Identifying New Targets for Treatment of Pulmonary Hypertension

FOR RELATED ARTICLE, SEE PAGE 1586

Pulmonary hypertension (PH), defined by elevated pulmonary artery pressure, is commonly encountered in clinical practice of cardiovascular and pulmonary medicine. The World Symposium on PH divides PH into groups based on common underlying conditions, pathophysiology, or treatment response.¹ Accurate group assignment in PH informs appropriate medical management and our understanding of prognosis. For example, early recognition and prompt treatment of pulmonary arterial hypertension (group 1 PAH) with evidence-based pulmonary vasodilator therapy has been a central thesis of World Symposium guidelines.² However, in developed countries, most PH cases are attributed to underlying left-sided heart disease or lung disease (groups 2 and 3 PH, respectively).³ Like patients with PAH, those with group 2 or 3 PH commonly develop progressive right ventricle dysfunction and failure, driving significant morbidity and mortality. In fact, recent reports suggest poorer survival in these common forms of PH compared with PAH.^4,5 Pulmonary vasodilator therapies that improve symptoms, exercise tolerance, and mortality in PAH unfortunately have not shown the same promise in group 2 or 3 PH.^6,7 Collectively these observations emphasize both the large burden of group 2 and 3 PH and the compelling need for effective treatment strategies for these patients. Targeting relevant mechanisms in PH pathogenesis seems the best way forward.

Identifying those mechanisms has proved more elusive. Although the traditional pipeline of drug development from basic science investigation to bedside clinical trial contributed to effective pulmonary vasodilator therapy in PAH, similar progress has proven challenging in group 2 and 3 PH. This stems in part from the inability of preclinical models to accurately recapitulate complex and multisystem human PH pathobiology, thereby limiting their ability to identify therapies that translate to human PH with high fidelity. Nonetheless, preclinical and translational studies have suggested numerous pathways in PH-related pulmonary vascular remodeling and right ventricular dysfunction. Common themes include neurohormonal activation, dysregulated metabolism, abnormal cellular growth factor signaling, and sex hormone imbalance.^8,9 Clinical trials targeting several of these pathways are ongoing, with most enrolling only PAH patients.⁹ In group 2 and 3 PH, incomplete understanding of basic disease mechanisms hinders the traditional “bottom-up” approach to therapy development. Although ongoing rigorous studies using “omics” approaches may reveal promising new avenues of therapy in the future,¹⁰ the many patients with group 2 and 3 PH need effective treatments now.

A perhaps obvious but underused approach to accelerate advances in our understanding and treatment of common forms of PH involves the use of rigorous hypothesis-driven observational studies. In this issue of CHEST, Lahm et al¹¹ report the impact of medications targeting the renin angiotensin aldosterone system on outcome in patients with PH.¹¹ The cohort was identified from data collected in Veterans Affairs cardiac catheterization laboratories and includes 24,221 veterans who had right heart catheterization confirming PH. Veterans included in this study often had elevated pulmonary artery wedge pressure or precapillary PH hemodynamics with comorbid lung disease, suggesting the cohort predominantly consisted of patients with group 2 and 3 PH. In a series of analyses designed to account for confounding, the authors show that a filled prescription for an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) within 3 months from the hemodynamic recognition of PH was associated with 18% to 22% lower risk of future mortality. This effect is comparable to benefits of ACEI use in patients with left heart failure with reduced ejection fraction: a meta-analysis of five prospective ACEI trials had a pooled OR of death of 0.80 (95%CI, 0.74-0.87) compared with placebo.¹² In the current study by Lahm et al,¹¹ the association of ACEI/ARB therapy with improved outcome was independent of the presence of elevated left heart filling pressures, suggesting that patients with precapillary forms of PH also benefit from ACEI/ARB therapy. In contrast, aldosterone antagonists did not show convincing benefit in analyses adjusted for disease severity.

This report by Lahm et al¹¹ provides an excellent example of how available and rich clinical and pharmacy data can be used to advantage to investigate mechanistically supported hypotheses and inform definitive prospective trials. In their study, the authors used data from the Veterans Health Administration, the largest integrated health-care system in the United States. Rigor of their study was supported by expansive data, including demographics, comorbid conditions, outpatient medication use, and consistent longitudinal follow-up within the health-care system. Notable is the pairing of these data with hemodynamic confirmation and characterization of PH by right heart catheterization, which is often lacking from retrospective PH studies. This study, done with the intent of causal inference, however, must be interpreted considering the inherent risk of selection bias or limited generalizability of all retrospective studies. More specifically, this study based on data from US veterans may not be applicable to younger or more sex-balanced populations. Although the patients’ PH group could not be specifically characterized, it can be assumed that PAH is less common in this elderly, predominantly male population, who are frequently afflicted with chronic cardiopulmonary comorbidities. Furthermore, because of known differences in morphology, pressure-volume responses, and metabolic needs of the right and left heart, it should not be assumed that other therapeutic strategies proven to be effective for left heart failure (eg, beta-adrenergic blockers) would necessarily be advantageous in patients with PH.

Despite these limitations, studies such as this are powerful tools to understand whether mechanisms known to be relevant from model systems or from related diseases may be applicable in a less-studied condition such as PH. Rather than dismiss retrospective analyses on account of their known limitations, the field should appreciate the value they bring. Well-designed retrospective and observational studies, including that of Lahm et al¹¹ in this issue of CHEST, can allow investigators to design more efficient, targeted, and productive prospective studies to shape tomorrow’s management approaches for group 2 and 3 PH patients.