Protection Against Cardiac Injury by Small Ca\u3csup\u3e2 +\u3c/sup\u3e-Sensitive K\u3csup\u3e+\u3c/sup\u3e Channels Identified in Guinea Pig Cardiac Inner Mitochondrial Membrane

We tested if small conductance, Ca2 +‐sensitive K+ channels (SKCa) precondition hearts against ischemia reperfusion (IR) injury by improving mitochondrial (m) bioenergetics, if O2‐derived free radicals are required to initiate protection via SKCa channels, and, importantly, if SKCa channels are present in cardiac cell inner mitochondrial membrane (IMM). NADH and FAD, superoxide (O2−), and m[Ca2 +] were measured in guinea pig isolated hearts by fluorescence spectrophotometry. SKCa and IKCa channel opener DCEBIO (DCEB) was given for 10 min and ended 20 min before IR. Either TBAP, a dismutator of O2−, NS8593, an antagonist of SKCa isoforms, or other KCa and KATP channel antagonists, were given before DCEB and before ischemia. DCEB treatment resulted in a 2-fold increase in LV pressure on reperfusion and a 2.5 fold decrease in infarct size vs. non-treated hearts associated with reduced O2− and m[Ca2 +], and more normalized NADH and FAD during IR. Only NS8593 and TBAP antagonized protection by DCEB. Localization of SKCa channels to mitochondria and IMM was evidenced by a) identification of purified mSKCa protein by Western blotting, immuno-histochemical staining, confocal microscopy, and immuno-gold electron microscopy, b) 2-D gel electrophoresis and mass spectroscopy of IMM protein, c) [Ca2 +]‐dependence of mSKCa channels in planar lipid bilayers, and d) matrix K+ influx induced by DCEB and blocked by SKCa antagonist UCL1684. This study shows that 1) SKCa channels are located and functional in IMM, 2) mSKCa channel opening by DCEB leads to protection that is O2−dependent, and 3) protection by DCEB is evident beginning during ischemia

Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: Review and recommendations of the COSBID research group.

Spreading depolarizations (SD) are waves of abrupt, near-complete breakdown of neuronal transmembrane ion gradients, are the largest possible pathophysiologic disruption of viable cerebral gray matter, and are a crucial mechanism of lesion development. Spreading depolarizations are increasingly recorded during multimodal neuromonitoring in neurocritical care as a causal biomarker providing a diagnostic summary measure of metabolic failure and excitotoxic injury. Focal ischemia causes spreading depolarization within minutes. Further spreading depolarizations arise for hours to days due to energy supply-demand mismatch in viable tissue. Spreading depolarizations exacerbate neuronal injury through prolonged ionic breakdown and spreading depolarization-related hypoperfusion (spreading ischemia). Local duration of the depolarization indicates local tissue energy status and risk of injury. Regional electrocorticographic monitoring affords even remote detection of injury because spreading depolarizations propagate widely from ischemic or metabolically stressed zones; characteristic patterns, including temporal clusters of spreading depolarizations and persistent depression of spontaneous cortical activity, can be recognized and quantified. Here, we describe the experimental basis for interpreting these patterns and illustrate their translation to human disease. We further provide consensus recommendations for electrocorticographic methods to record, classify, and score spreading depolarizations and associated spreading depressions. These methods offer distinct advantages over other neuromonitoring modalities and allow for future refinement through less invasive and more automated approaches

Algorithm for real-time analysis of intracoronary electrocardiogram.

Introduction Since its first implementation in 1985, intracoronary (ic) electrocardiogram (ECG) has shown ample evidence for its diagnostic value given the higher sensitivity for myocardial ischemia detection in comparison to surface ECG. However, a lack of online systems to quantitatively analyze icECG in real-time prevents its routine use. The present study aimed to develop and validate an autonomous icECG analyzing algorithm. Materials and methods This is a retrospective observational study in 100 patients with chronic coronary syndrome. From each patient, a non-ischemic as well as ischemic icECG at the end of a 1-min proximal coronary balloon occlusion was available. An ECG expert as well as the newly developed algorithm for autonomous icECG analysis measured the icECG ST-segment shift in mV for each icECG tracing. Results Intraclass correlation coefficient (ICC) demonstrated low variability between the two methods (ICC = 0.968). Using the time point of icECG recording as allocation reference for absent or present myocardial ischemia, ROC-analysis for ischemia detection by the manually determined icECG ST-segment shift showed an area under the curve (AUC) of 0.968 ± 0.021 (p < 0.0001). AUC for the algorithm analysis was 0.967 ± 0.023 (p < 0.0001; p = 0.925 for the difference between the ROC curve AUCs). Time to complete analysis was below 1,000 ms for the autonomous icECG analysis and above 5 min for manual analysis. Conclusion A newly developed autonomous icECG analysing algorithm detects myocardial ischemia with equal accuracy as manual ST-segment shift assessment. The algorithm provides the technical fundament for an analysing system to quantitatively obtain icECG in real-time

