Author + information
- J. Eduardo Rame, MD∗ ( and )
- Anjali Vaidya, MD
- ↵∗Reprint requests and correspondence:
Dr. J. Eduardo Rame, Cardiovascular Institute, University of Pennsylvania, 2 East Perelman Center for Advanced Medicine, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104.
Pulmonary arterial hypertension (PAH) is a progressive syndrome of right heart failure that encompasses multiple etiologies and risk factors. The presentation, clinical progression, and response to therapeutic intervention are variable across patients, and much interest has been directed in clinical and translational studies to identify the high-risk patient with a poor prognosis.
Current clinical practice standards incorporate a functional assessment with 6-min walk distance as well as echocardiographic indexes of right ventricular (RV) size and function to effectively risk stratify the PAH patient on the index presentation as well as during the follow-up evaluation post-implementation of a therapeutic strategy to modify the pulmonary vascular resistance. It is widely accepted and demonstrated in PAH registries from both sides of the Atlantic Ocean that, in general, the patients who remain in a poor functional status (World Health Organization functional class III to IV) and who have persistent evidence of an uncoupled state of RV dysfunction (increased RV size, decreased RV function, and deformed septal position throughout the cardiac cycle) have a consistently worse survival (1–3).
The role for using specific assays of biological targets circulating in blood to improve diagnostic and prognostic accuracy in patients with pulmonary vascular disease has been the subject of several investigations, including brain natriuretic peptides (4–6), cardiac troponin T (7), uric acid (8), endothelin (9), plasma von Willebrand factor (10), circulating endothelial microparticles (11), and, more recently, soluble ST2 (12) and oxidative stress biomarkers representing lipid peroxidation (malondialdehyde), glutathione, and vitamin E (13). Altogether, these studies have identified predominantly increased levels of these biomarkers in patients with PAH and, to a lesser or greater degree, have also discovered some correlation with an accepted clinical parameter of disease severity. Although the biological mechanisms behind these empirical observations are not always known, a plausible explanation for the correlations based on the pathogenesis of PAH has grounded these clinical observations and indicated that the discoveries were not due to chance alone.
It is with this background that we can understand the study by Safdar et al. (14) in this issue of JACC: Heart Failure as the investigation of a novel biomarker in PAH linking collagen metabolism with pulmonary vascular disease in humans. The hypothesis is well-seated, with several studies in animal models and some translational work already invoking collagen metabolism in pulmonary vascular remodeling. In their study with a modest sample size, the authors are able to convincingly demonstrate that these markers of collagen turnover are elevated in PAH and, furthermore, that the degree of elevation is correlated with disease severity—as measured with clinically relevant factors such as the 6-min walk test and hemodynamic indexes of compensated RV function. The strength of the signal associating these collagen metabolite markers with disease progression is significant enough that the association of the N-terminal propeptide of type III procollagen (PIIINP) with age (usually correlated in a positive manner) and duration of disease became inversely correlated as the patients that were younger and more recently diagnosed in this cohort were noted to have the more advanced forms of PAH. The inverse association of PIIINP—a biological marker of collagen metabolism—with duration of disease is especially compelling in pointing to a mechanism of active collagen turnover correlating with a more acute or active phase of pulmonary vascular remodeling and right heart failure.
As the authors correctly point out in their discussion, the mechanism of increased circulating PIIINP and other collagen markers such as matrix metalloproteinase-9 (the gelatinase that degrades the bulk of fibrillar collagen) is not necessarily due to active pulmonary vascular remodeling, as the degree of adverse RV remodeling in these more advanced cases could also explain increased levels. Furthermore, we would like to propose another mechanism to explain the source of collagen metabolites: extracellular remodeling in the unloaded left ventricle (LV) that is underfilled in the more advanced cases of PAH, which may cause LV hypotrophy with a reduction in LV mass. In another clinical scenario in which the LV is also unloaded—mechanical assist device support in chronic heart failure—it is known that the biological response to decreased filling/stretch is the activation of collagen synthesis and extracellular matrix remodeling (15). In PAH, it may be the case that the biological response to decreased LV filling may also involve activation of collagen metabolism, and thus, the biology of LV remodeling in PAH may be contributory in this sense.
Beyond the interest in the biology of collagen metabolism and ECM remodeling as it may apply to pulmonary vascular and myocardial remodeling, this paper presents an important contribution to another area of interest in our field: the development of biomarkers that may provide prognostic import in the syndrome of right heart failure due to PAH. The choice to add-on therapy is currently based on markers of clinical progression, which may not be sufficient in certain cases, especially when RV function may not be able to keep up with the increase in pulmonary impedance (RV uncoupling) and the patient experiences significant clinical decline. If the biology of collagen metabolism is able to link the vasculo-ventricular remodeling that is clearly taking place in the syndrome of chronic pulmonary vascular disease, these biomarkers may be an important addition to the clinical database that allows the practitioner to risk-stratify patients and decide on additional pulmonary vascular disease–specific therapies.
As the first observation linking collagen metabolism to the syndrome of human right heart failure due to idiopathic/hereditary and anorexigen-mediated PAH, several key questions remain which may be the subject of future investigation:
1. What is the origin of the circulating biomarkers of collagen metabolism in this clinical phenotype: RV, pulmonary circulation, or LV?
2. If this is indeed a biological assay for active pulmonary vascular disease, as the authors postulate in their explanation of why they observed higher levels of PIIINP in younger patients with a shorter duration of disease, can these collagen biomarkers form the basis for identifying the patients with the highest risk for disease progression who should be considered for the most aggressive clinical strategy, such as upfront combination therapy or parenteral prostanoid therapy?
3. In a retrospective analysis, the authors found that the patients with PAH who were being actively treated with mineralocorticoid receptor antagonism had lower circulating levels of these collagen biomarkers, suggesting that this pathologic or adaptive response could be modified by this neurohormonal blockade. Given the current interest with a randomized clinical trial of mineralocorticoid receptor antagonism using spironolactone in PAH (16), an important consideration may be whether these circulating biomarkers of collagen metabolism may identify patients who are likely to have an enhanced treatment effect to this medication or other therapies that impact mineralocorticoid receptor signaling in the pulmonary vasculature or myocardium.
4. The authors carefully evaluated patients who had idiopathic, hereditary, or anorexigen-associated PAH. An important and relevant patient population not assessed in this study is those with PAH associated with connective tissue disease. Systemic sclerosis (SSc) is characterized by excess collagen formation, and when combined with endothelial damage, leads to PAH. Other biomarkers, such as hepatocyte growth factor and von Willebrand factor, have been shown to be predictive of the development of PAH in SSc (17). Collagen biomarkers, including PIIINP, have been studied in SSc and shown to be associated with fibrosing alveolitis, but not necessarily with PAH (18). In this important subpopulation within PAH that is known to have aggressive and sometimes refractory disease, the use of collagen biomarkers may offer an additional screening tool to identify high-risk patients.
Beyond the specific mechanisms linking these biomarkers of collagen metabolism to PAH, it is clear from this and other studies that the era of targeting biomarkers to refine the phenotype of disease progression in right heart failure due to PAH is here, and our knowledge will continue to evolve and inform this complex disease state.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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