Metabolomic profiling reveals distinct patterns of myocardial substrate use in humans with coronary artery disease or left ventricular dysfunction during surgical ischemia/reperfusion

Abstract

Background: Human myocardial metabolism has been incompletely characterized in the setting of surgical cardioplegic arrest and ischemia/reperfusion. Furthermore, the effect of preexisting ventricular state on ischemia-induced metabolic derangements has not been established.

Methods and results: We applied a mass spectrometry-based platform to profile 63 intermediary metabolites in serial paired peripheral arterial and coronary sinus blood effluents obtained from 37 patients undergoing cardiac surgery, stratified by presence of coronary artery disease and left ventricular dysfunction. The myocardium was a net user of a number of fuel substrates before ischemia, with significant differences between patients with and without coronary artery disease. After reperfusion, significantly lower extraction ratios of most substrates were found, as well as significant release of 2 specific acylcarnitine species, acetylcarnitine and 3-hydroxybutyryl-carnitine. These changes were especially evident in patients with impaired ventricular function, who exhibited profound limitations in extraction of all forms of metabolic fuels. Principal component analysis highlighted several metabolic groupings as potentially important in the postoperative clinical course.

Conclusions: The preexisting ventricular state is associated with significant differences in myocardial fuel uptake at baseline and after ischemia/reperfusion. The dysfunctional ventricle is characterized by global suppression of metabolic fuel uptake and limited myocardial metabolic reserve and flexibility after global ischemia/reperfusion stress in the setting of cardiac surgery. Altered metabolic profiles after ischemia/reperfusion are associated with postoperative hemodynamic course and suggest a role for perioperative metabolic monitoring and targeted optimization in cardiac surgical patients.

Figure 1

Duration of inotropic support following surgery in patients whose myocardium (a) continued to extract lactate and (b) was a net producer of lactate, suggesting predominantly anaerobic metabolism. The median duration of inotrope infusions (0 vs 9 hours) were significantly different (p<0.02).

Figure 2

Correlation between Factor 1 scores and (a) fractional shortening and (b) fractional area change measurements. Regression lines with 95% C.I. of the mean are shown. There is a significant positive correlation between these measures of LV function by pre-procedural transesophageal echocardiography and factor scores derived from principal component analysis of post-I/R metabolic gradients. The predominant features of this factor are related to the extraction of major myocardial fuels (FFA, glucose, lactate, pyruvate and ketones) and acetyl-carnitine (C2).

Figure 3

Mean cardiac output (a) off-CPB and (b) average over the first four hours following surgery differed across quartiles of principal component 2 (PC2) scores. There was an early graded response (a) which diminished over the time in the ICU (b) although the highest quartile PC2 group consistently had the highest cardiac outputs. P-values derived from ANOVA.

Figure 4

Proposed model of myocardial metabolism following I/R summarizing the findings from this study. Myocardial uptake of substrates is impaired, particularly in the case of LV dysfunction. Fatty acids and ketones are bound to carnitine and transported into the inner mitochondrial matrix where they are oxidized to acetyl-CoA. Oxidation of acetyl-CoA (and 3-hydroxy-butryl-CoA) is impaired, and as it accumulates, is released into plasma in the form of acetylcarnitine. The increased acetyl-CoA levels inhibit pyruvate dehydrogenase, promoting anaerobic metabolism of pyruvate into lactate. Additionally, the increased post-reperfusion alanine elution suggests pyruvate and glutamate undergo enhanced trans-amination to alanine and α-ketoglutarate to restore TCA intermediates.

Table 6

Results of the exploratory principal component analysis on post-I/R gradients. Eigenvalues and percent contribution to the total sample variance is presented for each of the first three principal components of the model. Individual features of each principal components are shown, along with their rotated loading coeffiecients. Loading coefficients are rounded to the nearest tenth and only features over 0.4 are displayed.