Modeling and simulation of the electric activity of the heart using graphic processing units

Mathematical modelling and simulation of the electric activity of the heart (cardiac electrophysiology) offers and ideal framework to combine clinical and experimental data in order to help understanding the underlying mechanisms behind the observed respond under physiological and pathological conditions. In this regard, solving the electric activity of the heart possess a big challenge, not only because of the structural complexities inherent to the heart tissue, but also because of the complex electric behaviour of the cardiac cells. The multi- scale nature of the electrophysiology problem makes difficult its numerical solution, requiring temporal and spatial resolutions of 0.1 ms and 0.2 mm respectively for accurate simulations, leading to models with millions degrees of freedom that need to be solved for thousand time steps. Solution of this problem requires the use of algorithms with higher level of parallelism in multi-core platforms. In this regard the newer programmable graphic processing units (GPU) has become a valid alternative due to their tremendous computational horsepower. This thesis develops around the implementation of an electrophysiology simulation software entirely developed in Compute Unified Device Architecture (CUDA) for GPU computing. The software implements fully explicit and semi-implicit solvers for the monodomain model, using operator splitting and the finite element method for space discretization. Performance is compared with classical multi-core MPI based solvers operating on dedicated high-performance computer clusters. Results obtained with the GPU based solver show enormous potential for this technology with accelerations over 50× for three-dimensional problems when using an implicit scheme for the parabolic equation, whereas accelerations reach values up to 100× for the explicit implementation. The implemented solver has been applied to study pro-arrhythmic mechanisms during acute ischemia. In particular, we investigate on how hyperkalemia affects the vulnerability window to reentry and the reentry patterns in the heterogeneous substrate caused by acute regional ischemia using an anatomically and biophysically detailed human biventricular model. A three dimensional geometrically and anatomically accurate regionally ischemic human heart model was created. The ischemic region was located in the inferolateral and posterior side of the left ventricle mimicking the occlusion of the circumflex artery, and the presence of a washed-out zone not affected by ischemia at the endocardium has been incorporated. Realistic heterogeneity and fi er anisotropy has also been considered in the model. A highly electrophysiological detailed action potential model for human has been adapted to make it suitable for modeling ischemic conditions (hyperkalemia, hipoxia, and acidic conditions) by introducing a formulation of the ATP-sensitive K+ current. The model predicts the generation of sustained re-entrant activity in the form single and double circus around a blocked area within the ischemic zone for K+ concentrations bellow 9mM, with the reentrant activity associated with ventricular tachycardia in all cases. Results suggest the washed-out zone as a potential pro-arrhythmic substrate factor helping on establishing sustained ventricular tachycardia.Colli-Franzone P, Pavarino L. A parallel solver for reaction-diffusion systems in computational electrocardiology, Math. Models Methods Appl. Sci. 14 (06):883-911, 2004.Colli-Franzone P, Deu hard P, Erdmann B, Lang J, Pavarino L F. Adaptivity in space and time for reaction-diffusion systems in electrocardiology, SIAM J. Sci. Comput. 28 (3):942-962, 2006.Ferrero J M(Jr), Saiz J, Ferrero J M, Thakor N V. Simulation of action potentials from metabolically impaired cardiac myocytes: Role of atp-sensitive K+ current. Circ Res, 79(2):208-221, 1996.Ferrero J M (Jr), Trenor B. Rodriguez B, Saiz J. Electrical acticvity and reentry during acute regional myocardial ischemia: Insights from simulations.Int J Bif Chaos, 13:3703-3715, 2003.Heidenreich E, Ferrero J M, Doblare M, Rodriguez J F. Adaptive macro finite elements for the numerical solution of monodomain equations in cardiac electrophysiology, Ann. Biomed. Eng. 38 (7):2331-2345, 2010.Janse M J, Kleber A G. Electrophysiological changes and ventricular arrhythmias in the early phase of regional myocardial ischemia. Circ. Res. 49:1069-1081, 1981.ten Tusscher K HWJ, Panlov A V. Alternans and spiral breakup in a human ventricular tissue model. Am. J.Physiol. Heart Circ. Physiol. 291(3):1088-1100, 2006.<br /

