What does this research mean for the field?

Patients with structural CMD (CFR+/IMR+) had significantly increased all-cause mortality (RR: 2.30) compared to normal controls, indicating worse outcomes. Novelty: ClaimNovelty.SYNTHESIS. Consensus alignment: ConsensusAlignment.SUPPORTS_CONSENSUS.

What question did this study set out to answer?

This review evaluates the prognostic differences among endotypes of coronary microvascular dysfunction in relation to mortality and major adverse cardiovascular events.

February 6, 2026

Prognostic significance of different endotypes of coronary microvascular dysfunction: a systematic review and meta-analysis

Q: What is the clinical evidence from this study?

Study design: Meta-Analysis. Population: Coronary microvascular dysfunction (CMD) (n=7188). Intervention: Coronary microvascular dysfunction endotypes (structural, functional, compensated) vs. Normal cohorts (CMR-/IMR-). Primary outcome: All-cause mortality (RR 2.30, 95% CI 2.36-3.88).

Key Result

The structural CMD endotype (CFR+/IMR+) was associated with significantly increased all-cause mortality (RR 2.30; 95% CI 2.36-3.88) and MACE (RR 2.97; 95% CI 2.16-4.06) compared to normal cohorts.

Key Points

This review evaluates the prognostic differences among endotypes of coronary microvascular dysfunction in relation to mortality and major adverse cardiovascular events.
Systematic search across MEDLINE/PubMed, Web of Science, and Scopus
Followed PRISMA guidelines for study selection
Conducted a random effect meta-analysis on included studies
CFR+/IMR+ endotype showed a notable increase in all-cause mortality and cardiovascular death.
CFR+/IMR- endotype also demonstrated a trend towards increased mortality but was less significant.
CFR-/IMR+ patients showed no significant differences when compared to normal cohorts.
Both CFR+/IMR- and CFR+/IMR+ endotypes had significant increases in major adverse cardiovascular events and heart failure hospitalizations.

Study Design

Type

Meta-Analysis (n=7,188)

Structured PICO

Do specific coronary microvascular dysfunction endotypes (structural, functional, compensated) increase the risk of mortality and MACE compared to normal controls?

Population

7,188 patients from 5 studies evaluated for the prognostic difference of recognized coronary microvascular dysfunction endotypes regarding mortality and MACE.

Exposure

Structural CMD (CFR+/IMR+), functional CMD (CFR+/IMR-), and compensated structural CMD (CFR-/IMR+) endotypes.

Comparator

Normal cohorts (CFR-/IMR-).

Outcome

All-cause mortality and MACE.hard clinical

Structural and functional endotypes of coronary microvascular dysfunction are associated with significantly worse clinical outcomes compared to normal controls, highlighting the need for endotype-specific therapies.

Main Result

Relative Risk: 2.3 (95% CI 2.36–3.88)

Abstract

Abstract Background Coronary microvascular dysfunction (CMD) is an increasingly recognized clinical entity, holding worse prognosis and increased adverse events in patients with abnormal invasive CMD indices, compared to normal controls. Pathophysiologically, CMD can be categorized into the distinct endotypes of structural, functional and compensated structural CMD, which have different pathophysiological and prognostic implications as well as different values of the coronary flow reserve (CFR) and the index of microvascular resistance (IMR). Purpose We performed a systematic review and meta-analysis aiming to evaluate the prognostic difference of recognized CMD endotypes, in regards to mortality and MACE. Methods We performed a systematic search in 3 different databases (MEDLINE/PubMed, Web of Science and Scopus). After selecting all appropriate studies according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a random effect meta-analysis was performed. Results A total of 5 studies and 7,188 patients were included. Patients with structural CMD were defined as CFR+/IMR+ phenotype, patients with functional CMD as CFR+/IMR- phenotype, patients with compensated structural CMD as CFR-/IMR+ and normal cohorts as CMR-/IMR-. In regards to all-cause mortality, with the normal individuals serving as controls, there was a trend towards significantly increased rates in the CFR+/IMR- endotype (RR: 1.72; 95%CI: 0.99-2.98), a significant increase in CFR+/IMR+ patients (RR: 2.30; 95%CI: 2.36-3.88) and no difference in the CFR-/IMR+ patients (RR: 0.63; 95%CI: 0.25-1.62). Similar results were found for cardiovascular death, (RR: 2.00; 95%CI: 1.12-3.54; RR: 3.61; 95%CI: 2.17-6.01; RR: 0.44; 95%CI: 0.12-1.46 for CFR+/IMR-, CFR+/IMR+ and CFR-/IMR+, respectively). Considering MACE, there was also a significant increase of events identified in both CFR+/IMR- (RR: 2.51, 95%CI: 1.82-3.45) and CFR+/IMR+ endotypes (RR: 2.97; 95%CI: 2.16-4.06), with no difference in those with only abnormal IMR (CFR-/IMR+) (RR: 1.00; 95%CI: 0.60-1.67). Finally, CFR+/IMR- and CFR+/IMR+ subgroups had increased HF hospitalizations (RR: 2.74; 95%CI: 1.57-4.76 and RR: 2.41; 95%CI: 1.46-3.98), with a non-significant increase noted in the CFR-/IMR+ subgroup (RR: 1.41; 95%CI: 0.64-3.14). Conclusion This systematic review and meta-analysis shows that the structural CMD endotype is associated with the worse outcomes, followed by the functional endotype. Patients with increased IMR, but normal CFR do not have significant differences in comparison to normal cohorts. Therefore, identifying endotype-specific therapies is necessary, in order to improve patient outcomes in each CMD category.

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