Treatment of calmodulinopathy with verapamil

Webster, Gregory; Schoppen, Zachary J.; George, Alfred L.

doi:10.1136/bcr-2017-220568

Cited by 8 publications

(9 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The field potential (FP) duration, measured with MEA, was rescued with acute exposure to verapamil, holding promise for a rapid implementation of this pharmacological approach in the clinical setting. This observation was immediately translated by Webster and coworkers in clinical practice and in a single calmodulinopathy patient (52) verapamil showed some promising results.…”

Section: Induced Pluripotent Stem Cell-derived Cardiomyocyte Platformmentioning

confidence: 81%

“…From the clinical data and descriptions available thus far in the literature, and from our own clinical experience (45), commonly used anti-arrhythmic therapies and procedures (i.e., left cardiac sympathetic denervation) largely fail to treat these young patients. Indeed, β blocker therapy- the mainstay treatment for LQTS and CPVT- seems to offer minimal benefit at controlling the life-threatening arrhythmias, while other antiarrhythmics, such as sodium channel blockers, have also not produced promising results (6, 52). Ca 2+ channel blockade may seem a rational therapeutic option since impaired CDI of the Ca 2+ channel Ca v 1.2 is the prominent underlying mechanism of LQTS related to CaM mutations (20, 49, 51).…”

Section: Calmodulinopathy Therapymentioning

confidence: 99%

“…Ca 2+ channel blockade may seem a rational therapeutic option since impaired CDI of the Ca 2+ channel Ca v 1.2 is the prominent underlying mechanism of LQTS related to CaM mutations (20, 49, 51). However, the Ca 2+ antagonist verapamil, despite some positive results in one case (52), largely fails to prevent cardiac event recurrences in other clinical cases (6, 45). This may be attributed to the fact that verapamil principally targets peak calcium current rather than modulating channel inactivation (52).…”

Section: Calmodulinopathy Therapymentioning

confidence: 99%

“…However, the Ca 2+ antagonist verapamil, despite some positive results in one case (52), largely fails to prevent cardiac event recurrences in other clinical cases (6, 45). This may be attributed to the fact that verapamil principally targets peak calcium current rather than modulating channel inactivation (52).…”

Section: Calmodulinopathy Therapymentioning

confidence: 99%

See 3 more Smart Citations

Calmodulinopathy: A Novel, Life-Threatening Clinical Entity Affecting the Young

Kotta

Sala

Ghidoni

et al. 2018

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Sudden cardiac death (SCD) in the young may often be the first manifestation of a genetic arrythmogenic disease that had remained undiagnosed. Despite the significant discoveries of the genetic bases of inherited arrhythmia syndromes, there remains a measurable fraction of cases where in-depth clinical and genetic investigations fail to identify the underlying SCD etiology. A few years ago, 2 cases of infants with recurrent cardiac arrest episodes, due to what appeared to be as a severe form of long QT syndrome (LQTS), came to our attention. These prompted a number of clinical and genetic research investigations that allowed us to identify a novel, closely associated to LQTS but nevertheless distinct, clinical entity that is now known as calmodulinopathy. Calmodulinopathy is a life-threatening arrhythmia syndrome, affecting mostly young individuals, caused by mutations in any of the 3 genes encoding calmodulin (CaM). Calmodulin is a ubiquitously expressed Ca2+ signaling protein that, in the heart, modulates several ion channels and participates in a plethora of cellular processes. We will hereby provide an overview of CaM's structure and function under normal and disease states, highlighting the genetic etiology of calmodulinopathy and the related disease mechanisms. We will also discuss the phenotypic spectrum of patients with calmodulinopathy and present state-of-the art approaches with patient-derived induced pluripotent stem cells that have been thus far adopted in order to accurately model calmodulinopathy in vitro, decipher disease mechanisms and identify novel therapies.

show abstract

Section: Induced Pluripotent Stem Cell-derived Cardiomyocyte Platformmentioning

confidence: 81%

Section: Calmodulinopathy Therapymentioning

confidence: 99%

Section: Calmodulinopathy Therapymentioning

confidence: 99%

Section: Calmodulinopathy Therapymentioning

confidence: 99%

See 2 more Smart Citations

Calmodulinopathy: A Novel, Life-Threatening Clinical Entity Affecting the Young

Kotta

Sala

Ghidoni

et al. 2018

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

“…A phenotypic rescue has been attempted in hiPSC-CMs through novel pharmacological or biotechnological strategies, with promising results that have already obtained preliminary translation to patients. [33,81,82,86]…”

Section: Long Qt Syndrome Type 14 and 15mentioning

confidence: 99%

Long QT Syndrome Modelling with Cardiomyocytes Derived from Human-induced Pluripotent Stem Cells

Sala

Gnecchi

Schwartz

2019

Arrhythm Electrophysiol Rev

View full text Add to dashboard Cite

Long QT syndrome (LQTS) is a potentially severe arrhythmogenic disorder, associated with a prolonged QT interval and sudden death, caused by mutations in key genes regulating cardiac electrophysiology. Current strategies to study LQTS in vitro include heterologous systems or animal models. Despite their value, the overwhelming power of genetic tools has exposed the many limitations of these technologies. In 2010, human-induced pluripotent stem cells (hiPSCs) revolutionised the field and allowed scientists to study in vitro some of the disease traits of LQTS on hiPSC-derived cardiomyocytes (hiPSC-CMs) from LQTS patients. In this concise review we present how the hiPSC technology has been used to model three main forms of LQTS and the severe form of LQTS associated with mutations in calmodulin. We also introduce some of the most recent challenges that must be tackled in the upcoming years to successfully shift hiPSC-CMs from powerful in vitro disease modelling tools into assets to improve risk stratification and clinical decision-making.

show abstract