<p>Sudden death from arrhythmia is a major cause of mortality in the United States. Unfortunately, no current diagnostic test can accurately predict risk for sudden arrhythmic death. Because ventricular arrhythmias often result from abnormalities of repolarization, assessment of myocardial repolarization using the electrocardiogram (ECG) can aid in prediction of arrhythmia risk. Non-linear, rate-dependent changes in myocardial repolarization can promote the development of arrhythmia, but few studies examine how these dynamic changes in repolarization affect the ECG. This dissertation describes the use of a computer model to investigate the effect of dynamic changes in myocardial repolarization on the ECG T wave.</p><p>To simulate action potential conduction from the endocardium to the epicardium of the free wall of the canine left ventricle, 1-dimensional multicellular computer fiber models were created. Each fiber model was composed of endocardial, midmyocardial, and epicardial cells. For each cell type, existing mathematical models were modified to approximate experimental data for four types of dynamic repolarization behavior: (1) dynamic restitution, the response to steady-state pacing; (2) S1-S2 restitution, the response to a premature or postmature stimulus; (3) short-term memory (STM), the response to an abrupt change in pacing rate; and (4) repolarization alternans, beat-to-beat alternation in cellular repolarization time. Repolarization times were obtained from endocardial, midmyocardial, and epicardial regions in the fiber model and compared to parameters measured from a computed transmural ECG.</p><p>Spatial differences in repolarization created two voltage gradients that influenced the ECG: an endocardial-midmyocardial (endo-mid) gradient and a midmyocardial-epicardial (mid-epi) gradient. Epicardial dynamic restitution changes altered the mid-epi gradient, influencing the rising phase of the ECG T wave, and endocardial dynamic restitution changes altered the endo-mid gradient, influencing the falling phase of the T wave. Changes in epicardial or endocardial repolarization due to S1-S2 restitution or STM caused transient changes in the rising or falling phase of the T wave, respectively.</p><p>During repolarization alternans, an alternating, asymmetric distribution of extracellular potential around the fiber influenced the measurement of T-wave alternans (TWA) in the ECG. Presence of a resistive barrier in the fiber model altered the magnitude of repolarization alternans as well as the TWA amplitude in the ECG with effects dependent on barrier location. The resistive barrier also modified the relationship between cellular repolarization alternans magnitude and TWA amplitude.</p><p>The results presented in this dissertation explain basic mechanisms by which dynamic changes in myocardial repolarization affect the ECG T wave. These mechanisms form the foundation for the development of techniques to identify arrhythmogenic, dynamic changes in the myocardium using the ECG. Future studies in higher-dimensional, more complex models will build upon these results by considering the influence of additional voltage gradients, more realistic tissue geometries, and heterogeneities in the volume conductor.</p> / Dissertation

Yes / Spatial dispersion of repolarization is known to play an important role in arrhythmogenesis. Electrotonic modulation of repolarization by the activation sequence has been observed in some species and tissue preparations, but to varying extents. Our study sought to determine the mechanisms underlying species- and tissue-dependent electrotonic modulation of repolarization in ventricles. Epi-fluorescence optical imaging of whole rat hearts and pig left ventricular wedges were used to assess epicardial spatial activation and repolarization characteristics. Experiments were supported by computer simulations using realistic geometries. Tight coupling between activation times (AT) and action potential duration (APD) were observed in rat experiments but not in pig. Linear correlation analysis found slopes of −1.03 ± 0.59 and −0.26 ± 0.13 for rat and pig, respectively (p < 0.0001). In rat, maximal dispersion of APD was 11.0 ± 3.1 ms but dispersion of repolarization time (RT) was relatively homogeneous (8.2 ± 2.7, p < 0.0001). However, in pig no such difference was observed between the dispersion of APD and RT (17.8 ± 6.1 vs. 17.7 ± 6.5, respectively). Localized elevations of APD (12.9 ± 8.3%) were identified at ventricular insertion sites of rat hearts both in experiments and simulations. Tissue geometry and action potential (AP) morphology contributed significantly to determining influence of electrotonic modulation. Simulations of a rat AP in a pig geometry decreased the slope of AT and APD relationships by 70.6% whereas slopes were increased by 75.0% when implementing a pig AP in a rat geometry. A modified pig AP, shortened to match the rat APD, showed little coupling between AT and APD with greatly reduced slope compared to the rat AP. Electrotonic modulation of repolarization by the activation sequence is especially pronounced in small hearts with murine-like APs. Tissue architecture and AP morphology play an important role in electrotonic modulation of repolarization.

