Quantitative cross-species translators of cardiac myocyte electrophysiology: Model training, experimental validation, and applications.
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ABSTRACT:
SUBMITTER: Morotti S
PROVIDER: S-EPMC8598003 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The relative importance of regulatory versus structural evolution for the evolution of different biological systems is a subject of controversy. The primacy of regulatory evolution in the diversification of morphological traits has been promoted by many evolutionary developmental biologists. For physiological traits, however, the role of regulatory evolution has received less attention or has been considered to be relatively unimportant. To address this issue for electrophysiological systems, we examined the importance of regulatory and structural evolution in the evolution of the electrophysiological function of cardiac myocytes in mammals. In particular, two related phenomena were studied: the change in action potential morphology in small mammals and the scaling of action potential duration across mammalian phylogeny. In general, the functional properties of the ion channels involved in ventricular action potential repolarization were found to be relatively invariant. In contrast, there were large changes in the expression levels of multiple ion channel and transporter genes. For the Kv2.1 and Kv4.2 potassium channel genes, which are primary determinants of the action potential morphology in small mammals, the functional properties of the proximal promoter regions were found to vary in concordance with species-dependent differences in mRNA expression, suggesting that evolution of cis-regulatory elements is the primary determinant of this trait. Scaling of action potential duration was found to be a complex phenomenon, involving changes in the expression of a large number of channels and transporters. In this case, it is concluded that regulatory evolution is the predominant mechanism by which the scaling is achieved.
| S-EPMC2585018 | biostudies-literature
Project description:BackgroundCardiac electrophysiology training of young cardiologists forms the foundation of optimal heart rhythm patient care. In particular, cardiac electrophysiology is characterized by continuous innovation and has progressed rapidly over the last few years. This may have led to a gap between clinical training and the new technologies and could significantly change training requirements.ObjectiveThe aim of the survey was to obtain the opinion of young cardiologists about the current importance and satisfaction of cardiac electrophysiology training and to identify areas for improvement.MethodsThe survey was conducted in May 2020. Young DGK (Deutschen Gesellschaft für Kardiologie, German Society for Cardiology) members were contacted via e‑mail and asked to answer an online-based questionnaire. The questionnaire containing information about the current status, satisfaction, and structures of educational and clinical proficiency of cardiac electrophysiology in Germany.ResultsOverall, 131 young DGK members completed the survey. Mean age was 33 ± 3.3 years and 68% of the participants were male. Among the participants, 64% were cardiology fellows, while 36% were qualified. A total of 72 participants (53%) reported overall satisfaction with their clinical training and 50% of the participants held the opinion that cardiac electrophysiology should become a larger part of their education. Training courses and fellowships were rated mostly positive (70% vs. 93%, respectively); however, the later were unknown to 41% of the participants. Areas identified for improvement included the following: establishment of general cardiac electrophysiology rotation; enabling access to procedures to gain invasive skills; increased advertising for training courses and fellowships; increase of online-based training courses.ConclusionThe survey underlines the interest of young cardiologists in an intensified cardiac electrophysiology training within their cardiology training.
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Project description:Recent developments in cardiac simulation have rendered the heart the most highly integrated example of a virtual organ. We are on the brink of a revolution in cardiac research, one in which computational modeling of proteins, cells, tissues, and the organ permit linking genomic and proteomic information to the integrated organ behavior, in the quest for a quantitative understanding of the functioning of the heart in health and disease. The goal of this review is to assess the existing state-of-the-art in whole-heart modeling and the plethora of its applications in cardiac research. General whole-heart modeling approaches are presented, and the applications of whole-heart models in cardiac electrophysiology and electromechanics research are reviewed. The article showcases the contributions that whole-heart modeling and simulation have made to our understanding of the functioning of the heart. A summary of the future developments envisioned for the field of cardiac simulation and modeling is also presented. Biophysically based computational modeling of the heart, applied to human heart physiology and the diagnosis and treatment of cardiac disease, has the potential to dramatically change 21st century cardiac research and the field of cardiology.
