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Papers by P Tavi

European Heart Journal

Introduction Atrial fibrillation (AF) is the most common, complex, and clinically relevant arrhyt... more Introduction Atrial fibrillation (AF) is the most common, complex, and clinically relevant arrhythmia [1]. It is a growing medical condition associated with significant morbidity and mortality, but its pathophysiology has remained widely unknown [2]. Aims We aim to unravel the complex pathophysiological mechanisms of AF and identify clinically relevant AF-related metabolites. We aim to identify targets for therapeutical interventions and biomarkers for AF diagnostics. Our study material is unique as we can safely study human heart and pericardial fluid in addition to blood, that has been mainly examined in previous studies. Material and methods Patients recruited were undergoing cardiac surgery due to valve defects at the University Hospital. For our research, we collected preoperative blood samples and intraoperative right atrial appendage biopsy and pericardial fluid. For our metabolomics study on AF patients, we selected 16 patients with permanent AF and 17 age, gender and underl...

Frontiers in Physiology, 2018

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged a... more Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising experimental tool for translational heart research and drug development. However, their usability as a human adult cardiomyocyte model is limited by their functional immaturity. Our aim is to analyse quantitatively those characteristics and how they differ from adult CMs. Methods and Results: We have developed a novel in silico model with all essential functional electrophysiology and calcium handling features of hiPSC-CMs. Importantly, the virtual cell recapitulates the immature intracellular ion dynamics that are characteristic for hiPSC-CMs, as quantified based our in vitro imaging data. The strong "calcium clock" is a source for a dual function of excitation-contraction coupling in hiPSC-CMs: action potential and calcium transient morphology vary substantially depending on the activation sequence of underlying ionic currents and fluxes that is altered in spontaneous vs. paced mode. Furthermore, parallel simulations with hiPSC-CM and adult cardiomyocyte models demonstrate the central differences. Results indicate that hiPSC-CMs translate poorly the disease specific phenotypes of Brugada syndrome, long QT Syndrome and catecholaminergic polymorphic ventricular tachycardia, showing less robustness and greater tendency for arrhythmic events than adult CMs. Based on a comparative sensitivity analysis, hiPSC-CMs share some features with adult CMs, but are still functionally closer to prenatal CMs than adult CMs. A database analysis of 3000 hiPSC-CM model variants suggests that hiPSC-CMs recapitulate poorly fundamental physiological properties of adult CMs. Single modifications do not appear to solve this problem, which is mostly contributed by the immaturity of intracellular calcium handling. Conclusion: Our data indicates that translation of findings from hiPSC-CMs to human disease should be made with great caution. Furthermore, we established a mathematical platform that can be used to improve the translation from hiPSC-CMs to human, and to quantitatively evaluate hiPSC-CMs development toward more general and valuable model for human cardiac diseases.

Disease Models & Mechanisms, 2017

Neural stem/progenitor cells (NPCs) generate new neurons in the brain throughout the lifetime in ... more Neural stem/progenitor cells (NPCs) generate new neurons in the brain throughout the lifetime in an intricate process called neurogenesis. Neurogenic alterations are a common feature of several adult-onset neurodegenerative diseases. The neuronal ceroid lipofuscinoses (NCLs) are the most common group of inherited neurodegenerative diseases that mainly affect children. Pathological features of the NCLs include accumulation of lysosomal storage material, neuroinflammation, and neuronal degeneration, yet the exact cause of this group of diseases remains poorly understood. The function of the CLN5 protein, causative of the CLN5 disease form of NCL, is unknown. In the present study, we sought to examine neurogenesis in the neurodegenerative disorder caused by loss of Cln5. Our findings demonstrate a novel, critical role for CLN5 in neurogenesis. We report for the first time that neurogenesis is increased in Cln5-deficient mice, which model the childhood neurodegenerative disorder caused ...

