Monocrotaline – ABC CARDIOL

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Original Article

Right Ventricular Function and Oxidative Stress Improve with the Administration of Thyroid Hormones and Grape Juice in a Pulmonary Hypertension Model

Isabel Proença et al. Patrick Turck Vanessa Ortiz Cristina Campos-Carraro … Adriane Bello Klein Alexandre de Castro Caroline Dani Alex Sander da Rosa Araujo

Abstract

Background

Adverse remodeling of lung vessels elevates pulmonary pressure and provokes pulmonary arterial hypertension (PAH). PAH results in increased right ventricle (RV) afterload, causing ventricular hypertrophy and the onset of heart failure. There is no specific treatment for maladaptive RV remodeling secondary to PAH.

Objectives

This study aims to explore two therapeutic approaches, grape juice (GJ) and thyroid hormones (TH), on PAH-induced oxidative stress and cardiac functional changes.

Methods

Parameters of echocardiography related to lung vessel resistance (AT/ET ratio), RV contractility (TAPSE), and RV diastolic function (E/A peaks ratio) were evaluated. Also, total ROS, lipid peroxidation, antioxidant enzymes, calcium handling proteins, pro-oxidant and antioxidant protein expression were measured. Values of p<0.05 were considered statistically significant.

Results

Both GJ and TH treatments demonstrated reductions in pulmonary resistance (~22%) and improvements in TAPSE (inotropism ~11%) and AT/ET ratio (~26%) (p<0.05). There were no changes amongst groups regarding the E/A peak ratio. Although ROS and TBARS were not statistically significant, GJ and TH treatments decreased xanthine oxidase (~49%) levels and normalized HSP70 and calcium handling protein expression (p<0.05). However, only TH treatment ameliorated diastolic function (~50%) and augmented NRF2 immunocontent (~48%) (p<0.05).

Conclusions

To the best of our knowledge, this study stands as a pioneer in showing that TH administered together with GJ promoted functional and biochemical improvements in a PAH model. Moreover, our data suggest that GJ and TH treatments were cardioprotective, combined or not, and exhibited their beneficial effects by modulating oxidative stress and calcium-handling proteins.

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Original Article

Isolated Left Atrium Morphofunctional Study of an Experimental Pulmonary Hypertension Model in Rats

Jorge Lucas Teixeira-Fonseca et al. Julliane Vasconcelos Joviano-Santos Fabiana da Silva Alcântara Polyana Leal da Silva … Michael Ramon Lima Conceição Danilo Roman-Campos

Abstract

Background

The high incidence of atrial arrhythmias in pulmonary hypertension (PH) might be associated with poor prognosis, and the left atrium (LA) may play a role in this. An important finding in PH studies is that LA remodeling is underestimated.

Objective

This study investigated LA morphology and mechanical function, as well as the susceptibility to develop arrhythmias in a monocrotaline-induced PH (MCT-PH) model.

Methods

Wistar rats aged 4 weeks received 50 mg/kg of MCT. Electrocardiography and histology analysis were performed to evaluate the establishment of the MCT-PH model. The tissue was mounted in an isolated organ bath to characterize the LA mechanical function

Results

Compared with the control group (CTRL), the MCT-PH model presented LA hypertrophy and changes in cardiac electrical activity, as evidenced by increased P wave duration, PR and QT interval in MCT-PH rats. In LA isolated from MCT-PH rats, no alteration in inotropism was observed; however, the time to peak contraction was delayed in the experimental MCT-PH group. Finally, there was no difference in arrhythmia susceptibility of LA from MCT-PH animals after the burst pacing protocol.

Conclusion

The morphofunctional remodeling of the LA did not lead to increased susceptibility to ex vivo arrhythmia after application of the burst pacing protocol.

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Editorial

A New Therapeutic Alternative for the Treatment of Pulmonary Hypertension?

Ricardo J Gelpi

In this issue of the journal Arquivos Brasileiros de Cardiologia, important and original research work on rats is published. The work is important because pulmonary hypertension represents a serious pathology that is very difficult to treat. The only way to relieve patients is lung transplantation, but are very well known the difficulties and limitations of this treatment. The work is also original because a lot has been published about the beneficial effects of copaiba oil, such as its anti-inflammatory action, analgesic effect, and ability to prevent infections and improve the healing process. However, the beneficial effect of copaiba oil on pulmonary hypertension had not been described. In this sense, the group led by Adriane Belló Klein has been working for several years on this important issue of pulmonary hypertension in general,^– and the effects of copaiba oil on this particular pathology,^, which has made this research group an international benchmark on this theme.

