echocardiographic-measurement-right-ventricular-diastolic-parameters

Echocardiographic Measurement of Right Ventricular Diastolic Parameters in Mouse

Diastolic dysfunction is a prominent feature of right ventricular (RV) remodeling associated with conditions of pressure overload. However, the RV ...

Noninvasive diagnostic tools for right ventricular (RV) dysfunction measurements are increasingly being used, although their association with the pathologic mechanisms of dysfunction is poorly understood. Although investigations have focused mainly on RV systolic function, RV diastolic function remains mostly neglected. The aim of this study was to test which echocardiographic parameters best reflect RV diastolic function in mice.

Pressure Overload Creates Right Ventricular Diastolic Dysfunction in a Mouse Model: Assessment by Echocardiography.

Adaptation of the right ventricle (RV) to increased afterload is crucial for survival in pulmonary hypertension (PH), but it is challenging to assess RV function and identify associated molecular mechanisms. The aim of the current study was to analyze the relationship between invasive and noninvasive parameters of RV morphology and function and associated molecular changes. The response of mice to normobaric hypoxia was assessed by hechocardiography, invasive hemodynamics, and histological and molecular analyses. Plasma levels of possibly novel markers of RV remodeling were measured by ELISA in patients with idiopathic pulmonary arterial hypertension (IPAH) and matched healthy controls. Chronic hypoxia-induced PH was accompanied by significantly decreased tricuspid annular plane systolic excursion (TAPSE) and unchanged RV contractility index and tau. RV hypertrophy was present without an increase in fibrosis. There was no change in α- and β-major histocompatibility class or natriuretic peptides expression. Comparative microarray analysis identified two soluble factors, fibroblast growth factor-5 (FGF5) and interleukin-22 receptor alpha-2 (IL22RA2), as being possibly associated with RV remodeling. We observed significantly higher plasma levels of IL22RA2, but not FGF5, in patients with IPAH. Hypoxic pulmonary hypertension in a stage of RV remodeling with preserved systolic function is associated with decreased pulmonary vascular compliance, mild diastolic RV dysfunction, and significant decrease in TAPSE. Subtle gene expression changes in the RV vs. the left ventricle upon chronic hypoxia suggest that the majority of changes are due to hypoxia and not due to changes in afterload. Increased IL22RA2 levels might represent a novel RV adaptive mechanism.

Functional and molecular factors associated with TAPSE in hypoxic pulmonary hypertension.

 The ATP-binding cassette (ABC)G2 transporter protects the heart from pressure overload-induced ventricular dysfunction but also protects cancer cells from chemotherapeutic agents. It is upregulated in the myocardium of heart failure patients and clears hypoxia-induced intracellular metabolites. This study employs ABCG2 knockout (KO) mice to elucidate the relevance of ABCG2 for cardiac and pulmonary vascular structure and function in chronic hypoxia, and uses human primary cardiac fibroblasts to investigate the potential role of ABCG2 in cardiac fibrosis.  ABCG2 KO and control mice ( = 10) were subjected to 4 weeks normoxia or hypoxia. This allowed for investigation of the interaction between genotype and hypoxia (GxH). In hypoxia, KO mice showed pronounced right (RV) and left (LV) ventricular diastolic dysfunction. Compared to normoxia, end-diastolic pressure (EDP) was increased in control vs. KO mice by +1.1 ± 0.3 mmHg vs. +4.8 ± 0.3 mmHg,  for GxH < 0.001 (RV) and +3.9 ± 0.5 mmHg vs. +11.5 ± 1.6 mmHg, p for GxH = 0.110 (LV). The same applied for myocardial fibrosis with +0.3 ± 0.1% vs. 1.3 ± 0.2%, p for GxH = 0.036 (RV) and +0.06 ± 0.03% vs. +0.36 ± 0.08%,  for GxH = 0.002 (LV), whereas systolic function and capillary density was unaffected. ABCG2 deficiency did not influence hypoxia-induced pulmonary hypertension or vascular remodeling. In line with these observations, human cardiac fibroblasts showed increased collagen production upon ABCG2 silencing in hypoxia (p for GxH = 0.04).  Here we provide evidence for the first time that ABCG2 membrane transporter can play a crucial role in ventricular dysfunction and fibrosis in hypoxia-induced pulmonary hypertension.

Lack of ABCG2 Leads to Biventricular Dysfunction and Remodeling in Response to Hypoxia.

Fibrosis and remodeling of the right ventricle (RV) are associated with RV dysfunction and mortality of patients with pulmonary hypertension (PH) but it is unknown how much RV fibrosis contributes to RV dysfunction and mortality. RV fibrosis manifests as fibroblast accumulation and collagen deposition which may be excessive. Although extracellular matrix deposition leads to elevated ventricular stiffness, it is not known to which extent it affects RV function. Various animal models of pulmonary hypertension have been established to investigate the role of fibrosis in RV dysfunction and failure. However, they do not perfectly resemble the human disease. In the current review we describe the major characteristics of RV fibrosis, molecular mechanisms regulating the fibrotic process, and discuss how therapeutic targeting of fibrosis might affect RV function.

Right ventricular fibrosis and dysfunction: Actual concepts and common misconceptions.

Remodeling and fibrosis of the right ventricle (RV) may cause RV dysfunction and poor survival in patients with pulmonary hypertension (PH).

Article	Year
Pressure Overload Creates Right Ventricular Diastolic Dysfunction in a Mouse Model: Assessment by Echocardiography. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography\| PubMed ID: 25840639	2015
Functional and molecular factors associated with TAPSE in hypoxic pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology\| PubMed ID: 27106290	2016
Lack of ABCG2 Leads to Biventricular Dysfunction and Remodeling in Response to Hypoxia. Frontiers in physiology\| PubMed ID: 28270772	2017
Right ventricular fibrosis and dysfunction: Actual concepts and common misconceptions. Matrix biology : journal of the International Society for Matrix Biology\| PubMed ID: 29343458	2018
Disconnect between Fibrotic Response and Right Ventricular Dysfunction. American journal of respiratory and critical care medicine\| PubMed ID: 30557518	2018

Bakytbek Egemnazarov

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