三次元心臓モデルと不均一振動モデルによる心臓活動電位のコンピュータシミュレーション

Tohoku University西條芳文論

Visions of Cardiomyocyte

In the field of cardiology, some of the most dramatic advances in recent years have come from understanding the molecular and cellular basis of cardiovascular disease. Knowledge of the pathological basis of disease in some cases allows the development of new strategies for prevention and treatment. This book was planned not only to convey new facts on cardiovascular diseases, but also to boost the excitement and challenges of research in the dynamic area of modern molecular and cellular biology of cardiology. The integration of multilevel biological data and the connection with clinical practice reveal the potential of personalized medicine, with future implications for prognosis, diagnosis, and management of cardiovascular diseases

Investigation of arrhythmogenesis in the desmoplakin knockout mouse: A model of arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM), in contrast with other cardiomyopathies, often presents with lethal ventricular arrhythmias with athletes affected more severely. It has the characteristic feature of fibrofatty replacement of the right ventricular myocardium, although left ventricular variants have been reported. It has been associated with desmosomal protein mutations – structural proteins involved in cell-cell adhesion at the intercalated disk between cardiomyocytes. Arrhythmias are often noted to occur in a ‘concealed phase’ with minimal or no evidence of structural change. There is a need for better understanding of the mechanisms promoting arrhythmogenesis in order to improve arrhythmic risk prediction. A cardiac restricted heterozygous desmoplakin (DSP) knockout mouse was developed using the Cre-lox system with the cardiac restricted αMHC promoter (αMHC-Cre DSP flox/+) as a model of ‘concealed phase’ ACM and was studied with ECG, electrophysiology study and histology. This model recapitulated the ventricular arrhythmias seen in patients with evidence of conduction delay at electrophysiology study. This was no evidence of fibrofatty replacement of the myocardium on histology. Immunohistochemistry, however, revealed connexin 43 (Cx43) mislocalization away from the intercalated disk and a reduction in mRNA expression. Cx43 is a protein that makes up gap junctions which are involved in allowing rapid electrical conduction in the heart. The sodium channel is also located at the intercalated disk, but no change in its distribution, mRNA expression or change in the sodium current was noted. This suggests that interactions between Cx43 and desmosomal proteins are a key driver of arrhythmogenesis in ACM. In order to assess the effect of exercise on the arrhythmic phenotype, the mice were allowed to exercise freely before electrophysiology study. One group had slow release β blocker pellets implanted prior to exercise. Exercise made the mice more prone to arrhythmia, consistent with human studies. β blockers significantly reduced the numbers of mice developing ventricular arrhythmia as well as reducing the conduction delay observed at electrophysiology study. Cx43 showed less mislocalization in the β blocker treated mice, suggesting a role in slowing disease progression. Using the CreER promoter, which knocks DSP out in the adult mouse, the effect of DSP loss in adulthood was investigated. Mice with a complete knockout of DSP in adulthood became rapidly unwell and died, with bradycardia the only notable arrhythmia. However, heterozygous CreER knockout mice did not develop arrhythmia. The αMHC promoter is maximally expressed in early postnatal life. This suggests that this period, when desmosomes and adherens junctions are forming the mixed cell-cell junctions called the area composita, is significant in forming functional gap junctions to allow normal conduction. This mechanism may be relevant to arrhythmogenesis in other inherited cardiomyopathies. HL-1 cells were used as a cellular cardiomyocyte model to express DSP mutations identified in our ACM patient cohort. These two mutations (R1113X and T586fsX594) were both nonsense mutations at the N terminus. Cx43 was also found to be mislocalised in this model and shows similarity between the heterozygous knockout murine model and a cellular m0del of disease causing mutations. Sodium channel localisation was variable and showed less membrane localisation with the R1113X mutation. This may account for differences in the arrhythmia burden amongst ACM patients and shows the complex nature of the interactions at the intercalated disk. Plakoglobin was found to be localised at the nucleus with mutant DSP. This shows it is a key binding partner for desmoplakin at the intercalated disk and may also promote arrhythmogenesis by alterations in nuclear signalling. In conclusion, this work has established the heterozygous DSP knockout mouse and HL-1 cells as useful models for investigating the mechanisms of arrhythmogenesis in ACM. The key mechanism is interaction of desmoplakin and Cx43 at the intercalated disk. Restriction on exercise and treatment with β blockers for ACM patients is supported by this model. Further investigation of the mechanisms of interaction of DSP with other desmosomal proteins, the sodium channel and Cx43 may allow better prediction of arrhythmic risk and targeted therapies for ACM patients

