New Engineering Approaches to Arrhythmias and Myocardial Infarction

In this thesis, we present new engineering approaches to several important cardiac diseases. Chapter 1 considers the dynamics of arrhythmias. The most dangerous arrhythmias are reentrant arrhythmias, including ventricular fibrillation and ventricular tachycardia. During these arrhythmias, there are one or several rotating excitation waves present in the heart. Because of their shape, these waves are called scroll waves; their center of rotation is a one-dimensional curve called the filament. Filaments largely constrain the configuration of a scroll wave but are much simpler, so much effort has gone into describing scroll wave dynamics in terms of the dynamics of their filaments. In particular, the “geodesic principle” for filaments, which says that stable filaments are geodesics in a metric derived from the diffusivity, has been proposed and established for certain restrictive conditions. In this project, we show that the geodesic principle applies much more broadly, including for very large filament curvatures. We also discuss under which conditions the geodesic principle fails, particularly the case that the filament gets close to very heterogeneous substrate. Chapters 2-4 introduce a new approach to cardiac defibrillation. The only existing effective treatment to ventricular fibrillation is to deliver high-energy electric shocks to the heart using a defibrillator to terminate fibrillation and restore organized rhythm. Defibrillators currently available are effective in treating ventricular fibrillation, however, because of the large amount of energy deposited during the treatment can cause damaging effects to the tissue. In this project, we present results of a new technology using nanosecond pulsed electric fields to defibrillate the heart, while depositing only a fraction of energy needed by conventional defibrillators. In the final part of this thesis, Chapters 5-7, we present results of an injectable therapeutic agent to regenerate the myocardium (heart muscle) affected by infarction. Myocardial infarction is a serious coronary artery disease that occurs when a coronary artery is so severely blocked that there is a dramatic reduction or complete disruption of blood supply, causing damage or death to the territory of the myocardium that was supplied by the blocked coronary vessel. Our results show how the injection of the therapeutic agent helps in preserving the electrical activity in the affected area, and also reduces pathological effects on the ejection fraction and heart rate. In summary, we contribute to the understanding of the mechanisms of reentrant arrhythmias, develop new technology for ventricular defibrillation, and test a therapeutic agent for myocardial infarction

Cardiac Arrhythmias

Cardiac arrhythmias are common triggers of emergency admission to cardiology or high-dependency departments. Most cases are easy to diagnose and treat, while others may present a challenge to healthcare professionals. A translational approach to arrhythmias links molecular and cellular scientific research with clinical diagnostics and therapeutic methods, which may include both pharmacological and non-pharmacologic treatments. This book presents a comprehensive overview of specific cardiac arrhythmias and discusses translational approaches to their diagnosis and treatment

Inhaled xenon neuro- and cardioprotection following out-of-hospital cardiac arrest. A randomized, controlled trial

