Opposite Effects of Training in Rats With Stable and Progressive Pulmonary Hypertension

Abstract

Background-Exercise training in pulmonary arterial hypertension (PH) is a promising adjunct to medical treatment.However, it is still unclear whether training is beneficial for all PH patients. We hypothesized that right ventricular adaptation plays a pivotal role in the response to training. Methods and Results-Two different dosages of monocrotaline were used in rats to model stable PH with preserved cardiac output and progressive PH developing right heart failure. Two weeks after injection, PH was confirmed by echocardiography, and treadmill training was initiated. Rats were trained for 4 weeks unless manifest right heart failure developed earlier. At the end of the study protocol, all rats were functionally assessed by endurance testing, echocardiography, and invasive pressure measurements. Lungs and hearts were further analyzed in quantitative histomorphologic analyses. In stable PH, exercise training was well tolerated and markedly increased exercise endurance (from 25Ϯ3.9 to 62Ϯ3.9 minutes; PϽ0.001). Moreover, capillary density increased significantly (from 1.21Ϯ0.12 to 1.51Ϯ0.07 capillaries per cardiomyocyte; PϽ0.05). However, in progressive PH, exercise training worsened survival (hazard ratio, 2.7; 95% confidence interval, 1.1 to 14.2) and increased pulmonary vascular remodeling. In addition, training induced widespread leukocyte infiltration into the right ventricle (from 135Ϯ14 to 276Ϯ18 leukocytes per 1 mm 2 ; PϽ0.001). Conclusions-In our rat model, exercise training was found to be beneficial in stable PH but detrimental in progressive PH. Future studies are necessary to address the clinical implications of our findings. Key Words: capillaries Ⅲ exercise Ⅲ hypertension, pulmonary Ⅲ inflammation Ⅲ pulmonary heart disease P ulmonary arterial hypertension (PH) is characterized by progressive pulmonary vascular remodeling, which importantly increases right ventricular (RV) afterload, eventually leading to right heart failure and premature death. 1 Traditionally, PH patients were advised to limit physical activity because of risk of fatal cardiovascular compromise. 2 Clinical Perspective on p 49Recent developments, however, have challenged this view. 3 First, the prognosis of PH patients improved with the introduction of various potent PH-specific medications in the last decades. 4 Second, several studies have demonstrated beneficial effects of training in patients with chronic obstructive pulmonary disease and with congestive heart failure, and training was beneficial even for the most severely affected patients (GOLD IV, New York Heart Association class IV) often suffering from secondary PH. 5,6 Finally, in a recent clinical trial of 30 stable PH patients under optimized medical treatment, Mereles et al 7 reported marked improvement in exercise capacity and quality of life after exercise training.Although training might be a promising adjunct to medical treatment in PH, it remains to be elucidated whether exercise training is beneficial for all PH patients and what its effect is on RV function and remo...

State of the Art: Advanced Imaging of the Right Ventricle and Pulmonary Circulation in Humans (2013 Grover Conference Series)

“…In animal models of PH, capillary rarefaction and reduced VEGF expression have been demonstrated both in the RV and in the lungs. [98][99][100][101] Although not yet quantified in the lungs, PET imaging with 64 CU- labeled VEGF 121 or 18 F arginine-glycine-aspartic acid peptide (RGD) with affinity for the α v β 3 integrins have enabled measurements of angiogenic myocardial repair processes in rat models with myocardial infarction. [102][103][104] Other tissue processes, such as apoptosis, can be localized and quantified using in vivo CMR annexin imaging.…”

<b>Time course of ubiquitin-proteasome and macroautophagy-lysosome pathways in skeletal muscle in rats with heart failur</b><b>e </b>

“…At 21 days after monocrotaline injection, animals in the MCT group expressed clinical signs of heart failure including weight loss, tachypnea, lethargy, cold extremities, and piloerection. These have been shown to correlate with decompensated right ventricular dysfunction in this model (2,16). The animals in the Cont group were sacrificed at the same time points as the MCT group (n = 7 at each time point).…”

“…However, exercises to combat skeletal muscle atrophy induced by heart failure can worsen myocardial dysfunction. Handoko et al (16) reported that regular exercise after heart failure induced myocardial inflammation and increased the survival rate. In this study (16), exercise was found to be beneficial in the stable stage but detrimental in the progressive stage, suggesting that the effects of exercise on skeletal muscle atrophy could depend on the stage in heart failure.…”

Reversibility of the monocrotaline pulmonary hypertension rat model

“…Other features of MCT-induced pulmonary vascular remodelling are arterial medial hyperplasia of axial arteries, interstitial oedema, adventitial inflammation, haemorrhage and, eventually, fibrosis [1,2,5,6]. As a result, pulmonary vascular resistance (PVR) increases and the right ventricle compensates by hypertrophy and eventually fails [7,8].…”

“…Since it is known that a high dose of MCT (60 or 80 mg?kg -1 ) is fatal within 3-6 weeks, the only possible way to study the long-term effects of MCT was to use a lower dose [7,8,10,11]. Alterations in the lungs and heart were measured 4, 8, and 12 weeks after administration of MCT or saline.…”