EKG-parametrien käyttö kammioperäisten rytmihäiriöiden lyhyen aikavälin ennustamisessa

Malignant spontaneous ventricular arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), are the most common trigger of sudden cardiac death (SCD) in and out of hospital. For a hospitalized patient, occurrence of such arrhythmia is a struggle of life and death where every second of oxygen deprivation, resulting from reduced blood flow, decreases chances of survival. Despite recent advances in resuscitation strategies, survival rates in in-hospital cardiac arrests remain unacceptably low. Main factors contributing to the poor prognosis are lack of patient monitoring and delay in the initiation of resuscitation. Thus, in order to increase the likelihood of successful resuscitation, or prevent the arrhythmia from happening in the first place, continuous and quantitative risk of arrhythmia assessment is required. Currently, however, cardiac monitoring is utilized to detect the onset of life threatening cardiac episodes only. Thus, development of risk indices and the study of precursors of lethal arrhythmias have great clinical value and will lead to better cardiac monitoring. In this thesis, changes in ECG signal preceding lethal cardiac arrhythmias are studied both in different patient groups and in individual patients. Furthermore, an algorithm predicting imminent ventricular tachyarrhythmias is presented. Current knowledge of underlying mechanisms of onset of ventricular arrhythmias is used to assess the risk of arrhythmia continuously during cardiac monitoring of a patient. Our approach is novel and similar assessment of such algorithm has not been published previously. A review of existing methods and applications for risk assessment of SCD with discussion of future trends and possibilities is also given.Malignit kammioperäiset rytmihäiriöt, kuten kammiotakykardia ja kammiovärinä, ovat yleisimpiä syitä sydänperäiseen äkkikuolemaan sekä sairaalassa että sen ulkopuolella. Sairaalassa kuten sen ulkopuolellakin tällaiset rytmihäiriöt ovat aina hengenvaarallisia ja pitkittyessään vähentynyt tai pysähtynyt hapenkuljetus elimistöön pienentää todennäköisyyttä selviytyä. Huolimatta viimeaikaisista ponnisteluista viiveettömän ja tehokkaamman elvytyksen eteen, sairaalassa tapahtuvien sydänkohtausten ennuste on pysynyt huonona. Tämä johtuu lähinnä viiveestä elvytyksen aloittamisessa ja monitoroinnin puutteesta, joten oleellisinta ennusteen parantamisen kannalta olisi jatkuva rytmihäiriöriskin kvantitatiivinen arviointi potilasmonitoroinnilla. Näin useat rytmihäiriöt voitaisiin estää ja alkaviin voitaisiin reagoida nopeammin. Nykyisin potilasmonitorointi on kuitenkin keskittynyt jo alkaneiden rytmihäiriöiden tunnistamiseen eikä ennustavia ratkaisuja ole tarjolla. äkillistä sydänkohtausta edeltävien ilmiöiden tutkiminen ja rytmihäiriöriskin määrittäminen kajoamattomalla potilasmonitoroinnilla ovat ensisijaisen tärkeitä, mikäli rytmihäiriöpotilaiden ennustetta halutaan parantaa sairaalaympäristössä. Tässä opinnäytteessä tutkitaan rytmihäiriöitä edeltäviä muutoksia EKG-signaalista mitattavissa parametreissa eri potilasryhmissä ja yksittäisillä potilailla. Esittelemme algoritmin, joka arvioi EKG:sta mitatuista parametreista yksittäisen potilaan riskiä rytmihäiriön käynnistymiseen. Valitsemamme lähestymistapa poikkeaa täysin olemassa olevista eikä vastaavia tuloksia ole aikaisemmin julkaistu. Algoritmin kehityksessä hyödynnetään laajasti olemassa olevaa tutkimustietoa rytmihäiriöiden käynnistymisestä ja ylläpidosta. Olemassa olevat menetelmät on esitelty laajassa kirjallisuuskatsauksessa. Opinnäytetyön lopussa algoritmin kliinistä hyödyllisyyttä ja tulevia kehitysnäkymiä on arvioitu saavutettujen tulosten valossa

