Pulmonary arterial hypertension (PAH) is a lung disease characterized by increased blood pressure (BP) in the pulmonary circulation ultimately causing right ventricular (RV) failure (RVF). Although in the last decades progress has been made in the pharmacological treatment of PAH, little attention has been paid on nutrition and lifestyle strategies. For this, the only recommendation in the most recent consensus article is the mentioning of avoiding salt and high-fluid intake . Significantly, in patients with left heart failure (LHF) the important role of nutritional education and interventions has been well recognized and are an integral part of LHF management [2,3].
The current review will describe the known mechanisms of malnutrition in PAH, summarize studies exploring nutrition-related interventions in PAH and identify knowledge gaps.
Intake, appetite and malabsorption
Malnutrition in patients with LHF has been extensively described and is a result from many different components, including appetite loss, bowel congestion due to hepatic or gastrointestinal dysfunction, metabolic disturbances, medication-related effects, fatigue, higher resting metabolic rate and increased work of breathing . In patients with PAH, malnutrition has been less studied although venous congestion and lower BMI are typical features of severe right heart failure [5,6]. At this moment, there is no information available about appetite and metabolism rate in PAH [6,7]. Malabsorption as a consequence of gastrointestinal edema due to decreased RV function, alterations in the gut microbiome and impact of PAH medication on the bowel however will result in decreased nutrient uptake  (Fig. 1).
Medication and malabsorption
High-dose diuretics are used on a regular base in PAH to prevent fluid retention. Long-term use of furosemide in patients with LHF results in a thiamine deficiency, which is an important vitamin for energy and carbohydrate regulation . Whether thiamine and proton pump inhibitor (PPI)-related vitamin deficiencies are relevant in PAH is currently unknown. A recent study among 343 geriatric patients, shows hypomagnesemia as a consequence of long-term use of PPI and other medications, such as vitamin K antagonists. The number of drugs used was inversely and linear related to the plasma level of magnesium. Hypomagnesemia is closely associated with cardiovascular disease and events. Whether hypomagnesemia is relevant in PAH is not investigated jet . Symptoms of hypomagnesemia are: muscle cramps, palpitations and cardiovascular disease . A frequent used drug in the treatment of PAH is prostacyclin and a common side effect is diarrhea. Prostacyclin activates adenylate cyclase, which increases cyclic adenosine monophosphate (cAMP). cAMP causes secretion of chlorine from interstitial tissue to the gut lumen along with sodium and water. Fluid and electrolyte proliferation in the intestinal lumen leads to diarrhea [11,12], which causes malabsorption. Selexipag, a prostacyclin analogue, gives identical side effects.
Gastrointestinal edema and fluid retention
PAH-patients suffer from fluid retention, due to RVF, which leads to venous congestion and a low cardiac output (CO) and has as a consequence a low systemic BP. To prevent fluid retention at the kidney level, diuretics are standard in the treatment of RVF. Although it is likely that a strict diet based on fluid and salt restriction has beneficial effects on the management of RVF, this has not been studied until now. Finally, high-glucose and insulin levels have been shown to increase salt and water retention and are closely associated with kidney dysfunction and PAH [13–19].
Glucose and insulin resistance
In recent years, more interest has developed in the role of insulin resistance and diabetes in pulmonary hypertension. Several reports showed increased glucose intolerance and resting expenditure with reduced insulin secretion in PAH patients, worse 6-min walking distance in patients with more insulin resistance, and even worse survival in patients with PAH and concomitant diabetes [20,21]. It is unclear whether insulin resistance play a role in the development of the disease or is just a marker of disease severity.
In addition, RV adaptation is crucial in PAH and might be influenced by diet. In a mouse model, a western diet-induced higher pulmonary artery pressure, RV diastolic dysfunction and RV steatosis. In mice where pulmonary hypertension was induced by pulmonary artery banding, a more pronounced effect was seen of the western (high fat) diet compared with healthy mice [22▪]. Metformin was able to prevent all these effects.
