Supplementing Pulmonary Arterial Hypertension Therapy With Nutritional Changes

Fatigue and exercise intolerance are common features of pulmonary arterial hypertension (PAH), and poor exercise capacity is a predictor of worse prognosis.¹ Emerging research suggests that nutritional status may have a role in the etiology and severity of these symptoms.

“While patients [with PAH] have a number of risk factors for poor nutrition and nutritional deficiencies, there has been a lack of large-scale studies reporting these nutritional deficiencies directly in patients [with PAH] and how they relate to outcomes,” Stephen Chan, MD, PhD, FAHA, director of the Center for Pulmonary Vascular Biology and Medicine at the University of Pittsburgh Medical Center in Pennsylvania, told Pulmonology Advisor. “As the disease progresses, exercise intolerance and skeletal muscle dysfunction can lead to difficulty mobilizing, muscle atrophy, and further deconditioning. In that regard, nutritional intake can be affected, particularly [in] those [who have] heart failure manifesting.”

A sizable body of research has shown associations between various forms of exercise training (aerobic exercise, resistance training, and respiratory training) and improvements in heart rate, systemic pulmonary artery pressure, exercise capacity, peak oxygen capacity, and quality of life in patients with PH. However, “[a]lthough the pathophysiology of PAH involves many mechanisms that may influence nutritional status and may induce muscle wasting, potentially limiting the effect of exercise interventions, there is only little scientific knowledge about the nutritional status of PAH patients and the way this may impact physical activity,” according to a study published in Heart Failure Reviews.¹

The authors reviewed the limited available data on the role of nutrition in PAH.

Iron Deficiency

Findings from various studies indicate that an estimated 30% to 65% of individuals with PAH have iron deficiency, which occurs in the absence of anemia and is associated with disease severity and mortality in these patients.^1,2 Iron deficiency “contributes to the disease itself and to exercise intolerance by influencing the pulmonary circulation, myocardial and skeletal muscle function, and oxidative energy metabolism,” as explained in the review. “High levels of hepcidin, induced by inflammatory cytokines and/or dysfunctional [bone morphogenetic protein type II receptor] signaling, lead to inhibition of dietary iron uptake.” This is supported by results demonstrating a poor response to oral iron supplementation in patients with PAH.^3,4

Subsequent research has examined the potential benefits of intravenous iron infusion in this population. A 2014 pilot study investigated the effects of a single infusion of ≤1000 mg ferric carboxymaltose on iron status, 6-minute walk distance, and quality of life, as assessed by the 36-Item Short-Form Survey (SF-36) in 20 iron-deficient patients with PAH who were receiving targeted PAH therapy.² Two months after an iron infusion, participants showed improvements in iron status (serum iron 5.7±0.4 to 11.1±1.1 μmol/L [P =.001], ferritin 29.3±6.3 to 145.2±25.4 μg/L [P <.001], and transferrin saturation 7.5%±0.7% to 19.3%±2.3% [P <.001]), as well as 6-minute walk distance (346.5±28.3 m to 374.0±25.5 m; P =.007) and quality of life (SF-36 score from 44.3±3.7 to 50.6±3.6; P =.01). Reported adverse effects were minimal.

A similar study published in 2015, using the same dose of intravenous iron in 15 iron-deficient patients with PAH, also found improvements in iron serum iron status and quality of life, as well as exercise endurance time, aerobic capacity, and mitochondrial oxidative capacity 12 weeks after iron treatment.⁴ However, Rutier et al did not find any significant improvements in 6-minute walk distance. The researchers attributed this partly to the different types of exercises (eg, biking vs walking).

A phase 2 randomized, placebo-controlled trial is currently underway in the United Kingdom, which aims to investigate the effects of intravenous iron infusion on various measures in at least 60 patients with PAH.⁵  

“It should be noted, however, that in certain types of pulmonary hypertension, such as sickle cell disease, iron overload, rather than deficiency, has been linked to more severe pulmonary hypertension, so there may be great complexity to this story,” Dr Chan stated.

Vitamin D Deficiency

Vitamin D deficiency has also been linked to numerous diseases including pulmonary hypertension. In a recent prospective uncontrolled study, weekly vitamin D replacement therapy for a period of 3 months increased serum vitamin D levels by 54.8 ng/mL (P =.01) and 6MWD by 81.6 m in 22 patients with PAH (P <.001). In addition, there was significant improvement in right ventricular RV size (P =.01).⁶

Further research is needed regarding the effects of iron, vitamin D, and other nutritional therapies on PAH symptoms and quality of life. “If nutritional support can be directly linked to improved outcomes in PAH, this could be an important new avenue for clinical management of the disease,” Dr Chan noted. “Currently, while nutritional support for all chronically ill patients is emphasized, there has been little direct recommendation for concentrating our efforts on monitoring and bolstering nutritional intake in this disease.”

Larger, more rigorous studies supporting the benefits of nutritional therapy in PAH could ultimately promote its widespread acceptance among clinicians. “Furthermore, preclinical studies should be geared toward understanding molecular mechanisms by which poor nutrition or lack of a specific nutrient, such as iron, may be directly linked to the development or worsening of this disease,” Dr Chan said.

References

1. Vinke P, Jansen SM, Witkamp RF, van Norren K. Increasing quality of life in pulmonary arterial hypertension: is there a role for nutrition? [published online June 16, 2018]. Heart Fail Rev. doi:10.1007/s10741-018-9717-9
2. 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(2):233-239.
3. Rhodes CJ, Wharton J, Howard L, Gibbs JS, Vonk-Noordegraaf A, Wilkins MR. Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target. Eur Respir J. 2011;38(6):1453-1460.
4. Ruiter G, Manders E, Happé CM, et al. Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency. Pulm Circ. 2015;5(3):466-472.
5. Howard LSGE, Watson GM, Wharton J. Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension. Pulm Circ. 2013;3(1):100-107.
6. Mirdamadi A, Moshkdar P. Benefits from the correction of vitamin D deficiency in patients with pulmonary hypertension. Caspian J Intern Med. 2016;7(4):253-259.6.