The Interplay Between Pulmonary Hypertension and Atrial Fibrillation: A Comprehensive Overview

Sultan D, Brundel BJJM, Kurakula K. The Interplay Between Pulmonary Hypertension and Atrial Fibrillation: A Comprehensive Overview. Cells. 2025;14(11):839. Published 2025 Jun 4.

doi:10.3390/cells14110839

Abstract

Pulmonary hypertension (PH) is a progressive lung disease characterized by abnormal pulmonary vascular pressure and right ventricular (RV) dysfunction. Atrial arrhythmias, including atrial fibrillation (AF) and atrial flutter, are common in patients with PH and significantly contribute to disease progression and mortality. A bidirectional pathophysiological link exists between PH and AF, encompassing shared mechanisms such as endothelial dysfunction, DNA damage, autophagy, inflammation, and oxidative stress, as well as mutual risk factors, including diabetes, obesity, heart disease, and aging. Despite these shared pathways, limited research has been conducted to fully understand the intertwined relationship between PH and AF, hindering the development of effective treatments. In this review, we provide a comprehensive overview of the epidemiology of PH, the molecular mechanisms underlying the development of AF in PH, and the overlap in their pathophysiology. We also identify novel druggable targets and propose mechanism-based therapeutic approaches to treat this specific patient group. By shedding light on the molecular connection between PH and AF, this review aims to fuel the design and validation of innovative treatments to address this challenging comorbidity.

Conclusions

The complex interplay between PH and AF represents a significant clinical challenge, necessitating a comprehensive understanding of their shared pathophysiological mechanisms. By illuminating the molecular intersections between these conditions, this review highlights the urgent need for multidisciplinary research efforts to develop targeted treatments. Future directions in PH-AF research should prioritize the identification of novel therapeutic targets and the validation of mechanism-based approaches through (pre)clinical trials. The integration of cutting-edge technologies, such as genomics and systems biology, will be essential for deciphering the intricate relationships between PH and AF. Moreover, the implementation of precision medicine principles will permit the development of tailored therapeutic strategies tailored to the unique characteristics of each patient. Ultimately, a deeper understanding of the PH-AF connection holds the promise of improving patient outcomes, quality of life, and reducing mortality, paving the way for a brighter future for patients affected by these devastating comorbidities.

Keywords: DNA damage; atrial fibrillation; autophagy; proteostasis; pulmonary hypertension.

Figure 1: Clinical classification of PH according to 2022 ESC/ERS guidelines. PH is divided into five clinical groups that are further subdivided into subgroups based upon underlying disease mechanisms, clinical presentations, hemodynamic parameters, and therapeutic interventions. ESC: European Society of Cardiology, ERS: European Respiratory Society, HFrEF: heart failure with reduced ejection fraction, HFpEF: heart failure with preserved ejection fraction.

Figure 2: Overview of pathways and mechanisms involved in pathogenesis of AF in PH and associated pathophysiological implications. RA: right atrium, RV: right ventricle, DAD: delayed after depolarization, HF: heart failure. Created with BioRender.com (BioRender, RU28BW4XQD).

Figure 3: Schematic diagram depicting the molecular mechanisms driving AF in PH. In both cases, disease-mediated cellular stress caused proteostasis derailment, resulting in exhaustion of the cardioprotective HSP. The exhaustion of HSPs results in the activation of endoplasmic reticulum (ER) stress, resulting in excessive activation of the autophagic protein degradation pathway. PH and AF also cause mitochondrial dysfunction, ROS production, and subsequent DNA damage and Ca2+ abnormalities, as well as mTOR-induced autophagy followed by activation of inflammation and endothelial dysfunction (ED) pathways. RTK = receptor tyrosine kinases; GPCR = G protein-coupled receptors; NOX = NADPH oxidases GF = growth factors, PARP1 = poly(ADP-ribose) polymerase 1; mTOR 1/2 = Mammalian target of rapamycin 1/2; PDK1= serine/threonine kinase-3′-phosphoinositide-dependent kinase 1; TSC1/2 = tuberous sclerosis complex 1/2; AMPK = adenosine monophosphate-activated protein kinase; Redd1 = DNA damage response 1; Rheb: GTP binding protein Ras homolog enriched in brain; PDGF: platelet-derived growth factor; EGF: epidermal growth factor; VEGF: vascular endothelial growth factor; IL-6: interleukin 6; TNF-α: tumor necrosis factor alpha; TGF-β: transforming growth factor beta; ALK: anaplastic lymphoma kinase; ET: endothelin; ATP = adenosine triphosphate; CaSR: calcium-sensing receptor;.

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