Cardiac arrest leads often to death or permanent neurological damage, despite prompt advanced life support and resuscitation. Ischaemia-reperfusion injury persists, although circulation and cardiac function has been restored. The most vulnerable organs for hypoxemia and reperfusion injury are the brain and heart. The only proven intervention against ongoing ischaemia-reperfusion injury is targeted temperature management to core temperature of 33–36 C for 24 hours after cardiac arrest. Still, at least on average third of the succesfully from ventricular fibrillation-generated cardiac arrest resuscitated patients die, particularly to hypoxic-ischaemic brain injury. The noble gas xenon is an anaesthetic gas, which has been demonstrated in preclinical animal models to attenuate posthypoxic brain and myocardial injury. Xenon has many properties of ”an ideal anaesthetic”, but being so scarce and laborous to extract makes it expensive. In this clinical trial, the standard-of-care after out-of-hospital cardiac arrest, targeted temperature management to 33 °C for 24 hours, was compared to hypothermia supplemented with inhaled xenon for 24 hours. Both study groups consisted of 55 cardiac arrest victims and the postarrest care was identical in both groups and in accordance with current international guidelines. Cerebral hypoxic-ischaemic injury was assessed with brain diffusion tensor magnetic resonance imaging after rewarming. Fractional anistrophy (FA) value corresponds to the microintegrity of brain white matter tracts and is diminished after injury. Cardiac troponin-T is a marker of cardiomyocyte injury, which was serially assessed during 72 hours following resuscitation. The main findings of this study were, that combining inhaled xenon and therapeutic hypothermia in cardiac arrest patients was safe and feasible. The combination of xenon and hypothermia significantly attenuated brain white matter injury illustrated with higher FA-values. After adjustements for age, sex, study site, primary coronary percutaneous intevention (PCI) and noradrenaline dose, Troponin-T values were lower at 72 hours post OHCA in the xenon group corresponding to an mitigating effect in myocardial injury. These results translate to significant neuro- and cardioprotection against ongoing ischaemia-reperfusion injury by xenon inhalation combined with hypothermia. The overall mortality in this study was 30,9 %. The study was underpowered to demonstrate differences in outcome or functional neurological recovery.Sydänpysähdys johtaa viiveettä aloitetusta elvytyksestä huolimatta usein potilaan kuolemaan tai vakavaan neurologiseen vammautumiseen. Hapenpuutteen ja reperfuusion aiheuttama kudosvaurio jatkuu, vaikka verenkierto ja sydämen toiminta onnistutaan elvytystoimin palauttamaan. Erityisen alttiita hapenpuutteelle ja reperfuusiovauriolle ovat aivot ja sydän. Ainoa tehokkaaksi todettu reperfuusiovaurion hoito on potilaan jäähdyttäminen 33 – 36 C lämpötilaan vuorokaudeksi elvytyksen jälkeen. Hoidosta huolimatta noin kolmannes onnistuneesti kammiovärinästä elvytetyistä potilaista kuolee, tavallisimmin hapenpuuteaivovaurion seurauksiin. Jalokaasu ksenon on anestesiakaasu, jonka on tämän lisäksi lukuisissä prekliinisissä eläintutkimuksissa todettu vähentävän hermo- ja sydänlihaskudoksen vauriota hapenpuutteen jälkeen. Ksenon-anestesialla on monia ihanteellisen anestesian piirteitä, mutta sen käytettävyyttä rajoittaa kaasun harvinaisuus ja työläs puhdistamisprosessi, minkä takia ksenon on kallista. Tässä tutkimuksessa verrattiin vakiintunutta sydänpysähdyspotilaan jatkohoitoa teho-osastolla – vuorokauden jäähdytyshoitoa – jäähdytyshoitoon ja samanaikaiseen ksenon-kaasun hengittämiseen yhteensä 110:llä onnistuneesti kammiovärinästä elvytetyillä potilailla. Näiden kahden tutkimusryhmän potilaita (55 potilasta kummassakin ryhmässä) hoidettiin muuten samankaltaisesti noudattaen viimeisimpiä kansainvälisiä suosituksia sydänpysähdyksestä elvytettyjen jatkohoidossa. Keskushermoston hapenpuutevauriota arvioitiin potilaan normaaliin lämpötilaan lämmittämisen jälkeen aivojen magneettitutkimuksen diffuusiotensorikuvauksen fraktioidun anisotrofia (FA) -arvon perusteella, jonka pieneneminen viittaa aivojen valkean aineen vaurioon ja mikrointegraation hajoamiseen. Sydänpysähdyksen jälkeistä sydänvauriota arvioitiin sydänlihassoluvaurion merkkiaineen troponiini-T:n muutosten perusteella. Tutkimuksen perusteella ksenonin ja jäähdytyshoidon yhdistelmä oli turvallista ja hengitys ja verenkierto olivat hoidon aikana vakaita myös juuri elvytetyillä sydänpysähdyspotilailla, joilla valtaosalla oli merkittävä sepelvaltimotauti. Ksenon-yhdistelmähoito vähensi merkitsevästi aivojen valkean aineen vauriota magneettikuvauksen FA-arvoja verrattaessa. Myös sydänlihaksen vauriomerkkiaineen, troponiini-T:n arvot vähenivät elvytystä seuranneen 72 tunnin kuluessa merkitsevästi, sopien pienempään sydänlihasvaurioon yhdistelmähoitoa saaneessa tutkimusryhmässä. Nämä tulokset viittaavat ksenonin merkittävään neuro- ja kardioprotektiiviseen vaikutukseen käynnissä olevan hapenpuute-reperfuusiovaurion rajoittamisessa. Tutkimuspotilaiden kuolleisuus oli 30,9 %. Hoitoryhmien koko oli liian pieni merkitsevän eron havainnointiin henkiinjäämisessä tai toiminnallisessa neurologisessa selviytymisessä

Preclinical Optimization of Treatment with Inhaled Argon to Improve Neurological Outcome and Survival After Cardiac Arrest