Many bacteria and other microorganisms colonize the human gut. The microbiome produces many metabolites that can exert biological effects and is responsible for maintaining the gut barrier function. Changes in the microbiome have been previously shown in several diseases such as LHF, diabetes, chronic kidney failure and obesity where a less diverse microbiome was found [23,24]. Adding probiotics or prebiotics have been shown to restore the microbiome and reduce BP in systemic hypertension [24,25].
In pulmonary hypertensive rats, the gut microbiome was less diverse compared with controls. There were more short-chain fatty acid (FA) producing bacteria and a trend toward more acetate producing bacteria [26▪]. These specific alterations in microbiome can lead to bacterial translocation, resulting in higher plasma bacterial lipopolysaccharide (LPS), which is the main ligand for Toll-like receptor four (TLR4). Strikingly, TLR4 alone is already associated with development of pH even without LPS [27,28]. An additional factor that favors bacterial translocation is intestinal edema, which also compromises the guts barrier function [26▪,27]. Whether the microbiome is changed in PAH and if a diet can restore these possible changes, needs to be explored in future.
Although little is known about the nutritional state of PAH patients, two deficiencies have been explored in more debt: iron and vitamin D.
Iron deficiency is common in PAH patients and is associated with reduced exercise capacity, higher New York Heart Association Classification functional class and worse survival, irrespective of the presence of anemia [29–32]. Iron deficiency in PAH patients most likely develops due to a combination of lower intake and absorption of iron, increased iron loss, and iron utilization due to increased erythropoiesis [32–34]. Disturbed iron handling due to high hepcidin levels, however, is probably the most important contributor to iron deficiency development in PAH, as hepcidin reduces intracellular iron release into the bloodstream [31,35]. Although hepcidin is increased by inflammatory marker IL-6, which is generally increased in PAH patients, no direct relation between IL-6 and hepcidin was found in iron deficient PAH cohorts [31,35]. Other factors that influence hepcidin in PAH are BMPR2 mutations, resulting in BMP-6 stimulated hepcidin expression, increased erythroid precursor growth differentiation factor-15 and mutations in GATA-4 [31,36]. Supplying intravenous iron resulted in improved 6-min walking tests, exercise endurance time and aerobic capacity, and quality of life. Increased quadriceps muscle oxygen handling could be the cause of the improvement since RVF remained unaltered [35,37].
Tanaka et al. showed that 61% of 41 patients with PAH and chronic thromboembolic pulmonary hypertension, was vitamin D deficient. A lower 25(OH)D levels was associated with a poor hemodynamic phenotype  Mirdamadi et al. prescribed supplemental vitamin D to PAH patients and showed improved 6-min walking distance after treatment. However, only 22 patients were included with all different kinds of pulmonary hypertension and these results should therefore be interpreted with caution . A few studies investigated whether vitamin D plays a pathophysiological role in PAH [38,40]. In an in-vitro setup, adding a precursor of vitamin D to rat pulmonary artery endothelial cells, led to a reversal of hypoxia-induced activation of pathways of inflammation, fibrosis and proliferation. This was represented by reduced expression of transforming growth factor-beta1, alpha smooth muscle actin and Smad7 with induced expression of microRNA-204, p21 and Smad2, which have been reported to be involved in the development of pH . Similar biomarker results were then found in vivo in pH rats were vitamin D was given intraperitoneal . In another pH rat model, supplementation of dietary vitamin D improved survival and inhibited RV remodeling although hemodynamic parameters were not different. Also medial wall thickness of pulmonary arteries was unaltered by supplemental vitamin D . For this, further research is required to explore the impact of screening on vitamin D deficiency and the impact of suppletion.