Arrhythmogenic cardiomyopathy - beyond monogenetic disease

Interpreting genetic variants, describing their associated clinical characteristics, and identifying new genetic loci involved in arrhythmogenic cardiomyopathy (ACM) is the focus of this thesis. By investigating various aspects of these genetic variants, we were able to correctly classify two variants occurring in the lamin A/C (LMNA) and titin (TTN) gene. We demonstrated that the reduced force generation seen in cardiomyocytes with the LMNA variant (LMNA c.992G&gt;A) is due to remodelling within the cardiomyocytes and that patients with this specific variant have a milder phenotype compared to what is known from other pathogenic LMNA variants. By extensive phenotyping of carriers of a truncating TTN variant (TTN c.59926+1G&gt;A) we were the first to show that (paroxysmal) atrial fibrillation is an important clinical feature in carriers of truncated TTN variants, even in the absence of dilated cardiomyopathy, atrial enlargement or generally accepted risk factors for atrial fibrillation. Thanks to extensive international collaboration it was possible to compile one of the largest cohorts of patients carrying truncating variants in desmoplakin (DSP). We showed that the location of such a genetic variant within the gene is associated with disease severity. Moreover, these studies show that enrichment of truncating genetic variants in specific regions of DSP variants in ACM patients, when compared to controls, facilitating interpretation of such variants. The multifactorial nature of ACM was underscored in a systematic analysis of the clinical outcome of patients from ACM cohorts carrying multiple variants in ACM related genes, showing that carrying multiple variants influences disease severity. Finally, by analysing genes encoding the sarcomere, the contractile unit of the heart muscle and the plectin (PLEC) gene for rare variants in ACM patients, we showed that these genes do not have a major role in the development of ACM

