New approaches to predicting the risk of sudden death

Behr, Elijah R.; Ensam, Bode

doi:10.7861/clinmedicine.16-3-283

Cited by 9 publications

(3 citation statements)

References 60 publications

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“…Risk stratification strategies have been primarily adult based and those specific to the young have been limited to specific disease populations, retrospective, small cohort studies and should be applied cautiously 128 . Multicentre registry studies with thorough phenotyping are required to better determine risk factors of SCA and accurately direct medical management and ICD therapy 131 .…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Sudden Cardiac Arrest in the Paediatric Population

Franciosi

Abrams

Ingles

et al. 2022

CJC Pediatric and Congenital Heart Disease

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Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Sudden Cardiac Arrest in the Paediatric Population

Franciosi

Abrams

Ingles

et al. 2022

CJC Pediatric and Congenital Heart Disease

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“…Even two seemingly healthy cardiomyocytes can differ in their robustness against arrhythmia when under the influence of a perturbation (Weiss et al, 2012; Ballouz et al, 2021; Miller et al, 2023). Unfortunately, a mechanistic understanding of repolarization abnormality development, and improvement of pharmacological mitigation strategies, is complicated by the many different ion-channel conductance profiles that can define a cardiomyocyte (Behr and Ensam, 2016). Therefore, defining the conductance values of key ion-channels, or quantifying a unique ion-channel conductance profile for each cell, can allow for a better understanding of the different degrees of robustness between cells.…”

Section: Introductionmentioning

confidence: 99%

Optimization of a Cardiomyocyte Model Illuminates Role of Increased I_NaLin Repolarization Reserve

Fullerton,

Clark,

Krogh-Madsen

et al. 2023

Preprint

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Cardiac ion currents may compensate for each other when one is compromised by a congenital or drug-induced defect. Such redundancy contributes to a robust repolarization reserve that can prevent the development of lethal arrhythmias. Most efforts made to describe this phenomenon have quantified contributions by individual ion currents. However, it is important to understand the interplay between all major ion channel conductances, as repolarization reserve is dependent on the balance between all ion currents in a cardiomyocyte. Here, a genetic algorithm was designed to derive a profile of nine ion-channel conductances that optimizes repolarization reserve in a mathematical cardiomyocyte model. Repolarization reserve was quantified using a previously defined metric, repolarization reserve current, i.e., the minimum constant current to prevent normal action potential repolarization in a cell. The optimization improved repolarization reserve current by 77 % compared to baseline in a human adult ventricular myocyte model and increased resistance to arrhythmogenic insult. The optimized conductance profile was characterized by increased repolarizing current conductances, but also uncovered a previously un-reported behavior by the late sodium current. Simulations demonstrated that upregulated late sodium increased action potential duration, without compromising repolarization reserve current. The finding was generalized to multiple models. Ultimately, this computational approach in which multiple currents were studied simultaneously illuminated mechanistic insights into how the metric’s magnitude could be increased, and allowed for the unexpected role of late sodium to be elucidated.NEW & NOTEWORTHYGenetic algorithms are typically used to fit models or extract desired parameters from data. Here, we utilize the tool to produce a ventricular cardiomyocyte model with increased repolarization reserve. Since arrhythmia mitigation is dependent on multiple cardiac ion-channel conductances, study using a comprehensive, unbiased, and systems-level approach is important. This use of this optimization strategy allowed us to find a robust profile that illuminated unexpected mechanistic determinants of key ion-channel conductances in repolarization reserve.

