Selective Hypothermia Research Articles

Hypothermia for Cardioprotection in Acute Coronary Syndrome Patients: From Bench to Bedside.

Early revascularization for patients with acute myocardial infarction (AMI) is of outmost importance in limiting infarct size and associated complications, as well as for improving long-term survival and outcomes. However, reperfusion itself may further damage the myocardium and increase the infarct size, a condition commonly recognized as myocardial reperfusion injury. Several strategies have been developed for limiting the associated with reperfusion myocardial damage, including hypothermia. Hypothermia has been shown to limit the degree of infarct size increase, when started before reperfusion, in several animal models. Systemic hypothermia, however, failed to show any benefit, due to adverse events and potentially insufficient myocardial cooling. Recently, the novel technique of intracoronary selective hypothermia is being tested, with preclinical and clinical results being of particular interest. Therefore, in this review, we will describe the pathophysiology of myocardial reperfusion injury and the cardioprotective mechanics of hypothermia, report the animal and clinical evidence in both systemic and selective hypothermia and discuss the potential future directions and clinical perspectives in the context of cardioprotection for myocardial reperfusion injury.

Selective brain cooling with a novel catheter reduces infarct growth after recanalization in a canine large vessel occlusion model.

Therapeutic hypothermia has shown potential in cardiac intervention for years; however, its adoption into the neurovascular space has been limited. Studies have pointed to slow cooling and limited depth of hypothermia yielding negative outcomes. Here we present an insulated catheter that allows for consistent infusion of chilled saline directly to the brain. Direct delivery of cold saline allows a faster depth of hypothermia, which could have a benefit to the growth of ischemic lesions. Ten canines were randomized to either receive selective brain cooling or no additional therapy. Eight animals were successfully enrolled (n = 4 per group). Each animal underwent a temporary middle cerebral artery occlusion (MCAO) for a total of 45 min. Five minutes prior to flow restoration, chilled saline was injected through the ipsilateral internal carotid artery using an insulated catheter to ensure delivery temperature. The treatment continued for 20 min, after which the animal was transferred to an MRI scanner for imaging. Of the 8 animals that were successfully enrolled in the study, 3 were able to survive to the 30-day endpoint with no differences between the cooled and control animals. There was no difference in the initial mean infarct size between the groups; however, animals that did not receive cooling had infarcts continuing to progress more rapidly after the MCAO was removed (13.8% vs 161.3%, p = 0.016, cooled vs control). Selective hypothermia was able to reduce the post-MCAO infarct progression in a canine model of temporary MCAO.

A novel intracoronary hypothermia device reduces myocardial reperfusion injury in pigs.

Hypothermia therapy has been suggested to attenuate myocardial necrosis; however, the clinical implementation as a valid therapeutic strategy has failed, and new approaches are needed to translate into clinical applications. This study aimed to assess the feasibility, safety, and efficacy of a novel selective intracoronary hypothermia (SICH) device in mitigating myocardial reperfusion injury. This study comprised two phases. The first phase of the SICH was performed in a normal porcine model for 30 minutes ( n = 5) to evaluate its feasibility. The second phase was conducted in a porcine myocardial infarction (MI) model of myocardial ischemia/reperfusion which was performed by balloon occlusion of the left anterior descending coronary artery for 60 minutes and maintained for 42 days. Pigs in the hypothermia group ( n = 8) received hypothermia intervention onset reperfusion for 30 minutes and controls ( n = 8) received no intervention. All animals were followed for 42 days. Cardiac magnetic resonance analysis (five and 42 days post-MI) and a series of biomarkers/histological studies were performed. The average time to lower temperatures to a steady state was 4.8 ± 0.8 s. SICH had no impact on blood pressure or heart rate and was safely performed without complications by using a 3.9 F catheter. Interleukin-6 (IL-6), tumor necrosis factor-α, C-reactive protein (CRP), and brain natriuretic peptide (BNP) were lower at 60 min post perfusion in pigs that underwent SICH as compared with the control group. On day 5 post MI/R, edema, intramyocardial hemorrhage, and microvascular obstruction were reduced in the hypothermia group. On day 42 post MI/R, the infarct size, IL-6, CRP, BNP, and matrix metalloproteinase-9 were reduced, and the ejection fraction was improved in pigs that underwent SICH. The SICH device safely and effectively reduced the infarct size and improved heart function in a pig model of MI/R. These beneficial effects indicate the clinical potential of SICH for treatment of myocardial reperfusion injury.