Cardiac electrophysiology and mechanoelectric feedback : modeling and simulation

Cardiac arrhythmia such as atrial and ventricular fibrillation are characterized by rapid and irregular electrical activity, which may lead to asynchronous contraction and a reduced pump function. Besides experimental and clinical studies, computer simulations are frequently applied to obtain insight in the onset and perpetuation of cardiac arrhythmia. In existing models, the excitable tissue is often modeled as a continuous two-phase medium, representing the intracellular and interstitial domains, respectively. A possible drawback of continuous models is the lack of flexibility when modeling discontinuities in the cardiac tissue. We introduce a discrete bidomain model in which the cardiac tissue is subdivided in segments, each representing a small number of cardiac cells. Active membrane behavior as well as intracellular coupling and interstitial currents are described by this model. Compared with the well-known continuous bidomain equations, our Cellular Bidomain Model is better aimed at modeling the structure of cardiac tissue, in particular anisotropy, myofibers, fibrosis, and gap junction remodeling. An important aspect of our model is the strong coupling between cardiac electrophysiology and cardiomechanics. Mechanical behavior of a single segment is modeled by a contractile element, a series elastic element, and a parallel elastic element. Active force generated by the sarcomeres is represented by the contractile element together with the series elastic element. The parallel elastic element describes mechanical behavior when the segment is not electrically stimulated. Contractile force is related to the intracellular calcium concentration, the sarcomere length, and the velocity of sarcomere shortening. By incorporating the influence of mechanical deformation on electrophysiology, mechanoelectric feedback can be studied. In our model, we consider the immediate influence of stretch on the action potential by modeling a stretch-activated current. Furthermore, we consider the adap- tation of ionic membrane currents triggered by changes in mechanical load. The strong coupling between cardiac electrophysiology and cardiac mechanics is a unique property of our model, which is reflected by its application to obtain more insight in the cause and consequences of mechanical feedback on cardiac electrophysiology. In this thesis, we apply the Cellular Bidomain Model in five different simulation studies to cardiac electrophysiology and mechanoelectric feedback. In the first study, the effect of field stimulation on virtual electrode polarization is studied in uniform, decoupled, and nonuniform cardiac tissue. Field stimulation applied on nonuniform tissue results in more virtual electrodes compared with uniform tissue. Spiral waves can be terminated in decoupled tissue, but not in uniform, homogeneous tissue. By gradually increasing local differences in intracellular conductivities, the amount and spread of virtual electrodes increases and spiral waves can be terminated. We conclude that the clinical success of defibrillation may be explained by intracellular decoupling and spatial heterogeneity present in normal and in pathological cardiac tissue. In the second study, the role of the hyperpolarization-activated inward current If is investigated on impulse propagation in normal and in pathological tissue. The effect of diffuse fibrosis and gap junction remodeling is simulated by reducing cellular coupling nonuniformly. As expected, the conduction velocity decreases when cellular coupling is reduced. In the presence of If, the conduction velocity increases both in normal and in pathological tissue. In our simulations, ectopic activity is present in regions with high expression of If and is facilitated by cellular uncoupling. We also found that an increased If may facilitate propagation of the action potential. Hence, If may prevent conduction slowing and block. Overexpression of If may lead to ectopic activity, especially when cellular coupling is reduced under pathological conditions. In the third study, the influence of the stretch-activated current Isac is investigated on impulse propagation in cardiac fibers composed of segments that are electrically and mechanically coupled. Simulations of homogeneous and inhomogeneous cardiac fibers have been performed to quantify the relation between conduction velocity and Isac under stretch. Conduction slowing and block are related to the amount of stretch and are enhanced by contraction of early-activated segments. Our observations are in agreement with experimental results and explain the large differences in intra-atrial conduction, as well as the increased inducibility of atrial fibrillation in acutely dilated atria. In the fourth study, we investigate the hypothesis that electrical remodeling is triggered by changes in mechanical work. Stroke work is determined for each segment by simulating the cardiac cycle. Electrical remodeling is simulated by adapting the L-type Ca2+ current ICa,L such that a homogeneous distribution of stroke work is obtained. With electrical remodeling, a more homogeneous shortening of the fiber is obtained, while heterogeneity in APD increases and the repolarization wave reverses. These results are in agreement with experimentally observed distributions of strain and APD and indicate that electrical remodeling leads to more homogeneous shortening during ejection. In the fifth study, we investigate the effect of stretch on the vulnerability to AF. The human atria are represented by a triangular mesh obtained from MRI data. To model acute dilatation, overall stretch is applied to the atria. In the presence of Isac, the membrane potential depolarizes, which causes inactivation of the sodium channels and results in conduction slowing or block. Inducibility of AF increases under stretch, which is explained by an increased dispersion in refractory period, conduction slowing, and local conduction block. Our observations explain the large differences in intra-atrial conduction measured in experiments and provide insight in the vulnerability to AF in dilated atria. In conclusion, our model is well-suited to describe cardiac electrophysiology and mechanoelectric feedback. For future applications, the model may be improved by taking into account new insights from cellular physiology, a more accurate geometry, and hemodynamics

Do changes in the expression of Gαi2 affect cardiac electrophysiology?