WHAT CAN WE LEARN FROM NUTRITION STUDIES IN PATIENTS WITH LEFT HEART FAILURE
Although mechanisms of disease are different in LHF and PAH patients, the impact of heart failure on the body share almost similar characteristics leading to malnutrition and muscle wasting. Since no studies exploring the impact of dietarian interventions in PAH so far, it is worthwhile to take lessons from LHF. Several diets have been tested in LHF which could give some information about possible benefit in PAH. A 6-week high-calorie high-protein diet in patients with LHF resulted in increased edema-free body weight, body composition and quality of life. Increased serum lipoproteins and reduced serum TNFα levels were found . A Mediterranean diet, characterized by intake of FAs such as olive oil and fish, vegetables, grains, nuts and red wine, was associated with improved cardiac function, less cardiac remodeling and cardiovascular events, and a reduction of LHF risk and LHF-related mortality [42–46]. Furthermore, the Dietary Approach to Stop Hypertension (DASH) diet, characterized by low-salt, red meat, saturated fat, sugar-intake and low-fat dairy products, with high magnesium, potassium, calcium, amino-acids, fiber, fruit, vegetables and whole grains, was associated with improved cardiac function, exercise capacity and quality of life [47–50].
Although malnutrition and waste loss are frequently found in PAH, little is known on the effectiveness of nutrition and lifestyle interventions in PAH-patients. Mechanisms underlying malnutrition and food deficiencies include low CO state, intestinal edema, inflammation, abnormal kidney function, changes in microbiome and side effects of PAH-specific medication and diuretics. Common deficiencies include iron and vitamin D. Although small studies showed the beneficial impact of iron and vitamin D, large-scaled studies on dietary interventions are lacking in PAH. Further research in this area in PAH should focus on a systematic analysis of nutritional state in PAH, development of a validated and disease-specific score for malnutrition in PAH and dietarian intervention studies.
Financial support and sponsorship
C.T.K. and A.V.N. were supported by The Netherlands Organization for Scientific Research (NWO-VICI: 66484.029.18).
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Rev Esp Cardiol 2016; 69:177.
2. Abshire M, Xu J, Baptiste D, et al. Nutritional interventions in heart failure: a systematic review of the literature. J Card Fail 2015; 21:989–999.
3. Ferrante D, Varini S, Macchia A, et al. Long-term results after a telephone intervention in chronic heart failure: DIAL (randomized trial of phone intervention in chronic heart failure) follow-up. J Am Coll Cardiol 2010; 56:372–378.
4. Saitoh M, Rodrigues Dos Santos M, von Haehling S. Muscle wasting in heart failure: the role of nutrition
. Wien Klin Wochenschr 2016; 128 (Suppl 7):455–465.
5. Pfeuffer E, Krannich H, Halank M, et al. Anxiety, depression, and health-related QOL in patients diagnosed with PAH or CTEPH. Lung 2017; 195:759–768.
6. Kawamoto A, Kato T, Minamino-Muta E, et al. Relationships between nutritional status and markers of congestion in patients with pulmonary arterial hypertension. Int J Cardiol 2015; 187:27–28.
7. McKenna SP, Doughty N, Meads DM, et al. The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR): a measure of health-related quality of life and quality of life for patients with pulmonary hypertension. Qual Life Res 2006; 15:103–115.
8. Katta N, Balla S, Alpert MA. Does long-term furosemide therapy cause thiamine deficiency in patients with heart failure? A focused review. Am J Med 2016; 129:753.e7–753.11.
9. van Orten-Luiten ACB, Janse A, Verspoor E, et al. Drug use is associated with lower plasma magnesium levels in geriatric outpatients; possible clinical relevance. Clin Nutr 2018; [Epub ahead of print].
10. Van Laecke S. Hypomagnesemia and hypermagnesemia. Acta Clinica Belgica 2019; 74:41–47.
11. Wagner SM, Mekhjian HS, Caldwell JH, Thomas FB. Effects of caffeine and coffee on fluid transport in the small intestine. Gastroenterology 1978; 75:379–381.