Transnasal cooling: New prospect of selective hypothermia in acute ischemic stroke

Rapid and selective therapeutic hypothermia is a promising neuroprotective method for acute ischemic stroke. A recent study developed a simple but efficient technique of transnasal cooling, in which air at ambient temperature was passed through standard nasal cannula to induce evaporative cooling of the brain. Selective brain temperature decrease was achieved within 25 minutes in piglets. It is a major step forward to initiate early brain cooling. However, it is still necessary to devise a more comprehensive strategy to enhance the benefits of selective brain cooling in the era of effective reperfusion.

Dual-sized hollow particle incorporated fibroin thermal insulating coatings on catheter for cerebral therapeutic hypothermia

Selective endovascular hypothermia has been used to provide cooling-induced cerebral neuroprotection, but current catheters do not support thermally-insulated transfer of cold infusate, which results in an increased exit temperature, causes hemodilution, and limits its cooling efficiency. Herein, air-sprayed fibroin/silica-based coatings combined with chemical vapor deposited parylene-C capping film was prepared on catheter. This coating features in dual-sized-hollow-microparticle incorporated structures with low thermal conductivity. The infusate exit temperature is tunable by adjusting the coating thickness and infusion rate. No peeling or cracking was observed on the coatings under bending and rotational scenarios in the vascular models. Its efficiency was verified in a swine model, and the outlet temperature of coated catheter (75μm thickness) was 1.8-2.0°C lower than that of the uncoated one. This pioneering work on catheter thermal insulation coatings may facilitate the clinical translation of selective endovascular hypothermia for neuroprotection in patients with acute ischemic stroke.

Mechanisms of low-temperature rehabilitation technologies. Natural and artificial hypothermia

The literature review covers an analysis of the typical protective and adaptive reaction mechanisms that develop in small rodents that spontaneously hibernate under the cold snap, together with warm-blooded animals and humans during circadian fall of the body temperature at night time and in a course of a slow-wave sleep, along with induced artificial therapeutic hypothermia.
 The general features of neuroprotection states development in natural endogenous and induced hypothermia are highlighted, which include metabolic, epigenetic and biophysical reactions that ensure the formation of nonspecific tolerance of the brain to potentially damaging effects. Significant attention has been devoted to the participation of hibernation proteins, opioids and antioxidant systems in the processes of safe exit from state of torpor in animals and in implementation of sleep restoration functions. Taking into account the circadian nature formation of endogenous brains hypothermia at night and in the phases of slow sleep, it is suggested that periodic temperature exposure on the cerebral cortex can be applied in order to restore the disturbed circadian rhythms. From the standpoint of common mechanisms of endogenous and induced hypothermia, selective hypothermia of the cerebral cortex can be considered as a nature-like technology.
 Based on the extensive experimental material indicating a significant neuroprotective potentials of low temperatures during hibernation, diurnal hypothermia as well as artificially induced hypothermia, it was stated that implementation of the technology for selective hypothermia of the cerebral cortex in order to prevent the negative consequences of cerebral catastrophes are a perspective trend.

Hypothermic neuroprotection by targeted cold autologous blood transfusion in a non-human primate stroke model

Over decades, nearly all attempts to translate the benefits of therapeutic hypothermia in stroke models of lower-order species to stroke patients have failed. Potentially overlooked reasons may be biological gaps between different species and the mismatched initiation of therapeutic hypothermia in translational studies. Here, we introduce a novel strategy of selective therapeutic hypothermia in a non-human primate ischemia-reperfusion model, in which autologous blood was cooled ex vivo and the cool blood transfusion was administered at the middle cerebral artery just after the onset of reperfusion. Cold autologous blood cooled the targeted brain rapidly to below 34 °C while the rectal temperature remained around 36 °C with the assistance of a heat blanket during a 2-h hypothermic process. Therapeutic hypothermia or extracorporeal-circulation related complications were not observed. Cold autologous blood treatment reduced infarct sizes, preserved white matter integrity, and improved functional outcomes. Together, our results suggest that therapeutic hypothermia, induced by cold autologous blood transfusion, was achieved in a feasible, swift, and safe way in a non-human primate model of stroke. More importantly, this novel hypothermic approach conferred neuroprotection in a clinically relevant model of ischemic stroke due to reduced brain damage and improved neurofunction. This study reveals an underappreciated potential for this novel hypothermic modality for acute ischemic stroke in the era of effective reperfusion.

