Targeting the cause, affecting the course – PhD defense of Michiel Alexander de Raaf
Pulmonary Arterial Hypertension (PAH) is a progressive disease, characterized by pulmonary vascular remodeling and right ventricular remodeling in hypertrophy, but eventually dilatation and right heart failure . Today, there are several drug classes registered to hamper the disease progression . However, no curative medication for PAH is available. Due to dedicated research, several factors playing an important role in the pathobiology of PAH are identified . Many of these factors also play an important role for the compensatory cardiac adaptation, which stretches a treatment paradox – what is beneficial to the lungs, might be harmful for the heart - when comes to medication targeting these factors.
From the PH center at the VU University medical center, Michiel Alexander de Raaf defended his PhD entitled: “targeting the cause, affecting the course”. The thesis discussed the treatment paradox using experimental models resembling important aspects of PAH.
Important conclusions which could be made from the PhD program were that the different experimental models, like (chronic) hypoxia, monocrotaline and Sugen Hypoxia for example, supply different answers to the treatment paradox . This is due to the fact that every animal model resembles only a ‘set’ of aspects seen in the human disease. Especially with the better understanding of endothelial dysfunction, cellular signaling and ‘quasi-malignant phenotypes’ of the disease, the interpretation what we understand about PAH is still evolving. The scientific progress made also translates to the evolution of animal models; there is a continuous need to characterize and improve animal models by including the representation of aspects which has become more appreciated to have an important role in PAH . This also means, that using older animal models such as monocrotaline or chronic hypoxia to study the efficacy of medication targeting endothelial proliferation – an aspect not represented in these animal models -, may lead to unpredictable translation to the clinic [4, 6, 7].
The best solution to solve the treatment paradox preclinically, making the translation gap smaller, is to use multiple animal models; pulmonary vascular remodeling models representing the drug target for ‘targeting the cause’, and right ventricular pressure overload models to understand if the drug is not worsening cardiac function by ‘affecting the course’. To answer the latter, Pulmonary Artery Banding could be used. With Pulmonary Artery Banding, right ventricular adaptation under exposure of the medication can be measured and evaluated. A good example of the understanding gained from using multiple animal models is the evaluation of histone deacetylases (HDACs) for PAH. In animal models not representing the hyperproliferative endothelium, several HDACs showed a beneficial treatment effect. The thesis shows that HDAC activity in these experimental models is already low in the lungs and elevated in the right heart. Testing these HDAC’s in the Pulmonary Artery Banding model resulted in cardiac worsening and within the Sugen Hypoxia model, no treatment effect was visible [6, 8]. This would conclude that using multiple animal models, predictability of the contemplated beneficial treatment potential can be made.
Bridges were made to the field of the developmental biology to understand the treatment paradox in PAH . During the prenatal phase, the increased pulmonary vascular resistance is needed for the development of the right heart. Medication which lowers the pulmonary vascular resistance results in cardiovascular malformations. Indeed, with the reactivation of fetal aspects in PAH in both pulmonary vascular remodeling as cardiac adaptation, is shows many parallels with cardiopulmonary development.
Michiel Alexander de Raaf, PhD
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5. de Raaf MA, Schalij I, Gomez-Arroyo J, Rol N, Happé C, de Man FS, Vonk-Noordegraaf A, Westerhof N, Voelkel NF, Bogaard HJ. SuHx rat model: partly reversible pulmonary hypertension and progressive intima obstruction. Eur. Respir. J. 2014; 44: 160–168.
6. De Raaf MA, Hussaini AA, Gomez-Arroyo J, Kraskaukas D, Farkas D, Happé C, Voelkel NF, Bogaard HJ. Histone deacetylase inhibition with trichostatin A does not reverse severe angioproliferative pulmonary hypertension in rats (2013 Grover Conference series). Pulm. Circ. 2014; 4: 237–243.
7. De Raaf MA, Kroeze Y, Middelman A, de Man FS, de Jong H, Vonk Noordegraaf A, de Korte C, Voelkel NF, Homberg J, Bogaard HJ. Serotonin transporter is not required for the development of severe pulmonary hypertension in the Sugen hypoxia rat model. Am. J. Physiol. Lung Cell. Mol. Physiol. 2015; : ajplung.00127.2015.
8. Bogaard HJ, Mizuno S, Hussaini AAA, Toldo S, Abbate A, Kraskauskas D, Kasper M, Natarajan R, Voelkel NF. Suppression of Histone Deacetylases Worsens Right Ventricular Dysfunction after Pulmonary Artery Banding in Rats. Am. J. Respir. Crit. Care Med. 2011; 183: 1402–1410.
9. de Raaf MA, Beekhuijzen M, Guignabert C, Vonk Noordegraaf A, Bogaard HJ. Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension. Reprod. Toxicol. Elmsford N 2015; .