Despite the progress in the therapy of acute myocardial infarction (AMI), nearly 30%–40% of patients will develop cardiac dysfunction after reperfusion with primary angioplasty (1). Early after the index event, cardiac dilatation occurs to preserve hemodynamics via Starling’s effect. Although this response is adaptive in the short term, it seems to be maladaptive in the long term. Cardiac stretch leads to pathologic growth and ultimately to cardiac dysfunction and heart failure (2). Left ventricular ejection fraction (LVEF) appears to be the strongest independent predictor of major adverse cardiovascular events (MACEs) in patients with AMI (3). Patients who experienced new-onset heart failure (HF) or death have a lower LVEF during the acute phase compared with those who did not (4). Along this line, infarct size (IS) is also one of the main determinants of prognosis in patients with AMI, with every 5% increase in infarct size contributing to a 20% increase in the relative hazard for all-cause mortality or hospitalization for HF within 1 year after primary percutaneous coronary intervention (PCI) (5).

Currently, there are no effective treatments to prevent cardiac remodeling, particularly in patients with large infarct size. Thyroid hormone is known to be a regulator of physiologic growth, which is crucial for organ maturation during development. Over the past years, numerous preclinical studies have shown that thyroid hormone can repair the postischemic myocardium by upregulating physiologic growth signaling (6–12). This novel action was recently tested in a pilot, randomized, double-blind, placebo-controlled trial (13), which showed that early triiodothyronine (LT3) administration can prevent cardiac dilatation and improve cardiac function in patients with acute myocardial infarction. Furthermore, LT3 had no effect on cardiac magnetic resonance (CMR) infarct volume at hospital discharge but facilitated infarct healing after 6 months (13).

Here, a post-hoc analysis of the data from the ThyRepair study was performed in order to provide more insights into the novel effects of LT3 on postinfarcted human myocardium. Specifically, we explored whether the effects of LT3 therapy on the human postinfarcted myocardium are dependent on the severity of infarct size. This analysis may be of importance for the design of future studies translating thyroid hormone into clinical practice.

ThyRepair is the first of its kind pilot, randomized, double-blind, placebo-controlled trial that investigated the effects of acute, high-dose LT3 treatment in patients with anterior myocardial infarction. LT3 was administered immediately after reperfusion and for 48 h thereafter. LT3 was used in high doses according to dose-dependent studies in animal models of myocardial ischemia–reperfusion (13). This therapeutic regimen resulted in favorable effects on the recovery of cardiac function without major safety issues (13).

The effects of LT3 treatment were assessed by CMR. CMR is considered the gold standard imaging modality for quantitative and qualitative assessment of myocardial infarct size, left ventricular volumes, and ejection fraction (14). CMR LVEF% was the primary end-point of the ThyRepair study; CMR cardiac volumes, infarct volume, LVMi, and MVO indices were the secondary end-points. CMR LVEF% was found to be higher in LT3-treated patients, and although the magnitude of the difference compared to placebo was of clinical importance, it did not reach statistical significance (13). This was attributed to an inadequate number of patients included in the study and the early functional compensatory mechanisms that occur at an early stage after myocardial infarction (13).

In the present study, we performed a post-hoc analysis in order to explore whether the effects of LT3 therapy on the human postinfarcted myocardium are dependent on the severity of infarct size. This may offer a possible explanation for the variation in the recovery of CMR LVEF% after LT3 treatment, as seen in the ThyRepair Study. To address this issue, we divided the patients into two groups: one group included patients with large infarct size with CMR infarct volume above 20% of left ventricular volume, and the other group had small infarct size with CMR infarct volume less than or equal to 20% of left ventricular volume. Baseline characteristics, such as age, total ischemic time, and co-morbidities, were not significantly different between LT3-treated and placebo patients in either the small infarct or large infarct group. Total ischemic time had a trend to be lower in LT3-treated patients, but this difference was not statistically significant. There is much controversy over the use of this index in clinical practice because reporting bias is an inherent limitation of studying symptom-to-balloon time. Patients may find it difficult to estimate the time of symptom onset, particularly in the acute setting of illness. Furthermore, the optimal time still has not been defined (15). Thus, troponin release and CMR infarct volume are more accurate to estimate the ischemic damage. Both indices were similar between LT3-treated and placebo patients in either the small infarct or large infarct group. To our surprise, LT3 resulted in significant improvement of all CMR functional indices (LVEF% and cardiac volumes) only in patients with large infarct size. This finding probably indicates that LT3 treatment can potentially benefit the group of patients with large infarct size and worse prognosis (5). However, taking into consideration the small number of patients included in the analysis, this issue merits further investigation.