Correlates of Spreading Depolarization, Spreading Depression, and Negative Ultraslow Potential in Epidural Versus Subdural Electrocorticography

Spreading depolarizations (SDs) are characterized by near-complete breakdown of the transmembrane ion gradients, neuronal oedema and activity loss (=depression). The SD extreme in ischemic tissue, termed 'terminal SD,' shows prolonged depolarization, in addition to a slow baseline variation called 'negative ultraslow potential' (NUP). The NUP is the largest bioelectrical signal ever recorded from the human brain and is thought to reflect the progressive recruitment of neurons into death in the wake of SD. However, it is unclear whether the NUP is a field potential or results from contaminating sensitivities of platinum electrodes. In contrast to Ag/AgCl-based electrodes in animals, platinum/iridium electrodes are the gold standard for intracranial direct current (DC) recordings in humans. Here, we investigated the full continuum including short-lasting SDs under normoxia, long-lasting SDs under systemic hypoxia, and terminal SD under severe global ischemia using platinum/iridium electrodes in rats to better understand their recording characteristics. Sensitivities for detecting SDs or NUPs were 100% for both electrode types. Nonetheless, the platinum/iridium-recorded NUP was 10 times smaller in rats than humans. The SD continuum was then further investigated by comparing subdural platinum/iridium and epidural titanium peg electrodes in patients. In seven patients with either aneurysmal subarachnoid hemorrhage or malignant hemispheric stroke, two epidural peg electrodes were placed 10 mm from a subdural strip. We found that 31/67 SDs (46%) on the subdural strip were also detected epidurally. SDs that had longer negative DC shifts and spread more widely across the subdural strip were more likely to be observed in epidural recordings. One patient displayed an SD-initiated NUP while undergoing brain death despite continued circulatory function. The NUP's amplitude was -150 mV subdurally and -67 mV epidurally. This suggests that the human NUP is a bioelectrical field potential rather than an artifact of electrode sensitivity to other factors, since the dura separates the epidural from the subdural compartment and the epidural microenvironment was unlikely changed, given that ventilation, arterial pressure and peripheral oxygen saturation remained constant during the NUP. Our data provide further evidence for the clinical value of invasive electrocorticographic monitoring, highlighting important possibilities as well as limitations of less invasive recording techniques

Intracoronary electrocardiogram as a direct measure of myocardial ischemia

The electrocardiogram is a valuable diagnostic method providing insight into pathologies of the heart, especially rhythm disorders or insufficient myocardial blood supply (myocardial ischemia). The commonly used surface ECG is, however, limited in detecting short-lasting myocardial ischemia, in particular in the territory of the left circumflex coronary artery supplying the postero-lateral wall of the left ventricle. Conversely, an ECG recorded in close vicinity to the myocardium, i.e., within a coronary artery (intracoronary ECG, icECG) has been thought to overcome these limitations. Since its first implementation during cardiac catheterization in 1985, icECG has shown ample evidence for its diagnostic value given the higher sensitivity for myocardial ischemia detection when compared to the surface ECG. In addition, icECG has been demonstrated to be a direct measure of myocardial ischemia in real-time, thus, providing valuable information during percutaneous coronary diagnostics and interventions. However, a lack of analysing systems to obtain and quantify icECG in real-time discourages routine use. The goals of this MD-PhD thesis are two-fold: First, to determine the diagnostic accuracy of icECG ST-segment shift during pharmacologic inotropic stress in comparison to established indices for coronary lesion severity assessment using quantitative angiographic percent diameter stenosis as reference (Project I). Second, to determine the optimal icECG parameter for myocardial ischemia detection and quantification (Project II and III). In essence, this thesis demonstrates that the icECG is an easy available diagnostic method providing highly accurate information on the amount of myocardial ischemia in real-time. Quantitative assessment of acute, transmural myocardial ischemia by icECG is most accurately performed by measuring ST-segment shift at the J-point, while the quantitative assessment during physical exercise, respectively its pharmacologic simulation, is most accurately performed by measuring ST-segment shift 60ms after the J-point