The presented studies investigate dynamics of action potential duration (APD) tobetter understand the underlying mechanism for repolarization alternans.We recorded trans-membrane potentials (TMP) in canine endocardial muscle tissueusing standard glass microelectrode under the control of an explicit diastolic interval (DI)control pacing protocol, i.e. feedback protocol. During sequential sinusoidal DI activation,the trajectory of APD dynamics has multiple values of APD correspondent to the sameDI, i.e. restitution is a bi-modal relationship. Our results indicate that: 1) there is a delay,similar to hysteresis, of change in APD responding to change in DI, 2) and the timecourse of the delay is asymmetric for fast or slow pacing history. The alternans wasobserved during constant DI pacing, i.e. the DI preceding each APD was invariant orchanged within a limited range. This finding suggests that alternans of APD do not needthe oscillation of preceding DI, i.e. DI dependent restitution is not a necessary conditionfor the alternans. This result implies that DI independent component exists in themechanism of the alternans. Nonetheless, the amplitude of alternans was statisticallylarger during constant pacing cycle length (PCL) pacing than that during constant DIpacing, even though both PCL and DI pacing trials used similar average activation rate.These results also demonstrate the ability of the feedback protocol to analyze the memoryeffects and dissect different components in the mechanism of alternans.Two computational models, Luo-Rudy dynamics (LRD) and cardiac ventricle model(CVM) were used to study the hysteresis in restitution. By perturbing membrane current:L-type calcium current, rapid and slow potassium rectifier, and intracellular calciumtransfer rate in sarcoplasmic reticulum (SR) and using sinusoidal DI pacing sequence, weshowed that the asymmetric calcium current across the membrane and its interaction withcalcium buffer in SR during increasing and decreasing DI phase plays an important rolein the hysteresis. CVM was used to study the alternans during constant DI pacing.However CVM failed to replicate the alternans that occurred in the experiments. Thisresult implies that CVM lacks the electrophysiological kinetics related to alternans thatwas shown in our experiment.

<p>Repolarization inhomogeneity is arrhythmogenic. QT dispersion (QTd) is an easily accessible ECG-variable, related to the repolarization and shown to carry prognostic information. It was originally thought to reflect repolarization inhomogeneity. Lately, arguments have been risen against this hypothesis. Other measures of inhomogeneity are being investigated, such as nondipolar components from principal component analysis (PCA) of the T-wave. In all here described populations, continuous 12-lead ECG was collected during the initial hours of observation and secondary parameters used for description of a large number of ECG-recordings.</p><p>Paper I studied QTd in 548 patients with chest pain with a median number of 985 ECG-recordings per patient. Paper II explored a spatial aspect of QTd in 276 patients with unstable coronary artery disease. QTd and a derived localized ECG-parameter were compared to angiographical measures. QTd, expressed as the mean value during the observation was a powerful marker of risk. It was however not effective in identifying high-risk patients. Variations in QTd contained no additional prognostic information. In unstable coronary artery disease, QTd was increased by a mechanism unrelated to localization of the disease.</p><p>Two relevant conditions for observing repolarization inhomogeneity might occur with conduction disturbances and during initial course of ST-elevation myocardial infarction (STEMI). Paper III compared the PCA-parameters of the T-wave in 135 patients with chest pain and conduction disturbance to 665 patients with normal conduction. Nondipolar components were quantified by medians of the nondipolar residue (TWRabsMedian) and ratio of this residue to the total power of the T-wave (TWRrelMedian). Paper IV described the changes in the nondipolar components of the T-wave in 211 patients with thrombolyzed STEMI. TWRabsMedian increased with increasing conduction disturbance and contained a moderate amount of prognostic information. In thrombolyzed STEMI, TWRabsMedian was elevated and has an increased variability. A greater decrease in absolute TWR during initial observation was seen in patients with early ST-resolution. Nondipolar components do however not reflect identical ECG-properties as the ST-elevation and their change does not occur at the same time.</p>