The Journal of physiology, 2015

Adult cardiomyocytes exhibit complex Ca(2+) homeostasis, enabling tight control of contraction an... more Adult cardiomyocytes exhibit complex Ca(2+) homeostasis, enabling tight control of contraction and relaxation. This intricate regulatory system develops gradually, with progressive maturation of specialized structures and increasing capacity of Ca(2+) sources and sinks. In this review, we outline current understanding of these developmental processes, and draw parallels to pathophysiological conditions where cardiomyocytes exhibit a striking regression to an immature state of Ca(2+) homeostasis. We further highlight the importance of understanding developmental physiology when employing immature cardiomyocyte models such as cultured neonatal cells and stem cells.

In Aydin et al. (2007), part (b) of Figure 2 was not published. Figure 2 should have been present... more In Aydin et al. (2007), part (b) of Figure 2 was not published. Figure 2 should have been presented as follows: (a) (b) We apologize for the error.

PLoS Computational Biology, 2011

Electrophysiological studies of the human heart face the fundamental challenge that experimental ... more Electrophysiological studies of the human heart face the fundamental challenge that experimental data can be acquired only from patients with underlying heart disease. Regarding human atria, there exist sizable gaps in the understanding of the functional role of cellular Ca 2+ dynamics, which differ crucially from that of ventricular cells, in the modulation of excitation-contraction coupling. Accordingly, the objective of this study was to develop a mathematical model of the human atrial myocyte that, in addition to the sarcolemmal (SL) ion currents, accounts for the heterogeneity of intracellular Ca 2+ dynamics emerging from a structurally detailed sarcoplasmic reticulum (SR). Based on the simulation results, our model convincingly reproduces the principal characteristics of Ca 2+ dynamics: 1) the biphasic increment during the upstroke of the Ca 2+ transient resulting from the delay between the peripheral and central SR Ca 2+ release, and 2) the relative contribution of SL Ca 2+ current and SR Ca 2+ release to the Ca 2+ transient. In line with experimental findings, the model also replicates the strong impact of intracellular Ca 2+ dynamics on the shape of the action potential. The simulation results suggest that the peripheral SR Ca 2+ release sites define the interface between Ca 2+ and AP, whereas the central release sites are important for the fire-diffuse-fire propagation of Ca 2+ diffusion. Furthermore, our analysis predicts that the modulation of the action potential duration due to increasing heart rate is largely mediated by changes in the intracellular Na + concentration. Finally, the results indicate that the SR Ca 2+ release is a strong modulator of AP duration and, consequently, myocyte refractoriness/ excitability. We conclude that the developed model is robust and reproduces many fundamental aspects of the tight coupling between SL ion currents and intracellular Ca 2+ signaling. Thus, the model provides a useful framework for future studies of excitation-contraction coupling in human atrial myocytes.

Circulation, 1998

Background —Adrenomedullin (ADM), a new vasorelaxing and natriuretic peptide, may function as an ... more Background —Adrenomedullin (ADM), a new vasorelaxing and natriuretic peptide, may function as an endogenous regulator of cardiac function, because ADM and its binding sites have been found in the heart. We characterize herein the cardiac effects of ADM as well as the underlying signaling pathways in vitro. Methods and Results —In isolated perfused, paced rat heart preparation, infusion of ADM at concentrations of 0.1 to 1 nmol/L for 30 minutes induced a dose-dependent, gradual increase in developed tension, whereas proadrenomedullin N-20 (P& 10 to 100 nmol/L), a peptide derived from the same gene as ADM, had no effect. The ADM-induced positive inotropic effect was not altered by a calcitonin gene–related peptide (CGRP) receptor antagonist, CGRP 8–37 , or H-89, a cAMP-dependent protein kinase inhibitor. ADM also failed to stimulate ventricular cAMP content of the perfused hearts. Ryanodine (3 nmol/L), a sarcoplasmic reticulum Ca 2+ release channel opener, suppressed the overall ADM-i...