Correction of Local Brain Temperature after Severe Brain Injury Using Hypothermia and Medical Microwave Radiometry (MWR) as Companion Diagnostics

The temperature of the brain can reflect the activity of its different regions, allowing us to evaluate the connections between them. A study involving 111 patients in a vegetative state or minimally conscious state used microwave radiometry to measure their cortical temperature. The patients were divided into a main group receiving a 10-day selective craniocerebral hypothermia (SCCH) procedure, and a control group receiving basic therapy and rehabilitation. The main group showed a significant improvement in consciousness level as measured by CRS-R assessment on day 14 compared to the control group. Temperature heterogeneity increased in patients who received SCCH, while remaining stable in the control group. The use of microwave radiometry to assess rehabilitation effectiveness and the inclusion of SCCH in rehabilitation programs appears to be a promising approach.

Selective intraarterial hypothermia combined with mechanical thrombectomy for acute cerebral infarction based on microcatheter technology: A single-center, randomized, single-blind controlled study.

To investigate the safety and efficacy of selective intraarterial hypothermia combined with mechanical thrombectomy in the treatment of acute cerebral infarction based on microcatheter technology. A total of 142 patients with anterior circulation large vessel occlusion were randomly assigned to the hypothermic treatment group (test group) and the conventional treatment group (control group). National Institutes of Health Stroke Scale (NIHSS) scores, postoperative infarct volume, the 90-day good prognosis rate (modified Rankin Scale (mRS) score ≤ 2 points), and the mortality rate of the two groups were compared and analyzed. Blood specimens were collected from patients before and after treatment. Serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-6 (IL-6), IL-10, and RNA-binding motif protein 3 (RBM3) were measured. The 7-day postoperative cerebral infarct volume [(63.7 ± 22.1) ml vs. (88.5 ± 20.8) ml] and NIHSS scores at postoperative Days 1, 7, and 14 [(6.8 ± 3.8) points vs. (8.2 ± 3.5) points; (2.6 ± 1.6) points vs. (4.0 ± 1.8) points; (2.0 ± 1.2) points vs. (3.5 ± 2.1) points] in the test group were significantly lower than those in the control group. The good prognosis rate at 90 days postoperatively (54.9 vs. 35.2%, P = 0.018) was significantly higher in the test group than in the control group. The 90-day mortality rate was not statistically significant (7.0 vs. 8.5%, P = 0.754). Immediately after surgery and 1 day after surgery, SOD, IL-10, and RBM3 levels in the test group were relatively higher than those in the control group, and the differences were statistically significant. Immediately after surgery and 1 day after surgery, MDA and IL-6 levels in the test group were relatively reduced compared with those in the control group, and the differences were statistically significant (P < 0.05). In the test group, RBM3 was positively correlated with SOD and IL-10. Mechanical thrombectomy combined with intraarterial cold saline perfusion is a safe and effective measure for the treatment of acute cerebral infarction. Postoperative NIHSS scores and infarct volumes were significantly improved with this strategy compared with simple mechanical thrombectomy, and the 90-day good prognosis rate was improved. The mechanism by which this treatment exerts its cerebral protective effect may be by inhibiting the transformation of the ischaemic penumbra of the infarct core area, scavenging some oxygen free radicals, reducing inflammatory injury to cells after acute infarction and ischaemia-reperfusion, and promoting RBM3 production in cells.

Research progress of selective brain cooling methods in the prehospital care for stroke patients: A narrative review.

Over the past four decades, therapeutic hypothermia (TH) has long been suggested as a promising neuroprotective treatment of acute ischemic stroke (AIS). Much attention has focus on keeping the hypothermic benefits and removing side effects of systemic hypothermia. In the past few years, the advent of intravenous thrombolysis and endovascular thrombectomy has taken us into a reperfusion era of AIS treatment. With recent research emphasizing ways to plus neuroprotective treatments to reperfusion therapy, the spotlight is now shifting toward the study of how selective brain hypothermia can offset the drawbacks of systemic hypothermia and be applied in prehospital condition. This mini-review summarizes current brain cooling methods that can be used for inducing selective hypothermia in prehospital care. It will guide the future development of selective cooling methods, extend the application of TH in prehospital care, and provide insights into the prospects of selective hypothermia in AIS.

