Upregulated Neurohumoral Factors are Associated With Left Ventricular Remodeling and Poor Prognosis in Rats With Monocrotaline-Induced Pulmonary Arterial Hypertension

Abstract

ulmonary arterial hypertension (PAH) is a disorder induced by various causes, such as collagen or pulmonary obstructive/restrictive disease-associated vasculopathy, pulmonary artery embolism, hypoxia, and inflammatory diseases, as well as genetic abnormalities. 1,2 Although the etiology of PAH is diverse, the essential pathophysiology is an elevation in the resistance of the pulmonary arteries characterized by vascular remodeling and smooth muscle spasm with continuous progression of luminal obliteration. Therefore, the strategy for treating PAH patients has focused on decreasing the resistance of the pulmonary arteries and/or preventing progression of pulmonary vascular remodeling. So far, vasodilatation therapy with Ca 2+ antagonists and prostaglandin derivatives has been used for PAH patients, but the improvement of prognosis and/or quality of life (QOL) has been limited. Recently, several clinical trials have revealed that an endothelin (ET)-1 receptor blocker, bosentan, is the most promising drug for the treatment of PAH, 3-5 and evidence for a beneficial effect of a phosphodiesterase V inhibitor, sildenafil, has accumulated, 6-9 with the Food and Drug Administration in the United States approving sildenafil as treatment for PAH in June 2005. However, these treatment strategies have not always been satisfactory for all PAH patients because of incomplete reversibility of the pulmonary vasculopathy, and the long-term benefits and side effects are not yet defined. The management of right ventricular failure should be considered together with treatment for pulmonary vasculopathy.Many recent clinical mega-trials have clearly shown that angiotensin-converting enzyme (ACE) inhibitors/angiotensin (AT) II receptor blockers (ARB) 10,11 and -adrenergicreceptor blockers (BB) 12-14 are beneficial drugs for patient with left-sided heart failure. Mechanical stress is an important factor in the progression of left ventricular (LV) hypertrophy/failure. In addition, circulating and/or locally produced ATII and catecholamines are now thought to directly contribute to LV remodeling and progression of hypertrophy/failure. However, it is a matter of debate whether the LV is affected by such neurohumoral factors in isolated right-sided heart failure due to PAH. The effect of ACE Background Left ventricular remodeling might be involved in the pathophysiology of right ventricular hypertrophy/failure due to pulmonary arterial hypertension (PAH), while the left ventricle is considered not under pressure/volume overload. Methods and ResultsRats with monocrotaline-induced PAH were used in the present study to examine whether upregulated neurohumoral factors may induce left ventricular (LV) remodeling and(/or) contribute to prognosis. Morphological analysis revealed a significant increase in the weight of the free walls of both ventricles and the interventricular septum, indicating biventricular hypertrophy, although systemic blood pressure was not elevated. RNase protection assay demonstrated the activation of a fetal gene program in t...

Magnetic Resonance Characterization of Cardiac Adaptation and Myocardial Fibrosis in Pulmonary Hypertension Secondary to Systemic-To-Pulmonary Shunt

“…19 In this previous study, only a nonsignificant trend toward higher ECV at the septum and LV lateral wall was observed. 25 In the current model, ECV was again significantly higher at the RV insertion points, showing a good correlation with the severity of PH, but differences in ECV at the septum and LV lateral wall were also significant, reflecting an inherent damage at the LV. Pressure overload and, remarkably, significant lung parenchymal damage 26 seem to induce greater myocardial fibrosis than volume overload.…”

Rodent models of heart failure: an updated review

“…Crotalaria spectabilis that can be administered by intraperitoneal, subcutaneous or intravenous injection to induce right ventricular dysfunction and HF within 4-6 weeks [30,299]. Current hypotheses of the pathogenesis of MCTinduced pneumotoxicity suggest that MCT is transformed in a bioactive pyrrole metabolite in the liver and is then transported by red blood cells to the lung, where it initiates endothelial injury.…”

Effects of a Pure .ALPHA./.BETA.-Adrenergic Receptor Blocker on Monocrotaline-Induced Pulmonary Arterial Hypertension With Right Ventricular Hypertrophy in Rats

“…It is reported that carvedilol improves survival rate in MCT-induced PAH rats. 21 Therefore, we need to perform further study to clarify the effect of arotinolol on the long-term outcome.…”