Right ventricular failure in pulmonary arterial hypertension: Squaring the circle

    Research output: PhD ThesisPhD-Thesis - Research and graduation internal

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    Abstract

    Idiopathic pulmonary arterial hypertension (iPAH) is a rare, and severe, pulmonary vascular disease. Narrowing of the vascular lumen leads to right ventricular (RV) overload and ultimately RV failure. The continuous pressure load on the RV induces a vicious circle of tissue hypoxia, altered metabolism, neurohormonal activation and further deterioration of RV function. We explored three possible strategies to slow down the vicious circle of RV deterioration and eventually RV failure in iPAH: improvement of oxygen supply (Chapter 2 and 3), reduction of oxygen demand (Chapter 4 and 5), and restoration of the neurohormonal balance (Chapter 6 and 7). Oxygen supply In chapter 2, we investigated the regulation of myoglobin expression in the hypertrophied RV in the monocrotaline (MCT) model of PH. While total oxidative capacity, and thus oxygen demand, increased in the MCT rats, myoglobin (Mb) mRNA expression did not. Yet, the absolute amount of Mb protein increased, indicating increased translation. The minimal extracellular oxygen tension needed to prevent hypoxic cell cores when mitochondria are maximally active (PO2crit) was calculated to be almost twice as high in the MCT animals compared to control. This indicates that the increase in Mb protein expression was just enough to compensate for the increase in cell size but not for the increased oxygen demand. In chapter 3, we applied different levels of hypoxia in combination with fatty acid supplementation to cultured skeletal muscle myotubes. In addition, we applied insulin-like growth factor (IGF)-1 to induce hypertrophy. We showed that IGF-1 can partly prevent hypoxia-induced atrophy but also inhibits Mb expression, which complicates combining hypertrophy and increasing Mb expression. Oxygen demand In chapters 4 and 5, we investigated the possibilities of reducing oxygen demand. In chapter 4, we were able to quantify a histochemical determination to estimate mitochondrial efficiency ex vivo in small amounts of tissue. Using this technique, we observed a heterogeneous reduction in RV mitochondrial efficiency in experimental PH, possibly underlying the reported reductions in mechanical efficiency in rats and PAH patients [20, 21]. In chapter 5, we studied the role of monoamine oxidase (MAO)-A, a potential major source of ROS, and large consumer of oxygen in experimental PH. We observed that MAO-A inhibition by clorgyline reduced RV afterload and pulmonary vascular remodeling in a Sugen-Hypoxia model of PH, through reduced vascular proliferation and oxidative stress. However, using a PTB model of PH, we observed no direct effects of MAO-A inhibition on the RV, despite strong upregulation of MAO-A. The neurohormonal balance The regulation of cardiovascular homeostasis is largely under control of the autonomic nervous system (ANS) and renin-angiotensin-aldosterone system (RAAS). In iPAH, there is neurohormonal imbalance both in the ANS and RAAS. Chronic overactivation of the sympathetic nervous system (SNS) is thought to underlie hyperventilation, which is common among iPAH patients. Therefore, in chapter 6, we studied the effect of two relatively simple interventions that lower SNS activity on ventilation in iPAH patients. Although both long-term beta blocker treatment and short-term hyperoxic breathing reduced heart rate, indicating reduced sympathetic activation, we did not see any effect on ventilation, neither at rest nor during exercise. Finally, in chapter 7 we reviewed the neurohormonal system in iPAH in more detail, as well as the interventions on it that have been tested clinically and preclinically. Despite the promising results in some studies, the small number of patients limits the confirmation by larger clinical trials. In addition, retrospective analysis to identify differences between responders and non-responders is difficult and patient tissue for research is scarce. Therefore, we argue for a more personalized approach and better insight into the neurohormonal changes over the course of the disease.
    Original languageEnglish
    QualificationDr.
    Awarding Institution
    • Vrije Universiteit Amsterdam
    Supervisors/Advisors
    • Vonk Noordegraaf, A., Supervisor, External person
    • Bogaard, Herman Jan, Co-supervisor, External person
    • de Handoko-Man, Frances Sarah, Co-supervisor, External person
    Award date9 Dec 2021
    Place of PublicationAmsterdam
    Publisher
    Print ISBNs9789464167696
    Publication statusPublished - 9 Dec 2021

    Keywords

    • Pulmonary Arterial Hypertension
    • PAH
    • Pulmonology
    • Right Heart Failure
    • Heart Failure
    • Oxygen
    • Neurohormonal System

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