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Adiponectin Signaling Dysfunction and Pro-inflammation in Perivascular Adipose Tissue in Non-obstructive Ischemic
Paulina Elizabeth Cisneros Clavijo1,2, Diego Fernando Pinzón Tejada3, John Manuel Dorado Ramírez4
1Endovascular Surgery, Hospital General Enrique Garcés, Quito, ECU.
Insights
Perivascular adipose tissue (PVAT) dysfunction contributes to non-obstructive coronary artery disease. Targeting PVAT offers a promising therapeutic strategy for ischemia with non-obstructive coronary arteries (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA).
Area of Science:
- Cardiology
- Metabolic Syndrome
- Vascular Biology
Background:
- Ischemia with non-obstructive coronary arteries (INOCA) and myocardial infarction with non-obstructive coronary arteries (MINOCA) affect many patients, but their causes are not fully understood.
- Current management strategies for INOCA/MINOCA are limited due to incomplete knowledge of the underlying pathophysiology.
- Pericoronary perivascular adipose tissue (PVAT) dysfunction is increasingly implicated in these conditions.
Purpose of the Study:
- To review and synthesize current evidence on the role of PVAT dysfunction in INOCA/MINOCA.
- To explore the mechanisms linking PVAT dysfunction to coronary microvascular dysfunction (CMD) and vasomotor dysregulation.
- To identify potential therapeutic targets within PVAT for non-obstructive ischemic heart disease.
Main Methods:
- A comprehensive literature search was performed across major databases (PubMed/MEDLINE, Scopus, Cochrane Library, Google Scholar) up to March 2025.
- The review synthesized findings from preclinical studies, observational cohorts, imaging studies, and clinical trials.
- Thematic domains included PVAT physiology, adiponectin signaling, PVAT transition in INOCA/MINOCA, pericoronary fat attenuation index (FAI), and therapeutic targets.
Main Results:
- Healthy PVAT maintains coronary homeostasis via adiponectin-AMPK-eNOS-nitric oxide signaling and anti-inflammatory effects.
- Metabolic dysfunction alters PVAT, reducing adiponectin and increasing inflammatory mediators (TNF-α, IL-6), leading to impaired vasodilation and CMD.
- Mechanisms in MINOCA include Rho-kinase activation and TNF-α-driven α1-adrenergic upregulation; pericoronary FAI shows prognostic value.
Conclusions:
- PVAT dysfunction is a key contributor to INOCA/MINOCA pathophysiology, driving CMD and vasomotor dysregulation.
- Therapeutic agents like SGLT-2 inhibitors, GLP-1 receptor agonists, and PPAR-γ agonists show promise for PVAT remodeling.
- Repositioning PVAT as a therapeutic target in non-obstructive ischemic disease warrants further investigation and prospective validation.
Abstract:
Ischemia with non-obstructive coronary arteries (INOCA)/myocardial infarction with non-obstructive coronary arteries (MINOCA) affects a substantial proportion of patients undergoing coronary angiography; however, its pathophysiology remains incompletely understood, and evidence-based management remains limited. This narrative review synthesizes mechanistic, translational, and clinical evidence linking pericoronary perivascular adipose tissue (PVAT) dysfunction to coronary microvascular dysfunction (CMD) and vasomotor dysregulation in the absence of epicardial stenosis. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, the Cochrane Library, and Google Scholar up to March 2025, encompassing preclinical studies, observational cohorts, imaging studies, and clinical trials across five thematic domains: PVAT physiology, adiponectin signaling, PVAT phenotypic transition in INOCA/MINOCA, pericoronary fat attenuation index (FAI), and endocrine-metabolic therapeutic targets. In healthy individuals, PVAT maintains coronary homeostasis through adiponectin-mediated AMP-activated protein kinase (AMPK)-endothelial nitric oxide synthase (eNOS)-nitric oxide signaling and anti-inflammatory paracrine effects. Under metabolic dysfunction, PVAT undergoes a phenotypic transition characterized by reduced adiponectin secretion and increased production of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and reactive oxygen species, thereby impairing endothelium-dependent vasodilation and promoting microvascular dysfunction. In MINOCA, distinct mechanisms including Rho-kinase activation and TNF-α-driven α1-adrenergic upregulation drive vasospasm. Pericoronary FAI has demonstrated independent prognostic value across obstructive and non-obstructive coronary disease. Therapeutic strategies including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists show mechanistic promise for PVAT remodeling, though dedicated randomized evidence in non-diabetic INOCA populations remains limited. These findings support repositioning PVAT as a therapeutic target in non-obstructive ischemic disease, pending prospective validation.
