STRAIN-DEPENDENT DEFECT IN RIGHT VENTRICULAR ADAPTATION IN FISCHER RATS WITH SEVERE PULMONARY ARTERIAL HYPERTENSION IS ASSOCIATED WITH DYSREGULATION IN METABOLIC AND ANGIOGENIC PATHWAYS

2016 ◽  
Vol 32 (10) ◽  
pp. S82
Author(s):  
C.M. Seun ◽  
K.R. Chaudhary ◽  
Y. Deng ◽  
B. Jiang ◽  
D.J. Stewart
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Pulmonary Arterial ◽  
Fischer Rats ◽  
Strain Dependent ◽  
Severe Pulmonary Arterial Hypertension

Abstract 15922: Fischer Rats Exhibit High Mortality in the Su5416 Model of Severe Pulmonary Arterial Hypertension Related to Failure of Right Ventricular Adaptation

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Colin Suen ◽  
Baohua Jiang ◽  
Yupu Deng ◽  
Mohamad Taha ◽  
Ketul Chaudhary ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Exercise Capacity ◽  
High Mortality ◽  
Systolic Pressure ◽  
Sd Rats ◽  
Pulmonary Arterial ◽  
Fischer Rats ◽  
Severe Pulmonary Arterial Hypertension

Introduction: Inhibition of VEGFR2 with SU5416 (SU) in combination with chronic hypoxia (CH), produces severe pulmonary arterial hypertension (PAH) in rats with complex arterial remodeling that closely resembles plexiform lesions typical of human PAH. Survival in severe PAH is related to the ability of the right ventricle (RV) to adapt to increased afterload. In this study, we explored the effect of genetic background on right ventricular adaptation and survival in the Methods: PAH was induced by a single subcutaneous injection of SU5416 (20mg/kg) in 6-week old Sprague-Dawley (SD, Harlan, USA) or Fischer rats (CDF, Charles River), followed by a 3-week exposure to CH (10% O2). RV structure and function was assessed by echocardiography (Vevo 2100, Visual Sonics) and cardiac MRI (Agilent 7.0T). Exercise capacity was evaluated at 4 weeks post-SU by treadmill testing. At end study (4 or 7 weeks post-SU), right ventricular systolic pressure (RVSP) was assessed by right heart catheterization. Results: SD and Fischer rats exhibited in similar elevations in RVSP (104± 13 vs 102 ±6 mmHg, respectively), number of occlusive pulmonary vascular lesions and RV hypertrophy (RV/LV+S) in response to SU/CH. However, Fischer rats exhibited markedly higher mortality, with only 27% surviving to 7 weeks compared with 100% survival in SD rats (p<0.01), which was associated with significantly greater RV dilatation (RV/LV end diastolic diameter: 2.16 ± 0.24 vs. 1.19 ± 0.09 mm, p<0.001) at 4 weeks post-SU (Figure 1). Additionally, RV capillary density (516 ± 55 vs 786 ± 38 capillaries/mm2) and exercise capacity (treadmill distance, 59 ± 29 vs 210 ± 52 m, p<0.05) were also significantly reduced in Fischer vs SD SU/CH rats. Conclusions: These data suggest that the high mortality in Fischer compared to SD rats in the SU/CH model of severe PAH is related to a strain-dependent abnormality in RV adaptation at least in part due to lack of adequate microvascular angiogenesis in the hypertrophied RV.

Abstract 18362: Cardiac-targeted Therapy With Cardiotrophin-1 Rescues Defective Right Ventricular Adaptation in Severe Pulmonary Arterial Hypertension in Fischer Rats

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Colin Suen ◽  
Mohammad Abdul-Ghani ◽  
Yupu Deng ◽  
Lynn Megeney ◽  
Duncan J Stewart
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Capillary Density ◽  
Internal Diameter ◽  
Pulmonary Hemodynamics ◽  
Fold Reduction ◽  
Physiological Cardiac Hypertrophy ◽  
Pulmonary Arterial ◽  
Fischer Rats