Repolarization inhomogeneity is arrhythmogenic. QT dispersion (QTd) is an easily accessible ECG-variable, related to the repolarization and shown to carry prognostic information. It was originally thought to reflect repolarization inhomogeneity. Lately, arguments have been risen against this hypothesis. Other measures of inhomogeneity are being investigated, such as nondipolar components from principal component analysis (PCA) of the T-wave. In all here described populations, continuous 12-lead ECG was collected during the initial hours of observation and secondary parameters used for description of a large number of ECG-recordings. Paper I studied QTd in 548 patients with chest pain with a median number of 985 ECG-recordings per patient. Paper II explored a spatial aspect of QTd in 276 patients with unstable coronary artery disease. QTd and a derived localized ECG-parameter were compared to angiographical measures. QTd, expressed as the mean value during the observation was a powerful marker of risk. It was however not effective in identifying high-risk patients. Variations in QTd contained no additional prognostic information. In unstable coronary artery disease, QTd was increased by a mechanism unrelated to localization of the disease. Two relevant conditions for observing repolarization inhomogeneity might occur with conduction disturbances and during initial course of ST-elevation myocardial infarction (STEMI). Paper III compared the PCA-parameters of the T-wave in 135 patients with chest pain and conduction disturbance to 665 patients with normal conduction. Nondipolar components were quantified by medians of the nondipolar residue (TWRabsMedian) and ratio of this residue to the total power of the T-wave (TWRrelMedian). Paper IV described the changes in the nondipolar components of the T-wave in 211 patients with thrombolyzed STEMI. TWRabsMedian increased with increasing conduction disturbance and contained a moderate amount of prognostic information. In thrombolyzed STEMI, TWRabsMedian was elevated and has an increased variability. A greater decrease in absolute TWR during initial observation was seen in patients with early ST-resolution. Nondipolar components do however not reflect identical ECG-properties as the ST-elevation and their change does not occur at the same time.

Repolarization alternans, i.e. beat-to-beat variation of repolarization of action potential, is proposed as a predictor of life-threatening arrhythmias. Restitution relates repolarization duration with its previous relaxation time, i.e. diatstolic interval (DI), and is considered a dominant mechanism for alternans. Previously, we observed that different repolarization durations at the same DI during decelerating and accelerating pacing, i.e. restitution displays hysteresis, which is a measure of “cardiac memory”. Objective of the current study was to investigate in the pig 1) the mechanism for a previously observed hysteresis type phenomenon, where alternans, once started at higher heart rate, persists even when heart rate decreases below its initiating rate, 2) regional differences in expression of hysteresis, i.e. memory in restitution in the heart, and 3) changes in restitution and memory during manipulation of an important repolarization current, the slow delayed rectifier, IKs. Action potentials were recorded in pig ventricular tissues using microelectrodes. Regional differences were explored in endocardial and epicardial tissues from both ventricles. DIs were explicitly controlled in real time to separate restitution mechanism from non-restitution related effects. Stepwise protocols were used to explore the existence in hysteresis in alternans threshold, where DIs were held constant for each step and progressively decreased and then increased. Quantification of cardiac memory was achieved by sinusoidally changing DI protocols, which were used to investigate memory changes among myocytes from different regions of the heart and during IKs manipulation. Results show that during stepwise protocol, hysteresis in alternans still existed, which indicates that restitution is not the only mechanism underlying the hysteresis. When comparing hysteresis obtained from sinusoidally oscillatory DIs among different regions, results show memory is expressed differently with endocardium expressing the most and epicardium the least memory. This provides important implications about the location where arrhythmia would initiate. Results also show that measures for hysteresis loops obtained by sinusoidal DI protocols decreased (increased) after enhancement (attenuation) of IKs, suggesting decreased (increased) hysteresis, i.e. memory in restitution. This effect needs to be considered during drug development.