Cardiovascular Research, 2010

Mitochondrial cardiomyopathy is associated with deleterious remodelling of cardiomyocyte Ca 2+ si... more Mitochondrial cardiomyopathy is associated with deleterious remodelling of cardiomyocyte Ca 2+ signalling that is partly due to the suppressed expression of the sarcoplasmic reticulum (SR) Ca 2+ buffer calsequestrin (CASQ2). This study was aimed at determining whether CASQ2 downregulation is directly caused by impaired mitochondrial function. Methods and results Mitochondrial stress was induced in cultured neonatal rat cardiomyocytes by means of the mitochondrial uncoupler carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). Ca 2+ transients and reactive oxygen species (ROS) were measured by confocal microscopy using the indicators fluo-4 and MitoSOX red, respectively. Mitochondrial stress led to concentration-dependent downregulation of calsequestrin (CASQ2) and changes in the Ca 2+ signals of the cardiomyocytes that were accompanied by reduction in SR Ca 2+ content and amplitude and duration of Ca 2+ sparks. Caspase 3, p38, and p53 inhibitors had no effect on FCCP-induced CASQ2 downregulation; however, it was attenuated by the ROS scavenger N-acetylcysteine (NAC). Importantly, NAC not only decreased FCCP-induced ROS production, but it also restored the Ca 2+ signals, SR Ca 2+ content, and Ca 2+ spark properties to control levels. Conclusion Mitochondrial uncoupling results in fast transcriptional changes in CASQ2 expression that manifest as compromised Ca 2+ signalling, and these changes can be prevented by ROS scavengers. As impaired mitochondrial function has been implicated in several cardiac pathologies as well as in normal ageing, the mechanisms described here might be involved in a wide spectrum of cardiac conditions.

Biophysical Journal, 2010

The ability to generate homogeneous intracellular Ca 2+ oscillations at high frequency is the bas... more The ability to generate homogeneous intracellular Ca 2+ oscillations at high frequency is the basis of the rhythmic contractions of mammalian cardiac myocytes. While the specific mechanisms and structures enabling homogeneous high-frequency Ca 2+ signals in adult cardiomyocytes are well characterized, it is not known how these kind of Ca 2+ signals are produced in developing cardiomyocytes. Here we investigated the mechanisms reducing spatial and temporal heterogeneity of cytosolic Ca 2+ signals in mouse embryonic ventricular cardiomyocytes. We show that in developing cardiomyocytes the propagating Ca 2+ signals are amplified in cytosol by local Ca 2+ releases. Local releases are based on regular 3-D sarcoplasmic reticulum (SR) structures containing SR Ca 2+ uptake ATPases (SERCA) and Ca 2+ release channels (ryanodine receptors, RyRs) at regular intervals throughout the cytosol. By evoking [Ca 2+ ] i-induced Ca 2+ sparks, the local release sites promote a 3-fold increase in the cytosolic Ca 2+ propagation speed. We further demonstrate by mathematical modelling that without these local release sites the developing cardiomyocytes lose their ability to generate homogeneous global Ca 2+ signals at a sufficiently high frequency. The mechanism described here is robust and indispensable for normal mammalian cardiomyocyte function from the first heartbeats during the early embryonic phase till terminal differentiation after birth. These results suggest that local cytosolic Ca 2+ releases are indispensable for normal cardiomyocyte development and function of developing heart.

BMC Physiology, 2009

Background The cardiomyocyte is a prime example of inherently complex biological system with inte... more Background The cardiomyocyte is a prime example of inherently complex biological system with inter- and cross-connected feedback loops in signalling, forming the basic properties of intracellular homeostasis. Functional properties of cells and tissues have been studied e.g. with powerful tools of genetic engineering, combined with extensive experimentation. While this approach provides accurate information about the physiology at the endpoint, complementary methods, such as mathematical modelling, can provide more detailed information about the processes that have lead to the endpoint phenotype. Results In order to gain novel mechanistic information of the excitation-contraction coupling in normal myocytes and to analyze sophisticated genetically engineered heart models, we have built a mathematical model of a mouse ventricular myocyte. In addition to the fundamental components of membrane excitation, calcium signalling and contraction, our integrated model includes the calcium-calm...