PhDThe heterotrimeric G protein subunit, Gαi2, is involved in signal transduction from muscarinic acetylcholine and other receptor systems in cardiomyocytes. Gαi2 expression is elevated in human heart failure, though whether this is beneficial or maladaptive remains unknown. Better understanding could guide therapeutics development. Previous work with Gαi2 knockout mice suggested a pro-arrhythmic phenotype. We hypothesised that increased Gαi2 expression is anti-arrhythmic in the ventricles. To investigate this, an in vivo murine model of myocardial infarction was used to approximate the human pathophysiology, with wild-type (WT) mice compared to those with cardiospecific Gαi2 knockout. Subsequently, an ex vivo model of cardiac tissue slices was used to evaluate normal electrophysiological properties of murine ventricular tissue, alterations with β-adrenoceptor and muscarinic agonists and temperature, and comparison of these properties in WT mice and those with Gαi2 globally deleted. With the myocardial infarction model, there were no significant cardiac phenotypic differences between cardiospecific knockouts and WTs. The cardiac slice model, which utilised a micro-electrode array, showed stable activation and repolarisation properties in WT slices. Comparison of WTs to Gαi2 global knockouts in the presence of carbachol found no significant differences between groups in terms of repolarisation or conduction properties. In WT slices, isoprenaline was associated with a small increase in effective refractory period, but did not alter conduction properties. There was a highly significant negative linear relationship between temperature and both activation, and repolarisation. Murine models were used to investigate the electrophysiological effects of autonomic signalling pathways, and in particular, the protein Gαi2. No observable electrophysiological differences between WT and Gαi2 knockout mice were demonstrated. β-adrenergic agonism produced small changes in repolarisation only. Effects of temperature on activation and refractoriness suggest modulation of sodium and potassium currents, in keeping with published work. These findings contribute to our understanding of autonomic modulation of murine cardiac electrophysiolog

Optogenetic Control of Cardiac Arrhythmias

The regular, coordinated contraction of the heart muscle is orchestrated by periodic waves generated by the heart’s natural pacemaker and transmitted through the heart’s electrical conduction system. Abnormalities occurring anywhere within the cardiac electrical conduction system can disrupt the propagation of these waves. Such dis- ruptions often lead to the development of high frequency spiral waves that override normal pacemaker activity and compromise cardiac function. The occurrence of high frequency spiral waves in the heart is associated with cardiac rhythm disorders such as tachycardia and fibrillation. While tachycardia may be terminated by rapid periodic stimulation known as anti-tachycardia pacing (ATP), life-threatening ventricular fibril- lation requires a single high-voltage electric shock that resets all the activity and restore the normal heart function. However, despite the high success rate of defibrillation, it is associated with significant side effects including tissue damage, intense pain and trauma. Thus, extensive research is conducted for developing low-energy alternatives to conventional defibrillation. An example of such an alternative is the low-energy anti-fibrillation pacing (LEAP). However, the clinical application of this technique, and other evolving techniques requires a detailed understanding of the dynamics of spiral waves that occur during arrhythmias. Optogenetics is a tool, that has recently gained popularity in the cardiac research, which serves as a probe to study biological processes. It involves genetically modifying cardiac muscle cells such that they become light sensitive, and then using light of specific wavelengths to control the electrical activity of these cells. Cardiac optogenetics opens up new ways of investigating the mechanisms underlying the onset, maintenance and control of cardiac arrhythmias. In this thesis, I employ optogenetics as a tool to control the dynamics of a spiral wave, in both computer simulations and in experiments.In the first study, I use optogenetics to investigate the mechanisms underlying de- fibrillation. Analogous to the conventional single electric-shock, I apply a single globally-illuminating light pulse to a two-dimensional cardiac tissue to study how wave termination occurs during defibrillation. My studies show a characteristic transient dynamics leading to the termination of the spiral wave at low light intensities, while at high intensities, the spiral waves terminate immediately. Next, I move on to explore the use of optogenetics to study spiral wave termina- tion via drift, theoretically well-known mechanism of arrhythmia termination in the context of electrical stimulation (e.g. ATP). I show that spiral wave drift can be induced by structured illumination patterns using lights of low intensity, that result in a spatial modulation of cardiac excitability. I observe that drift occurs in the positive direction of light intensity gradient, where the spiral also rotates with a longer period. I further show how modulation of the excitability in space can be used to control the dynamics of a spiral wave, resulting in the termination of the wave by collision with the domain boundary. Based on these observations, I propose a possible mechanism of optogenetic defibrillation. In the next chapter, I use optogenetics to demonstrate control over the dynamics of the spiral waves by periodic stimulation with light of different intensities and pacing frequencies resulting in a temporal modulation of cardiac excitability. I demonstrate how the temporal modulation of excitability leads to efficient termination of arrhythmia. In addition, I use computer simulations to identify mechanisms responsible for arrhyth- mia termination for sub- and supra-threshold light intensities. My numerical results are supported by experimental studies on intact hearts, extracted from transgenic mice. Finally, I demonstrate that cardiac optogenetics not only allows control of excita- tion waves, but also by generating new waves through the induction of wave breaks. We demonstrate the effects of high sub-threshold illumination on the morphology of the propagating wave, leading to the creation of new excitation windows in space that can serve as potential sites for re-entry initiation. In summary, this thesis investigates several approaches to control arrhythmia dy- namics using optogenetics. The experimental and numerical results demonstrate the potential of feedback-induced resonant pacing as a low-energy method to control arrhythmia.2022-01-1

