flow and cerebral microcirculation blood perfusion, and ultimately reduce neuron death and blood brain barrier (BBB) injury after CPR, ultimately, improve the prognosis. However, the underlying mechanisms are complicated and remain largely unknown. Therefore, this study investigated the specific mechanisms so as to make contribution to the popularization of TWCC.Methods:Cardiac arrest-CPR-return of spontaneous circulation (CA-CPR-ROSC) mouse models attained by TWCC/sinusoidal wave chest compression (SWCC) and the oxygen-glucose deprivation reoxygenation (OGD/R) model of primary neurons treated by brain tissue derived sEVTWCC/sEVSWCCwere established, and the level of neuronal ferroptosis was detected. AAV-BR1-CD63-GFP was injected via lateral cerebral ventricle to lable brain microvascular endothelial cells-derived small extracellular vesicles (BMEC-sEV), and AAV9-BR1- Rab27a-shRNA was used to suppress the generation of BMEC-sEV. The effects of ferroptosis on ROSC rate and neurological prognosis in mice were confirmed by ferroptosis activators/inhibitors.Results:It was confirmed that, compared with SWCC/ OGDR+sEVTWCCgroup, the ferroptosis level of neurons in TWCC/OGDR+sEVTWCCgroup was significantly higher, which was mainly manifested by the changes of mitochondrial morphology, ferroptosis related proteins and lipid peroxidation levels. Immunofluorescence showed that BMEC-sEV labeled by green fluorescent protein (GFP) could be taken in by neurons. Compared with SWCC+AAV-BR1-CD63-Rab27a-NC group, the ferroptosis level of neurons in SWCC+ AAV-BR1-CD63-RAB27A-shRNA group was significantly reduced, indicating that the neuroprotective effect of TWCC was closely related to BMEC-sEV. In addition, the ROSC rate, neurological function score and 7-day survival rate were higher in SWCC group treated with Fer-1 and Lip-1 than SWCC group, while, mice given RSL3 and Erastin were completely opposite to that.Conclusion:In general, our results demonstrate that TWCC exacerbates brain damage after CPR by facilitating neuronal ferroptosis via BMEC-sEV.Key words:cardiac arrest; neurons; ferroptosis; small extracellular vesicles

Circulation, Volume 150, Issue Suppl_1, Page A4139640-A4139640, November 12, 2024. Introduction:Transthyretin cardiac amyloidosis (ATTR-CA) is an important cause of heart failure for which tafamidis is the only FDA-approved therapy. Diflunisal is an NSAID that is also effective in improving cardiovascular outcomes in ATTR-CA and is utilized in regions where tafamidis is unavailable or cost-prohibitive. Data comparing the efficacy of these agents are lacking.Research Question:To compare longitudinal changes in cardiac structure by echocardiography and cardiac biomarkers among patients with ATTR-CA treated with tafamidis or diflunisal over 36 months.Methods:Among 425 sequential ATTR-CA patients seen at the Boston University Amyloidosis Center between 2016 and 2022, following exclusion for single visits (194) and for receiving TTR-silencer or multiple therapies (67), the final cohort was 164 patients: 109 were treated with tafamidis (ATTR-CA-T, 86% wild-type) and 55 with diflunisal (ATTR-CA-D, 54% wild-type). Echocardiographic wall thickness was re-measured by a single observer, while LVEF, global longitudinal strain (GLS, expressed in absolute value), NT-proBNP, troponin I, prealbumin, and creatinine were collected from the electronic health record at baseline and 36 months with differences between the measures calculated for each patient and compared using paired t-tests.Results:At baseline, while the ATTR-CA-D cohort was older and had a higher proportion of variant ATTR-CA (p

