Dataset Information

Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure.

ABSTRACT:

Aims

The ability of the right ventricle (RV) to adapt to increased afterload is the major determinant of survival in patients with pulmonary hypertension (PH). In this study, we explored the effect of genetic background on RV adaptation and survival in a rat model of severe pulmonary arterial hypertension (PAH).

Methods and results

PH was induced by a single injection of SU5416 (SU) in age-matched Sprague Dawley (SD) or Fischer rats, followed by a 3-week exposure to chronic hypoxia (SUHx). SD and Fischer rats exhibited similar elevations in RV systolic pressure, number of occlusive pulmonary vascular lesions, and RV hypertrophy (RV/LV+S) in response to SUHx. However, no Fischer rats survived beyond 7 weeks compared with complete survival for SD rats. This high early mortality of Fischer rats was associated with significantly greater RV dilatation and reduced ejection fraction, cardiac output, and exercise capacity at 4 weeks post-SU. Moreover, microarray analysis revealed that over 300 genes were uniquely regulated in the RV in the severe PAH model in the Fischer compared with SD rats, mainly related to angiogenesis and vascular homoeostasis, fatty acid metabolism, and innate immunity. A focused polymerase chain reaction array confirmed down-regulation of angiogenic genes in the Fischer compared with SD RV. Furthermore, Fischer rats demonstrated significantly lower RV capillary density compared with SD rats in response to SUHx.

Conclusion

Fischer rats are prone to develop RV failure in response to increased afterload. Moreover, the high mortality in the SUHx model of severe PAH was caused by a failure of RV adaptation associated with lack of adequate microvascular angiogenesis, together with metabolic and immunological responses in the hypertrophied RV.

SUBMITTER: Suen CM

PROVIDER: S-EPMC6432055 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure.

Suen Colin M CM Chaudhary Ketul R KR Deng Yupu Y Jiang Baohua B Stewart Duncan J DJ

Cardiovascular research 20190301 4

<h4>Aims</h4>The ability of the right ventricle (RV) to adapt to increased afterload is the major determinant of survival in patients with pulmonary hypertension (PH). In this study, we explored the effect of genetic background on RV adaptation and survival in a rat model of severe pulmonary arterial hypertension (PAH).<h4>Methods and results</h4>PH was induced by a single injection of SU5416 (SU) in age-matched Sprague Dawley (SD) or Fischer rats, followed by a 3-week exposure to chronic hypoxi ...[more]

PMID: 30357319

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Project description:Pulmonary hypertension is a condition with high morbidity and mortality. Resting transthoracic echocardiography is a pivotal diagnostic and screening test for pulmonary hypertension. The role of exercise stress echocardiography in the diagnosis of pulmonary hypertension is not well-established. We studied right ventricular size changes during exercise using exercise stress echocardiography to assess differences between normal and pulmonary hypertension patients and evaluate test safety, feasibility, and reproducibility. Healthy control and pulmonary hypertension patients performed recumbent exercise using a bicycle ergometer. Experienced echocardiography sonographers recorded the following resting and peak exercise right ventricular parameters using the apical four chamber view: end-diastolic area; end-systolic area; mid-diameter; basal diameter; and longitudinal diameter. Two cardiologists masked to clinical information subsequently analyzed the recordings. Parameters with acceptable inter-rater reliability were analyzed for statistical differences between the normal and pulmonary hypertension patient groups and their association with pulmonary hypertension. We enrolled 38 healthy controls and 40 pulmonary hypertension patients. Exercise stress echocardiography testing was found to be safe and feasible. Right ventricular size parameters were all readily obtainable and all had acceptable inter-observer reliability except for right ventricular longitudinal diameter. During exercise, healthy controls demonstrated a decrease in right ventricular end-systolic area, end-diastolic area, mid-diameter, and basal diameter ( P?<?0.05). Conversely, pulmonary hypertension patients demonstrated an increase in right ventricular end-systolic area, end-diastolic area, and mid-diameter ( P?<?0.05). These changes were unaffected by multivariate corrections. The sensitivity for pulmonary hypertension of an increase in right ventricular size was 97.2% with a negative predictive value of 95.2%. The ROC C-statistic for increase in right ventricular size was 0.93. This transient exertional dilation (TED) of the right ventricle is observed in pulmonary hypertension patients but not in healthy controls. Recumbent right ventricular exercise stress echocardiography is a feasible and safe diagnostic test for pulmonary hypertension which warrants additional study.

Project description:BackgroundThe cardioprotective properties of sevoflurane have been reported in studies of the left ventricle. However, whether this volatile anesthetic would also be beneficial for pulmonary vascular remodeling and associated right ventricular hypertrophy (RVH) remained to be explored. Here, we investigated the potential benefit of sevoflurane to right heart function in experimental pulmonary arterial hypertension (PAH).MethodsAdult Wistar rats received one dose peritoneal injection of monocrotaline (MCT, 60 mg/kg) or the equal volume of normal saline. Two weeks later, rats were treated with sevoflurane or sham exposure. PAH status and cardiac function were assessed by echocardiography weekly, and the body weight (BW) was monitored every week. After 6 weeks of exercise, Fulton's index calculation, histological observation, IL-6 and TNF-α immunohistochemical analyses, evaluation of MDA, SOD and GSH-Px levels and NF-κB and MAPK active determination were performed in lung and RV tissue samples.ResultsMCT induced pulmonary vascular remodeling, RVH, increased Fulton's index (P<0.01), and right ventricular failure (RVF) in rats. Animals inhaled sevoflurane had an increased cardiac output (P<0.05) and lower incidence of RVF (P<0.05). Also, these animals had a reduced RVEDD, RVWTd and PAID (P<0.05), increased PV (P<0.05), reduced wall thickness and vascular wall area of pulmonary small vascular (vascular external diameter 50-150 um) (P<0.01), reduced RV fibrosis, and increased RV cardiomyocyte area (P<0.01). Furthermore, sevoflurane reduced IL-6 and TNF-α expression in lungs and heart (P<0.01), decreased level of MDA (P<0.01) and increased activity of SOD and GSH-Px (P<0.01). In addition, it decreased the activities of NF-κB and MAPK pathways (P<0.01).ConclusionSevoflurane reduces pulmonary vascular remodeling and RVH in PAH induced by MCT in rats. This effect is likely due to down-regulation of inflammatory factors IL-6 and TNF-α, reduced level of oxidative stress and the inhibition of NF-κB and MAPK pathways.

Dataset Information

Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure.

Aims

Methods and results

Conclusion

Publications

Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure.

Similar Datasets

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