Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction

1 Introduction

The heart uses several energy sources, including fatty acids, glucose, lactate, amino acids, and ketone bodies, to produce ATP. The healthy adult heart obtains 60–80% of its energy from fatty acids and 20–40% from glucose [1]. Additionally, it rapidly switches between these energy sources, depending on hormonal factors [2]. During myocardial ischemia, the oxygen supply to the myocardial mitochondria is reduced, and glucose, which is more efficient for producing ATP than fatty acids, becomes the primary energy source for the heart [3]. Some studies have reported that blood ketone body (acetoacetate and β-hydroxybutyrate) levels increase during acute myocardial infarction [4]. Severe chest pain caused by acute myocardial infarction increases endogenous catecholamine, cortisol, and glucagon levels [5], which activate hormone-sensitive lipase and metabolize triglycerides into free fatty acids and glycerol [6]. Free fatty acids are metabolized into ketone bodies in the liver and transported to peripheral tissues. Finally, ATP is produced in the mitochondria through the tricarboxylic acid cycle [7]. We considered that ketone bodies require less oxygen than fatty acids to produce 1 kcal of energy [8]. Thus, ketone bodies may produce more ATP than fatty acids, even during myocardial ischemia with a low oxygen supply. To date, this phenomenon has not been sufficiently investigated. Additionally, the relationship between blood ketone body levels and major adverse cardiac and cerebrovascular events (MACCEs) in patients with acute myocardial infarction remains unknown. Therefore, this study aimed to investigate the relationship between ketone body levels and MACCE incidence after the onset of acute myocardial ischemia.

2 Methods

2.1 Study population

This study was designed as a single-institution, retrospective observational investigation of data from 169 patients treated for acute myocardial infarction at Nihon University Hospital from May 1, 2018, to November 1, 2022. A flow diagram of the study participants’ selection process is shown in Figure 1. Fifty-five patients were excluded for the following reasons: 26 out-of-hospital patients experienced cardiopulmonary arrest, 13 received sodium-glucose cotransporter-2 (SGLT2) inhibitors, 11 did not undergo arterial blood ketone body (acetoacetate and β-hydroxybutyrate) measurements at admission, 2 were not followed up for cardiac enzyme levels (creatine kinase [CK], creatine kinase myocardial band [CK-MB], and troponin I [TnI]), and 3 were transferred to another hospital prior to coronary angiography (CAG). Finally, 114 patients were enrolled in this study.

Figure 1

Flow diagram for study participant selection.

Although early and effective treatment of acute myocardial infarction with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) can reduce mortality, adverse events, such as stroke or recurrent myocardial infarction, can hamper a patient’s activities of daily living. Therefore, MACCEs during hospitalization were analyzed as an endpoint. In-hospital MACCEs included all-cause mortality, non-fatal myocardial infarction, and non-fatal stroke. The cut-off value of acetoacetate to predict the incidence of in-hospital MACCE was determined by plotting a receiver operating characteristic curve (ROC) and defining patients with acetoacetate above the optimal cut-off point value as the high-acetoacetate group and those below it as the low-acetoacetate group. Propensity score matching was performed between the low-acetoacetate (LA) and high-acetoacetate (HA) groups.

Myocardial infarction was defined based on the Fourth Universal Definition of Myocardial Infarction published in 2018 [9]. The following patient characteristics were examined: age, sex, body mass index, vital signs, comorbidities, medication use, and echocardiographic parameters. Laboratory data included CK, CK-MB, TnI, arterial blood gas, and arterial blood ketone body levels at admission. All patients transported to our hospital’s emergency room had an arterial blood ketone body ratio (AKBR), which was measured to indirectly assess hepatocyte viability, including patients with acute myocardial infarction. The patients underwent CAG on admission. If the coronary culprit lesion was treatable by PCI, they underwent PCI; otherwise, they underwent CABG. The antegrade radiocontrast flow of the infarct-related artery was determined through CAG by the operator who used thrombolysis in myocardial infarction criteria. To monitor cardiac enzyme levels during hospitalization, blood samples were collected first at admission (before PCI) and subsequently 3, 6, 9, 12, and 24 h after PCI.