Non-invasive Brain Temperature Measurement in Acute Ischemic Stroke.

Selective therapeutic hypothermia in the setting of mechanical thrombectomy (MT) is promising to further improve the outcomes of large vessel occlusion stroke. A significant limitation in applying hypothermia in this setting is the lack of real-time non-invasive brain temperature monitoring mechanism. Non-invasive brain temperature monitoring would provide important information regarding the brain temperature changes during cooling, and the factors that might influence any fluctuations. This review aims to provide appraisal of brain temperature changes during stroke, and the currently available non-invasive modalities of brain temperature measurement that have been developed and tested over the past 20 years. We cover modalities including magnetic resonance spectroscopy imaging (MRSI), radiometric thermometry, and microwave radiometry, and the evidence for their accuracy from human and animal studies. We also evaluate the feasibility of using these modalities in the acute stroke setting and potential ways for incorporating brain temperature monitoring in the stroke workflow.

The Effect of Selective Hypothermia of the Cerebral Cortex on Metabolism in Patients with Prolonged Impairment of Consciousness

A pilot study was conducted among patients with chronic impaired consciousness in order to assess the response of energy expenditure at rest (REE) during craniocerebral hypothermia. It was found that REE increased in 70.59% of patients, and decreased in 29.41%. It is assumed that the decrease in REE is associated with preserved metabolic activity in the intact parts of the cerebral cortex and may indicate the presence of rehabilitation potential, and the decrease indicates the presence of gross damage that excluded the selectivity of hypothermic exposure.

The effect of selective hypothermia of the cerebral cortex on metabolism in patients with prolonged impairment of consciousness

BACKGROUND: Selective craniocerebral hypothermia, used in the acute period of brain damage, ensures the development of positive clinical effects (rapid and persistent reduction of neurological deficit, increased consciousness, and maintenance of normothermy in feverish patients). The safety and efficacy of craniocerebral hypothermia in the acute period of cerebrovascular lesions prompted the use of craniocerebral cooling in patients with chronic disorders of consciousness. For this category of patients, the craniocerebral hypothermia technique has been developed, which requires careful study including its effect on overall metabolism.&#x0D; AIMS: To determine the nature of the metabolic response to craniocerebral hypothermia procedures in patients in a vegetative state and minimal conscious state.&#x0D; MATERIALS AND METHODS: A pilot study was conducted from February 3, 2021 until March 3, 2022. This study included 34 patients who were in a state of chronic disorders of consciousness, CRS-R score of 8 (vegetative state and minimally conscious state), after severe brain damage (stroke, 25; brain injury, 5; anoxic brain injuries, 4). Hypothermia was induced using the ATG-01 device, lowering the temperature of the scalp to 47C with a cooling procedure lasting for 120 min. The indirect calorimetry method was conducted before cooling and after 105 min of the craniocerebral hypothermia session. Statistical analysis was performed using the program StatTech v. 2.6.5 (StarTech LLC, Russia).&#x0D; RESULTS: Craniocerebral cooling provided a decrease in the temperature of the frontal cortex of the large hemispheres already after 30 min from 36.4C to 34.90.41C in the left hemisphere and 34.70.47C in the right hemisphere. By the 120th minute, the temperature in the left hemisphere reached 34.00.40C, and that in the right hemisphere reached 33.30.51C, decreasing by 2.4C and 3.1C, respectively. Subsequently, 30 min after the completion of craniocerebral hypothermia, the brain temperature remained lowered by 0.7C. Changes in the level of metabolism under the influence of craniocerebral hypothermia were of a multidirectional nature. In 24 patients (70.59%), the resting energy expenditure (REE) index increased to varying degrees by the end of the cooling procedure, and in 10 participants, it decreased. A significant spread of data allowed only a descriptive analysis of the results obtained during a 120-min craniocerebral hypothermia session.&#x0D; CONCLUSIONS: Chronic disorders of consciousness are largely associated with severe damage of the cerebral cortex. It can be assumed that in patients who reacted with a decrease in REE to the induction of hypothermia, at least metabolic activity in the intact parts of the cerebral cortex was preserved to a certain extent, which may indicate some level of rehabilitation potential. The lack of expression of the reactions of the general metabolism to craniocerebral cooling may be due to the fact that the severe damage to the cerebral cortex excluded the selectivity of hypothermic exposure.

