Coronary Microvascular Dysfunction in HFpEF: Pathophysiologic Mechanisms, Diagnosis, Treatments, and the Amplifying Potential of Sepsis

Division

Far West

Hospital

Sunrise Hospital & Medical Center

Document Type

Manuscript

Publication Date

9-9-2026

Keywords

CMD, HFPEF, coronary microvascular dysfunction, phenotype, precision medicine, sepsis, septic shock

Disciplines

Cardiovascular Diseases | Critical Care | Internal Medicine | Medicine and Health Sciences

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome in which coronary microvascular dysfunction (CMD) emerges as a central, prevalent pathobiologic substrate across multiple phenotypic clusters. CMD in HFpEF arises from intertwined mechanisms including systemic inflammation, impaired NO-cGMP-PKG signaling, microvascular rarefaction and fibrosis, mitochondrial dysfunction, and ventriculoarterial decoupling that together promote subendocardial ischemia, diastolic stiffness, reduced reserve, and adverse outcomes. Advances in diagnostics, both invasive and non-invasive, as well as individualized medical and surgical intervention, create avenues of opportunity to prevent CMD-mediated HFpEF at a precise level. Sepsis and septic shock can superimpose an acute second hit on this chronically injured microvasculature, precipitating acute decompensation and potentially accelerating long-term CMD-driven remodeling in vulnerable HFpEF patients. While mechanistically plausible, this association remains hypothesis-generating. Advanced hemodynamics and diagnostics with tailored vasopressor and inotropic management need to be better studied in complex states of septic shock in HFpEF patients to understand the influence of CMD in such states.

Publisher or Conference

Frontiers in Medicine

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