← Back to October 2017


Evil Humors, the Right Ventricle, and Pulmonary Arterial Hypertension


Kurt Prins, MD, PhD
prin0088@umn.edu

Thenappan Thenappan, MD
tthenapp@umn.edu
University of Minnesota Medical School
Minneapolis, MN, USA



Medieval medicine was based on the theory that four humors: black bile, phlegm, blood and yellow bile had to be balanced for the body to function properly and imbalance of these humors was the basis of human disease. Blood-letting was a treatment strategy implemented to restore humoral balance and remove evil humors from the body. Thankfully, our knowledge of human physiology is much more sophisticated and bloodletting, outside of polycythemia, is a treatment from the days of yore. However, inflammation may be the modern day evil humor that physicians must combat in multiple disease states.

Inflammation plays a key role in pulmonary arterial hypertension (PAH) disease development and progression [1]. At the microscopic level, histopathological analysis shows an increased number of multiple inflammatory cell types including T- and B-lymphocytes, macrophages, plasma cells, mast cells and dendritic cells into the pulmonary vasculature with strong evidence that these cells promote pulmonary vascular remodeling [1]. Moreover, adventitial fibroblast also play a central role in inflammation-mediated pulmonary vascular remodeling [2]. While this is more commonly observed in PAH associated with connective tissue disease, human immunodeficiency virus infection and schistosomiasis infection, it is also observed in idiopathic and heritable PAH. In addition, circulating levels of inflammatory cytokines (interleukin-1?, -2, -4, -6, -8, -10, -12p70 chemokine-CXC3L1, -CCL5, -CCL2, and leukotriene B4) are elevated in patients with PAH [3-5]. Elevated levels of circulating inflammatory cytokines are associated with increased mortality in PAH; however, we currently do not have a strong grasp on ways to combat inflammation in PAH as a way to alter the disease course [3, 6].

In our most recent work, we turned the spotlight of inflammation from the pulmonary vasculature to the right ventricle (RV) and investigated how one particular evil humor, interleukin-6 (IL6), is associated with RV dysfunction in PAH. This study was conducted because preclinical data demonstrated that IL6 has a negative inotropic effect on cardiomyocytes mediated through nitric oxide [7] and calcium mishandling [8]. The amount of IL6 mRNA in heart samples from patients who underwent cardiac transplant was inversely correlated with left ventricular ejection fraction [9]. Therefore, we investigated the relationship between serum IL6 and RV function in 40 PAH patients. We showed a negative logarithmic relationship between serum IL6 and RV function as quantified by echocardiography. Moreover, patients with higher IL6 levels had worse RV function as quantified by TAPSE and RV fractional area change, higher right atrial pressures and lower cardiac index despite no significant differences in mean pulmonary arterial pressure, pulmonary vascular resistance (PVR) and pulmonary arterial compliance (PAC) when compared to patients with lower IL6 levels. Finally, there was a significant association between IL6 and RV function even after adjusting for PVR and PAC on multivariable analysis [10]. While our findings are hypothesis generating, we were unable to determine if elevated levels of IL6 cause RV dysfunction, or if they are simply a consequence of RV dysfunction in PAH patients. Therefore, more research is needed to further define the role of IL6 in RV dysfunction in PAH.

Moving forward, the PAH community will undoubtedly gain understanding of how the evil humors of inflammation play a role in PAH pathogenesis through ongoing clinical trials. Firstly, the effects of rituximab, a CD-20 monoclonal antibody, on PVR, six-minute walk test, time to clinical worsening and quality of life will be examined in patients with Systemic-Sclerosis associated PAH in a placebo-controlled trial (NCT01086540). Furthermore, the effects of tocilizumab, an IL6 receptor antagonist, on PVR, six-minute walk test and N-terminal pro-BNP will be examined in PAH patients in a single-armed study (NCT02676947). Finally, the Liberty trial, a phase 2 randomized, placebo-controlled, double-blind study, will evaluate the safety and the efficacy of leukotriene B4 inhibitor, Ubenimex, on PVR, exercise capacity and time to clinical worsening in patients with PAH on standard of care (NCT02664558). Hopefully, these three trials, in addition to other ongoing basic, translational and clinical research studies, will shed more light on how we can combat evil humors to improve outcomes in PAH. ■

Disclosure Statement: The authors have no conflicts of interest to disclose.


References:

  1. Rabinovitch M, Guignabert C, Humbert M, Nicolls MR: Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 2014;115:165-75.
  2. Pugliese SC, Poth JM, Fini MA, Olschewski A, El Kasmi KC, Stenmark KR: The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes. Am J Physiol Lung Cell Mol Physiol 2015;308:L229-52.
  3. Soon E, Holmes AM, Treacy CM, et al.: Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 2010;122:920-7.
  4. Humbert M, Monti G, Brenot F, et al.: Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am J Respir Crit Care Med 1995;151:1628-31.
  5. Qian J, Tian W, Jiang X, et al.: Leukotriene B4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension. Hypertension 2015;66:1227-39.
  6. Heresi GA, Aytekin M, Hammel JP, Wang S, Chatterjee S, Dweik RA: Plasma interleukin-6 adds prognostic information in pulmonary arterial hypertension. Eur Respir J 2014;43:912-4.
  7. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL: Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992;257:387-9.
  8. Kinugawa K, Takahashi T, Kohmoto O, et al.: Nitric oxide-mediated effects of interleukin-6 on [Ca2+]i and cell contraction in cultured chick ventricular myocytes. Circ Res 1994;75:285-95.
  9. Plenz G, Song ZF, Tjan TD, et al.: Activation of the cardiac interleukin-6 system in advanced heart failure. Eur J Heart Fail 2001;3:415-21.
  10. Prins K, Archer S, Pritzker M, et al.: Interleukin-6 is independently associated with right ventricular function in pulmonary arterial hypertension. Journal of Heart and Lung Transplantation; 2017.



Share via:

links image    links image    links image    links image