Updates on Selective Brain Hypothermia: Studies From Bench Work to Clinical Trials.

Thrombectomy or thrombolysis are the current standards of care for acute ischemic stroke (AIS), however, due to time constraints regarding operations and a multitude of contraindications, AIS remains one of the leading causes of death and chronic disability worldwide. In recent years, therapeutic hypothermia has been explored as an adjuvant therapy for AIS treatment and has shown potential to improve outcomes in patients with AIS. In particular, selective therapeutic hypothermia has shown to markedly reduce infarct volumes and have neuroprotective effects, while also minimizing many systemic side effects seen with systemic therapeutic hypothermia. Both preclinical and clinical trials have demonstrated that selective therapeutic hypothermia is a safe and feasible therapy for patients who have suffered an AIS. In this review, we summarize the current update on selective hypothermia through major studies that have been conducted in rodents, large animals, and clinical trials, and briefly discuss the prospects of selective hypothermic research. We hope this review helps facilitate the exploration of other possible adjuvant treatment modalities in the neuroprotection of ischemic stroke, whether upon symptom onset or after vascular recanalization.

Selective Brain Hypothermia in the Comprehensive Rehabilitation of Patients with Chronic Consciousness Disorders

Aim: to evaluate clinical effectiveness of selective hypothermia of cerebral cortex for the recovery of awareness in patients with chronic disorders of consciousness (CDC). Material and methods. 111 patients with CDC 30 and more days after a cerebral event (ischemic or hemorrhagic stroke, brain injury) were included in the study. Exclusion criteria were anoxic brain injury (sequelae of a prolonged asystole or asphyxia), active sepsis, arrhythmia, baseline hypothermia (body temperature lower than 35.5 °С). Experimental group included 60 patients, of them 39 patients were in a vegetative state (VS), 21 patients exhibited patterns of minimally conscious state (MCS). Control group incluted 51 patients, of them 32 patients were in VS and 19 patients were in MCS. Patients in the experimental group received 10 sessions (120 minutes each) of selective brain hypothermia (SBH) during the 14-days follow-up period. Patients of both groups received standard identical neurological treatment and rehabilitation procedures. Patients in the control group did not undergo brain hypothermia. The induction of SBH involved cooling of the whole surface of the craniocerebral area of scalp using special helmets. The temperature of the internal surface of the helmet was 3–7 °С. Temperature of the frontal lobes of the cortex was monitored with non-invasive microwave radiothermometry, axillary temperature was also registered. The level of consciousness was evaluated using «Coma Recovery Scale-Revised» (CRS-R) scale. Results. 120-minutes long SBH session reduced the temperature of the frontal lobes of the cerebral cortex by 2.4–3.1 °С with no impact on the axillary temperature. Evaluation using CRS-R revealed improvement in all studied functions (auditory, visual, motor, oromotor, communication, arousal) in patients in the experimental group after 10 SBH sessions. Level of consciousness in patients from the experimental group in VS increased from 4.5 ± 0.33 to 8.7 ± 0.91 points (P &lt; 0.001), for patients in MCS from 11.3 ± 1.0 to 18.2 ± 0.70 (P &lt; 0.001) points. In the control group, scores of patients in VS rose from 4.3 ± 0.37 to 6.8 ± 0.49 (P &lt; 0.001) points with the most significant changes in auditory and visual functions (P&lt;0.001). In the control group of patients in MCS the oromotor function improved (P &lt; 0.05), overall CRS-R scores changed insignificantly from 9.1 ± 0.57 to 10.1 ± 0.86 (P &lt; 0.1). The best outcome (CRS-R &gt; 19 points) was seen in patients from the experimental group [6 in VS (15.4 %) and 8 in MCS (31.8 %)]. In the control group, the best results did not exceed 10 points for the patents in VS, while 4 patients in MCS (21 %) reached 12–16 scores. During 30-day follow-up period of hospitalization after the SBH sessions mortality rate was 10 % (6 patients) in the experimental group and 21.6% (11 patients) in the control group. Conclusion. Patients with CDC could benefit from serial SBH sessions performed as a part of comprehensive treatment and rehabilitation strategy. We suggest that selective reduction of frontal lobe temperature improves neurogenesis, neuronal regeneration, and neuroplasticity.