3 Results

In the original cohort, the cut-off value of acetoacetate for in-hospital MACCEs incidence was 130.7 µmol/L, with a sensitivity of 56.4% and a specificity of 76.9% (area under the curve [AUC]: 0.704, standard error [SE] of AUC: 0.062, P = 0.017, 95% confidence interval [CI]: 0.584–0.825) (Figure 2). There were 54 cases in the LA group and 60 cases in the HA group above the cut-off value.

Figure 2

ROCs for acetoacetate to predict the incidence of in-hospital MACCEs. ROC: original cohort (n = 114).

We then determined the confounding factors between in-hospital MACCEs and acetoacetate. The relationship between the incidence of in-hospital MACCEs and each factor analyzed using logistic regression analysis in the original cohort is presented in Table 1. The univariate analysis revealed significant differences in the left ventricular ejection fraction (LVEF) on admission, peak CK, peak CK-MB, peak TnI, lactate level, blood glucose level, and acetoacetate level. Of these factors, LVEF was excluded from the confounding factors due to its small correlation coefficient with acetoacetate (ρ = −0.013, P = 0.891). Peak CK-MB and peak TnI were significantly correlated with peak CK (ρ = 0.906, P < 0.001 and ρ = 0.428, P < 0.001, respectively) and were excluded from the confounding factors because of multicollinearity. We added sex to the confounding factors, as it is an important factor. As a result, sex, peak CK, lactate, and blood glucose were defined as confounding factors between in-hospital MACCEs and acetoacetate, and 1:1 propensity score matching between the LA and HA groups was used, resulting in 40 patients from both groups enrolled in the analysis.

The baseline characteristics, laboratory data, procedural characteristics, and outcomes for the matched and original cohorts are presented in Table 2 and Table S1, respectively. The characteristics of the matched cohort are as follows. There was no significant difference in the median age between the LA and HA groups (LA group: 65 years [IQR: 55–71 years] vs HA group: 65 years [IQR: 53–74 years]; P = 0.912). There were no significant differences in the confounding factors used for propensity score matching (sex, peak CK, lactate, and blood glucose) between the two groups. AKBR was significantly lower in the HA group (LA group: median 0.82 [IQR: 0.57–1.13] vs HA group: median 0.53 [IQR: 0.46–0.64]; P < 0.001). There was a significantly lower incidence of in-hospital MACCEs in the HA group (LA group: 9 [22%] vs HA group: 1 [3%], P = 0.014). In the matched cohort, we plotted ROC curves for acetoacetate to predict the incidence of in-hospital MACCEs (Figure 2). The cut-off value of acetoacetate to predict the incidence of in-hospital MACCE in the original cohort (130.7 µmol/L) had a sensitivity of 55.7% and a specificity of 90.0% in the matched cohort (AUC: 0.724, SE of AUC: 0.063, P = 0.023, 95% CI: 0.601–0.846).

4 Discussion

Blood ketone bodies are elevated in acute myocardial infarction and chronic heart failure [4,10]. However, the role of blood ketone bodies in acute myocardial infarction remains unknown. To the best of our knowledge, this is the first study to analyze the effect of blood ketone bodies on in-hospital MACCE incidence in patients with acute myocardial infarction. In this study, the significantly lower incidence of in-hospital MACCEs in the high-acetoacetate group suggests that acetoacetate influences the in-hospital MACCEs’ incidence. This may be because acetoacetate is an important energy source during myocardial ischemia.

Acetoacetate and β-hydroxybutyrate are the two main types of ketone bodies. The third type is acetone, which is spontaneously metabolized from acetoacetate and exhaled; therefore, it has not been discussed in this study. Ketone bodies are produced in the liver and used in peripheral tissues under conditions of limited carbohydrate availability, such as fasting and starvation, exercise, and insulin failure [11]. The metabolic pathways of ketone bodies are shown in Figure 3. Ketone bodies transported to peripheral tissues enter the mitochondria through monocarboxylate transporters (MCTs) present on the inner membrane of the peripheral tissue mitochondria. MCTs transport ketone bodies into the mitochondria down their concentration gradient. When the blood ketone concentration is sufficiently high, the ketone body concentration in the peripheral tissue mitochondria increases with the number of MCTs. Subsequently, ketone bodies are converted to acetyl-CoA by β-hydroxybutyrate dehydrogenase (βDH1) and succinyl-CoA:3-ketoacid CoA transferase (SCOT). ATP is produced via the tricarboxylic acid cycle. When ketone bodies are used to produce ATP in myocardial mitochondria, oxygen consumption is lower than that when glucose and fatty acids are used, and the amount of energy produced is similar to that produced using glucose and fatty acids [8]. Therefore, ketone bodies are highly efficient in terms of oxygen consumption during myocardial ischemia, in which the oxygen supply is inadequate and can be efficiently used to produce ATP.

