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Echocardiographic assessment of right ventricular function in experimental pulmonary hypertension.

ABSTRACT: Echocardiography, a non-invasive and cost-effective method for monitoring cardiac function, is commonly used for evaluation and pre-clinical diagnostics of pulmonary hypertension (PH). Previous echocardiographic studies in experimental models of PH are fragmentary in terms of the evaluation of right ventricle (RV) function. In this study, three rodent models of PH: a mouse model of hypoxia-induced PH, a rat model of hypoxia+Sugen induced PH and a rat model of monocrotaline-induced PH, were employed to measure RV fractional area change (RVFAC), RV free wall thickness (RVFWT), pulmonary acceleration time (PAT), pulmonary ejection time (PET), and tricuspid annular plane systolic excursion (TAPSE). We found that, in these models, RVFWT significantly increased, but RVFAC, PAT, or PAT/PET ratios and TAPSE values significantly decreased. Accurate and complete TAPSE patterns were demonstrated in the three rodent models of PH. The RV echocardiography data matched the corresponding invasive hemodynamic and heart histologic data in each model. This serves as a reference study for real-time and non-invasive evaluation of RV function in rodent models of PH using echocardiography.

SUBMITTER: Zhu Z

PROVIDER: S-EPMC6566495 | biostudies-literature | 2019 Apr-Jun

REPOSITORIES: biostudies-literature

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Echocardiographic assessment of right ventricular function in experimental pulmonary hypertension.

Zhu Zhongkai Z Godana Dureti D Li Ailing A Rodriguez Bianca B Gu Chenxin C Tang Haiyang H Minshall Richard D RD Huang Wei W Chen Jiwang J

Pulmonary circulation 20190401 2

Echocardiography, a non-invasive and cost-effective method for monitoring cardiac function, is commonly used for evaluation and pre-clinical diagnostics of pulmonary hypertension (PH). Previous echocardiographic studies in experimental models of PH are fragmentary in terms of the evaluation of right ventricle (RV) function. In this study, three rodent models of PH: a mouse model of hypoxia-induced PH, a rat model of hypoxia+Sugen induced PH and a rat model of monocrotaline-induced PH, were emplo ...[more]

PMID: 30942120

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Project description:Importance:Current guidelines recommend evaluation for echocardiographically estimated right ventricular systolic pressure (RVSP) greater than 40 mm Hg; however, this threshold does not capture all patients at risk. Objectives:To determine if mild echocardiographic pulmonary hypertension (ePH) is associated with reduced right ventricular (RV) function and increased risk of mortality. Design, Setting, and Participants:In this cohort study, electronic health record data of patients who were referred for echocardiography at Vanderbilt University Medical Center, Nashville, Tennessee, from March 1997 to February 2014 and had recorded estimates of RVSP values were studied. Data were analyzed from February 2017 to May 2019. Exposures:Mild ePH was defined as an RVSP value of 33 to 39 mm Hg. Right ventricular function was assessed using tricuspid annular plane systolic excursion (TAPSE), and RV-pulmonary arterial coupling was measured using the ratio of TAPSE to RVSP. Main Outcomes and Measures:Associations of mild ePH with mortality adjusted for relevant covariates were examined using Cox proportional hazard models with restricted cubic splines. Results:Of the 47?784 included patients, 26?758 of 47?771 (56.0%) were female and 6040 of 44?763 (13.5%) were black, and the mean (SD) age was 59 (18) years. Patients with mild ePH had worse RV function compared with those with no ePH (mean [SD] TAPSE, 2.0 [0.6] cm vs 2.2 [0.5] cm; P?<?.001) and nearly double the prevalence of RV dysfunction (32.6% [92 of 282] vs 16.7% [170 of 1015]; P?<?.001). Compared with patients with RVSP less than 33 mm Hg, those with mild ePH also had reduced RV-pulmonary arterial coupling (mean [SD] ratio of TAPSE to RVSP, 0.55 [0.18] mm/mm Hg vs 0.93 [0.39] mm/mm Hg; P?<?.001). An increase in adjusted mortality began at an RVSP value of 27 mm Hg (hazard ratio, 1.32; 95% CI, 1.02-1.70). Female sex was associated with increased mortality risk at any given RVSP value. Conclusions and Relevance:Mild ePH was associated with RV dysfunction and worse RV-pulmonary arterial coupling in a clinical population seeking care. Future studies are needed to identify patients with mild ePH who are susceptible to adverse outcomes.

