Elsevier

American Heart Journal

Volume 258, April 2023, Pages 96-113
American Heart Journal

Review Articles
Pursuing functional biomarkers in complex disease: Focus on pulmonary arterial hypertension

https://doi.org/10.1016/j.ahj.2022.12.009Get rights and content

A major gap in diagnosis, classification, risk stratification, and prediction of therapeutic response exists in pulmonary arterial hypertension (PAH), driven in part by a lack of functional biomarkers that are also disease-specific. In this regard, leveraging big data-omics analyses using innovative approaches that integrate network medicine and machine learning correlated with clinically useful indices or risk stratification scores is an approach well-positioned to advance PAH precision medicine. For example, machine learning applied to a panel of 48 cytokines, chemokines, and growth factors could prognosticate PAH patients with immune-dominant subphenotypes at elevated or low-risk for mortality. Here, we discuss strengths and weaknesses of the most current studies evaluating omics-derived biomarkers in PAH. Progress in this field is offset by studies with small sample size, pervasive limitations in bioinformatics, and lack of standardized methods for data processing and interpretation. Future success in this field, in turn, is likely to hinge on mechanistic validation of data outputs in order to couple functional biomarker data with target-specific therapeutics in clinical practice.

Section snippets

The “multiple-hit hypothesis”

Over the preceding 2 decades, many variants in the bone morphogenetic receptor type 2 (BMPR2) gene, which encodes a serine/threonine receptor kinase belonging to the transforming growth factor-β (TGF-β) receptor superfamily, have been reported in patients with heritable PAH (HPAH).7,8 Heterozygous germline mutations in BMPR2 are the hub of PAH genetic susceptibility and progression (Figure 1).9 Mutations in BMPR2 show an autosomal dominant pattern of inheritance; however, incomplete penetrance

The “inflammatory origin” of PAH

Inflammatory vascular injury has been shown to recapitulate various aspects of the PAH pathophenotype in vivo30 akin to the accumulation of inflammatory infiltrates, particularly CD4+ T, CD8+ T and B lymphocytes, dendritic cells, and macrophages in vascular lesions of patients with severe PAH (Figure 1).31,32 One large multicenter study demonstrated that serum levels of the proinflammatory interleukin (IL)-6 was significantly higher in 2,017 PAH patients compared to 60 healthy controls.33 In

The Warburg effect

It has been proposed that many cardiovascular diseases share pathologic features with cancer; indeed, severe PAH has been characterized previously as a “quasi-malignancy.”36 This overlap is based on gross features, such as increased tissue mass37., 38., 39. observed in PAH as a proliferative vasculopathy, as well pathogenic cellular responses to hypoxia that promote hyper-proliferation, apoptosis resistance, and angiogenesis (Figure 1). In particular, the “Warburg effect” is a cancer-like

First challenge: diagnosis and classification

A molecular classification is not available currently for PAH. The only exception is for HPAH in which the presence of BMPR2 (or other rarer) variants can be useful for diagnosis (Table 2).44., 45., 46., 47., 48., 49., 50., 51., 52., 53., 54., 55., 56., 57., 58., 59., 60., 61., 62. Approximately 75% of families with PAH and 15% of IPAH cases are carriers of BMPR2 variants.48 The first evidence of this finding was derived from probands with a family history of PAH63,64; successively, BMPR2

Integrating transcriptomics and network visualization tools

Among the largest lung gene expression datasets set was acquired in a clinically heterogeneous cohort of 58 PAH patients at the time of lung transplantation and compared to 25 unused donor controls.71 The phospholipase C activation level differentiated patients with PAH associated with other diseases as compared to IPAH patients.71 Discovery of central pathways in PAH using the evaluation of differential dependencY (EDDY) algorithm and the REACTOME database indicated novel upstream regulators,

Integrating proteomics and risk score calculators

Commonly used point-of-care risk calculators rely on a combination of clinical information, circulating BNP or NT-proBNP concentration, and hemodynamic and echocardiographic parameters.4,73 Two studies compared the predictive value of the REVEAL risk score with potential omics-derived biomarkers (Table 3).74,75 Rhodes and colleagues75 performed an unbiased evaluation of 1,129 plasma proteins from 218 (incident and prevalent) IPAH and HPAH patients with about a 2-year follow-up as compared to 25

Third challenge: prediction of therapeutic response

Only a small percentage of IPAH, HPAH, and drug/toxin-associated PAH patients express a “vasoreactive subphenotype,” which is associated with substantial improvement following treatment with high-dose calcium channel blocker pharmacotherapy and, thus, better long-term prognosis.78 Three studies have addressed the potential usefulness of omics in predicting therapeutic response in patients with PA (Table 3).79., 80., 81.

Strengths and weaknesses of omics approaches

Although omics techniques offer a holistic molecular perspective of complex diseases as compared to traditional reductionist approaches, each platform still presents specific strengths and limitations based on its intrinsic nature. For example, linking genotype to phenotype is mainly affected by 2 factors, such as the ability of a genomics platform to amplify and quantify DNA from small amounts of starting material as well as the interpretation of how specific variants may mechanistically

Conclusions and future directions

Advances in understanding PAH pathobiology led to great progress identifying numerous molecular mechanisms that underpin vascular remodeling and RV dysfunction in the syndrome.1,2,84., 85., 86. Inflammation,6,15,72,71,75,76 dysregulated metabolism,19 and epigenetic reactivation of fetal lung genes12 are now recognized as central drivers of PAH. However, empiric data also emphasize integrated, overlapping, and convergent signaling pathways, which likely requires consideration of analytic

Funding

NIH R21HL1343201, R01HL139613-01, R01HL153502, R01HL155096-01, R01HL155107, U01HG007691, U54HL119145; 2021A007243 BWH/MIT-Broad Institute; AHA D700382, AHA957729; McKenzie Family Charitable Trust; PRIN2017F8ZB89 from “Italian Ministry of University and Research (MIUR)” (PI Prof Napoli) and Ricerca Corrente (RC) 2019 from “Italian Ministry of Health” (PI Prof. Napoli).

Author contributions

GB, CN, JL, and BAM: Drafting the work and revising it critically for important intellectual content; AND Final approval of the version to be published.

Conflict of interest

Actelion Pharmaceuticals (Steering committee; outside the scope of the current work), Deerfield Company (investigator sponsored research; outside the scope of the current work), Tenax Therapeutics (Scientific advisor board; within the scope of the current work). Dr Maron reports patent, patient pending, and patent applications related to pulmonary hypertension but outside the scope of the current work.

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  • 1

    These authors contributed equally to this paper.

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