Cardiac Diseases with Molecular and Clinical Aspect : JPH2-RyR2-SCN5A gene mutations

Sydänperäisen äkkikuoleman ilmaantuvuus kaikissa ikäryhmissä on yksi tuhatta henkilövuotta kohden. Viime vuosikymmeninä geenitutkimusten kehittymisen myötä on molekyyligenetiikan avulla kyetty selventämään vakavien nuorellakin iällä henkeä uhkaavien sydänsairauksien diagnostiikkaa, optimoimaan hoitoja sekä arvioimaan sairastuneen lähisukulaisten sairastumisriskiä ja sydänseurantatarvetta. Lisäksi kantasolutekniikoiden kehittyminen helpottaa geneettisten sairauksien tutkimista solutasolla. Perinnöllisiä sydänsairauksia hoitaessa löysimme mielenkiintoisia sukuja, joiden sairauksia tutkimme kliinisesti ja laboratorio-oloissa. Tämä väitöskirja käsittelee monogeenisia vallitsevasti periytyviä sydänsairauksia, joihin erityisesti diagnosoimattomana liittyy äkkikuoleman riski nuorena. Varhaisella diagnostiikalla ja oikein kohdennetuilla hoidoilla potilaiden sairauden ennustetta voidaan merkittävästi parantaa. Totesimme laajassa pirkanmaalaisessa suvussa esiintyvän natriumkanava SCN5A D1275N geenimutaation, joka aiheuttaa sydämessä vakavia johtumishäiriöitä ja eteisperäisiä rytmihäiriöitä johtaen fataaleihin sydänperäisiin tromboembolisiin komplikaatioihin. Selvitimme 12-kytkentäisen sydänsähkökäyrän (EKG) löydöksien liittymistä SCN5A D1275N geenivirheeseen ja geenivirheen tromboembolisille komplikaatioille altistavien EKG löydösten ja tahdistin hoitoa vaativien johtumishäiriöiden ennakoitavuutta. Löysimme geenivirheeseen liittyviä sydänsairauden etenemistä ennakoivia EKG-muutoksia, joiden perusteella voimme jatkossa suunnitella geenivirheen kantajien hoitoja mahdollisimman oikea-aikaisesti ennen komplikaatioiden ilmaantumista. Hypertrofinen eli paksuseinäinen sydänlihassairaus on yleinen vallitsevasti periytyvä sydänsairaus esiintyen yhdellä henkilöllä 500:sta. Toistaiseksi hypertrofista kardiomyopatiaa aiheuttavia geenivirheitä on eniten löytynyt sydämen supistumisesta vastaavista sarkomeeriproteiineista. Toisessa osatyössä pystyimme osoittamaan ensimmäistä kertaa ei-sarkomeerisen kalsiumin säätelyyn vaikuttavan junktofiliiniproteiinia koodaavan JPH2 – geenivirheen vaikuttavan perinnöllisen hypertrofisen kardiomyopatian syntyyn. Analysoimalla yhdeksän perheen JPH2 (Thr161Lys) geenivirheen kantajien sydänmanifestaatioita totesimme JPH2 geenivirheen yksinään aiheuttavan hypertrofista kardiomyopatiaa. Katekoliamiiniherkkä polymorfinen kammiotakykardia (CPVT) on harvinainen perinnöllinen rytmihäiriösairaus, joka ilmaantuu fyysisen tai henkisen rasituksen yhteydessä katekolamiinien provosoidessa kammiolisälyöntisyyttä ja monimuotoista kammiotakykardiaa terverakenteisessa sydämessä. Rytmihäiriöiden hoidossa käytettävien lääkitysten teho on huono ja vaihteleva tautia aiheuttavan ryanodiinireseptori 2 (RyR2) mutaation kantajilla. Yhdistimme kliinisen ja kantasolututkimuksen tutkimalla dantroleeni-lääkkeen vaikutusta RyR2 mutaatiopotilailla ja heidän kantasoluistaan johdetuilla sydänsoluilla. Erityisesti, tutkimme mutaatiospesifistä lääkevastetta – N-terminaalimutaatioiden vaste hoitoon oli hyvä, kun taas C-terminaaliosan geenivirheen kantajilla ei ollut vastetta tutkitulle lääkkeelle. Merkittävin havaintomme oli