The Complex Relationship Between Cooling Parameters and Neuroprotection in a Model of Selective Hypothermia.

BackgroundHypothermia remains the best studied neuroprotectant. Despite extensive positive large and small animal data, side effects continue to limit human applications. Selective hypothermia is an efficient way of applying neuroprotection to the brain without the systemic complications of global hypothermia. However, optimal depth and duration of therapeutic hypothermia are still unknown. We analyzed a large animal cohort study of selective hypothermia for statistical relationships between depth or duration of hypothermia and the final stroke volume.MethodsA cohort of 30 swine stroke subjects provided the dataset for normothermic and selective hypothermic animals. Hypothermic parameters including duration, temperature nadir, and an Area Under the Curve measurement for 34 and 30°C were correlated with the final infarct volumes measured by MRI and histology.ResultsBetween group comparisons continue to demonstrate a reduction in infarct volume with selective hypothermia. Histologically-derived infarct volumes were 1.2 mm3 smaller in hypothermia-treated pigs (P = 0.04) and showed a similar, but non-significant reduction in MRI (P = 0.15). However, within the selective hypothermia group, more intense cooling, as measured through increased AUC 34 and decreased temperature nadir was associated with larger infarct proportions by MRI [Pearson's r = 0.48 (p = 0.05) and r = −0.59 (p = 0.01), respectively]. Reevaluation of the entire cohort with quadratic regression demonstrated a U-shaped pattern, wherein the average infarct proportion was minimized at 515 degree-minutes (AUC34) of cooling, and increased thereafter. In a single case of direct brain tissue oxygen monitoring during selective hypothermia, brain tissue oxygen strongly correlated with brain temperature reduction over the course of selective hypothermia to 23°C.ConclusionsIn a large animal model of selective hypothermia applied to focal ischemia, there is a non-monotone relationship between duration and depth of hypothermia and stroke volume reduction. This suggests a limit to depth or duration of selective hypothermia for optimal neuroprotection. Further research is required to delineate more precise depth and duration limits for selective hypothermia.

Mechanisms of low-temperature rehabilitation technologies. Sports traumatic brain injury

According to various data, sports traumatic brain injury (TBI) accounts for up to 20% of all injuries in athletes, and the number of cases of traumatization is progressively increasing year by year due to an increase in the number of people involved in sports, the growing popularity of extreme and contact sports, as well as a high level of motivation to achieve record results. The structure of sports TBI is dominated by mild TBI, which can provoke the development of a very wide range of complications and negative consequences that affect not only the result, but, most importantly, the quality of life of athletes. The pathogenesis of mild TBI has been studied, therapy and rehabilitation programs have been developed. At the same time, the features of sports TBI that significantly distinguish it from domestic, road or criminal injuries are not sufficiently taken into account: repeated frequent TBI, increased body and brain temperature, peripheral redistribution of blood flow and hypocapnia associated with physical exertion and significantly affecting cerebral blood flow. An athlete receives a TBI during the most vulnerable period for the brain. To a large extent, these features are associated with the high incidence of various kinds of neurological complications of sports TBI (cognitive disorders, memory impairment, sleep disorders, migraines, etc.). Special techniques that can prevent complications of sports TBI have not been developed. Brain injury is an independent cause of the development of cerebral hyperthermia, which significantly worsens the course and consequences of TBI. The well-known technology of craniocerebral hypothermia (CCG) allows to reduce physical general and cerebral hyperthermia, to increase the resistance of neurons of the cerebral cortex to hypoxia and trauma. However, this technology is used sporadically, which, apparently, is due to the lack of awareness of coaches and doctors of sports teams specializing in sports medicine and rehabilitation. The purpose of the review is to analyze the features of the action of selective hypothermia of the cerebral cortex, used to prevent complications of mild sports TBI.

