Thinking Outside the Lungs: Extrapulmonary Manifestations in PAH

This points to the BMPR2 pathway as a potential contributing factor to albuminuria in PAH. These results suggest that “kidney dysfunction in patients with PAH carries a robust prognostic potential that is not solely attributable to the cardiopulmonary-renal interaction and could represent a systemic manifestation of PAH itself,” wrote Nickel et al.1

Metabolic and Endocrine Dysfunction

Results of various clinical and animal studies support links between insulin resistance, hyperlipidemia, and thyroid dysfunction in PAH. Studies have shown that a substantial portion of patients with hyperthyroidism had elevated pulmonary pressures that normalized with resolution of the condition, and other research has identified hypothyroidism in approximately 20% to 25% of patients with PAH.1,4 Both states have been connected to endothelial cell dysfunction, decreased nitric oxide production, and increased pulmonary vascular resistance.1

Skeletal and Respiratory Musculature Dysfunction

“While the typical symptoms of PAH, such as fatigue, shortness of breath, and exercise intolerance, have been traditionally considered to arise from right heart dysfunction, recent studies have revealed that abnormalities of both skeletal and respiratory musculature contribute to the pathology of PAH,” Nickel et al explained.1 These include reduced muscle strength, increased muscle protein degradation, a switch from type I toward type II muscle fibers, and impaired mitochondrial function, among other deficits. Clinicians “should advise patients to participate in pulmonary rehabilitation programs and engage in regular mild resistance training to counteract the adverse effects of the systemic myopathy in PAH.”

Even the presence of subtle extrapulmonary manifestations could significantly affect outcomes in PAH. Future research should investigate associated mechanisms and explore whether screening for these manifestations can facilitate risk stratification and treatment in patients with PAH. “Until then, structured physical exercise and controlling modifiable cardiovascular risk factors will be essential measures in the treatment of PAH,” Nickel et al concluded.

To glean further insights regarding systemic manifestations in PAH, Pulmonology Advisor interviewed Dr Nickel and one of his coauthors, Vinicio A de Jesus Perez, MD, FCCP, FAHA, ATSF, associate professor of medicine in the division of pulmonary and critical care medicine at Stanford University Medical Center and staff physician at the Stanford Adult Pulmonary Hypertension Clinic in California.

Pulmonology Advisor: What are the most notable findings thus far regarding extrapulmonary manifestations in PAH?

Drs de Jesus Perez and Nickel: The main finding from our review is that there is cumulating evidence for organ dysfunction outside the lungs in patients with PAH. This includes abnormalities in the circulation of the brain, eye, tongue, heart, and skeletal muscle. In addition, insulin resistance as well as thyroid and kidney dysfunction are highly prevalent in patients with PAH.

This has not been widely recognized among clinicians caring for patients with this deadly disease. Recognizing extrapulmonary comorbidities will have important implications for management, treatment, and potentially outcomes in this patient population.

Pulmonology Advisor: What are some of the proposed mechanisms underlying these systemic abnormalities?

Drs de Jesus Perez and Nickel: In this review we propose a paradigm in which metabolic abnormalities, genetic injury, and systemic inflammation create a state of global vascular dysfunction in patients with PAH. This renders these patients susceptible for organ dysfunction outside the pulmonary circulation.

Pulmonology Advisor: What are the relevant implications for clinicians, including screening and treatment considerations?

Drs de Jesus Perez and Nickel: Since the field of systematic research of extrapulmonary morbidities in patients with PAH is still in its early development, there are no defined screening or treatment guidelines. However, it is important to recognize that beyond thyroid dysfunction and insulin resistance, patients with PAH are at increased risk for kidney dysfunction and coronary artery disease. Clinicians caring for patients with PAH should screen for these comorbidities on a routine basis.

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Pulmonology Advisor: What should be next steps in terms of research on this topic?

Drs de Jesus Perez and Nickel: Carefully designed clinical studies need to be carried out to help us better understand the molecular underpinnings of organ dysfunction outside the pulmonary circulation in PAH. It is possible that pathways that are disturbed in the pulmonary circulation (such as BMP-signaling) are also affected outside the lungs, leading to a specific dysfunction.

Furthermore, we need to investigate other vascular beds in these patients. For instance, the retinal microcirculation is easily accessible and highly versatile in health and disease. There are preliminary data that the retinal circulation is affected in patients with PAH.5 It will be important to explore whether we can use changes in the retinal microcirculation as a potential biomarker that can help us predict response to treatment or clinical worsening in patients with PAH.


1. Nickel NP, Yuan K, Dorfmuller P, et al. Beyond the lungs: Systemic manifestations of pulmonary arterial hypertension [published online September 12, 2019]. Am J Respir Crit Care Med. doi:10.1164/rccm.201903-0656CI

2. Malenfant S, Brassard P, Paquette M, et al. Compromised cerebrovascular regulation and cerebral oxygenation in pulmonary arterial hypertension. J Am Heart Assoc. 2017;6(10):e006126.

3. Hughes R, Tong J, Oates C, Lordan J, Corris PA. Evidence for systemic endothelial dysfunction in patients and first-order relatives with pulmonary arterial hypertension. CHEST. 2005;128(6 Suppl):617S.

4. Siu CW, Zhang XH, Yung C, Kung AW, Lau CP, Tse HF. Hemodynamic changes in hyperthyroidism-related pulmonary hypertension: a prospective echocardiographic study. J Clin Endocrinol Metab. 2007;92:1736-1742.

5. Chyou AC, Klein BEK, Klein R, et al. Retinal vascular changes and right ventricular structure and function: the MESA-Right Ventricle and MESA-Eye studies. Pulm Circ. 2018;9(1):2045894018819781.