Figure 3

Hypothesized ketone body metabolic pathway. CoA = coenzyme A, AcAc = acetoacetate, HMGCS = hydroxymethylglutaryl-coenzyme A synthase, HMG = hydroxymethylglutaryl, NADH = nicotinamide adenine dinucleotide hydrate, NAD+ = nicotinamide adenine dinucleotide, βOHB = 3-hydroxybutyric acid, MCT = mitochondria through monocarboxylate transporters, βDH1 = β-hydroxybutyrate dehydrogenase, SCOT = succinyl-CoA:3-ketoacid CoA transferase, TCA = tricarboxylic acid cycle, ETC = electron transport chain, ATP = adenosine triphosphate.

Several studies have shown that blood ketone levels benefit myocardial energy production. SGLT2 inhibitors reduce the risk of MACCEs in patients with chronic heart failure with or without diabetes [12,13]. The mechanism underlying this effect is increased blood ketone levels induced by SGLT2 inhibitors and the efficient production of ATP using these ketones in myocardial mitochondria [14]. Previous studies have reported that the mRNA levels of MCT1, βDH1, and SCOT increased in acute myocardial infarction rat models fed a ketone diet [15] and that those of βDH1 and SCOT also increased in patients with chronic heart failure [16]. This implies that there may be increased ketone body availability in the myocardial mitochondria under these conditions; however, no study has examined this aspect in patients with acute myocardial infarction. Previous studies have reported that rats with elevated blood ketone body levels after short-term fasting and those that received β-hydroxybutyrate after long-term fasting exhibited reduced infarct size after ischemia–reperfusion treatment [17,18].

This study had a significant relationship between acetoacetate levels and in-hospital MACCEs, which was not observed for β-hydroxybutyrate before propensity score matching. This may be because of the balance between acetoacetate and β-hydroxybutyrate production in the liver, which is influenced by endogenous catecholamine stimulation. AKBR, which reflects the redox potential (nicotinamide adenine dinucleotide [NAD]+/NADH) of hepatic mitochondria, is decreased by shock liver and catecholamine stimulation [19,20]. This is due to increased NADH production in the liver mitochondria as well as increased acetoacetate metabolism to β-hydroxybutyrate. In this study, median AKBR before propensity score matching decreased to 0.59 [IQR: 0.49–0.79], suggesting that stimulation of endogenous catecholamine due to myocardial infarction increased acetoacetate metabolism to β-hydroxybutyrate. Therefore, acetoacetate levels were reduced to a greater extent in patients with high catecholamine stimulation, such as those with in-hospital MACCEs.

A key limitation of this study is that arterial blood ketone body levels were measured at admission without considering meal timing; arterial blood ketone body levels might have been elevated if the patient had fasted.

5 Conclusions

In patients with acute myocardial infarction, elevated blood acetoacetate levels are associated with a reduced risk of MACCEs. These results indicate that acetoacetate may serve as a potential protective factor in mitigating severe cardiovascular complications following myocardial infarction, possibly because acetoacetate is an important energy source during myocardial ischemia. Further research and investigations are warranted to elucidate the underlying mechanisms and explore the clinical implications of these findings.

List of abbreviations

CABG

coronary artery bypass grafting

CAG

coronary angiography

CK

creatine kinase

CK-MB

creatine kinase myocardial band

LVEF

left ventricular ejection fraction

MACCEs

major adverse cardiac and cerebrovascular events

MCTs

monocarboxylate transporters

PCI

percutaneous coronary intervention

SCOT

succinyl-CoA:3-ketoacid CoA transferase

SGLT2

sodium-glucose cotransporter-2

TnI

troponin I

βDH1

β-hydroxybutyrate dehydrogenase