BACKGROUNDEndovascular therapeutic hypothermia (ETH) reduces the damage by ischemia/reperfusion cell syndrome in cardiac arrest and has been studied as an adjuvant therapy to percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI). New available advanced technology allows cooling much faster, but there is paucity of resources for training to avoid delays in door-to-balloon time (DTB) due to ETH and subsequently coronary reperfusion, which would derail the procedure. The aim of the study was to describe the process for the development of a simulation, training & educational protocol for the multidisciplinary team to perform optimized ETH as an adjunctive therapy for STEMI.METHODS AND RESULTSWe developed an optimized simulation protocol using modern mannequins in different realistic scenarios for the treatment of patients undergoing ETH adjunctive to PCI for STEMIs starting from the emergency room, through the CathLab, and to the intensive care unit (ICU) using the Proteus® Endovascular System (Zoll Circulation Inc™, San Jose, CA, USA). The primary endpoint was door-to-balloon (DTB) time. We successfully trained 361 multidisciplinary professionals in realistic simulation using modern mannequins and sham situations in divisions of the hospital where real patients would be treated. The focus of simulation and training was logistical optimization and educational debriefing with strategies to reduce waste of time in patient's transportation from different departments, and avoiding excessive rewarming during transfer. Afterwards, the EHT protocol was successfully validated in a trial randomizing 50 patients for 18 minutes cooling before coronary recanalization at the target temperature of 32 ± 1.0 ∘C or PCI-only. A total of 35 patients underwent ETH (85.7% [30/35] in 90 ± 15 minutes), without delays in the mean door-to-balloon time for primary PCI when compared to 15 control group patients (92.1 minutes versus 87 minutes, respectively; p = 0.509).CONCLUSIONSRealistic simulation, intensive training and educational debriefing for the multidisciplinary team propitiated feasible endovascular therapeutic hypothermia as an adjuvant therapy to primary PCI in STEMI.CLINICALTRIALSgov: NCT02664194.

Endovascular Therapeutic hypothermia (ETH) reduces the damage caused by postischemia reperfusion injury syndrome in cardiopulmonary arrest and has already established its role in patients with sudden death; however, its role in ST-segment elevation myocardial infarction (STEMI) remains controversial. The objectives of this study were to investigate the safety, feasibility, and 30-day efficacy of rapid induction of therapeutic hypothermia as adjunctive therapy to percutaneous coronary intervention (PCI) in patients with anterior and inferior STEMIs. This was a prospective, controlled, randomized, two-arm, prospective, interventional study of patients admitted to the emergency department within 6 hours of angina onset, with anterior or inferior STEMI eligible for PCI. Subjects were randomized to the hypothermia group (primary PCI+ETH) or to the control group (primary PCI) at a 4:1 ratio. The ETH was induced by 1 L cold saline (1-4 degrees C) associated with the Proteus (TM) System, by cooling for at least 18 minutes before coronary reperfusion with a target temperature of 32 degrees C +/- 1 degrees C. Maintenance of ETH was conducted for 1-3 hours, and active reheating was done at a rate of 1 degrees C/h for 4 hours. Primary safety outcomes were the feasibility of ETH in the absence of (1) door-to-balloon (DTB) delay; (2) major adverse cardiac events (MACE) within 30 days after randomization. The primary outcomes of effectiveness were infarct size (IS) and left ventricular ejection fraction (LVEF) at 30 days. An as-treated statistical analysis was performed. Fifty patients were included: 35 (70%) randomized to the hypothermia group and 15 (30%) to the control group. The mean age was 58 +/- 12 years; 78% were men; and associated diseases were 60% hypertension, 42% diabetes, and 72% dyslipidemia. The compromised myocardial wall was anterior in 38% and inferior in 62%, and the culprit vessels were left anterior descending artery (LAD) (40%), right coronary artery (38%), and left circumflex (18%). All 35 patients who attempted ETH (100%) had successful cooling, with a mean endovascular coronary reperfusion temperature of 33.1 degrees C +/- 0.9 degrees C. The mean ischemic time was 375 +/- 89.4 minutes in the hypothermia group and 359.5 +/- 99.4 minutes in the control group. The mean DTB was 92.1 +/- 20.5 minutes in the hypothermia group and 87 +/- 24.4 minutes in the control group. The absolute difference of 5.1 minutes was not statistically significant (p = 0.509). The MACE rates were similar between both groups (21.7% vs. 20% respectively,p = 0.237). In the comparison between the hypothermia and control groups, no statistically significant differences were observed at 30 days between mean IS (13.9% +/- 8% vs. 13.8% +/- 10.8%, respectively,p = 0.801) and mean final LVEF (43.3% +/- 11.2% vs. 48.3 +/- 10.9%, respectively;p = 0.194). Hypothermia as an adjunctive therapy to primary PCI in STEMI is feasible and can be implemented without delay in coronary reperfusion. Hypothermia was safe regarding the incidence of MACE at 30 days. However, there was a higher incidence of arrhythmia and in-hospital infection in the hypothermia group, with no increase in mortality. Regarding efficacy, there was no difference in IS or LVEF at 30 days that would suggest additional myocardial protection with ETH.ClinicalTrials.gov:NCT02664194.