Sudden Cardiac Death (SCD) is the largest cause of natural deaths in the USA, accounting for over 300,000 deaths annually. The major reason for SCD is Ventricular Arrhythmia (VA). Therefore, there is need for exploration of approaches to predict increased risk for VA. Alternans of the T wave in the ECG (TWA) is widely investigated as a potential predictor of VA, however, clinical trials show that TWA has high negative predictive value but poor positive predictive value. A possible reason that TWA has a large number of false positives is that a pattern of alternans known as concordant alternans, may not be as arrhythmogenic as another pattern which is discordant alternans. Currently, it is not possible to discern the pattern of alternans using clinical ECGs. Prior studies from our group have showed that alternans of the maximum rate of depolarization of an action potential also can occur when Action Potential Duration (APD) alternans occurs and the relationship between these two has the potential to create spatial discord. These results suggest that exploration of the co-occurrence of depolarization and repolarization alternans has the potential to stratify the outcome of TWA tests. In order to investigate the link between depolarization alternans and changes in ECGs, we used a mathematical model created previously in our research group which simulated ECGs from the cellular level changes observed in our experimental studies. These results suggest that the changes in ECGs should appear as alternating pattern of the amplitude of the R wave. Because there are a variety of factors which may also cause the R wave amplitude to change, we used signal analysis and statistical modeling to determine the link between the observed changes in R wave amplitude and depolarization alternans. Results from ECGs recorded from patients show that amplitude of the R wave can change as predicted by our experimental results and mathematical model. Using TWA as the marker of repolarization alternans and R Wave Amplitude Alternans (RWAA) as the marker of depolarization alternans, we investigated the phase relation between depolarization and repolarization alternans in clinical grade ECG and observed that this relationship does change spontaneously, consistent with our prior results from animal studies. Results of the present study support further investigation of the use of RWAA as a complementary method to TWA to improve its positive predictive value.

Several studies suggest that action potential duration (APD) alternans play an important role in initiation of arrhythmias, while less is known about the alternans of early phases of action potential (AP) and phase relation between the two. Transmembrane potentials recorded from swine and canine ventricles were analyzed to determine the correlation and phase relation between alternans of early and late phases of an AP. In both species, for activation intervals ≤ 400 ms, action potential amplitude (APA) alternans occurred≥ 50% of times when APD alternans occurred and vice versa, both were mostly in phase. Also, alternans of APA and APD were mostly in phase with alternans of maximal rate of depolarization. The correlation between alternans in early and later parts of AP, however, was variable between species; APD10 and APD90 alternans were out of phase 81 % versus 34 % in canines and swines. These observations suggest that ionic mechanisms underlying alternans of depolarization and early repolarization phases may be distinct from those underlying later phases of repolarization. Simulations conducted to see the spatiotemporal effect of phase behavior between these alternans show that out of phase behavior suppresses oscillations in wavelength and minimizes the chances of spatial discordance.