Project description:Echocardiography is the gold standard non-invasive technique to diagnose pulmonary hypertension. It is also an important modality used to monitor disease progression and response to treatment in patients with pulmonary hypertension. Surprisingly, only few studies have been conducted to validate and standardize echocardiographic parameters in experimental animal models of pulmonary hypertension. We sought to define cut-off values for both invasive and non-invasive measures of pulmonary hemodynamics and right ventricular hypertrophy that would reliably diagnose pulmonary hypertension in three different rat models. The study was designed in two phases: (1) a derivation phase to establish the cut-off values for invasive measures of right ventricular systolic pressure, Fulton's index (right ventricular weight/left ventricle?+?septum weight), right ventricular to body weight ratio, and non-invasive echocardiographic measures of pulmonary arterial acceleration time, pulmonary arterial acceleration time to ejection time ratio and right ventricular wall thickness in diastole in the hypoxic and monocrotaline rat models of pulmonary hypertension and (2) a validation phase to test the performance of the cut-off values in predicting pulmonary hypertension in an independent cohort of rats with Sugen/hypoxia-induced pulmonary hypertension. Our study demonstrates that right ventricular systolic pressure ?35.5?mmHg and Fulton's Index ?0.34 are highly sensitive (>94%) and specific (>91%) cut-offs to distinguish animals with pulmonary hypertension from controls. When pulmonary arterial acceleration time/ejection time and right ventricular wall thickness in diastole were both measured, a result of either pulmonary arterial acceleration time/ejection time ?0.25 or right ventricular wall thickness in diastole ?1.03?mm detected right ventricular systolic pressure ?35.5?mmHg or Fulton's Index ?0.34 with a sensitivity of 88% and specificity of 100%. With properly validated non-invasive echocardiography measures of right ventricular performance in rats that accurately predict invasive measures of pulmonary hemodynamics, future studies can now utilize these markers to test the efficacy of different treatments with preclinical therapeutic modeling.

Project description:Background: Right ventricular (RV) performance is a key determinant of mortality in pulmonary arterial hypertension (PAH). RV failure is characterized by metabolic dysregulation with unbalanced anaerobic glycolysis, oxidative phosphorylation, and fatty acid oxidation (FAO). We previously found that acetazolamide (ACTZ) treatment modulates the pulmonary inflammatory response and ameliorates experimental PAH. Objective: To evaluate the effect of ACTZ treatment on RV function and metabolic profile in experimental PAH. Design/Methods: In the Sugen 5416/hypoxia (SuHx) rat model of severe PAH, RV transcriptomic analysis was performed by RNA-seq, and top metabolic targets were validated by RT-PCR. We assessed the effect of therapeutic administration of ACTZ in the drinking water on hemodynamics by catheterization [right and left ventricular systolic pressure (RVSP and LVSP, respectively)] and echocardiography [pulmonary artery acceleration time (PAAT), RV wall thickness in diastole (RVWT), RV end-diastolic diameter (RVEDD), tricuspid annular plane systolic excursion (TAPSE)] and on RV hypertrophy (RVH) by Fulton's index (FI) and RV-to-body weight (BW) ratio (RV/BW). We also examined myocardial histopathology and expression of metabolic markers in RV tissues. Results: There was a distinct transcriptomic signature of RVH in the SuHx model of PAH, with significant downregulation of metabolic enzymes involved in fatty acid transport, beta oxidation, and glucose oxidation compared to controls. Treatment with ACTZ led to a pattern of gene expression suggestive of restored metabolic balance in the RV with significantly increased beta oxidation transcripts. In addition, the FAO transcription factor peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc-1α) was significantly downregulated in untreated SuHx rats compared to controls, and ACTZ treatment restored its expression levels. These metabolic changes were associated with amelioration of the hemodynamic and echocardiographic markers of RVH in the ACTZ-treated SuHx animals and attenuation of cardiomyocyte hypertrophy and RV fibrosis. Conclusion: Acetazolamide treatment prevents the development of PAH, RVH, and fibrosis in the SuHx rat model of severe PAH, improves RV function, and restores the RV metabolic profile.

Project description:BackgroundPulmonary arterial hypertension (PAH) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (RV) dysfunction. Although RV function predicts outcomes in PAH, mechanisms of RV dysfunction are poorly understood, and RV-targeted therapies are lacking. We hypothesized that in PAH, abnormal microtubular structure in RV cardiomyocytes impairs RV function by reducing junctophilin-2 (JPH2) expression, resulting in t-tubule derangements. Conversely, we assessed whether colchicine, a microtubule-depolymerizing agent, could increase JPH2 expression and enhance RV function in monocrotaline-induced PAH.Methods and resultsImmunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics, RV function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline RV, but not the left ventricle, microtubule density is increased, and JPH2 expression is reduced, with loss of t-tubule localization and t-tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves t-tubule morphology in RV cardiomyocytes. Colchicine therapy diminishes RV hypertrophy, improves RV function, and enhances RV-pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity.ConclusionsMonocrotaline-induced PAH causes RV-specific derangement of microtubules marked by reduction in JPH2 and t-tubule disarray. Colchicine reduces microtubule density, increases JPH2 expression, and improves both t-tubule architecture and RV function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a RV-directed therapy for PAH.

Dataset Information

Echocardiographic assessment of right ventricular function in experimental pulmonary hypertension.

Publications

Echocardiographic assessment of right ventricular function in experimental pulmonary hypertension.

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