12. Ewe K. The physiological basis of laxative action. Pharmacology 1980; 20 (Suppl 1):2–20.
13. Rippe JM, Angelopoulos TJ. Fructose-containing sugars and cardiovascular disease. Adv Nutr 2015; 6:430–439.
14. Chen L, Caballero B, Mitchell DC, et al. Reducing consumption of sugar-sweetened beverages is associated with reduced blood pressure: a prospective study among United States adults. Circulation 2010; 121:2398–2406.
15. DiNicolantonio JJ, Lucan SC. The wrong white crystals: not salt but sugar as aetiological in hypertension and cardiometabolic disease. Open Heart 2014; 1:e000167.
16. Horita S, Nakamura M, Suzuki M, et al. Selective insulin resistance in the kidney. Biomed Res Int 2016; 2016:5825170.
17. Bedi KC Jr, Snyder NW, Brandimarto J, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 2016; 133:706–716.
18. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on ketone bodies as a fuel. Circulation 2016; 133:698–705.
19. Angelopoulos TJ, Lowndes J, Sinnett S, Rippe JM. Fructose containing sugars at normal levels of consumption do not effect adversely components of the metabolic syndrome and risk factors for cardiovascular disease. Nutrients 2016; 8:179.
20. Grinnan D, Farr G, Fox A, Sweeney L. The role of hyperglycemia and insulin resistance in the development and progression of pulmonary arterial hypertension. J Diabetes Res 2016; 2016:2481659.
21. Heresi GA, Malin SK, Barnes JW, et al. Abnormal glucose metabolism and high-energy expenditure in idiopathic pulmonary arterial hypertension. Ann Am Thorac Soc 2017; 14:190–199.
22▪. Brittain EL, Talati M, Fortune N, et al. Adverse physiologic effects of Western diet on right ventricular structure and function: role of lipid accumulation and metabolic therapy. Pulm Circ 2019; 9:2045894018817741.
Interesting article which highlights the direct effects of a high-fat diet on the right ventricle in an animal model.
23. Li DY, Tang WHW. Contributory role of gut microbiota and their metabolites toward cardiovascular complications in chronic kidney disease. Semin Nephrol 2018; 38:193–205.
24. Tang WHW, Li DY, Hazen SL. Dietary metabolism, the gut microbiome
, and heart failure. Nat Rev Cardiol 2019; 16:137–154.
25. Gomez-Guzman M, Toral M, Romero M, et al. Antihypertensive effects of probiotics Lactobacillus strains in spontaneously hypertensive rats. Mol Nutr Food Res 2015; 59:2326–2336.
26▪. Callejo M, Mondejar-Parreno G, Barreira B, et al. Pulmonary arterial hypertension affects the rat gut microbiome
. Sci Rep 2018; 8:9681.
One of the few studies which investigated the gut microbiome in relation with pulmonary hypertension (in a rat model).
27. Ranchoux B, Bigorgne A, Hautefort A, et al. Gut-lung connection in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 2017; 56:402–405.
28. Bauer EM, Chanthaphavong RS, Sodhi CP, et al. Genetic deletion of Toll-like receptor 4 on platelets attenuates experimental pulmonary hypertension. Circ Res 2014; 114:1596–1600.
29. Yu X, Zhang Y, Luo Q, et al. Iron deficiency in pulmonary arterial hypertension associated with congenital heart disease. Scand Cardiovasc J 2018; 52:378–382.
30. Ruiter G, Lankhorst S, Boonstra A, et al. Iron deficiency is common in idiopathic pulmonary arterial hypertension. Eur Respir J 2011; 37:1386–1391.
31. Rhodes CJ, Howard LS, Busbridge M, et al. Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: clinical prevalence, outcomes, and mechanistic insights. J Am Coll Cardiol 2011; 58:300–309.
32. van Empel VP, Lee J, Williams TJ, Kaye DM. Iron deficiency in patients with idiopathic pulmonary arterial hypertension. Heart Lung Circ 2014; 23:287–292.