Introduction: In patients with pulmonary arterial hypertension (PAH), right ventricular (RV) dysfunction is one of the strongest predictors of poor prognosis. Therapies targeting RV failure could lead to significant improvement in exercise tolerance and survival in patients with severe PAH. Cardiotrophin-1 (CT-1) is a member of the IL-6 cytokine family that promotes physiological cardiac hypertrophy and cardiomyocyte survival. Hypothesis: We hypothesized that RV-specific therapy using CT-1 therapy will improve RV adaptation to PAH. Methods: PAH was induced by a single subcutaneous injection of SU5416 (SU; 20 mg/kg) followed by exposure to chronic hypoxia (CH; 10% O2) for 3 weeks. On day 22 post SU, human recombinant cardiotrophin-1 (CT-1, Fate Therapeutics) (6 ug/kg/hr) or vehicle (PBS) was administered via subcutaneously implanted mini-osmotic pumps until end-study at 7 weeks. Echocardiography (Vevo 2100, VisualSonics) was performed weekly starting at baseline (day 21). Results: We observed a ~5-fold reduction in expression of endogenous CT-1 mRNA in the RV of rats treated with SU5416+hypoxia compared to healthy controls. Administration of CT-1 to Fischer rats with PAH had no significant effect on pulmonary hemodynamics (pulmonary acceleration time, RVSP), nor RV/LV+S. At 6 weeks post SU, CT-1 significantly reduced RV dilatation (end diastolic RV/LV internal diameter) (p<0.001), improved RV function (cardiac output, RV fractional area change, p<0.05) (Figure 1), which was associated with an increase in RV capillary density (p<0.05) and a 2-fold improvement in survival (31 vs 12%). Conclusions: Targeted cardiac therapy with CT-1 therapy improved RV adaptation in the SU/CH model of severe PAH without altering pulmonary hemodynamics, which in part was mediated by enhancing RV myocardial angiogenesis. These findings support the development of RV-targeted therapeutics for patients with severe PAH and RV failure.

BIOMECHANICAL APPROACH TO THE CLINICAL TREATMENT OF PULMONARY ARTERIAL HYPERTENSION

2013 ◽  
Vol 13 (05) ◽  
pp. 1340005 ◽  
Author(s):  
IVAN CORAZZA ◽  
CHIARA PINARDI ◽  
LUIGI MANCO ◽  
DAVID BIANCHINI ◽  
LAURA CERCENELLI ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Strain Curve ◽  
Right Ventricular Dysfunction ◽  
Mechanical Efficiency ◽  
Arterial Elastance ◽  
Pulmonary Arterial ◽  
Ventricular Efficiency ◽  
Severe Pulmonary Arterial Hypertension

Negative clinical trend of severe pulmonary arterial hypertension (PAH) is due to right ventricular chamber dilatation and consequent dysfunction. On a biomechanical basis the clinical evolution is associated to a progressive mismatching of the artero-ventricular junction and a possible mechanical intervention may be foreseen. This paper demonstrates how the progressive right ventricular dysfunction, in terms of biochemical–mechanical efficiency, is related to the stress–strain curve of the pulmonary artery, simulated by superimposing different elastance tubes in a cardiovascular mock. Applying the experimental signals to an "ideal" normal and dilated ventricle, it was demonstrated that the very high pulmonary elastance at high pressure is the prime cause of a sharp efficiency drop, in comparison with an aortic similar condition. This evidence supports the proposal of mechanical interventions to reduce pulmonary arterial elastance to improve the artero-ventricular matching, increase the reduced ventricular efficiency and change the negative trend of the illness.

scholarly journals Right ventricular dyssynchrony: from load-independent right ventricular function to wall stress in severe pulmonary arterial hypertension

2020 ◽  
Vol 10 (2) ◽  
pp. 204589402092575
Author(s):  
Manuel J. Richter ◽  
Roberto Badagliacca ◽  
Jun Wan ◽  
Rebecca Vanderpool ◽  
Antonia Dalmer ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Diastolic Function ◽  
Ventricular Function ◽  
Right Ventricular Function ◽  
Wall Stress ◽  
Ventricular Dyssynchrony ◽  
Pulmonary Arterial ◽  
Severe Pulmonary Arterial Hypertension

Right ventricular (RV) dyssynchrony has been related to outcome in pulmonary arterial hypertension. Prospectively, we performed echocardiography with measurement of right ventricular dyssynchrony and pressure–volume loop catheterization in 27 pulmonary arterial hypertension patients. Afterload and diastolic function emerged as determinates of wall stress, which results in dyssynchrony.

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