Acta Physiologica, 2015

ABSTRACT Aim Activity of early embryonic cardiomyocytes relies on spontaneuos Ca2+-oscillations t... more ABSTRACT Aim Activity of early embryonic cardiomyocytes relies on spontaneuos Ca2+-oscillations that are induced by interplay between sarcoplasmic reticulum (SR) - Ca2+-release and ion currents of the plasma membrane. In a variety of cell types Ca2+-activated K+ current (IK(Ca)) serves as a link between Ca2+ signals and membrane voltage. This study aimed to determine the role of IK(Ca) in developing cardiomyocytes. Methods Ion currents and membrane voltage of embryonic (E9-11) mouse cardiomyocytes were measured by patch-clamp; [Ca2+]i signals by confocal microscopy. Transcription of specific genes was measured with RT-qPCR and Ca2+-dependent transcriptional activity using NFAT-luciferase assay. Myocyte structure was assessed with antibody labelling and confocal microscopy. Results E9-11 cardiomyocytes express small conductance (SK) channel subunits SK2 and SK3 and have a functional apamin-sensitive K+ current, which is also sensitive to changes in cytosolic [Ca2+]i. In spontaneously active cardiomyocytes, inhibition of IK(Ca) changed action and resting potentials, reduced SR Ca2+ load and suppressed the amplitude and the frequency of spontaneously evoked Ca2+ oscillations. Apamin caused dose-dependent suppression of NFAT-luciferase reporter activity, induced downregulation of a pattern of genes vital for cardiomyocyte development and triggered changes in the myocyte morphology. Conclusion The results show that apamin sensitive IK(Ca) is required for maintaining excitability and activity of the developing cardiomyocytes as well as having a fundamental role in promoting Ca2+- dependent gene expression.

IFMBE Proceedings, 2009

In cardiac myocytes, the calcium flux through the release channels (Ryanodine Receptors; RyRs) de... more In cardiac myocytes, the calcium flux through the release channels (Ryanodine Receptors; RyRs) defines the transient changes of intracellular calcium corresponding to the trigger, i.e., the transmembrane calcium current, and therefore determines the dynamics of the contractile function of myocytes on a beat-to-beat basis. A controversy exists related to the exact mechanisms responsible for the activation and termination of calcium

Acta Ophthalmologica, 2015

PloS one, 2015

Multicellular organisms maintain vital functions through intercellular communication. Release of ... more Multicellular organisms maintain vital functions through intercellular communication. Release of extracellular vesicles that carry signals to even distant target organs is one way of accomplishing this communication. MicroRNAs can also be secreted from the cells in exosomes and act as paracrine signalling molecules. In addition, microRNAs have been implicated in the pathogenesis of a large number of diseases, including cardiovascular diseases, and are considered as promising candidate biomarkers due to their relative stability and easy quantification from clinical samples. Pericardial fluid contains hormones secreted by the heart and is known to reflect the cardiac function. In this study, we sought to investigate whether pericardial fluid contains microRNAs and if so, whether they could be used to distinguish between different cardiovascular pathologies and disease stages. Pericardial fluid was collected from heart failure patients during open-heart surgery. MicroRNA profiles of al...