Therapeutic hypothermia (TH) reduces the damage by ischemia/reperfusion cell syndrome in cardiac arrests; however, the role of cold saline as an adjuvant therapy to endovascular cooling in STEMI remains controversial. The aim was the evaluation of infusion of cold saline versus no cold saline

Background: Therapeutic hypothermia (TH) reduces the damage by ischemia/reperfusion cell syndrome in cardiac arrests, however, the role of cold saline as an adjuvant therapy to endovascular cooling in STEMI remains controversial. The aim was the evaluation of cold saline infusion versus no cold saline concomitant to endovascular cooling in the development of a TH protocol in STEMIs. Methods: Patients within the 6h onset of chest pain, presenting anterior or inferior STEMIs. TH induced through the Proteus® Endovascular System implant, by cooling for 18 minutes before coronary recanalization at the target temperature of 33±1.0°C before PCI. Patients were randomized to the administration of 1L cold saline solution at 1-4°C (CSS) versus no cold saline solution (NCSS). The primary endpoint was lower temperature by the opening of the vessel through primary PCI. Results: TH was successfully induced in 10 patients – 5 in the CSS group and 5 in the NCSS group. After 18 minutes of TH, all patients (100%) had already achieved core temperature <35ºC, and 90% of them within the pre-specified 33.0 ± 1.0ºC target temperature. In the CCS group, all five patients (100%) reached the target temperature, as compared with four patients (80%) in the NCCS group. The mean temperature reached was 33.0ºC (± 0.6) in the CCS group as compared to 33.3ºC (± 0.8) in the NCCS group (p=0.59), thus 0.3ºC lower temperature by the time of balloon angioplasty favoring the CSS group as compared with the NCSS group. After 30 min, the mean temperature was 32ºC (± 0.4ºC) in the CCS and 32.4ºC (± 0.5ºC) in the NCCS group (p=0.12). The MACE rates were similar between both groups (p=ns). Conclusions: We conclude that when using more powerful endovascular cooling systems such as Proteus, concomitant infusion of cold saline does not significantly improve the cooling rate, but cold saline may still play an important role in less powerful systems and thus should continue to be one of the steps of the endovascular TH protocol. ClinicalTrials.gov identification: NCT02664194.