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“…For more than 20 years, researchers have proposed various “indicators” for SCD due to their association with cardiac ischemic disease. Among them are non-invasive SCD risk indicators, which might prove helpful in cases of myocardial ischemia [20]. On the other hand, in spite of the encouraging early studies, none of these “prediction parameters” changed in the real world our daily clinical management of patients.…”

Section: Introductionmentioning

confidence: 99%

New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure—Targeting the Sympathetic Nervous System

Kiuchi

Nolde

Villacorta

et al. 2019

IJMS

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Cardiovascular diseases (CVDs) have been considered the most predominant cause of death and one of the most critical public health issues worldwide. In the past two decades, cardiovascular (CV) mortality has declined in high-income countries owing to preventive measures that resulted in the reduced burden of coronary artery disease (CAD) and heart failure (HF). In spite of these promising results, CVDs are responsible for ~17 million deaths per year globally with ~25% of these attributable to sudden cardiac death (SCD). Pre-clinical data demonstrated that renal denervation (RDN) decreases sympathetic activation as evaluated by decreased renal catecholamine concentrations. RDN is successful in reducing ventricular arrhythmias (VAs) triggering and its outcome was not found inferior to metoprolol in rat myocardial infarction model. Registry clinical data also suggest an advantageous effect of RDN to prevent VAs in HF patients and electrical storm. An in-depth investigation of how RDN, a minimally invasive and safe method, reduces the burden of HF is urgently needed. Myocardial systolic dysfunction is correlated to neuro-hormonal overactivity as a compensatory mechanism to keep cardiac output in the face of declining cardiac function. Sympathetic nervous system (SNS) overactivity is supported by a rise in plasma noradrenaline (NA) and adrenaline levels, raised central sympathetic outflow, and increased organ-specific spillover of NA into plasma. Cardiac NA spillover in untreated HF individuals can reach ~50-fold higher levels compared to those of healthy individuals under maximal exercise conditions. Increased sympathetic outflow to the renal vascular bed can contribute to the anomalies of renal function commonly associated with HF and feed into a vicious cycle of elevated BP, the progression of renal disease and worsening HF. Increased sympathetic activity, amongst other factors, contribute to the progress of cardiac arrhythmias, which can lead to SCD due to sustained ventricular tachycardia. Targeted therapies to avoid these detrimental consequences comprise antiarrhythmic drugs, surgical resection, endocardial catheter ablation and use of the implantable electronic cardiac devices. Analogous NA agents have been reported for single photon-emission-computed-tomography (SPECT) scans usage, specially the 123I-metaiodobenzylguanidine (123I-MIBG). Currently, HF prognosis assessment has been improved by this tool. Nevertheless, this radiotracer is costly, which makes the use of this diagnostic method limited. Comparatively, positron-emission-tomography (PET) overshadows SPECT imaging, because of its increased spatial definition and broader reckonable methodologies. Numerous ANS radiotracers have been created for cardiac PET imaging. However, so far, [11C]-meta-hydroxyephedrine (HED) has been the most significant PET radiotracer used in the clinical scenario. Growing data has shown the usefulness of [11C]-HED in important clinical situations, such as predicting lethal arrhythmias, SCD, and all-cause of mortality in reduced ejection fraction HF patients. In this article, we discussed the role and relevance of novel tools targeting the SNS, such as the [11C]-HED PET cardiac imaging and RDN to manage patients under of SCD risk.

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New approaches to predicting the risk of sudden death

Cited by 9 publications

References 60 publications

Sudden Cardiac Arrest in the Paediatric Population

Sudden Cardiac Arrest in the Paediatric Population

Optimization of a Cardiomyocyte Model Illuminates Role of Increased I_NaLin Repolarization Reserve

New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure—Targeting the Sympathetic Nervous System

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New approaches to predicting the risk of sudden death

Cited by 9 publications

References 60 publications

Sudden Cardiac Arrest in the Paediatric Population

Sudden Cardiac Arrest in the Paediatric Population

Optimization of a Cardiomyocyte Model Illuminates Role of Increased INaLin Repolarization Reserve

New Approaches in the Management of Sudden Cardiac Death in Patients with Heart Failure—Targeting the Sympathetic Nervous System

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Optimization of a Cardiomyocyte Model Illuminates Role of Increased I_NaLin Repolarization Reserve