Circadian dependence of infarct size and left ventricular function after ST elevation myocardial infarction

Abstract

Rationale: In rodents, infarct size after ischemia/reperfusion exhibits a circadian dependence on the time of coronary occlusion. It is not known if a similar circadian dependence of infarct size occurs in humans.

Objective: To determine if humans exhibit a circadian dependence of infarct size in the setting of ST elevation myocardial infarction (STEMI).

Methods and results: A retrospective analysis of 1031 patients with STEMI referred for primary percutaneous coronary intervention with known ischemic times between 1 and 6 hours identified 165 patients with occluded arteries on presentation without evidence of preinfarction angina or collateral blood flow. Both ischemic duration and angiographic area at risk were not dependent on time of infarct onset. We observed that the extent of infarct size measured by creatine kinase release was significantly associated with time of day onset of infarction (P<0.0001). The greatest myocardial injury occurred at 1:00 am onset of ischemia and 5:00 am onset of reperfusion, with the peak creatine kinase measured at the peak of the curve being 82% higher than that recorded at the trough. Similarly, left ventricular ejection fraction measured within 2 days of infarction was also dependent on time of onset of STEMI with the absolute left ventricular ejection fraction at peak >7% higher than at trough (43% vs 51%; P<0.03). These findings were supported by a subgroup of patients (n = 45) who underwent cardiac MRI measurements of infarct size and area-at-risk measurements.

Conclusions: The results of this study demonstrate for the first time in humans that myocardial infarct size and left ventricular function after STEMI have a circadian dependence on the time of day onset of ischemia.

Figure 1

Study Design: Of 1031 patients presenting with ST elevation and an ischemic Time ≤ 6hrs, 866 patients were excluded for a variety of reasons. Patients could have more than 1 reason for exclusion but only 1 per patient is noted in the diagram.

Figure 2

Correlation of peak CK with infarct size as measured by cardiac MRI: Infarct size was measured by cMRI (n=45), expressed as % of total myocardium and plotted against Peak CK. Correlation is highly significant (r=0.76, p<0.0001)

Figure 3

Time of day dependence of myocardial infarct size with coronary occlusion: Peak CK was plotted against time onset of ischemia. Line represents the fitted sinusoidal curve: CK= 2543+739 × sin (2π x (onset hour-18.72)/24). Amplitude of the fitted curve is significantly different from 0 (p<0.0001) indicating Circadian influence on myocardial infarct size.

Figure 4

Angiographic Area-at-Risk versus time of onset of ischemia over 24-hour cycle: No significant change in AAR is observed over time as expressed as four, 6-hour intervals

Figure 5

Ischemic time (IT) versus time of day onset of myocardial infarction: IT was plotted against time of onset of ischemia. Line represents the fitted sinusoidal curve: IT= 183.36+7.61 × sin (2π x (onset hour-18.47)/24). Amplitude of the fitted curve is not significantly different from 0 (p=0.35) thereby demonstrating no Circadian influence on ischemic time.

Figure 6

Correlation of area-at-risk assessment (AAR) by MRI with AAR assessment by angiography: AAR measured by MRI and angiography are plotted against each other. Correlation is highly significant (r=0.65, p<0.0001).

Figure 7

Circadian variation of myocardial infarct size when corrected for area at risk: Peak CK was divided by area at risk measured by angiography (a) and MRI (b). Lines represent the fitted sinusoidal curves. CK/AAR(angio)=99.95+22.16 × sin (2π x (onset hour-18.22)/24) (a) and CK/AAR(MRI)=73.2+16.64 × sin (2π x (onset hour-17.28)/24) (b). Amplitude of the fitted curves are significantly different from 0 (p<0.001(a) and p<0.02(b) confirming Circadian influence on myocardial infarct size when corrected for area at risk.

Figure 7

Circadian variation of myocardial infarct size when corrected for area at risk: Peak CK was divided by area at risk measured by angiography (a) and MRI (b). Lines represent the fitted sinusoidal curves. CK/AAR(angio)=99.95+22.16 × sin (2π x (onset hour-18.22)/24) (a) and CK/AAR(MRI)=73.2+16.64 × sin (2π x (onset hour-17.28)/24) (b). Amplitude of the fitted curves are significantly different from 0 (p<0.001(a) and p<0.02(b) confirming Circadian influence on myocardial infarct size when corrected for area at risk.

Figure 8

Left-ventricular ejection fraction versus time of day onset of STEMI. Ejection Fraction (EF) was plotted against time onset of ischemia. Line represents the fitted sinusoidal curve: EF=46.83+3.41 × sin (2π x (onset hour-6.20)/24). Amplitude of the fitted curve is significantly different from 0 (p<0.03) indicating circadian influence on ejection fraction following STEMI.