Introduction: Post-contrast acute kidney injury (PC-AKI) develops in a significant proportion of patients with CKD after invasive cardiology procedures and is strongly associated with adverse outcomes. Objective: We sought to determine whether increased intrarenal nitric oxide (NO) would prevent PC-AKI. Methods: To create a large animal model of CKD, we infused 250 micron particles into the renal arteries in 56 ± 8 kg pigs. We used a low-frequency therapeutic ultrasound device (LOTUS – 29 kHz, 0.4 W/cm2) to induce NO release. NO and laser Doppler probes were used to assess changes in NO content and blood flow. Glomerular filtration rate (GFR) was measured by technetium-diethylene-triamine-pentaacetic acid (Tc-99m-DTPA) radionuclide imaging. PC-AKI was induced by intravenous infusion of 7 cm3/kg diatrizoate. In patients with CKD, we measured GFR at baseline and during LOTUS using Tc-99m--DTPA radionuclide imaging. Results: In the pig model, CKD developed over 4 weeks (serum creatinine [Cr], mg/dL, 1.0 ± 0.2–2.6 ± 0.9, p < 0.01, n = 12). NO and renal blood flow (RBF) increased in cortex and medulla during LOTUS. GFR increased 75 ± 24% (p = 0.016, n = 3). PC-AKI developed following diatrizoate i.v. infusion (Cr 2.6 ± 0.7 baseline to 3.4 ± 0.6 at 24 h, p < 0.01, n = 3). LOTUS (starting 15 min prior to contrast and lasting for 90 min) prevented PC-AKI in the same animals 1 week later (Cr 2.5 ± 0.4 baseline to 2.6 ± 0.7 at 24 h, p = ns, n = 3). In patients with CKD (n = 10), there was an overall 25% increase in GFR in response to LOTUS (p < 0.01). Conclusions: LOTUS increased intrarenal NO, RBF, and GFR and prevented PC-AKI in a large animal model of CKD, and significantly increased GFR in patients with CKD. This novel approach may provide a noninvasive nonpharmacological means to prevent PC-AKI in high-risk patients.

Therapeutic Hypothermia and Temperature ManagementVol. 9, No. 1 Expert Panel DiscussionsStudies Targeting Stroke and Acute Myocardial InfarctionModerator: Michael C. Kurz, Participants: Patrick Lyden, Michael Dae, and Marko NocModerator: Michael C. KurzSearch for more papers by this author, Participants: Patrick LydenDepartment of Neurology, Cedars-Sinai Medical Center, Los Angeles, California.Search for more papers by this author, Michael DaeDepartment of Radiology, Biomedical Imaging and Medicine, University of California San Francisco, San Francisco, California.Search for more papers by this author, and Marko NocCenter for Intensive Internal Medicine, University Medical Center, Ljubljana, Slovenia.Search for more papers by this authorPublished Online:8 Mar 2019https://doi.org/10.1089/ther.2018.29054.mckAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetails Volume 9Issue 1Mar 2019 InformationCopyright 2019, Mary Ann Liebert, Inc., publishersTo cite this article:Moderator: Michael C. Kurz, Participants: Patrick Lyden, Michael Dae, and Marko Noc.Studies Targeting Stroke and Acute Myocardial Infarction.Therapeutic Hypothermia and Temperature Management.Mar 2019.8-12.http://doi.org/10.1089/ther.2018.29054.mckPublished in Volume: 9 Issue 1: March 8, 2019Online Ahead of Print:January 7, 2019PDF download

Endovascular therapeutic hypothermia (ETH) reduces the damage by ischemia/reperfusion cell syndrome in cardiac arrests; however, the role of cold saline as an adjuvant therapy to endovascular cooling in ST-segment elevation myocardial infarct (STEMI) remains controversial. We aimed to compare the

