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Sex Differences in Response to Pulmonary Arterial Hypertension TherapySex Differences in the Right Ventricle: Is What’s Good for the Goose, Good for the Gander? FREE TO VIEW

Nathan Hatton, MD; John J. Ryan, MD
Author and Funding Information

From the Division of Pulmonary Medicine (Dr Hatton) and Division of Cardiovascular Medicine (Dr Ryan), Department of Medicine, the University of Utah.

Correspondence to: John J. Ryan, MD, Division of Cardiovascular Medicine, University of Utah Health Science Center, 30 N 1900 E, Room 4A100, Salt Lake City, UT 84132; e-mail: john.ryan@hsc.utah.edu


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(6):1184-1186. doi:10.1378/chest.13-3061
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Pulmonary arterial hypertension (PAH) is predominantly a disease of women, with ratios of 4:1 in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry),1 2:1 in the UK and Ireland registry,2 and 2:1 in the French registry also.3 However, the prognosis is worse in men with PAH compared with female patients,4 with the 5-year survival from diagnosis of PAH being estimated at 62% in women compared with 52% in men.5 The reason for this discrepancy in survival has been poorly understood and understudied.

PAH is unique in cardiopulmonary clinical research because men are often underrepresented in randomized controlled trials (RCTs). In fact, in the largest studies performed evaluating various PAH vasodilator therapies to date, < 25% of the patients enrolled have been men. The reason for the different male to female ratios between RCTs and different registries is unclear and may reflect trial bias or diagnostic bias. Although the small numbers of men formally studied limits the ability to perform sex-specific analysis of the response to pulmonary vasodilator therapy, important work has been done to determine the pattern and etiology of these sex differences. Previously, analysis of patient-level data from six RCTs of endothelin receptor antagonists (ERAs) submitted to the US Food and Drug Administration (FDA) identified sex and race differences in response to ERAs. For example, after 12 weeks of ERA therapy, the placebo-adjusted 6-min walk distance improved by 44.1 m in women compared with only 16.7 m in men.6

A sex difference in right ventricular function has also been observed in registry data. In particular, the work of Kawut et al7 and Ventetuolo et al8 has identified that men without cardiovascular disease have a lower right ventricular ejection fraction (RVEF) compared with women7 and, furthermore, that higher estradiol levels are associated with higher RVEF in women using hormone therapy.8

Despite the lack of data in human trials, some mechanistic insight has been offered from the basic science arena as to why PAH is preferentially tolerated by female patients. Ironically, however, preclinical data have historically relied heavily on male animal models of PAH.9 Estrogen has been implicated as it is not only a potent pulmonary vasodilator through nitric oxide-dependent mechanisms,10 but estrogen therapy has also been shown to reverse right ventricular hypertrophy in a hypoxic pulmonary hypertension animal model.11 Correspondingly, in a mouse pulmonary artery banding model, which is truly a model of right ventricular hypertrophy without concomitant pulmonary vascular disease, survival in male mice is improved with reduction of testosterone via castration.12 In aggregate, these studies draw attention to the role of sex hormones in the right ventricular response to PAH.

It is with this background that the well-conducted study by Jacobs et al13 in this issue of CHEST (see page 1230) is particular timely and relevant. In this article, the authors investigated the reasons for the worsened prognosis in male patients with PAH. They performed a retrospective review of 101 patients referred with PAH to their single center in VU University Medical Centre Amsterdam. Prior to the initiation of therapy, these patients had undergone right-sided heart catheterization and cardiac MRI, as well as recording and indexing of their baseline clinical characteristics. The median follow-up time was 5.7 years, and the 5-year survival was worse in male patients at 63%, compared with female patients with 85%, consistent with prior studies. Men had shorter 6-min walk distances, worse functional class, and higher brain natriuretic peptide levels at follow-up compared with female patients. Importantly, neither the right heart hemodynamics (pulmonary artery pressures, cardiac output, pulmonary vascular resistance) at baseline nor at follow-up showed significant differences between men and women, demonstrating that men were not sicker at baseline, and neither were they less likely to demonstrate a pulmonary vascular response to vasodilator therapy. The type of therapy and escalation of therapy were also no different between men and women to account for the possible difference.

One possible explanation for the observed difference in outcomes could be the change in RVEF. In women, the RVEF improved by an average of 3.6% with the initiation of PAH-specific therapies but the RVEF decreased in men by 1.0%. After adjustment for confounders, mediator analysis showed that approximately 30% of the effect of sex on survival was accounted for by the differences in RVEF at follow-up. Of course, this study still leaves numerous other pathophysiologic reasons, which may contribute to the worsened outcome in male patients, not identified or evaluated by the work presented here. Also, it begs the question how no difference between sexes could be identified in terms of cardiac output and stroke volume, but yet one was observed with RVEF. This is likely explained by the larger increase in right ventricular end-systolic and end-diastolic volumes seen in men compared with women, implying more maladaptive right ventricular remodeling in men. The study is limited by the retrospective nature, as the impact of referral bias, practice bias, and the underlying etiology can be hard to discern. Furthermore, the authors do not report the time from diagnosis to entry into the registry or the mixture of incident and prevalent cases.