33. Soon E, Crosby A, Southwood M, et al. Bone morphogenetic protein receptor type II deficiency and increased inflammatory cytokine production. A gateway to pulmonary arterial hypertension. Am J Respir Crit Care Med 2015; 192:859–872.
34. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306:2090–2093.
35. Ruiter G, Manders E, Happe CM, et al. Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency. Pulm Circ 2015; 5:466–472.
36. Island ML, Fatih N, Leroyer P, et al. GATA-4 transcription factor regulates hepatic hepcidin expression. Biochem J 2011; 437:477–482.
37. Viethen T, Gerhardt F, Dumitrescu D, et al. Ferric carboxymaltose improves exercise capacity and quality of life in patients with pulmonary arterial hypertension and iron deficiency: a pilot study. Int J Cardiol 2014; 175:233–239.
38. Tanaka H, Kataoka M, Isobe S, et al. Therapeutic impact of dietary vitamin D supplementation for preventing right ventricular remodeling and improving survival in pulmonary hypertension. PLoS One 2017; 12:e0180615.
39. Mirdamadi A, Moshkdar P. Benefits from the correction of vitamin D deficiency in patients with pulmonary hypertension. Caspian J Intern Med 2016; 7:253–259.
40. Yu H, Xu M, Dong Y, et al. 1,25(OH)2D3 attenuates pulmonary arterial hypertension via microRNA-204 mediated Tgfbr2/Smad signaling. Exp Cell Res 2018; 362:311–323.
41. Rozentryt P, von Haehling S, Lainscak M, et al. The effects of a high-caloric protein-rich oral nutritional supplement in patients with chronic heart failure and cachexia on quality of life, body composition, and inflammation markers: a randomized, double-blind pilot study. J Cachexia Sarcopenia Muscle 2010; 1:35–42.
42. Wirth J, di Giuseppe R, Boeing H, Weikert C. A Mediterranean-style diet, its components and the risk of heart failure: a prospective population-based study in a non-Mediterranean country. Eur J Clin Nutr 2016; 70:1015–1021.
43. Tektonidis TG, Akesson A, Gigante B, et al. Adherence to a Mediterranean diet is associated with reduced risk of heart failure in men. Eur J Heart Fail 2016; 18:253–259.
44. Tektonidis TG, Akesson A, Gigante B, et al. A Mediterranean diet and risk of myocardial infarction, heart failure and stroke: a population-based cohort study. Atherosclerosis 2015; 243:93–98.
45. Chrysohoou C, Panagiotakos DB, Aggelopoulos P, et al. The Mediterranean diet contributes to the preservation of left ventricular systolic function and to the long-term favorable prognosis of patients who have had an acute coronary event. Am J Clin Nutr 2010; 92:47–54.
46. Pastori D, Carnevale R, Bartimoccia S, et al. Does Mediterranean diet reduce cardiovascular events and oxidative stress in atrial fibrillation? Antioxid Redox Signal 2015; 23:682–687.
47. Hummel SL, Seymour EM, Brook RD, et al. Low-sodium DASH diet improves diastolic function and ventricular-arterial coupling in hypertensive heart failure with preserved ejection fraction. Circ Heart Fail 2013; 6:1165–1171.
48. Hummel SL, Seymour EM, Brook RD, et al. Low-sodium dietary approaches to stop hypertension diet reduces blood pressure, arterial stiffness, and oxidative stress in hypertensive heart failure with preserved ejection fraction. Hypertension 2012; 60:1200–1206.
49. Mathew AV, Seymour EM, Byun J, et al. Altered metabolic profile with sodium-restricted dietary approaches to stop hypertension diet in hypertensive heart failure with preserved ejection fraction. J Card Fail 2015; 21:963–967.
50. Rifai L, Pisano C, Hayden J, et al. Impact of the DASH diet on endothelial function, exercise capacity, and quality of life in patients with heart failure. Proceedings 2015; 28:151–156.