It is important to mention that pulmonary hypertension induced in rats by monocrotaline produces vascular lesions very similar to those found in patients with this pathology.^, In essence, what the work published in this issue of the journal Arquivos Brasileiros de Cardiologia shows is that the administration of copaiba oil to a group of rats with pulmonary hypertension induced by monocrotaline produces a clear beneficial effect, through the decrease in peripheral blood indicators of oxidative stress, a reduction in pulmonary vascular resistance, and a favorable remodeling of the right ventricle, with a reduction in hypertrophy, which translates into a better systolic function of that ventricle. This finding is very important because it is well known that myocardial hypertrophy is one of the most important causes of heart failure and sudden death. The positive relationship between the degree of hypertrophy and the decrease in oxidative stress shown by the authors is clearly proven in this work by the high r-value obtained when these two variables were correlated. However, and beyond this important correlation, future studies should determine if the beneficial effect on the right ventricle is due to the reduction of oxidative stress or if there is also a direct effect of copaiba oil on myocardial fibers. Perhaps experiments that could be carried out on isolated hearts would make it possible to detect or not a direct impact of this natural agent. In this sense, it is important to mention that the authors of this study also published an interesting work previously where they showed that the administration of copaiba oil decreased apoptosis signals in the hypertrophic right ventricle and attributed the better remodeling to a possible decrease in the apoptosis mentioned above; obviously this same mechanism could be acting in the work that we are commenting now. Nevertheless, here it is important to make some clarifications that may allow a better understanding of what is happening in these hearts with hypertrophy secondary to pulmonary hypertension.

[…]

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Original Article

Plexiform Lesions in an Experimental Model of Monocrotalin-Induced Pulmonary Arterial Hypertension

Douglas Mesadri Gewehr et al. Gabriela Rodrigues Salgueiro Lucia de Noronha Fernando Bermudez Kubrusly … Luiz Fernando Kubrusly Gabriel Antonio Coltro Paola Cardoso Preto Andressa de Souza Bertoldi Heloisa Iacomo Vieira

Abstract

Background

The monocrotaline (MCT)-induced pulmonary arterial hypertension model is one of the most reproduced today, presenting as a limitation the absence of plexiform lesions, typical manifestations of the severe disease in humans.

Objective

To evaluate the severity of MCT-induced pulmonary arteriopathy by pathological findings of lung and heart tissue samples, clinical course and 37-day survival.

Methods

Fifty male Wistar rats were divided into one of the four groups – control (CG) (n = 10) and three intervention (MCT) groups. The MCT groups received intraperitoneal injection (60 mg/kg) of MCT and remained exposed to the substance for 15 days (G15, n = 10), 30 days (G30, n = 10) and 37 days (G37, n = 20). At the end of each period, the animals were sacrificed, and pulmonary and cardiac tissues were collected for anatomopathological and morphometric analysis. The Kruskal-Wallis test was used, considering a level of significance of 5%.

Results

In the lungs of MCT animals, lesions related to pulmonary arteriopathy were found, including muscularization of the arterioles, hypertrophy of the middle layer and concentric neointimal lesions. Complex lesions were observed in MCT groups, described as plexiform and plexiform-like lesions. Right ventricular hypertrophy was evidenced by increased thickness and diameter of the cardiomyocytes and a significant increase in the right ventricular wall thickness (p <0.0000).

Conclusion

The MCT model was able to generate moderate-severe pulmonary arteriopathy associated with secondary right ventricular hypertrophy. The 37-day survival rate was 50%. To our knowledge, this study was the first to note the presence of complex vascular lesions, similar to those observed in patients with severe pulmonary arterial hypertension, in an isolated MCT model. (Arq Bras Cardiol. 2020; 115(3):480-490)

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Original Article

Fractal Dimension in Quantifying Experimental-Pulmonary-Hypertension-Induced Cardiac Dysfunction in Rats

Francis Lopes Pacagnelli et al. Ana Karênina Dias de Almeida Sabela Thaoan Bruno Mariano Guilherme Akio Tamura Ozaki … Robson Chacon Castoldi Edna Maria do Carmo Robson Francisco Carvalho Loreta Casquel Tomasi Katashi Okoshi Luiz Carlos Marques Vanderlei

Abstract

Background:

Right-sided heart failure has high morbidity and mortality, and may be caused by pulmonary arterial hypertension. Fractal dimension is a differentiated and innovative method used in histological evaluations that allows the characterization of irregular and complex structures and the quantification of structural tissue changes.

Objective:

To assess the use of fractal dimension in cardiomyocytes of rats with monocrotaline-induced pulmonary arterial hypertension, in addition to providing histological and functional analysis.

Methods:

Male Wistar rats were divided into 2 groups: control (C; n = 8) and monocrotaline-induced pulmonary arterial hypertension (M; n = 8). Five weeks after pulmonary arterial hypertension induction with monocrotaline, echocardiography was performed and the animals were euthanized. The heart was dissected, the ventricles weighed to assess anatomical parameters, and histological slides were prepared and stained with hematoxylin/eosin for fractal dimension analysis, performed using box-counting method. Data normality was tested (Shapiro-Wilk test), and the groups were compared with non-paired Student t test or Mann Whitney test (p < 0.05).

Results:

Higher fractal dimension values were observed in group M as compared to group C (1.39 ± 0.05 vs. 1.37 ± 0.04; p < 0.05). Echocardiography showed lower pulmonary artery flow velocity, pulmonary acceleration time and ejection time values in group M, suggesting function worsening in those animals.

Conclusion:

The changes observed confirm pulmonary-arterial-hypertension-induced cardiac dysfunction, and point to fractal dimension as an effective method to evaluate cardiac morphological changes induced by ventricular dysfunction.

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