Therapeutic Hypothermia: A Potential New Paradigm in Acute MI Management

The clinical outcomes of acute MI, including acute and chronic congestive HF, cardiogenic shock and sudden cardiac death, are mainly due to the damaging effect of ischemia and reperfusion injury on the myocardium. The prevalence of infarct-related complications has remained relatively unchanged despite a variety of interventions and recent advances in CAD management.

Therapeutic hypothermia (TH) ameliorates the effects of ischemia and reperfusion in patients with out-of-hospital cardiac arrest, which has resulted in improved neurological recovery and better survival. The goal of this review is to summarize the effects of TH in patients with acute MI, and to provide an update on recent trials using TH for infarct size reduction.

Effect of Ischemia, Reperfusion on the Heart

During acute MI, the lack of oxygen in the ischemic myocardium inhibits oxidation phosphorylation and activates anaerobic metabolism to maintain energy production. Anaerobic glycolysis is the main source of energy during ischemia and is associated with the increased production of metabolic intermediates (such as lactate and hydrogen ions), which results in intra-cellular acidosis, high intracellular osmotic gradients and reactive oxygen species formation. Prolonged myocardial ischemia results in progressive reduction in the available energy and the development of irreversible necrosis. The various pathological changes involved in myocardial necrosis are described in Figure 1. Coronary reperfusion of the infarct-related artery restores the pre-ischemic oxygen and substrate levels and reactivates oxidation phosphorylation in the mitochondria. Additionally, reperfusion promotes a rapid pH correction by scavenging accumulating metabolic intermediates, an increase in local neutrophils infiltration, and an increase in pro-inflammatory cytokine generation.

Reperfusion injury negatively affects mechanical flow obstruction, which results in additional cellular injury. The microvascular obstruction is caused by the distal embolization of microthrombi, activated platelets and neutrophils, and increased microvascular resistance due to endothelial dysfunction. Microcirculatory dysfunction (microvascular obstruction and reperfusion injury) is the main cause of the “no reflow phenomenon,” which has been linked to adverse outcomes. No reflow in acute MI can be characterized invasively using Doppler flow wires to measure coronary flow reserve (CFR) or angiographically by using the TIMI flow grade, TIMI myocardial perfusion (TMP) grade or the myocardial blush grade (MBG). Lethal reperfusion injury results from a combination of paradoxical ischemic, metabolic and inflammatory responses that take place following reperfusion. These changes are illustrated in Figure 1.

The degree of pre-existing injury and available energy substrate in the ischemic myocardium determine the fate of cardiomyocytes following reperfusion. Reperfusion injury results in an initial accelerated myocardial injury due to necrosis, and a subsequent more progressive myocardial injury mainly due to apoptosis. Myocardial injury following reperfusion has been shown to induce a wavefront of cardiomyocyte death that progress in a similar pattern to that observed during ischemia. The effects of ischemia and reperfusion injury on the progression of MI are demonstrated in Figure 2.

Lowering body temperature minimizes the adverse myocardial outcomes associated with ischemia by affecting the metabolic rate, energy demand supply mismatch and ischemic tolerance. Reducing reperfusion injury involves modulating complex metabolic, ischemic and inflammatory mechanisms. The benefits of TH in acute MI result from the combined effects of TH on ischemia and reperfusion injury.

Effect of Hypothermia on Myocardial Ischemia

Irreversible myocardial necrosis in patients with acute MI is the most important factor in myocardial infarct size determination at the time of reperfusion. Whereas early coronary reperfusion (reflected by a door-to-balloon time <90 minutes) is the only proven strategy to influence the progression of myocardial necrosis, recent animal studies and one clinical trial suggested that the effective application of TH prior to coronary reperfusion can interrupt the progression of myocardial necrosis resulting in inhomogeneous, patchy MI, indicating the presence of viable cardiomyocytes within the injured myocardium. The potential benefits of effective pre-reperfusion TH induction in acute MI patients without immediate access to PCI-capable hospitals can potentially introduce a paradigm shift in the future management of acute MI by expanding the therapeutic window for coronary interventions.

Effect of Hypothermia on Reperfusion Injury

Establishing TH before reperfusion occurs (cool reperfusion) has been shown to inhibit myocardial cell death due to necrosis and apoptosis, which seems to be mediated by minimizing microvascular dysfunction. The effects of TH on reperfusion injury are illustrated in Figure 3 and include inhibition of platelet and neutrophil activation, preservation of endothelial function, intracellular calcium and pH regulation, reduction in reactive oxygen species generation, positive inflammatory and immune modulation, inhibition of caspase activation, and the promotion of pathways involved in survival signaling.

Survival signal transduction pathways — such as the reperfusion injury salvage kinase (RISK) and the survivor activating factor enhancement (SAFE) pathways — are among the newest discoveries in the field, which gained attention with better understanding of ischemic post-conditioning. Protein kinase C/nitric oxide pathway, protein kinase B (Akt)/ heat shock-cold shock proteins pathway, and tumor necrosis factor-alpha inhibition pathways are key mediators that get activated by TH during ischemia and result in myocardial protection following reperfusion.

