Molecular Synergy and Inflammatory Activation in Pathogenesis and Therapy of Atrial Cardio-Metabolic Cardiomyopathy

Corresponding Author

Cardio-metabolic disease is increasingly recognized as an important contributor to atrial remodeling and atrial fibrillation (AF). Inflammation and oxidative stress appear to play central roles in this process and are now considered key components of atrial cardiomyopathy (AtCM).¹ Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like petide-1 receptor (GLP-1) receptor agonists have changed the management of heart failure with preserved ejection fraction through cardiovascular effects that extend beyond glucose lowering alone, critically exploiting their anti-inflammatory and antioxidant actions.² Whether these pathways directly contribute to atrial substrate biology, and whether their combined modulation can influence atrial remodeling, remain unclear.

In this issue of the Journal, Fakih et al³ report the results of a study of the relationship between atrial inflammation, oxidative stress, and SGLT2/GLP-1R signaling in right atrial appendage samples from 80 patients undergoing cardiac surgery, including 18 with a history of AF and 62 without an AF history, the “sinus-rhythm” (SR) group. The authors combined analyses of human atrial tissue with complementary experiments in cultured human coronary artery endothelial cells, a human cardiomyocyte line system (AC16 cells, derived from adult human ventricular cardiomyocytes fused with simian virus 40 [SV40]-transformed fibroblasts), and peripheral blood mononuclear cells isolated from healthy human donors. The principal findings are summarized in Figure 1. Tumor necrosis factor alpha (TNFα)-expression was used as an indicator of inflammation. All patients with AF were in the high-TNFα group, whereas 65% of the SR group (40/62) were in the low-TNFα group. High-TNFα atrial samples demonstrated coordinated inflammatory-metabolic remodeling associated with enhanced SGLT2 and GLP-1 R signaling across distinct cellular compartments.

Figure 1.

Tumor Necrosis Factor Alpha (TNFα)-Driven Atrial Remodeling and Cell-Specific Sodium-Glucose Cotransporter 2 (SGLT2)/Glucagon-Like Petide-1 Receptor (GLP-1R) Expression in Atrial Fibrillation (AF)

CCL2 = C-C motif chemokine ligand 2; CD86 = cluster of differentiation 86; eNOS = endothelial nitric oxide synthase; MMP = matrix metalloproteinase; mRNA = messenger ribonucleic acid; NOS3 = nitric oxide synthase 3; NOX2 = nicotinamide adenine nucleotide phosphate oxidase 2; SR = sinus rhythm; TGFB1 = transforming growth factor beta 1; TF = tissue factor; VCAM-1 = vascular cell adhesion molecule 1.

Overall, the authors showed signs of inflammation, oxidative stress, and thrombotic activation in patients with AF, found that TNF-α accurately tracked signs of inflammation, and that in most cell types TNF-α upregulates both SGLT2 and GLP-1 R. They then went on to test the effects of SGLT2 inhibition and GLP-1 R agonism in atrial samples and model cells. They found that the GLP-1 R-agonist semaglutide attenuated reactive oxygen species (ROS) levels in high-TNF-α samples in a cyclic adenosine monophosphate/protein kinase A (cAMP/PKA)-dependent fashion but did not affect ROS in low-TNF-α tissues. TNF-α increased ROS production in model cells, and this effect was antagonized by GLP-1 R-agonists in all cell types except endothelial. Importantly, the authors then went on to study the effects of combined SGLT2-inhibition and GLP-1 R-agonism and showed synergistic actions in high-TNF-α atrial samples (eg, empagliflozin and semaglutide, at 10 nM, reduced ROS-production by 7.2% and 9.1%, respectively, but the combination reduced it by 42.4%). A similar effect was shown in cell models.

From Inflammatory Remodeling to Molecular Synergy

One of the most interesting findings of this study is the progressive inflammatory continuum across low TNF-SR, high TNF-SR, and AF atrial samples. SR-patients with heightened inflammatory signaling demonstrated atrial endothelial dysfunction, oxidative stress, fibrosis, and cellular senescence. These observations suggest that substantial atrial remodeling may occur before AF becomes clinically evident, supporting the concept that AF is often preceded by AtCM with an underlying inflammatory basis.

The study also suggests that inflammatory atrial remodeling may show differential cellular expression. SGLT2-expression predominantly localized to endothelial cells and macrophages, whereas GLP-1R was localized to cardiomyocytes and macrophages. These observations may help to explain why combined SGLT2 inhibition and GLP-1R activation produce greater effects than either intervention alone.

Indeed, one particularly interesting observation was the substantially greater effect of combined SGLT2 inhibition and GLP-1R activation on inflammatory/oxidative signaling compared with either intervention alone. These findings suggest that the effects of combined-pathway modulation may relate to interactions between different cellular components of the atrial substrate. In this context, molecular synergy may provide insight not only into therapeutic responses but also into the heterocellular interactions underlying inflammatory atrial remodeling.

