Coronary Microvascular Dysfunction, Left Ventricular Remodeling, and Clinical Outcomes in Patients With Chronic Kidney Impairment

Abstract

Background: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes.

Methods: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score <3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses.

Results: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR <60 mL·min-1·1.73 m-2, a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P<0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR.

Conclusions: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.

Keywords: chronic; renal insufficiency.

Figures

Figure 1:

Relationship between cardiac mechanics (diastolic and systolic indices), eGFR and CFR using a three dimensional scatter plot and restricted cubic spline linear regression plane (Black grid on gray surface). Panel A & B: Diastolic indices (Lateral and Septal E/e’), eGFR and CFR Panel C, D & E: Systolic indices (GLS, GRS & GCS), eGFR and CFR Adjusted linear regression models included CFR (coronary flow reserve), eGFR (estimated glomerular filtration rate), age, sex, race, hypertension, hyperlipidemia, diabetes, peripheral vascular disease, stroke, indexed left ventricular mass, and resting left ventricular ejection fraction E = Early wave of mitral inflow, e’= early diastolic mitral annular velocity, GLS= peak global longitudinal strain, GRS= peak global radial strain, GCS = peak global circumferential strain

Figure 2:

Relationship between MACE, eGFR & CFR Panel A: MACE and eGFR (Poisson model) Panel B: MACE and CFR (Poisson model) Panel C: MACE and eGFR (Cox proportional hazard model) Panel D: MACE and CFR (Cox proportional hazard model) Adjusted models included CFR (coronary flow reserve), eGFR (estimated glomerular filtration rate), age, sex, race, hypertension, hyperlipidemia, diabetes, peripheral vascular disease, stroke, indexed left ventricular mass, and resting left ventricular ejection fraction. Restricted cubic spline Poisson and Cox proportional hazard model regression model estimates with 95% confidence intervals are shown in black. The orange line in the Cox proportional hazard model is line of reference. (Gray histogram bars, secondary y-axis display % population with corresponding values of eGFR and CFR). MACE= major adverse cardiovascular event (composite of death, non-fatal myocardial infarction and heart failure).

Figure 3.

Cumulative Hazard of MACE in Unadjusted Models stratified by abnormal CFR (

Figure 4.

Annualized Rate of MACE by categories of LV structure/function by Coronary Flow Reserve (Panel A). Annualized Rate of Heart Failure or non-fatal myocardial hospitalizations by categories of LV structure/Function by Coronary Flow Reserve (Panel B). Higher rates of adverse events were seen when abnormalities in coronary microvascular dysfunction co-existed with abnormalities in LV geometry, systolic and diastolic function (all p