PLoS computational biology, 2014

Chronic atrial fibrillation (AF) is a complex disease with underlying changes in electrophysiolog... more Chronic atrial fibrillation (AF) is a complex disease with underlying changes in electrophysiology, calcium signaling and the structure of atrial myocytes. How these individual remodeling targets and their emergent interactions contribute to cell physiology in chronic AF is not well understood. To approach this problem, we performed in silico experiments in a computational model of the human atrial myocyte. The remodeled function of cellular components was based on a broad literature review of in vitro findings in chronic AF, and these were integrated into the model to define a cohort of virtual cells. Simulation results indicate that while the altered function of calcium and potassium ion channels alone causes a pronounced decrease in action potential duration, remodeling of intracellular calcium handling also has a substantial impact on the chronic AF phenotype. We additionally found that the reduction in amplitude of the calcium transient in chronic AF as compared to normal sinus...

The American journal of physiology, 1999

We sought to investigate whether atrial myocyte contraction and secretion of the atrial natriuret... more We sought to investigate whether atrial myocyte contraction and secretion of the atrial natriuretic peptide (ANP) are affected in the same manner by intervention in intracellular Ca(2+) handling by acidosis. The effects of propionate (20 mM)-induced intracellular acidosis on the stretch-induced changes in ANP secretion, contraction force, and intracellular Ca(2+) concentration ([Ca(2+)](i)) were studied in the isolated rat atrium. The stretch of the atrium was produced by increasing the intra-atrial pressure of the paced and superfused preparation. Contraction force was estimated from pressure pulses generated by the contraction of the atrium. Intracellular Ca(2+) was measured from indo 1-AM-loaded atria, and ANP was measured by radioimmunoassay from the perfusate samples collected during interventions. Intracellular pH of the atrial myocytes was measured by a fluorescent indicator (BCECF)-based imaging system. Intracellular acidification caused by 20 mM propionic acid (0.18 pH unit...

Pflügers Archiv, 2000

The stretch-induced changes in contraction force, cAMP and cGMP in isolated rat left atrium were ... more The stretch-induced changes in contraction force, cAMP and cGMP in isolated rat left atrium were studied. Increasing the diastolic intra-atrial pressure from 1 cmH2O to 8 cmH2O caused an immediate (<500 ms) increase in contraction force, the magnitude of which was 2.24+/-0.29 (n=6) times the force elicited by 1 cmH2O. This was followed by a slower, gradual increase of the force, which was maximal 8 min after the stretch (4.33+/-0.31, n=6). These phenomena were not accompanied by changes in the cAMP (n=24) or cGMP (n=24) concentrations within the tissue at any duration of stretch tested (2, 8, 20 and 36 min, n=6 at each time point). Furthermore, it was estimated that if the beta-adrenergic receptor agonist isoprenaline (100 nM) was used to produce an increase of the contraction force of the same magnitude as that induced by stretch, the cAMP concentration was greater (4.20+/-0.29 pmol/mg, n=5, P<0.001) when compared to that produced after 20 min of stretch (2.69+/-0.12 pmol/mg, n=6). Even without significantly changing the cGMP concentration, isoprenaline significantly increased the [cAMP]/[cGMP] ratio (3.4+/-0.36, n=5, P<0.01) compared to stretch (1.95+/-0.14, n=6). This result shows that in the rat atrium stretch does not regulate the production or breakdown of cyclic nucleotides (cAMP or cGMP). Thus it seems very unlikely that the effects of stretch on rat atrium function are caused by cAMP or cGMP.

Trends in Pharmacological Sciences, 2001

The process of sensing mechanical load and the consequent physiological responses is called mecha... more The process of sensing mechanical load and the consequent physiological responses is called mechanotransduction. In heart muscle, a mechanical stimulus is transformed into altered contraction force, altered ion balance, exocytosis or gene expression. In cardiac myocytes, mechanotransduction can be divided into a series of events, from the coding of the mechanical stimuli to second messengers and decoding the information into changes in heart function (Fig. 1). The same mechanosensors, signals, kinases and transcription factors are involved in both normal and pathological hypertrophy. Therefore, any given pharmacological intervention aimed at treating or preventing hypertrophy might influence not only pathological developments but also normal adaptation and mechanotransduction itself. In this article, present and future pharmacological approaches will be discussed in the context of mechanotransduction.