Translational and Mechanistic Questions Raised by the Study

Like all important mechanistic studies, the work by Fakih et al³ raises unresolved questions. Many are not unique to this study and reflect broader uncertainties regarding the biology and progression of atrial disease (Figure 2):

Figure 2.

Unresolved Biological Layers of Cardio-Metabolic Atrial Cardiomyopathy (AtCM)

AF = atrial fibrillation; CKD = chronic kidney disease; EAT = epicardial adipose tissue; HFpEF = heart failure with preserved ejection fraction; LA = left atrium; RA = right atrium.

One important question concerns the clinical definition of inflammatory-metabolic AtCM itself. The present study was performed in a relatively small and heterogeneous cohort of cardiac surgery patients, with limited characterization of metabolic phenotype. The findings suggest that inflammatory atrial remodeling may not be specific to AF alone. Although all patients with AF clustered within the high TNF-α group, a substantial proportion of patients in SR also demonstrated inflammatory activation associated with endothelial dysfunction, oxidative stress, fibrosis, and senescence. This observation suggests that inflammatory-metabolic atrial remodeling may precede clinically manifest AF. Whether AF, obesity, diabetes, heart failure with preserved ejection fraction, chronic kidney disease, epicardial adipose tissue, and systemic inflammation represent a shared inflammatory-metabolic phenotype or multiple biologically distinct substrates remains uncertain.⁴ Better integration of clinical, imaging, metabolic, inflammatory, and rhythm data may help to better define these conditions and their cardiac consequences.

The study also raises questions regarding the spatial organization of inflammatory atrial remodeling. The distinct cellular distribution of SGLT2 and GLP-1R signaling further suggests that inflammatory remodeling may not be spatially or biologically uniform. Different atrial regions may therefore contribute differently to substrate formation and therapeutic response.⁵ This may be particularly relevant at interfaces between epicardial adipose tissue and atrial myocardium, where metabolic, inflammatory, and fibrotic signaling pathways potentially converge.⁶ Better spatial characterization of atrial remodeling may help clarify how these regional differences contribute to AF progression, substrate heterogeneity, and response to therapy.

Questions also remain regarding the temporal evolution of inflammatory atrial remodeling. The present study was largely cross-sectional and evaluated acute responses to pharmacologic modulation. Consequently, the sequence linking endothelial dysfunction, inflammatory activation, oxidative stress, fibrosis, and cellular senescence remains uncertain. It is also unclear whether increased SGLT2 and GLP-1R signaling reflects causal mechanisms,4.adaptive responses, or broader activation of inflammatory pathways. However, the suppressive effects of SGLT2-inhibition and GLP-1R-agonism on AF-associated changes noted in this study, along with the clinical evidence for AF-protection from these mechanisms,^7,8 suggest a causal role. Longitudinal studies integrating serial biological and structural phenotyping would help to better define the temporal progression of inflammatory-metabolic AtCM and open windows for earlier disease modification.

Another important issue concerns the relationship between inflammatory remodeling and arrhythmogenesis. Although the study provides detailed characterization of inflammatory and oxidative atrial remodeling, it does not directly address the electrophysiological mechanisms linking these abnormalities to AF. Whether endothelial dysfunction, oxidative stress, fibrosis, and cellular senescence translate into conduction abnormalities, altered calcium handling, or increased susceptibility to re-entry remains uncertain.⁹ Better integration of inflammatory biology with electrophysiological and structural characterization may be needed to understand how inflammatory-metabolic AtCM progresses toward clinically sustained AF, particularly via conduction abnormalities and localized arrhythmogenic substrate.

The therapeutic implications of these findings also remain uncertain. The synergistic effects observed with combined SGLT2 inhibition and GLP-1R activation are biologically intriguing. However, the pharmacologic experiments were acute and performed ex vivo, without assessment of actions on long-term remodeling progression or rhythm outcomes. Whether combined pathway modulation can durably alter atrial inflammatory remodeling, reduce AF-susceptibility, or slow progression of AtCM in a way superior to either intervention alone requires further testing. Future clinical studies integrating biological, structural, and rhythm outcomes will be important in determining whether molecular synergy translates into meaningful disease modification.¹⁰

Ultimately, the study by Fakih et al³ suggests that inflammatory atrial remodeling may create a molecular environment in which SGLT2 and GLP-1R pathways become biologically relevant and therapeutically targetable. Beyond the observation that inflammation accompanies AF, these findings raise the possibility that combined cardio-metabolic target therapy may directly modulate an evolving atrial substrate before or during the transition to clinically manifest AF, potentially shifting the focus of AF management from rhythm control alone toward earlier modification of substrate biology.

Funding Support and Author Disclosures

Dr Guichard reports honoraria as a lecturer from Abbott, and unrestricted grant support for a fellowship from Abbott. He is also shereholder of Corify SL. Dr Nattel has reported that he has no relationships relevant to the contents of this paper to disclose.