Abstract “Early repolarization” (ER), consisting of J waves and ST-segment elevation in the standard 12-lead electrocardiogram (ECG), has been considered a benign finding for over 60 years until 2008 an over-presentation of ER ECG pattern in infero-lateral leads was described in patients with idiopathic ventricular fibrillation. The purpose of this thesis was to assess the prevalence and prognostic significance, and to characterize the clinical features of this ECG pattern primarily in the general population. This thesis investigated the electrocardiographic features of a total of 20,308 general population individuals, 565 athletes, 432 victims of sudden cardiac death and 532 survivors of an acute coronary event. The overall prevalence of infero-lateral ER ECG pattern in the general population samples was in range between 3.3 and 6.1 percent. ER seemed to have a heritable basis as siblings of individuals displaying the ER pattern had significantly increased odds for presenting this ECG pattern. Several strong associations between ER pattern and clinical factors were observed in all populations. The ER patterns with horizontal or descending ST-segments were associated with significantly increased arrhythmic mortality during a follow-up of 30±11 years, and high amplitude (&#62;0.2mV) J waves in the inferior leads were associated with a high risk of arrhythmic death (multivariate adjusted hazard ratio 3.13 (95% confidence interval 1.55 to 6.32). The ER ECG pattern was also independently associated with sudden cardiac death during an acute coronary event, with an odds ratio of 2.02 (95% CI 1.04 to 3.61) for suffering sudden death. The ER patterns with rapidly ascending ST-segments, the dominant type of ER ECG in young, healthy individuals, were not associated with any adverse outcomes. A multicentre meta-analysis of genome wide association study of ER ECG pattern performed in a total of 14,633 individuals pointed to an associated locus in KCND3 (Kv4.3) gene, which encodes a subunit of the Ito channel, but the association did not reach genome-wide significance and could not be replicated in all study populations. In conclusion, the results of these studies demonstrated that the ER ECG pattern with horizontal or descending ST-segments, especially in the inferior leads, is associated with an increased risk of sudden arrhythmic death in the general population, and that individuals carrying this ECG pattern are at increased risk of suffering fatal arrhythmia during an acute coronary event. The ER pattern with rapidly ascending ST-segments is common in young healthy athletes and is not associated with any increased risk of fatal events. Although the ER ECG pattern increases the relative risk of arrhythmic events, the absolute risk in an individual is low and therefore this ECG pattern should not be interpreted as a high-risk marker of mortality. The genetic background of this ECG pattern remains to be clarified. / Tiivistelmä Normaalissa 12-kytkentäisessä sydänfilmissä (EKG) J-aallosta ja ST-segmentin noususta koostuvaa varhaista repolarisaatiota (ER) pidettiin yli 60 vuotta hyvänlaatuisena muutoksena, kunnes vuonna 2008 ER:n esiintyminen alaseinä-lateraalikytkennöissä liitettiin idiopaattiseen kammiovärinään. Tämän väitöstutkimuksen tarkoitus oli selvittää EKG muutoksen esiintyvyys ja ennustearvo normaaliväestössä, sekä selvittää sen kliinisiä erityispiirteitä. Väitöstutkimusta varten tutkittiin 20,308 normaaliväestön henkilöä, 565 urheilijaa, 432 äkillisesti (sydänperäisesti) menehtynyttä henkilöä ja 532 akuutista sepelvaltimotautikohtauksesta selviytynyttä potilasta. ER-EKG:n kokonaisesiintyvyys alaseinä-lateraalikytkennöissä normaaliväestön otoksissa vaihteli 3.3&#160;% ja 6.1&#160;% välillä. ER-EKG:n esiintyessä merkittävästi muita useammin sisaruksilla ER-EKG vaikutti periytyvältä muutokselta, ja lisäksi kaikissa otoksissa ER-EKG liittyi useisiin muihin tunnettuihin kliinisiin muuttujiin. ER-EKG, ts. J-aallot, joita seurasivat horisontaalinen tai laskeva ST-segmentti, liittyivät merkittävästi lisääntyneeseen rytmihäiriökuolleisuuteen pitkän seuranta-ajan (30±11 vuotta) aikana, ja korkea-amplitudiset (&#62;0.2mV) J-aallot alaseinäkytkennöissä liittyivät korkeaan riskiin kuolla äkillisesti rytmihäiriöön (monimuuttuja-vakioitu riskisuhde 3.13, 95&#160;% luottamusväli 1.55–6.32). ER-EKG lisäsi lisäksi itsenäisesti sydänperäisen äkkikuoleman riskiä akuutin sepelvaltimotautikohtauksen aikana (vetosuhde 2.02, 95&#160;% luottamusväli 1.04–3.61). Etenkin nuorilla ja terveillä urheilijoilla esiintynyt EKG tyyppi, J-aallot ST-segmentin nousujen yhteydessä, ei liittynyt huonoon ennusteeseen. Monikeskusmeta-analyysi perimänlaajuisista assosiaatiotutkimuksista (GWAS) 14,633 henkilöllä antoi viitteitä geenimuutoksesta KCND3, joka koodittaa osaa Ito kanavasta, mutta löydöstä ei kyetty toistamaan kaikissa tutkituissa aineistoissa. Väitöstutkimuksen osatöiden perusteella ER-EKG muutos ilman ST-segmentin nousua, erityisesti alaseinäkytkennöissä esiintyessään, liittyy normaaliväestössä lisääntyneeseen riskiin sydänperäiselle rytmihäiriökuolemalle, ja että henkilöillä, joilla muutos esiintyy, on lisääntynyt riski menehtyä äkillisesti sepelvaltimotautikohtauksen aikana. ER-EKG ST-segmentin nousuihin liittyen on yleinen löydös nuorilla terveillä urheilijoilla ja se ei näytä liittyvän lisääntyneeseen riskiin rytmihöiriöille. Vaikka ER-EKG lisääkin suhteellista riskiä rytmihäiriöille ja ennenaikaiselle kuolemalle väestötasolla, absoluuttinen riski on pieni, eikä muutosta tulisi luokitella suureksi riskitekijäksi. Löydöksen geneettinen tausta on vielä avoin kysymys.

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