huomata potilailla ja heidän kantasoluistaan johdetuilla sydänsoluilla (hiPSC-CM) olevan samanlainen lääkevaste. Jos potilas respondoi, myös hänen hiPSC-CM respondoivat lääkeaineelle, ja jos lääke ei tehonnut potilaaseen, se ei toiminut myöskään soluviljelmillä. Tutkimustulos kuvastaa mutaation sijainnilla olevan merkittävän vaikutuksen lääkevasteeseen. Siten voimme hiPSC-sydänsolumalleja käyttäen optimoida geneettisesti sydänsairaan potilaan hoitoja testaamatta lääkettä potilaalla. Ihmisen alkion kantasoluja (hESC) ja indusoituja kantasoluja (hiPSC) kutsutaan yleisesti pluripotenteiksi kantasoluiksi (hPSC). Näitä soluja voidaan muuntaa erilaisiksi ihmisen soluiksi. Soluviljelytekniikoilla tuotettujen ihmisen sydänsolujen (hPSC-CM) sähköisiä ominaisuuksia voidaan mitata käyttäen mikroelektrodeja (MEA). Näiden avulla rekisteröidään solun sähköistä potentiaalia (FP), jonka ajatellaan vastaavan ihmiseltä otettavaa EKG-rekisteröintiä. QT-aika 12-kytkentäisessä EKG:ssa on sykeriippuvainen ja korjauskaavoilla pyritään poistamaan sykkeen muutoksen vaikutusta QT-aikaan. Tutkimme Bazettin kaavan soveltuvuutta hPSC-CM-solumalleissa. Vertasimme FP-aikaa (FPD) EKG:n QT-aikaan eri syketaajuuksilla terveillä henkilöillä syketaajuutta polkupyörärasituksella nopeuttaen. Totesimme hPSC-CM solujen repolarisaatioparametrien käyttäytyvän samoin kuin QT-aika EKG:ssa, siten sama korjauskaava sopii soluviljelmien sähköiseen rekisteröintiin. Molekyyligeneettinen diagnoosi helpottaa potilaiden ja heidän terveiden lähisukulaisten sydänsairauden sairastumisriskin arviota, sairauden diagnostiikkaa ja hoitoa. Lisäksi kantasolutekniikoilla voimme tulevaisuudessa optimoida potilas- ja mutaatiospesifisiä hoitotapoja.The incidence of sudden cardiac death (SCD) in all age groups is one per thousand life-years. In recent decades, with the development of genetic research, molecular genetics has been able to clarify the diagnosis of serious life-threatening heart disease and to optimize treatments, and to assess the risk of disease and necessity of heart monitoring for the affected relatives. Additionally, the development of stem cell-based technologies has further helped to study genetic disease at cellular level. In the outpatient clinic for genetic cardiac diseases, we found interesting families whose diseases we further studied in more detail clinically and under laboratory conditions. Monogenic, dominantly inherited cardiac diseases were the focus. All these diseases are associated with an increased risk of sudden death at a young age. Early diagnosis and well-targeted treatments can significantly improve patients' prognosis. A large family carrying a sodium channel SCN5A gene mutation D1275N was found in the Pirkanmaa area in Finland. A clinical phenotype of family members included severe conduction defect and atrial arrhythmias. In this thesis, we analyzed 12-lead electrocardiogram (ECG) in that family and discovered ECG changes that predict conduction defect progression and cardiogenic thromboembolic complication. With these results, we will be able to predict the need for anticoagulation and pacemaker treatments of gene mutation carriers before complications appear. Hypertrophic cardiomyopathy (HCM) is a common monogenic