Circulation, Volume 150, Issue Suppl_1, Page A4139545-A4139545, November 12, 2024. Introduction:CA has been shown to be superior to medical management in improving mortality and hospitalization in patients with heart failure with reduced ejection fraction. However, literature concerning the benefit of CA in patients with HFpEF are scarce. There have been some non-randomized clinical trials which have attempted to bridge the gap. Therefore, we conducted a systematic review and meta-analysis of RCTs focusing on the impact of catheter ablation in patients with HFpEF.Objective:To systematically review and perform a meta-analysis by comparing the outcomes of CA versus medical therapy in patients with HFpEF, focusing on all-cause mortality, cardiovascular mortality, all- cause hospitalizations and cardiovascular hospitalizations.Methods:We conducted a systematic search on PubMed, Cochrane library, Scopus database, and Web of Science using the appropriate search strategy through to April 2024. Only English original RCTs that compared CA with medical management were included for data extraction. The outcomes of interest were as follows- All-cause mortality, Cardiovascular mortality, all- cause hospitalizations and cardiovascular hospitalizations.Results:Four RCTs which included a total of 1620 patients (796 in the intervention group and 824 patients in the medical management group). Follow up duration ranged between (24 – 72 months). Improvement in Heart failure hospitalizations or events was seen in the CA group as compared with the medical management group (OR: 0.57, 95% CI 0.43-0.77, P= 0.0002). There was also a reduction in All- cause hospitalizations in the CA group with an OR of 0.67, 95% CI 0.44-0.82, p=0.005. With regards to cardiovascular mortality and all cause mortality in the CA group the OR was 0.74, 95% CI 0.40-1.35, P= 0.59 and 0.68, 95% CI 0.46-1.03, P= 0.07 respectively. These were found not to be statistically significant.Conclusion:Using CA in patients with atrial fibrillation and HFpEF showed a statistically significant reduction of heart failure hospitalizations and all cause hospitalizations. Despite the trend towards CA, cardiovascular mortality and all cause mortality were found not to be statistically significant when comparing catheter ablation and medical management. This is the largest meta-analysis in this sub-population till date. With the advent of pulsed field ablation, it will also be intriguing to see how those results contrast CA in atrial fibrillation management in patients with HFpEF.

Introduction
Continuous renal replacement therapy (CRRT) is a critical therapeutic intervention for patients with severe acute kidney injury in intensive care. However, premature filter clotting remains a significant challenge during CRRT, impacting treatment efficacy, costs and patient outcomes. Anticoagulation is essential to maintain circuit patency, with regional citrate anticoagulation (RCA) emerging as a preferred strategy due to its favourable bleeding profile. The standard target for post-filter ionised calcium (iCa) concentration during RCA-CRRT is set between 0.25 and 0.35 mmol/L, although evidence supporting this range is limited. We hypothesise that a higher post-filter iCa target (0.35–0.45 mmol/L) can provide comparable circuit patency while potentially reducing adverse effects associated with citrate administration.

Methods and analysis
This multicentre randomised controlled non-inferiority trial will compare a low post-filter iCa target (0.25–0.35 mmol/L) with a higher post-filter iCa target (0.35–0.45 mmol/L) in patients undergoing RCA-CRRT in the intensive care unit. A total of 412 CRRT sessions will be randomised with a 1:1 ratio into these two groups. The primary outcome is the incidence of filter clotting. Secondary outcomes include filter lifespan, post-filter iCa levels, citrate infusion rates, the occurrence of metabolic adverse effects, financial costs and blood loss.

Ethics and dissemination
The study has obtained approval from the ethics committee (Ethics Committee Est III, Nancy, France) and patients will be included after providing informed consent. The results will be disseminated at academic conferences and in peer-reviewed publications. All procedures were developed in order to assure data protection and confidentiality.

Trial registration number
NCT05814341.

Circulation, Volume 148, Issue Suppl_1, Page A18673-A18673, November 6, 2023. Introduction:Scores to stage amyloidosis include laboratory values of NT pro-BNP and BNP. However, no prior data on the correlation between the two markers is available for the same sample in ATTR patients with a spectrum of co-morbidities. While established staging systems for cardiac amyloidosis use NT-pro BNP, many centers routinely measure BNP. To facilitate universal staging, we explored the relationship between NT-pro BNP and BNP measured from a single blood sample in ATTR patients with a spectrum of co-morbidities.Hypothesis:The ratio of NT pro-BNP to BNP is influenced by atrial fibrillation, BMI, left ventricular and renal function.Methods:ATTR-CA patients had serial NT pro-BNP and BNP measured from a SINGLE blood sample. Ratios were compared in patients stratified by co-morbidities. A regression equation to derive BNP from NT pro- BNP was created.Results:Among 101 patients, (85% men, 84% Caucasian), co-morbidities were prevalent (atrial fibrillation: 56%, LVEF < 50%: 46%, GFR

Background
Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort.

Methods
We analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC.

Results
MAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002–2003, to 77.3% and 28.9% in 2018–2019, respectively, p

Circulation, Volume 146, Issue 22, Page e325-e325, November 29, 2022.

