International Verapamil SR/Trandolapril [INVEST] Genes Study
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PROVIDER: PRJNA686452 | ENA |
REPOSITORIES: ENA
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Project description:International Verapamil SR/Trandolapril [INVEST] Genes Study
| PRJNA686451 | ENA
Project description:In this study, we investigated the molecular and cellular mechanisms of verapamil treatment on β-cell function and survival using MIN6 cells. Verapamil's molecular processes were studied using transcriptomic data. MTT, cell count, and flow cytometry assessed cell proliferation, growth, and cycle. MIN6 cell function was assessed by glucose-stimulated insulin release and total insulin content. Seahorse and metabolic stress kits examined metabolic activity and oxygen consumption rate. The protective impact of verapamil on MIN6 cells was evaluated by challenging the verapamil treated cell with streptozotocin, T1D-cytomix, or T2D-cytomix cocktail. Our results demonstrate that verapamil treatment induced higher proliferation of MIN6 cells, altered expression of various proteins and genes, improved insulin secretion in hyperglycemic conditions, increased basal and maximal respiration levels, along with β-cell survival against streptozotocin, T1D-, or T2D-cytomix-induced toxicity, and rendered a protective effect.
2023-08-30 | GSE230803 | GEO
Project description:We sought to determine whether polymorphisms in the large-conductance calcium and voltage-dependent potassium (BK) channel beta1 subunit gene, KCNMB1, are associated with blood pressure response to verapamil SR or adverse outcomes in the GENEtic substudy of the INternational VErapamil SR/trandolapril STudy (INVEST-GENES).KCNMB1 is involved in calcium sensitivity and hypertension. The association between variability in KCNMB1 and calcium antagonist response, however, has not been assessed.Genetic samples were collected from 5979 patients in INVEST. Blood pressure response to verapamil SR and time to achieve blood pressure control was assessed in relation to Glu65Lys and Val110Leu genotypes. The primary outcome (all cause mortality, nonfatal myocardial infarction or nonfatal stroke) was compared between genotype groups, and interaction with verapamil SR therapy was assessed.Systolic blood pressure response to verapamil SR did not differ by KCNMB1 genotype. Lys65 variant carriers, however, achieved blood pressure control earlier than Glu65Glu individuals [1.47 (interquartile ratio 2.77) versus 2.83 (interquartile ratio 4.17) months, P=0.01] and were less likely to require multiple drugs at the time of blood pressure control (adjusted odds ratio 0.43, 95% confidence interval 0.19-0.95). Leu110 variant carriers had a reduced risk of primary outcome (hazard ratio 0.68, 95% confidence interval 0.47-0.998). Subgroup analysis revealed this finding to be more pronounced in verapamil SR-assigned patients (hazard ratio 0.587, 95% confidence interval 0.33-1.04) compared with atenolol-assigned patients (hazard ratio 0.946, 95% confidence interval 0.56-1.59). No difference was seen in the occurrence of the primary outcome compared by codon 65 genotype.Our findings suggest that KCNMB1 genotype influences responsiveness to verapamil SR and risk of adverse cardiovascular outcomes.
| S-EPMC2713584 | biostudies-literature
Project description:International Glioma Case-Control Study
| PRJNA377600 | ENA
Project description:Currently, no oral medications are available for individuals suffering from type 1 diabetes (T1D). Our randomized placebo-controlled phase 2 trial recently revealed that oral verapamil has short- term beneficial effects in subjects with new-onset type 1 diabetes (T1D) 1. However, what exact biological changes verapamil elicits in humans with T1D, how long they may last, and how to best monitor any associated therapeutic success has remained elusive. We therefore now conducted extended analyses of the effects of continuous verapamil use over a 2-year period, performed unbiased proteomics analysis of serum samples and assessed changes in proinflammatory T-cell markers in subjects receiving verapamil or just standard insulin therapy. In addition, we determined the verapamil-induced changes in human islets using RNA sequencing. Our present results reveal that verapamil regulates the thioredoxin system and promotes an anti-oxidative and anti-apoptotic gene expression profile in human islets, reverses T1D-induced elevations in circulating proinflammatory T-follicular-helper cells and interleukin-21 and normalizes serum levels of chromogranin A (CHGA), a recently identified T1D autoantigen 2,3. In fact, proteomics identified CHGA as the top serum protein altered by verapamil and as a potential therapeutic marker. Moreover, continuous use of oral verapamil delayed T1D progression, promoted endogenous beta cell function and lowered insulin requirements and serum CHGA levels for at least 2 years and these benefits were lost upon discontinuation. Thus, the current studies provide crucial mechanistic and clinical insight into the beneficial effects of verapamil in T1D.
