Nutrition as potential treatment strategy in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a chronic and progressive disease characterized by vasoconstriction and structural remodelling of the pulmonary arteries. Increased vascular resistance and elevated pulmonary arterial pressures contribute to right ventricular hypertrophy and eventually lead to heart failure and premature death. Symptoms of PAH include serious exercise intolerance, reducing the quality of life of patients.  Nutrition is increasingly being recognized as an important factor contributing to quality of life during disease, especially when exercise intolerance is present. There is however limited knowledge on the role of nutrition in PAH and nutritional guidelines are scarce. In the meantime, PAH patients are actively seeking advice on such matters. In the clinic, assessment of nutritional status or micronutrient concentrations are currently not standard practice and nutritional intervention is not part of regular treatment, due to the lack of evidence-based recommendations for PAH patients.In this thesis, the role of nutrition in PAH pathophysiology and the potential of nutritional intervention in the treatment of PAH is being explored. The aim of this thesis is to gain more knowledge on the prevalence of micronutrient deficiencies of patients with PAH and to explore possible nutritional interventions to reduce fatigue and improve exercise tolerance and quality of life in PAH patients. These objectives are addressed by 1) literature research and hypothesis generation, 2) measurement of micronutrient status in PAH and CTEPH patients, 3) exploration of the relation between levels of micronutrients and clinical and patient-related outcomes and 4) a study on the effect of nutritional intervention on muscle function in a mouse model of PAH.Chapter 2 summarizes current insights in the pathophysiological mechanisms underlying PAH. It zooms in on the potential involvement of nutritional status and micronutrient deficiencies on PAH exercise intolerance and fatigue, also summarizing the potential benefits of exercise and nutritional interventions. Available evidence suggests that exercise interventions can be effective in PAH patients to improve exercise tolerance and decrease fatigue. By contrast, knowledge on the prevalence of micronutrient deficiencies and the possible effects of nutritional interventions in PAH patients is limited. Although data on nutritional status and micronutrient deficiencies in PAH are scarce, the available knowledge, including that from adjacent fields, suggests that nutritional intervention to correct deficiencies and metabolic alterations may contribute to a reduction of disease burden.In Chapter 3, the prevalence of micronutrient deficiencies in both newly diagnosed and treated patients with PAH and chronic thrombo-embolic pulmonary hypertension (CTEPH) are described and correlations between micronutrients and clinical outcomes are assessed.Deficiencies in both iron and vitamin D are highly prevalent in both PAH and CTEPH patients at diagnosis as well as after 1,5 years of treatment. In the newly diagnosed group, 42% of PAH patients and 21% of CTEPH patients were iron deficient, compared to 29% of PAH patients and 20% of CTEPH patients in the treatment group. Vitamin D deficiency occurred in 42% of the newly diagnosed PAH patients, in 71% of the newly diagnosed CTEPH patients, in 68% of the treated PAH patients and in 70% of the treated CTEPH patients.Iron plasma levels correlate with 6-minute walk distance. Low iron levels seem to be related to inflammation via hepcidin levels. Vitamin D levels did not correlate with any of the outcome measures in our study. Therefore, the relevance of vitamin D deficiency in PAH and CTEPH patients remains unclear and further studies into this topic are needed. The high prevalence of deficiencies in vitamin D and iron however underline the need for monitoring their status. Studies evaluating the possible effects and safety of different supplementation strategies for iron as well as vitamin D in PAH and CTEPH patients are necessary. Chapter 4 discusses the hypothesis that the use of proton pump inhibitors can contribute to a reduction in muscle mass and function in chronically ill patients. Literature indicates that a PPI-induced reduction in acidity of the gastrointestinal tract can decrease the absorption of, amongst others, magnesium. Low levels of magnesium are associated with impaired muscle function. This unwanted side-effect of PPIs on muscle function has been described in different disease backgrounds, but has not been studied in PAH. Magnesium is necessary for activation of vitamin D. Low vitamin D and magnesium levels together can lead to increased inflammation involved in muscle wasting. In conclusion, use of PPIs has been reported to contribute to muscle function loss. Whether this will add to the risk factor for development of muscle function loss in patients with PAH needs further investigation.Chapter 5 describes the effect of a multi-targeted nutritional intervention with extra protein, leucine, and the anti-inflammatory components of fish oil and oligosaccharides on pathological changes in cardiac and skeletal muscle of a PAH mouse model. PAH was induced in female C57/BL6 mice by weekly injection of monocrotaline (MCT) for 8 weeks. One MCT group and the sham group received a control diet, while another MCT group received the isocaloric nutritional intervention. The results show that, compared to sham, MCT mice have an increase in heart weight, RV thickness and fibrosis, which were attenuated in MCT+NI mice. Microarray and qRT-PCR analysis on the RV confirmed effects on fibrotic pathways. Skeletal muscle fiber cross-sectional area (CSA) of the TA was reduced in MCT compared to sham mice, but preserved in the MCT+NI group. In the EDL a similar effect was seen. The findings show that nutritional intervention significantly attenuated changes in both cardiac and skeletal muscle in a mouse model of PAH, providing directions for future therapeutic strategies targeting functional decline of both tissues.The combined results of this thesis show that inflammation is a recurring factor in the pathophysiology of PAH that is not only related to disease outcome, but also to nutritional factors. Recommendations for the clinic and future directions for research are provided in chapter 6. The future has to reveal the full potential of nutritional intervention to complement treatment strategies in PAH.