The philosopher John Locke14 coined the phrase argumentum ad ignorantiam, wherein a position can only be upheld if there is sufficient evidence to prove the argument definitively. Currently, PAH RCTs are underpowered to determine the exact therapeutic response of men to PAH-specific medication. It would be unfair and unwise to infer that PAH therapies are ineffective in men, a position that would need to call on Locke’s argumentum ad ignorantiam to support that stance. A similar situation exists in the field of implantable cardioverter defibrillators for systolic heart failure. In this area, women are heretofore understudied, and a meta-analysis has observed a lack of mortality benefit for ICD therapy in women with systolic heart failure.15 However, to deny women potentially lifesaving therapy due to the absence of conclusive data would be naive and controversial. What is more important is to find out the reason for the discrepant data and to address it by performing well-designed studies. Similarly, in PAH, it is important to determine why men are burdened with a poorer therapeutic response to pulmonary vasodilators and why they carry a worse prognosis, namely to determine why what’s good for the goose may not be quite as good for the gander. To achieve this, we need larger randomized controlled trials or well-designed, longitudinal epidemiologic studies. In their article, Jacobs et al13 have provided us with 30% of the answer; the onus is on PAH investigators to solve the remainder of the puzzle.

References

Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-387. [CrossRef]
 
Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med. 2012;186(8):790-796. [CrossRef]
 
Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023-1030. [CrossRef]
 
Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122(2):156-163. [CrossRef]
 
Shapiro S, Traiger GL, Turner M, McGoon MD, Wason P, Barst RJ. Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Chest. 2012;141(2):363-373. [CrossRef]
 
Gabler NB, French B, Strom BL, et al. Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension. Chest. 2012;141(1):20-26. [CrossRef]
 
Kawut SM, Lima JA, Barr RG, et al. Sex and race differences in right ventricular structure and function: the multi-ethnic study of atherosclerosis-right ventricle study. Circulation. 2011;123(22):2542-2551. [CrossRef]
 
Ventetuolo CE, Ouyang P, Bluemke DA, et al. Sex hormones are associated with right ventricular structure and function: the MESA-Right Ventricle Study. Am J Respir Crit Care Med. 2011;183(5):659-667. [CrossRef]
 
Ryan JJ, Marsboom G, Fang YH, et al. PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;187(8):865-878. [CrossRef]
 
Lahm T, Crisostomo PR, Markel TA, et al. Selective estrogen receptor-alpha and estrogen receptor-beta agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism. Am J Physiol Regul Integr Comp Physiol. 2008;295(5):R1486-R1493. [CrossRef]
 
Lahm T, Albrecht M, Fisher AJ, et al. 17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects. Am J Respir Crit Care Med. 2012;185(9):965-980. [CrossRef]
 
Hemnes AR, Maynard KB, Champion HC, et al. Testosterone negatively regulates right ventricular load stress responses in mice. Pulm Circ. 2012;2(3):352-358. [CrossRef]
 
Jacobs W, van de Veerdonk MC, Trip P, et al. The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest. 2014;145(6):1230-1236.
 
Locke J. Essay Concerning Human Understanding. Book IV. London, England:1689.
 
Ghanbari H, Dalloul G, Hasan R, et al. Effectiveness of implantable cardioverter-defibrillators for the primary prevention of sudden cardiac death in women with advanced heart failure: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(16):1500-1506. [CrossRef]
 

Figures

Tables

References

Badesch DB, Raskob GE, Elliott CG, et al. Pulmonary arterial hypertension: baseline characteristics from the REVEAL Registry. Chest. 2010;137(2):376-387. [CrossRef]
 
Ling Y, Johnson MK, Kiely DG, et al. Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland. Am J Respir Crit Care Med. 2012;186(8):790-796. [CrossRef]
 
Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med. 2006;173(9):1023-1030. [CrossRef]
 
Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122(2):156-163. [CrossRef]
 
Shapiro S, Traiger GL, Turner M, McGoon MD, Wason P, Barst RJ. Sex differences in the diagnosis, treatment, and outcome of patients with pulmonary arterial hypertension enrolled in the registry to evaluate early and long-term pulmonary arterial hypertension disease management. Chest. 2012;141(2):363-373. [CrossRef]
 
Gabler NB, French B, Strom BL, et al. Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension. Chest. 2012;141(1):20-26. [CrossRef]
 
Kawut SM, Lima JA, Barr RG, et al. Sex and race differences in right ventricular structure and function: the multi-ethnic study of atherosclerosis-right ventricle study. Circulation. 2011;123(22):2542-2551. [CrossRef]
 
Ventetuolo CE, Ouyang P, Bluemke DA, et al. Sex hormones are associated with right ventricular structure and function: the MESA-Right Ventricle Study. Am J Respir Crit Care Med. 2011;183(5):659-667. [CrossRef]
 
Ryan JJ, Marsboom G, Fang YH, et al. PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;187(8):865-878. [CrossRef]
 
Lahm T, Crisostomo PR, Markel TA, et al. Selective estrogen receptor-alpha and estrogen receptor-beta agonists rapidly decrease pulmonary artery vasoconstriction by a nitric oxide-dependent mechanism. Am J Physiol Regul Integr Comp Physiol. 2008;295(5):R1486-R1493. [CrossRef]
 
Lahm T, Albrecht M, Fisher AJ, et al. 17β-Estradiol attenuates hypoxic pulmonary hypertension via estrogen receptor-mediated effects. Am J Respir Crit Care Med. 2012;185(9):965-980. [CrossRef]
 
Hemnes AR, Maynard KB, Champion HC, et al. Testosterone negatively regulates right ventricular load stress responses in mice. Pulm Circ. 2012;2(3):352-358. [CrossRef]
 
Jacobs W, van de Veerdonk MC, Trip P, et al. The right ventricle explains sex differences in survival in idiopathic pulmonary arterial hypertension. Chest. 2014;145(6):1230-1236.
 
Locke J. Essay Concerning Human Understanding. Book IV. London, England:1689.
 
Ghanbari H, Dalloul G, Hasan R, et al. Effectiveness of implantable cardioverter-defibrillators for the primary prevention of sudden cardiac death in women with advanced heart failure: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(16):1500-1506. [CrossRef]
 
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