Introduction. Treatment of post cardiac arrest (CA) syndrome represents a clinical priority. Inhalation of the noble gas Argon may represent an attractive option. The purpose of the current thesis is to determine the efficacy, safety and mechanisms of action of Argon in different experimental models. Methods. In order to assess the efficacy of argon treatment on post CA syndrome, a pig model of CA with underlying acute myocardial infarction and cardiopulmonary resuscitation (CPR) was used. Following resuscitation, animals were randomly assigned to receive ventilation with 70% Argon (Ar 70%) or 70% Nitrogen (N270%) in oxygen. Argon effects were studied in models of CA with different level of severity (i.e. short or long duration of untreated ventricular fibrillation). Furthermore, administration of low Argon concentration (i.e. 50%) was evaluated in a subset of animals. Hemodynamics, myocardial function, neurologic recovery, brain and cardiac histological injury and biomarkers together with survival were evaluated. The safety of Argon treatment was assessed in healthy pigs. In parallel, mechanisms of action were explored. Specifically, brain protection was investigated in a rat model of CA followed by CPR. After resuscitation, animals were randomized to receive Ar 70% or N270%. Brain glutamate, gamma-amino butyric acid, pyruvate and lactate were measured by in vivo micro-dialysis. In addition, myocardial protection by argon was explored in rats subjected to coronary artery occlusion followed by reperfusion and receiving Ar 70% or N270% during reperfusion. Six and 24 h after reperfusion, myocardial injury, plasma troponin T concentration and myocardial neutrophil infiltration were evaluated. Results. Efficacy of argon on preventing post CA brain injury has been demonstrated in swine. Indeed, a faster and complete neurologic recovery following CA and CPR was achieved in Argon-treated animals compared to controls, without detrimental effects on hemodynamics and respiratory gas exchanges. Beneficial effects of Argon tended to be higher at a concentration of 70% than of 50%. Results obtained in small rodents suggest that ventilation with Argon reduces brain lactate/ pyruvate level and troponin T release. However, further studies are needed in order explain the mechanism underpining Argon protective effects. Conclusion. The consistency of the results is highly suggestive to consider ventilation with Argon as a promising therapeutic approach after CA and CPR

Sensors for Vital Signs Monitoring

Sensor technology for monitoring vital signs is an important topic for various service applications, such as entertainment and personalization platforms and Internet of Things (IoT) systems, as well as traditional medical purposes, such as disease indication judgments and predictions. Vital signs for monitoring include respiration and heart rates, body temperature, blood pressure, oxygen saturation, electrocardiogram, blood glucose concentration, brain waves, etc. Gait and walking length can also be regarded as vital signs because they can indirectly indicate human activity and status. Sensing technologies include contact sensors such as electrocardiogram (ECG), electroencephalogram (EEG), photoplethysmogram (PPG), non-contact sensors such as ballistocardiography (BCG), and invasive/non-invasive sensors for diagnoses of variations in blood characteristics or body fluids. Radar, vision, and infrared sensors can also be useful technologies for detecting vital signs from the movement of humans or organs. Signal processing, extraction, and analysis techniques are important in industrial applications along with hardware implementation techniques. Battery management and wireless power transmission technologies, the design and optimization of low-power circuits, and systems for continuous monitoring and data collection/transmission should also be considered with sensor technologies. In addition, machine-learning-based diagnostic technology can be used for extracting meaningful information from continuous monitoring data

Computer modeling and signal analysis of cardiovascular physiology

This dissertation aims to study cardiovascular physiology from the cellular level to the whole heart level to the body level using numerical approaches. A mathematical model was developed to describe electromechanical interaction in the heart. The model integrates cardio-electrophysiology and cardiac mechanics through excitation-induced contraction and deformation-induced currents. A finite element based parallel simulation scheme was developed to investigate coupled electrical and mechanical functions. The developed model and numerical scheme were utilized to study cardiovascular dynamics at cellular, tissue and organ levels. The influence of ion channel blockade on cardiac alternans was investigated. It was found that the channel blocker may significantly change the critical pacing period corresponding to the onset of alternans as well as the alternans’ amplitude. The influence of electro-mechanical coupling on cardiac alternans was also investigated. The study supported the earlier assumptions that discordant alternans is induced by the interaction of conduction velocity and action potential duration restitution at high pacing rates. However, mechanical contraction may influence the spatial pattern and onset of discordant alternans. Computer algorithms were developed for analysis of human physiology. The 12-lead electrocardiography (ECG) is the gold standard for diagnosis of various cardiac abnormalities. However, disturbances and mistakes may modify physiological waves in ECG and lead to wrong diagnoses. This dissertation developed advanced signal analysis techniques and computer software to detect and suppress artifacts and errors in ECG. These algorithms can help to improve the quality of health care when integrated into medical devices or services. Moreover, computer algorithms were developed to predict patient mortality in intensive care units using various physiological measures. Models and analysis techniques developed here may help to improve the quality of health care

Coronary microvascular disease in hypertrophic and infiltrative cardiomyopathies

Pathologic hypertrophy of the cardiac muscle is a commonly encountered phenotype in clinical practice, associated with a variety of structural and non-structural diseases. Coronary microvascular disease is considered to play an important role in the natural history of this pathological phenotype. Non-invasive imaging modalities, most prominently positron emission tomography and cardiac magnetic resonance, have provided insights into the pathophysiological mechanisms of the interplay between hypertrophy and the coronary microvasculature. This article summarizes the current knowledge on coronary microvascular dysfunction in the most frequently encountered forms of pathologic hypertrophy. Keywords: CMD; CMR; Coronary microvascular disease; cardiac PET; coronary flow reserve; left ventricular hypertrophy