Coronary microvascular dysfunction and future risk of heart failure with preserved ejection fraction

Abstract

Aims: Coronary microvascular ischaemia, cardiomyocyte injury and stiffness may play an important role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). To date, the relationship between coronary flow reserve (CFR), myocardial injury, diastolic dysfunction, and future HFpEF risk is unknown.

Methods and results: Consecutive patients (n = 201) undergoing evaluation for suspected coronary artery disease (CAD) with stress myocardial perfusion positron emission tomography, serum troponin, and transthoracic echocardiography who did not have flow-limiting CAD or reduced left ventricular ejection fraction were identified. Patients were followed up (median 4.1 years) for cardiovascular death and hospitalization for non-fatal myocardial infarction or heart failure. Coronary flow reserve was quantified as stress/rest myocardial blood flow. Early diastolic flow (E) and relaxation (e') velocities were obtained via transmitral and tissue Doppler, respectively. Patients with impaired CFR (<2, n = 108) demonstrated linearly decreasing e' and increasing E/e' consistent with worsening diastolic function (P for trend <0.0001). A detectable troponin was associated with diastolic dysfunction only in the presence of impaired CFR (interaction P = 0.002). In adjusted analyses, impaired CFR was independently associated with diastolic dysfunction (E/e'septal > 15, adjusted OR 2.58, 95%CI 1.22-5.48) and composite cardiovascular outcomes or HFpEF hospitalization alone (adjusted HR 2.47, 95%CI 1.09-5.62). Patients with both impaired CFR and diastolic dysfunction demonstrated >five-fold increased risk of HFpEF hospitalization (P < 0.001).

Conclusion: In symptomatic patients without overt CAD, impaired CFR was independently associated with diastolic dysfunction and adverse events, especially HFpEF hospitalization. The presence of both coronary microvascular and diastolic dysfunctions was associated with a markedly increased risk of HFpEF events.

Figure 1

Relationship between coronary flow reserve (CFR) and markers of diastolic dysfunction. There is a direct relationship between CFR and e′ (A) and an inverse relationship between CFR and E/e′ (B) such that diastolic function sharply declined in patients with CFR < 2. Non-linear relationship is modelled using restricted cubic splines with 95% confidence intervals. Results are shown for e′_septal, but similar findings were obtained for e′_lateral.

Figure 2

Univariable and multivariable-adjusted associations for elevated E/e′ (E/e′_septal > 15 as compared to ≤ 15). Odds ratios (OR) with 95% confidence intervals (95% CI) are presented for binary covariates, as well as a 10-unit increase in pretest clinical score and age, and a 10-unit decrease in left ventricular ejection fraction. Pretest clinical score incorporates age, gender, presence of hypertension, dyslipidaemia, diabetes, tobacco use, family history of premature CAD, body mass index ≥27 kg/m², oestrogen status, and anginal history into a risk score for diagnosing significant CAD in a population of symptomatic patients presenting for stress testing: low (0–8), intermediate (9–15), and high (>15).

Figure 3

Adjusted freedom from major adverse cardiovascular events (MACE)*, (A) and hospitalization for heart failure with preserved ejection fraction (HFpEF, (B) by coronary flow reserve (CFR). Event-free survival, adjusted for pretest clinical score, history of atrial fibrillation, estimated glomerular filtration rate <60 mL•min⁻¹•1.73 m⁻², detectable troponin, left ventricular ejection fraction and E/e′_septal > 15. Freedom from events differed significantly among subgroups stratified by CFR such that patients with low CFR experienced higher rates of composite or HFpEF events (overall P < 0.001 in unadjusted and adjusted analyses).

Figure 4

Freedom from hospitalization for heart failure with preserved ejection fraction (HFpEF) by coronary flow reserve (CFR) and E/e′_septal(*). (A) The Kaplan–Meier (unadjusted) analysis of time to first event. (B) Event-free survival, adjusted for pretest clinical score and detectable troponin. (C) Adjusted annualized rates of events. Freedom from HFpEF hospitalization differed significantly among subgroups stratified by CFR and E/e′, such that only those patients with elevated E/e′ and impaired CFR demonstrated the highest risk of hospitalization for HFpEF (P < 0.001).

Take home figure

Conceptual model of the pathophysiology linking coronary microvascular ischaemia, low-level cardiomyocyte injury, and myocardial stiffness to major adverse cardiovascular outcomes (MACE), especially heart failure with preserved ejection fraction (HFpEF). This process may occur even in the absence of obstructive coronary artery or overt structural heart disease. Heart image is adapted from Servier Medical Art. CAD, coronary artery disease.