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Updated: Mar 31, 2026

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Unveiling Phenotypic Heterogeneity in Coronary Spastic Angina Through Multidimensional Risk Profiling: The FUJI-SPASM

Takamitsu Nakamura1, Tuan Hoang Nguyen1, Takeo Horikoshi1

  • 1Department of Cardiovascular Medicine, University of Yamanashi Faculty of Medicine, Chuo, Japan.

JACC. Advances
|March 30, 2026
PubMed

Insights

Coronary spastic angina (CSA) presents two distinct phenotypes: metabolic and inflammatory. Both share a vulnerability to low high-density lipoprotein cholesterol (HDL-C), with inflammation adding further risk for coronary spasm.

Area of Science:

  • Cardiology
  • Internal Medicine
  • Biochemistry

Background:

  • Coronary spastic angina (CSA) is a functional coronary disorder characterized by recurrent ischemia without significant atherosclerosis.
  • The interplay between metabolic and inflammatory abnormalities in CSA pathogenesis is not well understood.

Purpose of the Study:

  • To identify distinct CSA phenotypes based on metabolic and inflammatory profiles.
  • To determine phenotype-specific factors influencing coronary spasm and endothelial dysfunction.

Main Methods:

  • Analysis of 568 patients from the FUJI-SPASM registry with suspected CSA and no obstructive coronary artery disease.
  • Unsupervised k-means clustering using 20 clinical and biochemical variables to define phenotypes.
  • Regression analyses to identify phenotype-specific determinants of coronary spasm and endothelial dysfunction.

Main Results:

  • Two CSA phenotypes were identified: Cluster 0 (metabolic-dominant) and Cluster 1 (inflammation-dominant).
  • Low high-density lipoprotein cholesterol (HDL-C) was linked to coronary spasm in both phenotypes.
  • Elevated high-sensitivity C-reactive protein (hs-CRP) was independently associated with spasm in the inflammation-dominant cluster.

Conclusions:

  • CSA exhibits distinct metabolic and inflammatory phenotypes with varying spasm determinants.
  • Reduced HDL-C is a shared risk factor, while inflammation exacerbates spasm risk.
  • A stratification approach using HDL-C and hs-CRP offers a framework for personalized CSA risk assessment.
Abstract

Keywords:
acetylcholine testcoronary spasmendothelial dysfunctioninflammatory phenotypemetabolic phenotypeprincipal component analysis

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