Association between coronary vascular dysfunction and cardiac mortality in patients with and without diabetes mellitus

Abstract

Background: Diabetes mellitus increases the risk of adverse cardiac outcomes and is considered a coronary artery disease (CAD) equivalent. We examined whether coronary vascular dysfunction, an early manifestation of CAD, accounts for increased risk among diabetics compared with nondiabetics.

Methods and results: A total of 2783 consecutive patients (1172 diabetics and 1611 nondiabetics) underwent quantification of coronary flow reserve (CFR; CFR=stress divided by rest myocardial blood flow) by positron emission tomography and were followed up for a median of 1.4 years (quartile 1-3, 0.7-3.2 years). The primary end point was cardiac death. Impaired CFR (below the median) was associated with an adjusted 3.2- and 4.9-fold increase in the rate of cardiac death for diabetics and nondiabetics, respectively (P=0.0004). Addition of CFR to clinical and imaging risk models improved risk discrimination for both diabetics and nondiabetics (c index, 0.77-0.79, P=0.04; 0.82-0.85, P=0.03, respectively). Diabetic patients without known CAD with impaired CFR experienced a rate of cardiac death comparable to that for nondiabetic patients with known CAD (2.8%/y versus 2.0%/y; P=0.33). Conversely, diabetics without known CAD and preserved CFR had very low annualized cardiac mortality, which was similar to patients without known CAD or diabetes mellitus and normal stress perfusion and systolic function (0.3%/y versus 0.5%/y; P=0.65).

Conclusions: Coronary vasodilator dysfunction is a powerful, independent correlate of cardiac mortality among both diabetics and nondiabetics and provides meaningful incremental risk stratification. Among diabetic patients without CAD, those with impaired CFR have event rates comparable to those of patients with prior CAD, whereas those with preserved CFR have event rates comparable to those of nondiabetics.

Figure 1. Annual Cardiac Mortality by Perfusion Defect Size for Diabetics vs. Non-Diabetics

Effect of Diabetes and Perfusion Abnormalities on Cardiac Mortality. Unadjusted annualized cardiac mortality in categories of total extent of myocardial ischemia and scar for patients with and without diabetes. Even after accounting for the extent and severity of ischemia and scar, patients with diabetes experienced higher rates of cardiac mortality than those without diabetes.

Figure 2. Unadjusted Cardiac Mortality

Effects of CFR and Traditional MPI Findings on Cardiac Mortality. Unadjusted annualized cardiac mortality for patients with diabetes (panels A–D) and without (panels E–H) by in categories of total extent of myocardial ischemia and scar (panels A&E), total extent of myocardial ischemia (panels B&F), total extent of myocardial scar (panel C&G) or left ventricular ejection fraction (panels E&H) and impaired (red) versus preserved CFR (blue). The annual rate of cardiac death increased with increasing extent of ischemia and scar, decreasing LVEF and CFR. Importantly, lower CFR was consistently associated with higher rates of cardiac mortality regardless of the level of ischemia, scar extent or LVEF.

Figure 3. Cardiac Mortality

Cardiac Mortality Incidence of cardiac mortality for patients with diabetes (panels A&B) and without diabetes (panels C&D), with impaired (red) or preserved (blue) coronary flow reserve (CFR) presented in Kaplan-Meier form (panel A&C) showing significantly increased cardiac mortality with impaired CFR (p<0.0001) which continued after adjustment for Duke clinical risk score, BMI, nephropathy/retinopathy, early revascularization, rest left ventricular ejection fraction (LVEF), extent of myocardial ischemia and scar and LVEF reserve (panel B; p=0.0004). HR = hazard ratio.

Figure 4

Annualized Cardiac Mortality Among Patients with Diabetes or CAD. Adjusted cardiac mortality among patients with coronary artery disease (CAD, i.e. history of coronary revascularization or myocardial infarction) without diabetes (orange), diabetic patients without CAD who have impaired CFR (red), diabetic patients without CAD who have preserved CFR (blue) and patients without diabetes or CAD with normal scans (no scar, ischemia or left ventricular dysfunction, green) presented as survival curves (panel A) and annualized cardiac mortality rates (panel B). Data for patients with CAD and diabetes are also presented for comparison (purple).

Figure 4

Annualized Cardiac Mortality Among Patients with Diabetes or CAD. Adjusted cardiac mortality among patients with coronary artery disease (CAD, i.e. history of coronary revascularization or myocardial infarction) without diabetes (orange), diabetic patients without CAD who have impaired CFR (red), diabetic patients without CAD who have preserved CFR (blue) and patients without diabetes or CAD with normal scans (no scar, ischemia or left ventricular dysfunction, green) presented as survival curves (panel A) and annualized cardiac mortality rates (panel B). Data for patients with CAD and diabetes are also presented for comparison (purple).