Reduction of Myocardial Infarct Size

TH has been demonstrated to reduce infarct size in multiple animal models. Reduction in infarct size averaged 8% for every 1°C drop in core body temperature. A drop of 2°C or more in core temperature was required to achieve a significant improvement. The temperature at the time of reperfusion was an important variable for determining benefit. All of the animal studies were done under general anesthesia before cooling induction, which is not the case in a conscious MI patient. In a recent study using large human-size pigs, the rapid induction of TH at the time of reperfusion resulted in a 39% reduction in infarct size. Cardiac MRI (with higher spatial resolution than SPECT) allowed for a more accurate infarct size assessment.

Two pilot studies — the Feasibility of Endovascular Cooling as an Adjunct to Primary Percutaneous Coronary Intervention (LOWTEMP) and the Noninvasive Surface Cooling Thermoregulatory System for Mild Hypothermia Induction in Acute MI (NICAMI) — showed feasibility and safety for both surface cooling and endovascular cooling in patients with acute MI. The two largest randomized controlled trials with or without cooling of PCI for acute MI were the Cooling as an Adjunct to Primary Percutaneous Coronary Intervention for Myocardial Infarction (COOL MI) and the Intravascular Cooling Adjunctive to Percutaneous Coronary Intervention for Acute MI (ICE IT) trials, which were encouraging but did not demonstrate significant benefit.

In COOL MI, 325 acute MI patients were treated with endovascular TH to a target temperature of 33°C for 3 hours. Infarct size was assessed with nuclear imaging (SPECT) at 30 days. ICE IT enrolled 204 patients using endovascular cooling to a target temperature of 33°C for 6 hours. The infarct assessment also used SPECT at 30 days. In both studies, there was difficulty reaching target temperature. Overall, there was no significant difference for infarct size between groups (COOL MI: TH, 14.1% vs. control, 13.8%; P=.86; ICE IT: TH, 10.2% vs. control, 13.2%; P=.14). A post-hoc analysis of COOL MI data showed that patients with larger anterior MIs, in whom a core temperature of <35°C was achieved before reperfusion, demonstrated a significant benefit for TH.

Recently, the results of two landmark studies on TH in acute MI — the Rapid Cooling by Cold Saline and Endovascular Cooling Before Reperfusion in Patients with ST-Elevation Myocardial Infarction (RAPID MI-ICE) study and the Rapid Endovascular Catheter Core Cooling Combined with Cold Saline as an Adjunct to Percutaneous Coronary Intervention for the Treatment of AMI (CHILL-MI) study — became available. The objective of these studies was to examine the effect of TH on myocardial infarct size when the target core body temperature is established before reperfusion; using conscious sedation; and without inducing a significant delay in door-to-balloon time. A combination of IV iced saline and endovascular cooling was used. Cardiac MRI (on day 4 in the RAPID MI-ICE, and at 6 months in the CHILL-MI) was used to assess infarct size. Patients with anterior and inferior acute STEMI of less than 6 hours duration were included.

In the RAPID MI-ICE pilot study, 20 acute MI patients were enrolled. A core body temperature of less than 35°C was achieved before reperfusion in all patients in the hypothermia arm (n=9). The authors reported a 38% reduction in infarct size in the TH group compared with the control group (29.8 ± 12.6% vs. 48 ± 21.6%; P=.041), an effect that distinguishes RAPID MI-ICE as the first clinical trial of TH in acute MI to demonstrate a reduction in infarct size.

The prospective, randomized, multicenter CHILL-MI study included 120 acute MI patients and was conducted to validate the results of the RAPID MI-ICE study. Cooling to less than 35°C before reperfusion was achieved in 77% of patients. The authors reported a nonsignificant reduction in myocardial infarct size in the TH arm compared with the control (13% relative reduction; P=.15). An exploratory analysis of patients with early MI (<4 hours) demonstrated a significant infarct size reduction benefit (21% relative reduction; P=.049) favoring TH over the control group, a benefit that was mainly driven by the cooling effect in patients with acute anterior MI (anterior MI: 33% relative reduction; P=.046; inferior MI: 13% relative reduction; (P=NS).

Future of Therapeutic Hypothermia in Acute MI

CHILL-MI is the largest trial to demonstrate benefits in using TH for infarct size reduction in acute MI. Nevertheless, these benefits were observed in an exploratory subset analysis of the study results and were only observed in patients with anterior MI of less than 4 hours duration. Additional studies to further validate these results are needed. Remaining questions to be answered include the potential application of TH to improve cardiac and brain recovery in selected out-of-hospital cardiac arrest survivors in whom the majority have significant CAD. Finally, clinical reports indicate that TH may be a promising adjunctive therapy to improve outcomes in ischemic cardiogenic shock patients.

Disclosure: All authors report no relevant financial disclosures.