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Project description:We describe a sequence of methods to produce a partial differential equation model of the electrical activation of the ventricles. In our framework, we incorporate the anatomy and cardiac microstructure obtained from magnetic resonance imaging and diffusion tensor imaging of a New Zealand White rabbit, the Purkinje structure and the Purkinje-muscle junctions, and an electrophysiologically accurate model of the ventricular myocytes and tissue, which includes transmural and apex-to-base gradients of action potential characteristics. We solve the electrophysiology governing equations using the finite element method and compute both a 6-lead precordial electrocardiogram (ECG) and the activation wavefronts over time. We are particularly concerned with the validation of the various methods used in our model and, in this regard, propose a series of validation criteria that we consider essential. These include producing a physiologically accurate ECG, a correct ventricular activation sequence, and the inducibility of ventricular fibrillation. Among other components, we conclude that a Purkinje geometry with a high density of Purkinje muscle junctions covering the right and left ventricular endocardial surfaces as well as transmural and apex-to-base gradients in action potential characteristics are necessary to produce ECGs and time activation plots that agree with physiological observations.
| S-EPMC4262432 | biostudies-literature
Project description:The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross-species study using small and large animals, we comprehensively tested the agreement and validity of multiple single-beat surrogate metrics of LV contractility against the field-standard metrics derived from inferior vena cava occlusion (IVCO). Fifty-six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single-beat metrics of LV contractility. All single-beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load-independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single-beat metrics, only LV maximal pressure normalized to end-diastolic volume (EDV), end-systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate-to-excellent agreement with their IVCO-derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large-animal models. Our findings demonstrate that single-beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small- and large-animal models KEY POINTS: Validating and comparing indices of cardiac contractility that avoid caval occlusion would offer considerable advantages for the field of cardiovascular physiology. We comprehensively test the underlying assumptions of multiple single-beat indices of cardiac contractility in rodents and translate these findings to pigs and conscious dogs. We show that when performing caval occlusion is unfeasible, single-beat metrics can be utilized to accurately quantify cardiac inotropic function in basic and preclinical research employing various small and large animal species. We report that maximal left-ventricular (LV)-pressure normalized to end-diastolic volume (EDV), LV end-systolic pressure normalized to EDV and the maximal rate of rise of the LV pressure waveform normalized to EDV are the best three single-beat metrics to measure cardiac inotropic function in both small- and large-animal models.
| S-EPMC9669232 | biostudies-literature
Project description:Sheep are routinely used in experimental cardiac electrophysiology and surgery.The purpose of this study was to (1) ascertain the topography and architecture of the ovine epicardial neural plexus (ENP), (2) determine the relationships of ENP with vagal and sympathetic cardiac nerves and ganglia, and (3) evaluate gross anatomic differences and similarities of ENP in humans, sheep, and other species.Ovine ENP and extrinsic sympathetic and vagal nerves were stained histochemically for acetylcholinesterase in whole heart and/or thorax-dissected preparations from 23 newborn lambs, with subsequent examination by stereomicroscope.Intrinsic cardiac nerves extend from the venous part of the ovine heart hilum along the roots of the cranial (superior) caval and left azygos veins to both atria and ventricles via five epicardial routes: dorsal right atrial, middle dorsal, left dorsal, right ventral, and ventral left atrial nerve subplexuses. Intrinsic nerves proceeding from the arterial part of the heart hilum along the roots of the aorta and pulmonary trunk extend exclusively into the ventricles as the right and left coronary subplexuses. The dorsal right atrial, right ventral, and middle dorsal subplexuses receive the main extrinsic neural input from the right cervicothoracic and right thoracic sympathetic T(2) and T(3) ganglia as well as from the right vagal nerve. The left dorsal is supplied by sizeable extrinsic nerves from the left thoracic T(4)-T(6) sympathetic ganglia and the left vagal nerve. Sheep hearts contained an average of 769 +/- 52 epicardial ganglia. Cumulative areas of epicardial ganglia on the root of the cranial vena cava and on the wall of the coronary sinus were the largest of all regions (P <.05).Despite substantial interindividual variability in the morphology of ovine ENP, right-sided epicardial neural subplexuses supplying the sinoatrial and atrioventricular nodes are mostly concentrated at a fat pad between the right pulmonary veins and the cranial vena cava. This finding is in sharp contrast with a solely left lateral neural input to the human atrioventricular node, which extends mainly from the left dorsal and middle dorsal subplexuses. The abundance of epicardial ganglia distributed widely along the ovine ventricular nerves over respectable distances below the coronary groove implies a distinctive neural control of the ventricles in human and sheep hearts.