Objectives This study sought to examine the relationship between temperature at reperfusion and infarct size. Background Hypothermia consistently reduces infarct size when administered prior to reperfusion in animal studies, however, clinical results have been inconsistent. Methods We performed a patient‐level pooled analysis from six randomized control trials of endovascular cooling during primary percutaneous coronary intervention (PCI) for ST‐segment elevation myocardial infarction (STEMI) in 629 patients in which infarct size was assessed within 1 month after randomization by either single‐photon emission computed tomography (SPECT) or cardiac magnetic resonance imaging (cMR). Results In anterior infarct patients, after controlling for variability between studies, mean infarct size in controls was 21.3 (95%CI 17.4‐25.3) and in patients with hypothermia <35°C it was 14.8 (95%CI 10.1‐19.6), which was a statistically significant absolute reduction of 6.5%, or a 30% relative reduction in infarct size (P = 0.03). There was no significant difference in infarct size in anterior ≥35°C, or inferior infarct patients. There was no difference in the incidence of death, ventricular arrhythmias, or re‐infarction due to stent thrombosis between hypothermia and control patients. Conclusions The present study, drawn from a patient‐level pooled analysis of six randomized trials of endovascular cooling during primary PCI in STEMI, showed a significant reduction in infarct size in patients with anterior STEMI who were cooled to <35°C at the time of reperfusion. The results support the need for trials in patients with anterior STEMI using more powerful cooling devices to optimize the delivery of hypothermia prior to reperfusion.

This work describes a new iterative method for extracting time-activity curves (TAC) from dynamic imaging studies using a priori information from generic models obtained from TAC templates. Analytical expressions of the TAC templates were derived from TACs obtained by manual segmentation of three (13)NH3 pig studies (gold standard). An iterative method for extracting both ventricular and myocardial TACs using models of the curves obtained as an initial template was then implemented and tested. These TACs were extracted from masked and unmasked images; masking was applied to remove the lungs and surrounding non-relevant structures. The resulting TACs were then compared with TACs obtained manually; the results of kinetic analysis were also compared. Extraction of TACs for each region was sensitive to the presence of other organs (e.g., lungs) in the image. Masking the volume of interest noticeably reduces error. The proposed method yields good results in terms of TAC definition and kinetic parameter estimation, even when the initial TAC templates do not accurately match specific tracer kinetics.

Semi-quantitative, static positron emission tomography (PET) has been used to perform an initial approach to the assessment of [13N]-ammonia perfusion studies aimed to elucidating the effect of injecting human embryonic stem cell-derived (hES) hemangioblasts on infarcted rat hearts.

ObjectivesFor many cardiac clinics, list-mode PET is impractical. Therefore, separate dynamic and ECG-gated acquisitions are needed to detect harmful stenoses, indicate affected coronary arteries, and estimate stenosis severity. However, physicians usually order gated studies only because of dose, time, and cost limitations. These gated studies are limited to detection. In an effort to remove these limitations, we developed a novel curve-fitting algorithm [incomplete data (ICD)] to accurately calculate coronary flow reserve (CFR) from a combined dynamic-ECG protocol of a length equal to a typical gated scan. MethodsWe selected several retrospective dynamic studies to simulate shortened dynamic acquisitions of the combined protocol and compared (a) the accuracy of ICD and a nominal method in extrapolating the complete functional form of arterial input functions (AIFs); and (b) the accuracy of ICD and ICD-AP (ICD with a-posteriori knowledge of complete-data AIFs) in predicting CFRs. ResultsAccording to the Akaike information criterion, AIFs predicted by ICD were more accurate than those predicted by the nominal method in 11 out of 12 studies. CFRs predicted by ICD and ICD-AP were similar to complete-data predictions (PICD=0.94 and PICD-AP=0.91) and had similar average errors (eICD=2.82% and eICD-AP=2.79%). ConclusionAccording to a nuclear cardiologist and an expert analyst of PET data, both ICD and ICD-AP predicted CFR values with sufficient accuracy for the clinic. Therefore, by using our method, physicians in cardiac clinics would have access to the necessary amount of information to differentiate between single-vessel and triple-vessel disease for treatment decision making.

Conventional kinetic parameter estimation based on compartmental models requires an accurate estimation of arterial blood input function. To avoid invasive blood sampling, an image-derived input function can be obtained by manually defining a Region of Interest. Here we propose a new and simple, iterative method for automatic segmentation and input function calculation of PET cardiac studies using correlation as a distance metric between a priori information regarding the approximate shape of the final time-activity curve (TAC) and the actual TAC extracted from the image temporal series.