Circulation, Volume 146, Issue Suppl_1, Page A13377-A13377, November 8, 2022. Introduction:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to genetic defects of the sarcoplasmic reticulum (SR) Ca release channel complex of ryanodine receptor 2 (RyR2). Our recent study suggests that mitochondria function as a Ca buffer to absorb RyR2-mediated aberrant Ca release and thus mitigate its detrimental consequences in CPVT. Mitochondrial phosphate (Pi) transport has been shown to play a role in both mitochondrial Ca uptake and buffering.Hypothesis:We hypothesize that modulating mitochondrial Pi transport impacts arrhythmogenesis in CPVT by altering mitochondrial Ca uptake and buffering.Methods:Ventricular myocytes were isolated from a genetic CPVT model of CASQ2 knockout (Cnull) mouse. Fluorescent imaging experiments were performed with live cells to examine intracellular Ca dynamics and cellular arrhythmic burden. Mitochondrial Pi transport was modulated by a pharmacological inhibitor or manipulating cytosolic Pi concentration.Results:In the presence of β agonist isoproterenol, an inhibitor of mitochondrial Pi carrier N-ethylmaleimide (NEM) significantly exacerbated Ca handling of intact Cnull cells, resulting in more than 60% of cells displaying pacing-independent Ca oscillations. The NEM treatment also significantly increased the amplitude of cytosolic Ca transient and SR Ca content. Consistent with results obtained in intact cells, NEM treatment exacerbated arrhythmogenic Ca waves and reduced mitochondrial Ca uptake in permeabilized Cnull cells. Moreover, inhibiting mitochondrial Pi transport by lowering cytosolic Pi concentration also increased the frequency of Ca waves and reduced mitochondria Ca uptake in permeabilized Cnull cells. On the contrary, increasing cytosolic Pi concentration reduced the frequency of Ca waves and increased mitochondrial Ca uptake in permeabilized Cnull cells.Conclusions:Modulating mitochondrial Pi transport impacts arrhythmogenesis in CPVT cells through altering mitochondrial Ca uptake and buffering. Enhancing mitochondrial Pi transport may represent a promising therapeutic strategy to reduce arrhythmogenic Ca waves and cardiac arrhythmias in CPVT.

Circulation, Volume 146, Issue Suppl_1, Page A13523-A13523, November 8, 2022. Introduction:Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-induced arrhythmic syndrome due to genetic defects of the sarcoplasmic reticulum (SR) Ca release channel complex of ryanodine receptor 2 (RyR2). Recent studies suggest that mitochondria function as a protective Ca buffer to absorb RyR2-mediated aberrant Ca release in CPVT. However, the molecular mechanism underlying the protective Ca buffering function of CPVT mitochondria remains unclear.Hypothesis:We hypothesize that the tethering between SR and mitochondria, also known as mitochondria-associated-membranes (MAMs) are promoted in CPVT to facilitate SR-mitochondria Ca transfer. Moreover, manipulating SR-mitochondria tethering or MAMs impacts arrhythmogenesis in CPVT.Methods:Ventricular myocytes were isolated from a CPVT model of CASQ2 knockout (Cnull) mouse. Cellular immunofluorescence assays and western blots were employed to detect MAMs remodeling in CPVT cells. Pharmacological approach was employed to disrupt MAMs and examine its effect on cellular arrhythmogenesis using live-cell imaging.Results:SR-mitochondria tethering was assessed by examining the interaction between RyR2 and Voltage-dependent anion channel (VDAC), a protein localized in the mitochondrial-outer-membrane. As compared with wild-type (WT), we detected a higher degree of colocalization of immunofluorescence between RyR2 and VDAC in Cnull cells, as well as increased RyR2-VDAC interactions by proximity ligation assay. The expression of SR-mitochondria tethering protein Mitofusin2 was increased in MAMs isolated from CPVT hearts. Colchicine was employed to induce a partial disruption of MAMs in Cnull cells. In intact Cnull cells perfused with β agonist isoproterenol, colchicine exacerbated arrhythmogenic Ca waves. In permeabilized cells, colchicine increased the frequency of arrhythmogenic Ca waves and reduced mitochondrial Ca uptake.Conclusions:Our results support that MAMs are promoted in CPVT cells to facilitate SR-mitochondria Ca transfer so mitochondria can function as a protective Ca buffer. Pharmacological disruption of SR-mitochondria tethering limits SR-mitochondria Ca transfer, thus exacerbating cellular arrhythmic burden.

Circulation, Volume 146, Issue 16, Page 1259-1261, October 18, 2022.