Correlation of velocity and susceptibility in patients with aneurysmal subarachnoid hemorrhage

In many cerebral grey matter structures including the neocortex, spreading depolarization (SD) is the principal mechanism of the near-complete breakdown of the transcellular ion gradients with abrupt water influx into neurons. Accordingly, SDs are abundantly recorded in patients with traumatic brain injury, spontaneous intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage (aSAH) and malignant hemispheric stroke using subdural electrode strips. SD is observed as a large slow potential change, spreading in the cortex at velocities between 2 and 9 mm/min. Velocity and SD susceptibility typically correlate positively in various animal models. In patients monitored in neurocritical care, the Co-Operative Studies on Brain Injury Depolarizations (COSBID) recommends several variables to quantify SD occurrence and susceptibility, although accurate measures of SD velocity have not been possible. Therefore, we developed an algorithm to estimate SD velocities based on reconstructing SD trajectories of the wave-front's curvature center from magnetic resonance imaging scans and time-of-SD-arrival- differences between subdural electrode pairs. We then correlated variables indicating SD susceptibility with algorithm-estimated SD velocities in twelve aSAH patients. Highly significant correlations supported the algorithm's validity. The trajectory search failed significantly more often for SDs recorded directly over emerging focal brain lesions suggesting in humans similar to animals that the complexity of SD propagation paths increase in tissue undergoing injury

Automated ECG Analysis for Localizing Thrombus in Culprit Artery Using Rule Based Information Fuzzy Network

Cardio-vascular diseases are one of the foremost causes of mortality in today’s world. The prognosis for cardiovascular diseases is usually done by ECG signal, which is a simple 12-lead Electrocardiogram (ECG) that gives complete information about the function of the heart including the amplitude and time interval of P-QRST-U segment. This article recommends a novel approach to identify the location of thrombus in culprit artery using the Information Fuzzy Network (IFN). Information Fuzzy Network, being a supervised machine learning technique, takes known evidences based on rules to create a predicted classification model with thrombus location obtained from the vast input ECG data. These rules are well-defined procedures for selecting hypothesis that best fits a set of observations. Results illustrate that the recommended approach yields an accurateness of 92.30%. This novel approach is shown to be a viable ECG analysis approach for identifying the culprit artery and thus localizing the thrombus

Doctor of Philosophy

dissertationDespite a century of research and practice, the clinical accuracy of the electrocardiogram (ECG) to detect and localize myocardial ischemia remains less than satisfactory. Myocardial ischemia occurs when the heart does not receive adequate oxygen-rich blood to keep up with its metabolic requirements, and severe ischemia can lead to myocardial infarction and life-threatening arrhythmias. Early and accurate detection is an essential component of managing this condition. Ischemia is known to be a dynamic condition that reflects a changing imbalance between blood supply and metabolic demand so that it is natural that examination under physical stress conditions or exercise testing (ET) is in widespread clinical use. However, ET is characterized by poor sensitivity (68%) and specificity (77%), limiting its diagnostic usefulness and providing the motivation to address some gaps in our understanding of myocardial ischemia and its ECG signature. This dissertation is composed of three studies. The aim of the first study was to evaluate the conventionally held mechanisms for nontransmural ischemia using intramural electrodes to measure three-dimensional potential distributions in the ventricles of animals exposed to acute ischemia. We demonstrated that contrary to accepted dogma, the electrocar- diographic response of acute myocardial ischemia originated throughout the ventricular wall, i.e., in the subendocardium, midmyocardium, or the subepicardium, under various conditions. Our goal in the second study was to evaluate whether acute myocardial ischemia follows a similar pattern of spatial and temporal evolution as seen in myocardial infarction. Our findings show that the spatial and temporal evolution of acute ischemia is characterized by multiple distinct regions that expand in all three directions, with maximal expansion in the circumferential direction, especially in the early stages of ischemic development. Furthermore, with increased stress, these regions continue to expand and eventually merge into one another, and in the extreme become transmural. The progression of myocardial infarction, by contrast, was very quickly transmural in extent and formed a cohesive block of affected tissues. The aim of the third study was to evaluate the sensitivity of epicardial electrical markers of acute ischemia relative to direct evidence of ischemia derived from intramural electro- grams. The key finding from this study is that the epicardial T-wave is a more sensitive index of acute ischemia than epicardial ST segment changes, especially in the early stages of acute ischemia development