heart disease that is estimated to appear in one in 500 individuals. So far, hypertrophic cardiomyopathy-causing gene defects have been most commonly found in sarcomere proteins corresponding to cardiac contraction. In the second part of the work, we were able to demonstrate for the first time the calcium handling protein junctophilin-2 (JPH2) gene to cause hypertrophic cardiomyopathy. This protein is a non-sarcomeric calcium regulator. This JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM in many unrelated families. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable rare cardiac disorder associated with exercise- and emotional stress-induced ventricular extrasystole and tachycardia in the absence of structural heart disease. The efficacy of medications in these patients is poor. CPVT is caused by mutations in ryanodine receptor 2 (RyR2) gene. Combining a clinical trial with stem cell study, we investigate the effect of a certain medication (dantrolene) on patients and their stem cell-derived cardiomyocytes. First of all, we observed a clear mutation-specific response – N-terminal mutations responded well to the treatment while the drug had no effect in patients having mutations in the C-terminal part of the gene. Secondly, we did a major discovery the patients and their stem cell-derived cardiomyocytes responded similarly on the medication – if the patient responded, also his stem cell-derived cardiomyocytes responded, and if the patient did not, neither the cells did. The results demonstrated that the location of the mutation has a significant role in drug-responsiveness, and that stem cell-derived cell can be used for treatment optimization in patients with genetic cardiac diseases without testing the drugs in patients. Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) are generally called pluripotent stem cells (hPSCs). These cells can be differentiated into any cell of human body. In this thesis, we analyze stem cell derived cardiomyocytes. Some electrophysiological aspects of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) can be studied using microelectrode arrays (MEAs), where the cells are cultured on electrodes and ECG-type of field potential (FP) recordings can be obtained. The QT interval in 12-lead ECG is beating-rate-dependent and correction formulas have been created to abolish the effect of the rate. We investigated whether the same formulas could be used when studying stem cell-derived cardiomyocytes. We compared the FP duration (FPD) to the QT time of electrocardiogram (ECG) from healthy individuals with low basic heart rate and performed stress exercise test to increase heart rate. We found that the repolarization parameter FPD in hPSC-cardiomyocytes (hPSC-CMs) behaved similarly as QT time in ECG recordings, and thus the same rate correction formula can be applied to electrical recordings in cell culture situations. In conclusion, the identification of the underlying genetic detect aims at identi-fying individuals at increased risk, and clinical parameters can be found to predict the need of further treatments. Additionally, stem cell technologies will be powerful in the future to optimize treatments in patient- and mutation-specific manner