No-reflow phenomenon and reperfusion injury. Mechanisms and treatment

Currently, one of the key methods of treating a patient with ST-elevation myocardial infarction is to restore blood flow to the infarct-related artery as quickly, completely and steadily as possible. However, in some cases, it is not possible to achieve adequate myocardial reperfusion, despite the restoration of coronary blood flow. This phenomenon was named no-reflow. Due to the lack of a unified approach to the diagnosis of no-reflow, its occurrence varies widely – from 2 to 44 %. Failure to achieve adequate myocardial perfusion leads to a higher mortality rate – from 7.4 to 30.3 %, as well as to more aggressive remodeling of the myocardium. For a long time, distal embolization in percutaneous coronary intervention was considered one of the leading mechanisms. However, the routine use of protective devices did not show a pronounced effect on the outcome and prognosis, although it is justified in certain clinical situations. Ischemic injury directly plays a significant role due to overload of cardiomyocytes with calcium, cellular edema, necrosis and apoptosis, which is significantly aggravated by myocardial reperfusion and forms obstruction at the level of the microcirculatory bed. More data is being accumulated about immune-mediated injury through activation of cellular immunity, intense inflammation and thrombosis in situ. Despite the success in the animal experiment, the clinical use of certain groups of drugs showed an ambiguous results. According to the latest recommendations European Society of Cardiology / European Association for Cardio-Thoracic Surgery (ESC / EACTS) 2018, GPIIb / IIIa platelet receptor inhibitors are recommended in the case of no-reflow. Besides this, according to the literature nicorandil and sodium nitroprusside, as well as IL-1β antagonists, seem to be promising. As a non-drug therapy, selective intracoronary hypothermia also has shown its effectiveness and safety in a pilot study. To date, it is clear that the no-reflow phenomenon is a manifestation of a complex cascade of reactions, including ischemic, reperfusion and immune-related injury, as well as distal embolization. Considering its significant contribution to the frequency of adverse outcomes and late complications, it seems necessary to introduce unified approaches to the diagnosis, prevention and treatment of no-reflow, which requires high-quality clinical studies.

Ultrastructural Characteristics of Myocardial Reperfusion Injury and Effect of Selective Intracoronary Hypothermia: An Observational Study in Isolated Beating Porcine Hearts.

In acute myocardial infarction (AMI), myocardial reperfusion injury may undo part of the recovery after revascularization of the occluded coronary artery. Selective intracoronary hypothermia is a novel method aimed at reducing myocardial reperfusion injury, but its presumed protective effects in AMI still await further elucidation. This proof-of-concept study assesses the potential protective effects of selective intracoronary hypothermia in an ex-vivo, isolated beating heart model of AMI. In four isolated Langendorff perfused beating pig hearts, an anterior wall myocardial infarction was created by inflating a balloon in the mid segment of the left anterior descending (LAD) artery. After one hour, two hearts were treated with selective intracoronary hypothermia followed by normal reperfusion (cooled hearts). In the other two hearts, the balloon was deflated after one hour, allowing normal reperfusion (control hearts). Biopsies for histologic and electron microscopic evaluation were taken from the myocardium at risk at different time points: before occlusion (t = BO); 5 minutes before reperfusion (t = BR); and 10 minutes after reperfusion (t = AR). Electron microscopic analysis was performed to evaluate the condition of the mitochondria. Histological analyses included evaluation of sarcomeric collapse and intramyocardial hematoma. Electron microscopic analysis revealed intact mitochondria in the hypothermia treated hearts compared to the control hearts where mitochondria were more frequently damaged. No differences in the prespecified histological parameters were observed between cooled and control hearts at t = AR. In the isolated beating porcine heart model of AMI, reperfusion was associated with additional myocardial injury beyond ischemic injury. Selective intracoronary hypothermia preserved mitochondrial integrity compared to nontreated controls.

In vivo demonstration of a novel non-invasive model for inducing localized hypothermia to ameliorate hepatotoxicity

Moderate hypothermia (32 °C) has been previously shown to ameliorate drug-induced liver injuries in vitro. However, there are concerns regarding its clinical relevance as it remains a challenge to perform selective liver cooling in a non-invasive manner. To reconcile this dilemma, we propose the use of pulsed cooling for regional hypothermic conditioning in liver. This involves intermittent cooling applied in pulses of 15 min each, with a one-hour recovery interval between pulses. Cooling is achieved by applying ice packs to the cutaneous region overlying the liver. Through an in vivo C57BL/6NTac mouse study, we demonstrated the feasibility of attaining localized hypothermia close to the liver while maintaining core body temperature. This has successfully ameliorated acetaminophen-induced liver injury based on the liver function tests, liver histology and total weight change. Collectively, we provide a proof of concept for pulsed external localized cooling as being clinically actionable to perform induced selective hypothermia.