Dataset Information

Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations.

ABSTRACT:

Background and purpose

Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS.

Experimental approach

The effects of 8 weeks of treatment with either vitamin D? at 25,000 IU for 4 days a week alone or in combination with ramipril (0.5 mg·kg?¹) on aortic valve structure and function were examined in New Zealand white rabbits. Echocardiographic aortic valve backscatter (AV(BS)) and aortic valve:outflow tract flow velocity ratio were utilized to quantify changes in valve structure and function.

Key results

Treatment with ramipril significantly reduced AV(BS) and improved aortic valve :outflow tract flow velocity ratio. The intravalvular content of the pro-oxidant thioredoxin-interacting protein was decreased significantly with ramipril treatment. Endothelial function, as measured by asymmetric dimethylarginine concentrations and vascular responses to ACh, was improved significantly with ramipril treatment.

Conclusions and implications

Ramipril retards the development of AVS, reduces valvular thioredoxin-interacting protein accumulation and limits endothelial dysfunction in this animal model. These findings provide important insights into the mechanisms of AVS development and an impetus for future human studies of AVS retardation using an angiotensin-converting enzyme inhibitor.

SUBMITTER: Ngo DT

PROVIDER: S-EPMC3041260 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations.

Ngo Doan Tm DT Stafford Irene I Sverdlov Aaron L AL Qi Weier W Wuttke Ronald D RD Zhang Yuan Y Kelly Darren J DJ Weedon Helen H Smith Malcolm D MD Kennedy Jennifer A JA Horowitz John D JD

British journal of pharmacology 20110201 3

<h4>Background and purpose</h4>Aortic valve stenosis (AVS) is associated with significant cardiovascular morbidity and mortality. To date, no therapeutic modality has been shown to be effective in retarding AVS progression. We evaluated the effect of angiotensin-converting enzyme inhibition with ramipril on disease progression in a recently developed rabbit model of AVS.<h4>Experimental approach</h4>The effects of 8 weeks of treatment with either vitamin D₂ at 25,000 IU for 4 days a week alone o ...[more]

PMID: 20958293

Similar Datasets

Project description:BackgroundCalcific aortic valve stenosis (CAVS) is a common valvular heart disease, but there are limited reports on the construction of prediction models for CAVS. This study aimed to investigate the risk factors for CAVS and construct a predictive model for CAVS based on its common clinical features.MethodsPatients with CAVS who underwent surgical treatment in our hospital from 2016 to 2020 and those who underwent physical examination during the same period were retrospectively studied and placed in the CAVS group and normal group based on the area of aortic valve orifice less than or more than 3 cm2. A total of 548 patients were included in this study, including 106 CAVS patients and 442 normal patients. Subjects were randomly divided into training and validation sets at a 7:3 ratio. The features were dimensionally reduced using the Least Absolute Shrinkage and Selection Operator (LASSO) algorithm in the training set, and the optimal clinical features were selected. The independent predictors of patients with CAVS were determined by univariate and multivariate logistic regression, and nomogram was constructed. The calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to evaluate the model in both the training set and the validation set.ResultsIn this study, 11 independent predictors were distinguished by multivariate logistic regression analysis: history of hypertension, history of carotid atherosclerosis, age, diastolic blood pressure, C-reactive protein, direct bilirubin, alkaline phosphatase, low-density lipoprotein (LDL), lipoprotein(a) [Lp(a)], uric acid, and cystatin C. A nomogram was constructed using the above indicators. The model was well-calibrated and showed good discrimination and accuracy [the area under the curve (AUC) =0.981] in the training set, with a sensitivity of 91.89% and a specificity of 95.48%. More importantly, the nomogram displayed a good performance in the validation set (AUC =0.955, 95% CI: 0.925-0.985), with a sensitivity of 93.75% and a specificity of 84.09%. Additionally, DCA revealed that the nomogram had high clinical practicability.ConclusionsThis study successfully established a risk prediction model for CAVS based on 11 conveniently accessible clinical indicators, which might easily be used for individualized risk assessment of CAVS.