The use of thyroid hormone in the setting of myocardial ischemia has been a controversial issue over the past years. Thyroid hormone increases heart rate and oxygen consumption and could potentially be detrimental in the setting of ischemia. However, in the era of reperfusion, the role of thyroid hormone in ischemia–reperfusion injury has been redefined. During reperfusion, despite restoration of oxygen supply, glucose oxidation is suppressed and acidosis occurs, which leads to calcium overload and cardiac dysfunction. Triiodothyronine treatment has been shown to improve the coupling of glycolysis to glucose oxidation via its action on pyruvate dehydrogenase (PDH), reduce acidosis, and improve functional recovery (16, 17). Interestingly, the triiodothyronine effect on postischemic cardiac function has not been associated with increased myocardial oxygen consumption (16) and increased myocardial injury in animals (18) or in patients with bypass surgery, acute myocardial infarction, or chronic heart failure (13, 19, 20).

This post-hoc analysis of the ThyRepair data has also provided some novel mechanistic insights into the potential effect of LT3 on early myocardial edema and microvascular obstruction. This evidence may be of therapeutic relevance since effective treatments for MVO and edema are not currently available. The present analysis showed that in patients with large infarct size, LT3 treatment resulted in lower CMR LVMi and MVO. Although these differences did not reach statistical significance, they seem to be of physiological importance. LV mass increases acutely after myocardial infarction due to accumulation of myocardial edema from ischemia–reperfusion injury resulting in increased wall thickness and appears as increased LVMi in CMR imaging. Myocardial edema is not only a consequence of severe ischemia–reperfusion insult but, in turn, can contribute to impairment of microcirculation during reperfusion by mechanically compressing the microvasculature seen as increased MVO in CMR imaging (21). Obstruction of the microcirculation prevents the healing process and exacerbates remodeling after myocardial infarction. Thus, the presence of MVO following myocardial infarction is associated with reduced LV function, greater cardiac remodeling, and increased cardiac events such as heart failure and death (22). Therefore, potential treatments for preventing cardiac remodeling need to be initiated early after primary angioplasty. This is a plausible explanation for the failure of thyroid hormone treatment to show favorable effects on cardiac remodeling when administered at later stages of myocardial infarction (23, 24). Taken together, it seems that early LT3 treatment may have beneficial effects on myocardial edema and MVO, which merit further investigation in larger trials. The vast majority of past and current MVO trials have targeted the intravascular component of MVO using intracoronary vasodilators (adenosine, sodium nitroprusside, and calcium channel blockers) or antithrombotics with mixed results. Targeted intracardiac hypothermia is the only therapy that is currently investigated in a clinical trial as a potential treatment for myocardial edema (25).

The present study, based on post-hoc analysis of data obtained from the ThyRepair study, indicates that acute LT3 treatment may exert more favorable effects on the recovery of cardiac function in patients with large infarcts. Furthermore, it signals a potential effect of LT3 on myocardial edema and microvascular obstruction. However, the small number of patients included in this study has to be taken into consideration, and these data need to be validated in large clinical trials.

These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by the National Independent Ethics Committee (26/16, 31-3-2016) and the Greek Drug Agency. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

CP: Writing – review & editing, Writing – original draft, Project administration, Formal analysis, Conceptualization. KG: Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing. AT: Writing – review & editing, Supervision, Methodology, Investigation, Data curation. NA: Data curation, Methodology, Writing – review & editing. IM: Conceptualization, Formal analysis, Supervision, Validation, Writing – original draft, Writing – review & editing.