**3. Future speculations on the approach to channelopathy**

The explosive medical informatics that we have obtained as human species about SCD in the last three decades are landmarks in human history. In addition to continuation of the gracious efforts in the arena of cardiovascular genetics, epigenetics and molecular genetics, it is always advisable to dive more into the microperspective, as well as macroperspective. It is a way of interpreting facts with the true spectrum of the creature and biology from genes to galaxies. This is a visionary way of thinking that we and our team adopted since 2006 in the King of Organs series for advanced cardiac sciences conferences (2006, 2008, 2010, 2012 and 2019). Channelopathy and its related experimental research especially exploring the secrets of SCD are creating an ideal example of scientific incorporation of this new visionary understanding. Induced pluripotent stem cell–derived cardiomyocytes provide a new platform for studying arrhythmic disorders leading to sudden cardiac death. Cellular transfection models, which are the most commonly used cellular models, are able to mimic the expression of a single-ion channel. Both are amenable for the weak electromagnetic currents that are in common between genes and cosmos.

## **3.1 Future speculations in the genetic arena**

Tremendous progress has been made in the discovery of putative mutations and genes responsible for different channelopathies. In the way of advances to scrutinize the pathogenic mutations comes the growing number of variants of unknown significance (VUS). It is an allele, or variant form of a gene, that has been identified through genetic testing but whose significance to the function or health of an organism is not identified. Researchers continue to work on better understanding how to stratify the risk of life-threatening arrhythmia based on the genotype and phenotype of the individual. Giustetto and his colleagues reported finding on a study of 53 patients from the European Short QT Registry. They found that A familial or personal history of cardiac arrest was present in 89%. Sudden death was the clinical presentation in 32%. The average QTc was 314 ± 23 ms. A mutation in genes related to SQTS was found in 23% of the probands; most of them had a gain of function mutation in HERG (SQTS1). Almost 43(45%) of patients received an implantable cardioverter defibrillator, and 12(23%) patients received long-term prophylaxis with hydroquinidine. Patients with a HERG mutation had shorter QTc at baseline and a greater QTc prolongation after treatment with HQ. During follow-up, 2(4%) already symptomatic patients received appropriate implantable cardioverter defibrillator shocks and 1(2%) had syncope. The event rate was 4.9% per year in the patients without antiarrhythmic therapy. No arrhythmic events

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drug toxicity are unique.

*Inherited Ventricular Arrhythmias, the Channelopathies and SCD: Current Knowledge…*

arrhythmic events and to ultimately obviate the need for ICD implants.

**3.2 Decoding the channelopathies' mysteries using induced pluripotent stem** 

The available platforms, shaping the future, to develop and investigate pharmaceutical therapeutic mechanisms for successful channelopathies treatment can be classified into different levels. First is at the organism level including clinical as well as animal models. Second is at the tissue and organ level (Purkinje fibers). Third is at cellular and molecular level (cardiac ions, induced pluripotent stem cells) [82]. Since the first report in 2006, bench researchers have made use of "induced pluripotent stem cell" (iPS) systems to study the electrophysiological and pharmacological characteristics of cardiomyocyte cells that are specific to an individual patient and his/her mutation and channelopathy. This technology has huge potential to promote our understanding of individual channelopathies and further steer the management of channelopathies in an individualistic, genotype-specific manner in the future [83, 84]. It provides a robust platform to advance the science and clinical care of sudden cardiac death. Major ion channels of the human heart are expressed in the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM). The iPSC-CMs are created by somatic cells reprogramming into pluripotent stem cells using viral transduction or non-viral transfection or soluble proteins to introduce transcriptional factors to the somatic cell [85]. The resulting induced pluripotent stem cell can be differentiated specifically to induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) [86]. The iPSC-CMs can express encoded genes of the heart that might be absent in the original donor somatic cell. An ion channel disease can be expressed and recapitulated electrophysiologically so clinical diagnosis can be identified as well as genetic screening in the family. Variant of uncertain significance (VUS) can be developed where electrophysiological testing can be examined in the produced iPSC-CMs. Then comparison to the index case can be done. As the case in genetic testing, iPSC-CM may miss identifying the arrhythmia. In this situation, we will rely on clinical evaluation and family screening. Induced pluripotent stem of human cardiomyocyte (iPSC-CM) is superior to animal models or heterologous transfection models for channelopathies research (**Figure 1**) [87]. Its capabilities to create specific therapeutic options and its abilities to define disease-specific

This level of research is expected to illuminate our understanding of the true

pathophysiology of channelopathies and their targeted therapies.

occurred in patients receiving HQ [77]. The delta T50 is a measure of the variability of ventricular repolarization (at 50% of the T-wave downslope). It has been used to identify patients with LQTS in combination with QT interval cutoffs, as well as to identify patients at higher risk for cardiac events [78]. Rest and exercise QT interval measurements have been used to create a validated algorithm for diagnosing LQTS [79]. End-recovery QT interval measurements have also been used and, in combination with clinical history and mutation-specific information, can aid in understanding the pathogenicity of VUS [80]. Copy number variations (CNV) are a form of genetic abnormality that may explain the genetic basis of channelopathies in cases where there is no identifiable point mutation [81]. It is conceivable that in the future CNV may be added to genetic screens. Despite our increasingly sophisticated knowledge of the underlying pathophysiology, novel medical therapies tailored specifically for these syndromes have yet emerged in the clinical setting. Novel forms of treatment that specifically address the aberrant molecular pathophysiology defining these conditions will be our immediate priority step in order to effectively suppress

*DOI: http://dx.doi.org/10.5772/intechopen.92131*

**cell-derived cardiomyocyte research**

#### *Inherited Ventricular Arrhythmias, the Channelopathies and SCD: Current Knowledge… DOI: http://dx.doi.org/10.5772/intechopen.92131*

occurred in patients receiving HQ [77]. The delta T50 is a measure of the variability of ventricular repolarization (at 50% of the T-wave downslope). It has been used to identify patients with LQTS in combination with QT interval cutoffs, as well as to identify patients at higher risk for cardiac events [78]. Rest and exercise QT interval measurements have been used to create a validated algorithm for diagnosing LQTS [79]. End-recovery QT interval measurements have also been used and, in combination with clinical history and mutation-specific information, can aid in understanding the pathogenicity of VUS [80]. Copy number variations (CNV) are a form of genetic abnormality that may explain the genetic basis of channelopathies in cases where there is no identifiable point mutation [81]. It is conceivable that in the future CNV may be added to genetic screens. Despite our increasingly sophisticated knowledge of the underlying pathophysiology, novel medical therapies tailored specifically for these syndromes have yet emerged in the clinical setting. Novel forms of treatment that specifically address the aberrant molecular pathophysiology defining these conditions will be our immediate priority step in order to effectively suppress arrhythmic events and to ultimately obviate the need for ICD implants.