2021-12-03 | GSE181328 | GEO
Project description:Factors such as age and race/ethnicity might influence blood pressure (BP) response to drugs. Therapeutic response to the angiotensin-converting enzyme inhibitor trandolapril used as add-on therapy to stable calcium channel blocker therapy with verapamil sustained release 240 mg was addressed in a racially/ethnically diverse group of 1,832 hypertensive patients with coronary artery disease. Furthermore, the association with a polymorphism (1166A-->C) in the angiotensin II type 1 receptor gene (AGTR1) was tested. BP response was compared between groups using analysis of covariance after adjustment for covariates associated with BP response. Genotyping was performed using polymerase chain reaction and pyrosequencing. Trandolapril decreased mean unadjusted systolic and diastolic BPs by -9.1 +/- 17.3 (SD) and -4.1 +/- 10.1 mm Hg, respectively. The percentage of patients with BP under control (<140/90 mm Hg) increased from 6.7% to 41.3% (p <0.0001). Adjusted BP response was significantly associated with age and baseline systolic and diastolic BP (p <0.0001). Whereas the decrease in systolic BP was more pronounced in younger patients, the opposite was observed for diastolic BP decrease. Diastolic BP response was also significantly associated with race. Specifically, the adjusted diastolic BP decrease was significantly smaller in Hispanics and blacks than whites (p = 0.0032 and p = 0.0069, respectively). However, Hispanics achieved a decrease in systolic BP and an increase in BP control similar to the other ethnic groups. There was no genetic association between AGTR1 1166A-->C genotype and BP response. In conclusion, trandolapril add-on therapy was effective in increasing BP control, with age and baseline BP associated with both systolic and diastolic BP response. Race was associated with diastolic BP response, although the difference is likely not to be clinically significant and AGTR1 genotype was not associated with BP response.
| S-EPMC2720593 | biostudies-literature
Project description:To understand the response of M. tuberculosis (MTB) to the drug verapamil, we performed transcriptomics on MTB bacilli exposed to the drug.
2018-08-02 | GSE118021 | GEO
Project description:Verapamil treatment of β-cells
| PRJNA962576 | ENA
Project description:The optimal blood pressure (BP) to prevent major adverse outcomes (death, myocardial infarction, and stroke) for patients with hypertension and coronary artery disease who have undergone previous revascularization is unknown but might be influenced by the type of revascularization procedure. We analyzed data from the INternational VErapamil SR-Trandolapril STudy, focusing on the relation between BP and the outcomes of 6,166 previously revascularized patients, using the 16,410 nonrevascularized patients as a reference group. The previous revascularization strategy consisted of coronary artery bypass grafting (CABG, 45.2%), percutaneous coronary intervention (PCI, 42.1%), or both (CABG+PCI, 12.8%). Patients who had undergone both CABG+PCI and CABG-only had a greater adverse outcome risk (adjusted hazard ratio 1.27% and 1.20%, 95% confidence interval 1.06 to 1.53 and 1.07 to 1.35, respectively). The risk was similar for PCI-only patients (adjusted hazard ratio 1.04, 95% confidence interval 0.92 to 1.19). The relations between the adjusted hazard ratio and on-treatment BP appeared J-shaped for each revascularization strategy, accentuated for PCI and diastolic BP (DBP), but excepting CABG only and DBP for which the relation was linear and positive. In conclusion, major adverse outcomes were more frequent in patients with coronary artery disease who had undergone previous CABG, with or without PCI, compared to those with previous PCI only. This likely reflected more severe vascular disease. The relation to systolic BP was J-shaped for each strategy. Among those patients with previous CABG only, the linear relation with DBP suggested that more complete revascularization might attenuate hypoperfusion at a low DBP. The management of BP might, therefore, require modification of targets according to the revascularization strategy to improve outcomes.
| S-EPMC3005196 | biostudies-literature
Project description:The alpha-adducin (ADD1) Gly460Trp polymorphism has been associated with hypertension and response to diuretic therapy, but controversy exists.The present study was conducted to prospectively investigate the relationship among the ADD1 Gly460Trp polymorphism, diuretic use, and adverse cardiovascular outcomes among 5,979 patients with hypertensive coronary artery disease, who participated in the INVEST and provided genomic DNA. The primary outcome was defined as the first occurrence of nonfatal stroke, nonfatal myocardial infarction, or all-cause death. Secondary outcomes were the components of the primary outcome. Ancestry informative markers were used to control for population stratification.In blacks, ADD1 variant carriers were at higher risk for a primary outcome event than wild-type homozygotes (adjusted hazard ratio 2.62, 95% CI 1.23-5.58, P = .012), with a similar trend in whites and Hispanics, albeit a smaller magnitude of effect (adjusted hazard ratio 1.43, 0.86-2.39 in Hispanics; 1.24, 0.90-1.71 in whites). Secondary outcome analysis showed that the all-cause death was driving the differences in primary outcomes by genotype. There was no interaction between the ADD1 polymorphism and diuretic use for either primary outcome or secondary outcomes.In hypertensive patients with coronary artery disease, black ADD1 variant carriers showed a 2.6-fold excess risk for a primary outcome event and an 8-fold increase risk of death. White and Hispanic ADD1 variant carriers showed an increased but nonsignificant excess risk. However, the effect of diuretic use on risk of cardiovascular outcomes did not vary by ADD1 carrier status.
| S-EPMC2547143 | biostudies-literature