CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia

Pasquale, Elisa Di; Lodola, Francesco; Miragoli, Michele; Denegri, Marco; Avelino-Cruz, José Everardo; Buonocore, Michelangelo; Nakahama, Hiroko; Portararo, Paola; Bloise, Raffaella; Napolitano, Carlo; Condorelli, Gianluigi; Priori, Silvia G.

doi:10.1038/cddis.2013.369

Cited by 110 publications

(90 citation statements)

References 43 publications

(65 reference statements)

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“…In addition, hiPSC‐CMs are also being used as model systems to test the effect of both known and novel drugs on cardiac channelopathies (Matsa et al , 2011; Zhang et al , 2012; Bellin et al , 2013; Di Pasquale et al , 2013; Zhang et al , 2014), with suppression of pathological pro‐arrhythmic potential and restoration of altered AP duration (APD) being two main endpoints. Clinical evidence has shown that pharmacological treatments can be of more benefit when properly calibrated in a disease‐specific or even mutation‐specific manner (Nebert and Vesell, 2006; Cavallari, 2012; Amin and Wilde, 2016; Itoh et al , 2016; Martiniano et al , 2016).…”

Section: Cardiotoxicity Screening Methodologiesmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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Cardiotoxicity is a severe side effect of drugs that induce structural or electrophysiological changes in heart muscle cells. As a result, the heart undergoes failure and potentially lethal arrhythmias. It is still a major reason for drug failure in preclinical and clinical phases of drug discovery. Current methods for predicting cardiotoxicity are based on guidelines that combine electrophysiological analysis of cell lines expressing ion channels ectopically in vitro with animal models and clinical trials. Although no new cases of drugs linked to lethal arrhythmias have been reported since the introduction of these guidelines in 2005, their limited predictive power likely means that potentially valuable drugs may not reach clinical practice. Human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) are now emerging as potentially more predictive alternatives, particularly for the early phases of preclinical research. However, these cells are phenotypically immature and culture and assay methods not standardized, which could be a hurdle to the development of predictive computational models and their implementation into the drug discovery pipeline, in contrast to the ambitions of the comprehensive pro‐arrhythmia in vitro assay (CiPA) initiative. Here, we review present and future preclinical cardiotoxicity screening and suggest possible hPSC‐CM‐based strategies that may help to move the field forward. Coordinated efforts by basic scientists, companies and hPSC banks to standardize experimental conditions for generating reliable and reproducible safety indices will be helpful not only for cardiotoxicity prediction but also for precision medicine.Linked ArticlesThis article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.21/issuetoc

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Section: Cardiotoxicity Screening Methodologiesmentioning

confidence: 99%

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Sala

Bellin

Mummery

2016

British J Pharmacology

107

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“…Interestingly, at the ultrastructural level, these symptoms were associated with alterations to various components of the intracellular energetic unit, including intercalated disk and microtubules. In addition, hiPSC-derived cardiomyocytes carrying mutations to ryanodine receptors (RyR2) calcium/calmodulin-dependent protein kinase II (CaMKII) and calsequestrin (CLSQ) displayed calcium oversensitization, the hallmark of catecholaminergic polymorphic ventricular tachycardia (CPVT) [181–183]. Specifically, abnormalities in whole-cell calcium transients were observed, including proarrhythmic early/after depolarization events [181].…”

Section: Human Diseases-on-chips and The Intracellular Energetic Umentioning

confidence: 99%

Mechanotransduction and Metabolism in Cardiomyocyte Microdomains

Pasqualini

Nesmith

Horton

et al. 2016

BioMed Research International

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Efficient contractions of the left ventricle are ensured by the continuous transfer of adenosine triphosphate (ATP) from energy production sites, the mitochondria, to energy utilization sites, such as ionic pumps and the force-generating sarcomeres. To minimize the impact of intracellular ATP trafficking, sarcomeres and mitochondria are closely packed together and in proximity with other ultrastructures involved in excitation-contraction coupling, such as t-tubules and sarcoplasmic reticulum junctions. This complex microdomain has been referred to as the intracellular energetic unit. Here, we review the literature in support of the notion that cardiac homeostasis and disease are emergent properties of the hierarchical organization of these units. Specifically, we will focus on pathological alterations of this microdomain that result in cardiac diseases through energy imbalance and posttranslational modifications of the cytoskeletal proteins involved in mechanosensing and transduction.

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“…12% of the cells also developed DADs even when paced at low frequencies of 0.5Hz, and the DAD frequencies increased significantly after β-adrenergic stimulation. Interestingly, CaMKII inhibitor KN-93 stabilized the Ca 2+ activity and suppressed isoproterenol-induced DAD in this model [65]. The P2328S CPVT1 causing mutation cell-line [43] also displays aberrant Ca 2+ cycling, decreased Ca 2+ content, and a fractional Ca 2+ release that was significantly higher both in control and isoproterenol-treated myocytes.…”

Section: Ca2+ Signaling Profiles Of Catecholaminergic Polymorphic mentioning

confidence: 99%

Calcium signaling in human stem cell-derived cardiomyocytes: Evidence from normal subjects and CPVT afflicted patients

Zhang

Morad

2016

Cell Calcium

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Derivation of cardiomyocyte cell lines from human fibroblasts (induced pluripotent stem cells, iPSCs) has made it possible not only to investigate the electrophysiological and Ca2+ signaling properties of these cells, but also to determine the altered electrophysiological and Ca2+-signaling profiles of such cells lines derived from patients expressing mutation-inducing pathologies. This approach has the potential of generating in vitro human models of cardiovascular diseases where cellular pathology can be investigated in detail and possibly specific pharmacotherapy developed. Although this approach has been applied to a number of mutations in channel proteins that cause arrhythmias, there are only few detailed reports addressing Ca2+ signaling pathologies beyond measurements of Ca2+ transients in intact non-voltage clamped cells. Unfortunately full understanding of Ca2+ signaling pathologies remains elusive, not only because of the plethora of Ca2+ signaling proteins defects that cause arrhythmias and cardiomyopathies, but also because detailed functional properties of Ca2+ signaling proteins are difficult to obtain. Catecholaminergic polymorphic ventricular tachycardia (CPVT1) is a malignant inherited arrhythmogenic disorder predominantly caused by mutations in the cardiac ryanodine receptor (RyR2). Thus far over 150 mutations in RyR2 have been identified that appear to cause this arrhythmia, a number of which have been expressed and studied in transgenic mice or cell-line models. The development of human iPSC-technology makes it possible to create human heart cell-lines carrying these mutations, making detailed identification of Ca2+ signaling defects and its specific pharmacotherapy possible. In this review we shall first briefly summarize the essential characteristics of the mammalian cardiac Ca2+ signaling, then compare them to Ca2+ signaling phenotypes of human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) and to those of rat neonatal cardiomyocytes, and categorize the possible variance in Ca2+ signaling defects caused by different CPVT-inducing mutations as expressed in hiPSC-CMs.

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CaMKII inhibition rectifies arrhythmic phenotype in a patient-specific model of catecholaminergic polymorphic ventricular tachycardia

Cited by 110 publications

References 43 publications

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come?

Mechanotransduction and Metabolism in Cardiomyocyte Microdomains

Calcium signaling in human stem cell-derived cardiomyocytes: Evidence from normal subjects and CPVT afflicted patients

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