Resistance Exercise Training Mitigates Left Ventricular Dysfunctions in Pulmonary Artery Hypertension Model

Abstract

Background: The right ventricular hypertrophy and dilation observed in pulmonary artery hypertension (PAH) damages the left ventricle (LV) dynamics by flattening the interventricular septum.

Objective: To investigate whether low- to moderate-intensity resistance exercise training (RT) is beneficial to LV and cardiomyocyte contractile functions in rats during the development of monocrotaline (MCT)-induced PAH.

Methods: Male Wistar rats (Body weight: ~ 200 g) were used. To assess the time to potential heart failure onset (i.e., end point), rats were divided into sedentary hypertension until failure (SHF, n=6) and exercise hypertension until failure (EHF, n=6) groups. To test RT effects, rats were divided into sedentary control (SC, n = 7), sedentary hypertension (SH, n=7), and exercise hypertension (EH, n=7) groups. PAH was induced by two MCT injections (20 mg/kg, with 7 days interval). Exercise groups were submitted to an RT protocol (Ladder climbing; 55-65% of carrying maximal load), 5 times/week. Statistical significance was assumed at P < 0.05.

Results: RT prolonged the end point (~25 %), enhanced the physical effort tolerance (~ 55%), and mitigated the LV and cardiomyocyte contractility dysfunctions promoted by MCT by preserving the ejection fraction and fractional shortening, the amplitude of shortening, and the velocities of contraction and relaxation in cardiomyocytes. RT also prevented increases in left ventricle fibrosis and type I collagen caused by MCT, and maintained the type III collagen and myocyte dimensions reduced by MCT.

Conclusion: Low- to moderate-intensity RT benefits LV and cardiomyocyte contractile functions in rats during the development of MCT-induced PAH.

Figura 1. Efeito do treinamento resistido em possível surgimento de insuficiência cardíaca (ponto de desfecho) e tolerância ao esforço físico. (A) Máxima carga carregada de animais hipertensos até a insuficiência, determinada pela máxima carga carregada ajustada para peso corporal, antes da injeção (dia 0) e no 14º, 21º e 28º e 35º dias após a primeira injeção de monocrotalina. (B) Ponto de desfecho, medido em dias para apresentar sinais de possível surgimento de insuficiência cardíaca, foi significativamente mais curto em ratos em hipertensão com sedentarismo até a insuficiência (HSI, n=6) do que nos ratos em hipertensão com treinamento até a insuficiência (HTI, n=6). **P <0,01, análise da curva de Kaplan-Meier pelo teste de Log-rank. (C) Máxima carga carregada relativa para animais de controle, hipertensos, sedentários e em treinamento, determinada conforme o painel A. Ratos em hipertensão com treinamento (HT, n=7) apresentaram maior ganho em carga carregada do que o grupo de controle sedentário (CS, n=7) e o grupo de hipertensão com sedentarismo (HS, n=7), a partir do 14º dia. Medições de ANOVA repetidas seguidas do teste de correção de Tukey. aP <0,05 vs. HS; bP <0,05, vs. CS; *P <0,05 vs. antes da injeção de MCT.

Figura 2. Efeito do treinamento físico resistido na função do ventrículo esquerdo avaliado no 28º dia após a primeira injeção de monocrotalina. (A) Imagens ecocardiográficas representativas (B) Fração de ejeção (C) Encurtamento fracional. (D) Ventrículo esquerdo em forma de “D”. Os valores são médias ± DP (n=7 ratos em cada grupo), CS: controle sedentários; HS: hipertensão com sedentarismo; HT: hipertensão com treinamento; VD: ventrículo direito; VE: ventrículo esquerdo. A linha pontilhada indica os limites para a classificação da função prejudicada. Painéis B e C: ANOVA de uma via seguido de teste post hoc de Tukey. Painel D: Teste Qui-quadrado de Pearson (teste x2). *p <0,05.

Figura 3. Efeito do treinamento físico resistido na remodelação do ventrículo esquerdo. (A) Porcentagem de colágeno tipo I. (B) Porcentagem de colágeno tipo III. (C) Porcentagem de colágeno total. (D) Porcentagem de fibrose no VE. (E) Microfotografias representativas do tecido do VE corado com vermelho Sirius; (F) Microfotografias representativas do tecido do VE corado com tricromo de Masson. A seta azul indica colágeno tipo I; A seta branca indica colágeno tipo III; A seta preta indica fibrose cardíaca. Os valores são apresentados como medianas acompanhadas da faixa interquartil de 10 imagens por animal em cada grupo (n=5 ratos em cada grupo). CS: controle sedentários; HS: hipertensão com sedentarismo; HT: hipertensão com treinamento. Kruskal-Wallis, seguido pelo teste post-hoc de Dunn: * p <0,05, e ** p <0,01.

Figure 1. Effect of resistance training on the onset of potential heart failure (end point) and physical effort tolerance. (A) Relative maximal carrying load of hypertensive animals until failure, determined by the maximal carrying load normalized to body weight, at pre-injection (day 0) and on the 14th, 21st, 28th, and 35th day after the first monocrotaline injection. (B) End point, measured in days to present signs of the onset of potential heart failure, was significantly shorter in sedentary hypertension until failure (SHF, n = 6) than in exercise hypertension until failure (EHF, n = 6) rats. **P < 0.01, Kaplan-Meier curve analysis by the Log-rank test. (C) Relative maximal carrying load of control, hypertensive sedentary and exercise animals, determined as in panel A. Exercise hypertension (EH, n=7) rats exhibited higher carrying load gain than sedentary control (SC, n=7) and sedentary hypertension (SH, n=7) from the 14th day on. Repeated measures ANOVA followed by Tukey correction test. aP < 0.05 vs. SH; bP < 0.05, vs. SC; *P < 0.05 vs. Before MCT injection.

Figure 2. Effect of resistance exercise training on left ventricular function assessed on the 28th day after the first monocrotaline injection. (A) Representative echocardiograph images. (B) Ejection fraction. (C) Fractional shortening. (D) D-shaped left ventricle. Values are means ± SD (n = 7 rats in each group). SC: sedentary control; SH: sedentary hypertension; EH: exercise hypertension; RV: right ventricle; LV: left ventricle. Dotted line indicates limits for the classification of impaired function. Panel B and C: One-Way ANOVA followed by the Tukey’s post hoc test. Panel D: Pearson’ s Chi-squared test (x2 test). *p < 0.05.

Figure 3. Effect of resistance exercise training on left ventricle remodeling. (A) Percentage of type I collagen. (B) Percentage of type III collagen. (C) Percentage of total collagen. (D) Percentage of fibrosis in the LV. (E) Representative photomicrographs of LV tissue stained with Sirius Red; (F) Representative photomicrographs of LV tissue stained with Masson’s trichrome. Blue arrow indicates type I collagen; White arrow indicates type III collagen; Black arrow indicates cardiac fibrosis. Values are presented as median accompanied by the interquartile range of 10 images per animal in each group (n = 5 rats in each group). SC: sedentary control; SH: sedentary hypertension; EH: exercise hypertension. Kruskal-Wallis, followed by the Dunn’s post hoc test: * P < 0.05, and ** p < 0.01.