Coronary vascular dysfunction and prognosis in patients with chronic kidney disease

Abstract

Objectives: This study sought to evaluate whether impaired vasodilator function, an early manifestation of coronary artery disease, which precedes angiographic stenosis, accounts for increased risk among patients with moderate to severe renal dysfunction.

Background: Patients with renal dysfunction are at increased risk of adverse cardiac outcomes, even in the absence of overt myocardial ischemia or infarction.

Methods: We included 866 consecutive patients with moderate to severe renal dysfunction referred for rest and stress myocardial perfusion positron emission tomography and followed them for a median of 1.28 years (interquartile range: 0.64 to 2.34). Regional myocardial perfusion abnormalities were assessed by semiquantitative visual analysis of positron emission tomography images. Rest and stress myocardial blood flow were calculated using factor analysis and a 2-compartment kinetic model; they were also used to compute coronary flow reserve (stress/rest myocardial blood flow). The primary endpoint was cardiac death.

Results: Overall, 3-year cardiac mortality was 16.2%. After adjusting for clinical risk, left ventricular ejection fraction, as well as the magnitude of scar and/or ischemia, coronary flow reserve below the median (<1.5) was associated with a 2.1-fold increase in the risk of cardiac death (95% confidence interval [CI]: 1.3 to 3.5, p = 0.004). Incorporation of coronary flow reserve into cardiac death risk assessment models resulted in an increase in the C-index from 0.75 to 0.77 (p = 0.05) and in a net reclassification improvement of 0.142 (95% CI: 0.076 to 0.219). Among patients at intermediate risk based on all data other than coronary flow reserve, the net reclassification improvement was 0.489 (95% CI: 0.192 to 0.836). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated.

Conclusions: The presence of coronary vascular dysfunction in patients with moderate to severe renal dysfunction, as assessed by positron emission tomography, is a powerful, independent predictor of cardiac mortality and provides meaningful incremental risk stratification over conventional markers of clinical risk.

Figure 1. Unadjusted Cardiac Mortality

Unadjusted annualized cardiac mortality in categories of total extent of myocardial ischemia and scar (panel A); and by CFR above and below median (1.5) and categories of total extent of myocardial ischemia and scar (panel B); and by CFR above and below median and categories of left ventricular ejection fraction (panel C). The annual rate of cardiac death increased with increasing extent of ischemia and scar, decreasing LVEF and CFR. Importantly, lower CFR consistently identified higher risk patients at every level of ischemia and scar extent and LVEF, including among those with visually normal PET scans and normal LV function.

Figure 1. Unadjusted Cardiac Mortality

Unadjusted annualized cardiac mortality in categories of total extent of myocardial ischemia and scar (panel A); and by CFR above and below median (1.5) and categories of total extent of myocardial ischemia and scar (panel B); and by CFR above and below median and categories of left ventricular ejection fraction (panel C). The annual rate of cardiac death increased with increasing extent of ischemia and scar, decreasing LVEF and CFR. Importantly, lower CFR consistently identified higher risk patients at every level of ischemia and scar extent and LVEF, including among those with visually normal PET scans and normal LV function.

Figure 1. Unadjusted Cardiac Mortality

Unadjusted annualized cardiac mortality in categories of total extent of myocardial ischemia and scar (panel A); and by CFR above and below median (1.5) and categories of total extent of myocardial ischemia and scar (panel B); and by CFR above and below median and categories of left ventricular ejection fraction (panel C). The annual rate of cardiac death increased with increasing extent of ischemia and scar, decreasing LVEF and CFR. Importantly, lower CFR consistently identified higher risk patients at every level of ischemia and scar extent and LVEF, including among those with visually normal PET scans and normal LV function.

Figure 2. Cardiac Mortality

Incidence of cardiac mortality for patients coronary flow reserve (CFR) above and below the median (1.5) presented in Kaplan-Meier form (panel A) showing significantly increased risk of cardiac mortality with CFR <1.5 (p<0.0001) which continued after adjustment(18) for clinical risk (Duke clinical score(17)), early revascularization, rest left ventricular ejection fraction (LVEF), extent of myocardial ischemia and scar and LVEF reserve (panel B; p=0.0004). Graphs are censored at 3-years for simplicity. HR = hazard ratio.

Figure 2. Cardiac Mortality

Incidence of cardiac mortality for patients coronary flow reserve (CFR) above and below the median (1.5) presented in Kaplan-Meier form (panel A) showing significantly increased risk of cardiac mortality with CFR <1.5 (p<0.0001) which continued after adjustment(18) for clinical risk (Duke clinical score(17)), early revascularization, rest left ventricular ejection fraction (LVEF), extent of myocardial ischemia and scar and LVEF reserve (panel B; p=0.0004). Graphs are censored at 3-years for simplicity. HR = hazard ratio.

Figure 3. Risk Reclassification

Illustration of risk reclassification by addition of coronary flow reserve (CFR) to a model containing clinical risk factors, left ventricular ejection fraction (LVEF), LVEF reserve and combined extent of myocardial ischemia and scar. The height of each bar is proportional to the number of patients in each pre-CFR risk category (<2, 2–4 and >4% per year risk of cardiac death) as estimated by a model containing clinical risk factors, rest LVEF, LVEF reserve and extent of myocardial ischemia and scar (Model 4, Table 2). Each of these bars is subdivided proportionate to the number of patients reclassified as <2 (green), 2–4 (blue) and >4% (pink) per year risk of cardiac death categories after the addition of CFR to the risk model (Model 5, Table 2). The horizontal bar charts at right represent the observed annualized rates of cardiac mortality in each of the post-CFR risk categories.