Background The extracellular matrix plays an important role in tissue regeneration. We investigated whether extracellular matrix protein fragments could be targeted with antibodies to ischemically injured myocardium to promote angiogenesis and myocardial repair. Methodology/Principal Findings Four peptides, 2 derived from fibronectin and 2 derived from Type IV Collagen, were assessed for in vitro and in vivo tendencies for angiogenesis. Three of the four peptides—Hep I, Hep III, RGD—were identified and shown to increase endothelial cell attachment, proliferation, migration and cell activation in vitro. By chemically conjugating these peptides to an anti-myosin heavy chain antibody, the peptides could be administered intravenously and specifically targeted to the site of the myocardial infarction. When administered into Sprague-Dawley rats that underwent ischemia-reperfusion myocardial infarction, these peptides produced statistically significantly higher levels of angiogenesis and arteriogenesis 6 weeks post treatment. Conclusions/Significance We demonstrated that antibody-targeted ECM-derived peptides alone can be used to sufficiently alter the extracellular matrix microenvironment to induce a dramatic angiogenic response in the myocardial infarct area. Our results indicate a potentially new non-invasive strategy for repairing damaged tissue, as well as a novel tool for investigating in vivo cell biology.

Background Phase imaging derived from equilibrium radionuclide angiography presents the ventricular contraction sequence. It has been widely but only indirectly correlated with the sequence of electrical myocardial activation. Objectives We sought to determine the specific relationship between the sequence of phase progression and the sequence of myocardial activation, contraction and conduction, in order to document a noninvasive method that could monitor both. Methods In 7 normal and 9 infarcted dogs, the sequence of phase angle was correlated with the epicardial activation map in 126 episodes of sinus rhythm and pacing from three ventricular sites. Results In each episode, the site of earliest phase angle was identical to the focus of initial epicardial activation. Similarly, the serial contraction pattern by phase image analysis matched the electrical epicardial activation sequence completely or demonstrated good agreement in approximately 85% of pacing episodes, without differences between normal or infarct groups. Conclusions A noninvasive method to accurately determine the sequence of contraction may serve as a surrogate for the associated electrical activation sequence or be applied to identify their differences.

Background: A percutaneous system to implant a ventricular partitioning device (VPD) has been developed to partition the left ventricular (LV) cavity for treating regional wall motion abnormalities associated with post-left anterior descending (LAD) infarction, dilated left ventricle, and systolic dysfunction. The hemodynamic effects of this novel approach were evaluated in an ovine model with an anteroapical infarction created by a coil placed in the LAD.Methods and Results: LV anteroapical infarction (MI) was induced in 10 animals. The VPD device was implanted at 6 weeks after MI in 5 animals. The hemodynamic status of each animal was evaluated at 30 weeks post-MI in treated ("VPD + MI" group, n = 5) and nontreated ("MI" group, n = 5). The comparison of end-point hemodynamic variables shows a significantly smaller end-systolic LV volume in the animals receiving the implant (70.1 +/- 9.0 mL in "VPD + MI" group vs. 102.9 +/- 10.3 mL in "MI" group, P < .02), improved ejection fraction (46.9 +/- 5.2% in "VPD + MI" group vs. 34.7 +/- 6.8% in "MI" group, P < .04) and preserved cardiac output (5.2 +/- 0.7 L/min in "VPD + MI" group vs. 5.0 +/- 1.8 L/min in "MI" group, P = NS), suggesting more efficient mechanical performance of the LV with the implanted VPD.Conclusions: A significant reduction in LV volumes and corresponding improvement in LV function occurred after device implantation indicating a potential beneficial effect of this new device in treatment of post MI LV dilation. (I Cardiac Fad 2009:15:790-797)