Glycolipid dysregulation mediated Left ventricular diastolic dysfunction in coronary microvascular disease pathogenesis

Technical Summary: Glycolipid Dysregulation Mediated Left Ventricular Diastolic Dysfunction in Coronary Microvascular Disease Pathogenesis

Problem Statement
Ischemic heart disease (IHD) driven by coronary microvascular disease (CMVD) represents a critical mechanism in non-obstructive coronary heart disease, affecting a significant portion of patients presenting with chest pain despite the absence of significant coronary stenosis. While CMVD is known to involve structural and functional impairments of the coronary microvasculature, the specific pathophysiological link between CMVD and left ventricular diastolic dysfunction (LVDD) remains to be fully elucidated. Furthermore, the role of glycolipid dysregulation—specifically markers of insulin resistance and lipid metabolism such as the triglyceride-glucose (TyG) index, triglyceride/high-density lipoprotein (TG/HDL) ratio, and total cholesterol/high-density lipoprotein (TC/HDL) ratio—as a mediating factor in this association is not well established. This study addresses the need to explore the association between LVDD and CMVD and to determine if glycolipid dysregulation mediates this relationship.

Methodology
This prospective study enrolled 376 patients presenting with chest pain and no obstructive coronary artery disease (CAD) from four medical centers in China between January 2023 and May 2025.

• Study Groups: Patients were categorized into a CMVD group ($n=222$) and a control group (non-CMVD) based on coronary angiography (CAG) and functional assessments.
  • CMVD Definition: Defined by myocardial ischemia symptoms, objective evidence of ischemia, non-obstructive CAD (<50% stenosis), and impaired microcirculatory function (Coronary Flow Reserve <2.5 or <2.0, Slow Flow Phenomenon, or Index of Microvascular Resistance [IMR] >25).
  • Microvascular Resistance: Angiographic Microvascular Resistance (AMR) was calculated using quantitative flow ratio (QFR) technology derived from CAG images.
• LVDD Assessment: Diagnosed via transthoracic echocardiography based on 2016 ASE/EACVI criteria. LVDD was confirmed if at least two of the following indicators were positive: septal e' <7 cm/s or lateral e' <10 cm/s, average E/e' >14, left atrial volume index >34 ml/m², or tricuspid regurgitation velocity >2.8 m/s.
• Glycolipid Markers: The study evaluated the TyG index, TG/HDL ratio, and TC/HDL ratio as indicators of glycolipid dysregulation.
• Statistical Analysis: Logistic regression models (unadjusted and multivariable-adjusted) were used to assess associations. Restricted cubic splines (RCS) analyzed non-linear relationships. Linear correlation analysis and violin plots characterized differences between groups. Mediation analysis was performed to quantify the indirect effects of glycolipid markers on the LVDD-CMVD pathway.

Key Results

• Baseline Characteristics: The CMVD group exhibited significantly higher prevalence of LVDD (57.01% vs. 13.51%), smoking, and electrocardiographic ischemic manifestations compared to the control group. Laboratory results showed significantly elevated levels of uric acid, triglycerides, TyG, TG/HDL, and TC/HDL in the CMVD group.
• LVDD and CMVD Association: Logistic regression revealed a strong positive association between LVDD and CMVD (Odds Ratio [OR] = 8.49; 95% CI: 3.94–18.30). Specific echocardiographic indicators showed that lower lateral and septal e' velocities were negatively correlated with CMVD, while higher average E/e' ratios and tricuspid regurgitation (TR) velocities were positively correlated.
• Non-Linear Relationships: RCS analysis identified an L-shaped association between e' velocities and CMVD, and a mirrored L-shaped (inverted J-shaped) association between the average E/e' ratio, TR, and CMVD.
• Glycolipid Dysregulation: The TyG index, TG/HDL, and TC/HDL ratios were positively associated with CMVD. Specifically, the TyG index showed a significant positive correlation (OR = 2.18; 95% CI: 1.03–4.60) in the multivariable-adjusted model.
• Mediation Analysis: The study found that LVDD mediated 4% of the association between the TyG index and CMVD. Conversely, the indirect effects of TG/HDL and TC/HDL on LVDD were not statistically significant.
• Diagnostic Efficiency: The Area Under the Curve (AUC) for LVDD in diagnosing CMVD was 0.72, with average E/e' and TR showing AUCs of 0.71 and 0.74, respectively.

Significance and Claims
The authors claim that this study provides novel epidemiological evidence supporting a positive association between LVDD and CMVD. The primary contribution is the identification of glycolipid dysregulation, specifically the TyG index, as a factor where LVDD acts as a partial mediator in the pathway to CMVD. The study posits that LVDD may be a potent approach for the onset of CMVD, a process partially mediated by metabolic dysregulation.

The authors conclude that monitoring lipid ratios and the TyG index could serve as a cost-effective strategy for early CMVD risk stratification. However, the paper maintains a modest tone regarding its limitations, explicitly stating that the observational design precludes causal inference and that single-center recruitment (despite multi-hospital data collection) limits the generalizability of the findings. The study does not propose new therapeutic interventions but rather highlights these metabolic and functional markers as potential targets for clinical prevention and treatment strategies.