| S-EPMC3025183 | biostudies-literature
Project description:The traditional cardiac model-building paradigm involves constructing a composite model using data collected from many cells. Equations are derived for each relevant cellular component (e.g., ion channel, exchanger) independently. After the equations for all components are combined to form the composite model, a subset of parameters is tuned, often arbitrarily and by hand, until the model output matches a target objective, such as an action potential. Unfortunately, such models often fail to accurately simulate behavior that is dynamically dissimilar (e.g., arrhythmia) to the simple target objective to which the model was fit. In this study, we develop a new approach in which data are collected via a series of complex electrophysiology protocols from single cardiac myocytes and then used to tune model parameters via a parallel fitting method known as a genetic algorithm (GA). The dynamical complexity of the electrophysiological data, which can only be fit by an automated method such as a GA, leads to more accurately parameterized models that can simulate rich cardiac dynamics. The feasibility of the method is first validated computationally, after which it is used to develop models of isolated guinea pig ventricular myocytes that simulate the electrophysiological dynamics significantly better than does a standard guinea pig model. In addition to improving model fidelity generally, this approach can be used to generate a cell-specific model. By so doing, the approach may be useful in applications ranging from studying the implications of cell-to-cell variability to the prediction of intersubject differences in response to pharmacological treatment.
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Project description:A mouse mutation (p100H/p100H) has been identified that is associated with cardioskeletal myopathy, heart block, delayed growth and early postnatal death. The gene that is disrupted in this mutation encodes the transcription factor Sox6. P19CL6 cells were used as an in vitro cardiomyocyte differentiation system and revealed that Sox6 is expressed exclusively when the cells are committed to differentiate to beating cardiac myocytes. We used the yeast two-hybrid system to identify the Prtb (Proline-rich transcript of the brain) protein as a Sox6 interactor, and subsequently confirmed the interaction by co-immunoprecipitation. Prtb expression in P19CL6 cells increased with differentiation to beating cardiomyocytes. Using the P19CL6 cells stably transfected with noggin, an antagonist of BMP (Bone Morphogenic Protein), we found that BMP expression is required for Sox6 expression in cardiomyocyte differentiation. Surprisingly, the expression of the alpha1c-subunit gene of the L-type Ca2+ channel decreased in P19CL6 cells as they differentiated to beating cardiac cells. Ectopic expression of Sox6 or Prtb alone in P19CL6 cells caused down-regulation of L-type Ca2+ alpha1c expression, but when Sox6 and Prtb were co-transfected to the cells, L-type Ca2+ alpha1c remained at basal levels. A similar relationship of Sox6 and L-type Ca2+ alpha1c expression was seen in vivo (comparing wild-type and p(100H)/p(100H) mutant mice). Thus, Sox6 is within the BMP pathway in cardiac differentiation, interacts with Prtb and may play a critical role in the regulation of a cardiac L-type Ca2+ channel.
| S-EPMC219484 | biostudies-literature
Project description:Local signaling domains and numerous interacting molecular pathways and substrates contribute to the whole-cell response of myocytes during ?-adrenergic stimulation (?ARS). We aimed to elucidate the quantitative contribution of substrates and their local signaling environments during ?ARS to the canine epicardial ventricular myocyte electrophysiology and calcium transient (CaT). We present a computational compartmental model of ?ARS and its electrophysiological effects. Novel aspects of the model include localized signaling domains, incorporation of ?1 and ?2 receptor isoforms, a detailed population-based approach to integrate the ?AR and Ca(2+)/Calmodulin kinase (CaMKII) signaling pathways and their effects on a wide range of substrates that affect whole-cell electrophysiology and CaT. The model identifies major roles for phosphodiesterases, adenylyl cyclases, PKA and restricted diffusion in the control of local cAMP levels and shows that activation of specific cAMP domains by different receptor isoforms allows for specific control of action potential and CaT properties. In addition, the model predicts increased CaMKII activity during ?ARS due to rate-dependent accumulation and increased Ca(2+) cycling. CaMKII inhibition, reduced compartmentation, and selective blockade of ?1AR is predicted to reduce the occurrence of delayed afterdepolarizations during ?ARS. Finally, the relative contribution of each PKA substrate to whole-cell electrophysiology is quantified by comparing simulations with and without phosphorylation of each target. In conclusion, this model enhances our understanding of localized ?AR signaling and its whole-cell effects in ventricular myocytes by incorporating receptor isoforms, multiple pathways and a detailed representation of multiple-target phosphorylation; it provides a basis for further studies of ?ARS under pathological conditions.
| S-EPMC3075371 | biostudies-literature
Project description:RationaleFatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown.ObjectiveTo determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara.Methods and resultsWe discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation, and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels.ConclusionsCardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.
| S-EPMC4886555 | biostudies-literature