Project description:Congenital aortic valve stenosis (AS) progresses as an obstructive narrowing of the aortic orifice due to deregulated extracellular matrix (ECM) production by aortic valve (AV) leaflets and leads to heart failure with no effective therapies. Changes in glycoprotein and proteoglycan distribution are a hallmark of AS, yet valvular carbohydrate content remains virtually uncharacterized at the molecular level. While almost all glycoproteins clinically linked to stenotic valvular modeling contain multiple sites for N-glycosylation, there are very few reports aimed at understanding how N-glycosylation contributes to the valve structure in disease. Here, we tested for spatial localization of N-glycan structures within pediatric congenital aortic valve stenosis. The study was done on valvular tissues 0-17 years of age with de-identified clinical data reporting pre-operative valve function spanning normal development, aortic valve insufficiency (AVI), and pediatric endstage AS. High mass accuracy imaging mass spectrometry (IMS) was used to localize N-glycan profiles in the AV structure. RNA-Seq was used to identify regulation of N-glycan related enzymes. The N-glycome was found to be spatially localized in the normal aortic valve, aligning with fibrosa, spongiosa or ventricularis. In AVI diagnosed tissue, N-glycans localized to hypertrophic commissures with increases in pauci-mannose structures. In all valve types, sialic acid (N-acetylneuraminic acid) N-glycans were the most abundant N-glycan group. Three sialylated N-glycans showed common elevation in AS independent of age. On-tissue chemical methods optimized for valvular tissue determined that aortic valve tissue sialylation shows both α2,6 and α2,3 linkages. Specialized enzymatic strategies demonstrated that core fucosylation is the primary fucose configuration and localizes to the normal fibrosa with disparate patterning in AS. This study identifies that the human aortic valve structure is spatially defined by N-glycomic signaling and may generate new research directions for the treatment of human aortic valve disease.

Project description:BackgroundAortic valve stenosis is the most common type of valvular heart disease in the USA and Europe. Aortic valve stenosis is considered similar to atherosclerotic disease. Some studies have evaluated statins for aortic valve stenosis.ObjectivesTo evaluate the effectiveness and safety of statins in aortic valve stenosis.Search methodsWe searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS - IBECS, Web of Science and CINAHL Plus. These databases were searched from their inception to 24 November 2015. We also searched trials in registers for ongoing trials. We used no language restrictions.Selection criteriaRandomised controlled clinical trials (RCTs) comparing statins alone or in association with other systemic drugs to reduce cholesterol levels versus placebo or usual care.Data collection and analysisPrimary outcomes were severity of aortic valve stenosis (evaluated by echocardiographic criteria: mean pressure gradient, valve area and aortic jet velocity), freedom from valve replacement and death from cardiovascular cause. Secondary outcomes were hospitalisation for any reason, overall mortality, adverse events and patient quality of life.Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias. The GRADE methodology was employed to assess the quality of result findings and the GRADE profiler (GRADEPRO) was used to import data from Review Manager 5.3 to create a 'Summary of findings' table.Main resultsWe included four RCTs with 2360 participants comparing statins (1185 participants) with placebo (1175 participants). We found low-quality evidence for our primary outcome of severity of aortic valve stenosis, evaluated by mean pressure gradient (mean difference (MD) -0.54, 95% confidence interval (CI) -1.88 to 0.80; participants = 1935; studies = 2), valve area (MD -0.07, 95% CI -0.28 to 0.14; participants = 127; studies = 2), and aortic jet velocity (MD -0.06, 95% CI -0.26 to 0.14; participants = 155; study = 1). Moderate-quality evidence showed no effect on freedom from valve replacement with statins (risk ratio (RR) 0.93, 95% CI 0.81 to 1.06; participants = 2360; studies = 4), and no effect on muscle pain as an adverse event (RR 0.91, 95% CI 0.75 to 1.09; participants = 2204; studies = 3; moderate-quality evidence). Low- and very low-quality evidence showed uncertainty around the effect of statins on death from cardiovascular cause (RR 0.80, 95% CI 0.56 to 1.15; participants = 2297; studies = 3; low-quality evidence) and hospitalisation for any reason (RR 0.84, 95% CI 0.39 to 1.84; participants = 155; study = 1; very low-quality evidence). None of the four included studies reported on overall mortality and patient quality of life.Authors' conclusionsResult findings showed uncertainty surrounding the effect of statins for aortic valve stenosis.The quality of evidence from the reported outcomes ranged from moderate to very low. These results give support to European and USA guidelines (2012 and 2014, respectively) that so far there is no clinical treatment option for aortic valve stenosis.

Dataset Information

Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Ramipril retards development of aortic valve stenosis in a rabbit model: mechanistic considerations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets