**3.2 Decoding the channelopathies' mysteries using induced pluripotent stem cell-derived cardiomyocyte research**

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 drug toxicity are unique.

This level of research is expected to illuminate our understanding of the true pathophysiology of channelopathies and their targeted therapies.

*Sudden Cardiac Death*

might be used.

cosmos.

**dysfunction (SND) management plan**

**3.1 Future speculations in the genetic arena**

**2.6 Progressive cardiac conduction disease (PCCD) and inherited sinus node** 

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

Both PCCD and SND contain channelopathy elements and overlap with channelopathy syndromes in some cases. Until the research in genetic engineering and tissue engineering reaches to revolutionary solutions for those two conductions, device therapy with pacemakers and ICDs will be the standard management. ICD (which carries pacer capabilities) will be the choice in rare cases of the overlap nature with other tachyarrhythmias. In this condition, hybrid pharmaceutical agent

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

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

**120**

#### **Figure 1.**

*Potential role for iPSC-CMs in the evaluation of patients with known or at risk for arrhythmic disorders. Clinical genetic testing attempts to identify a rare variant in genes commonly associated with arrhythmic disorders. (illustration credit: Ben smith) [87].*

#### **3.3 Fine-tuning the sympathovagal balance**

Since the early 1990s, ICD have become a standard therapeutic option for VT/ VF in channelopathy subjects and in most of the times the first therapeutic choice to defibrillate the fatal rhythms. As time passed, we gained the knowledge of how to fine-tune our ICD subjects to minimize or abolish shocks without using medications as much as possible. Despite the effectiveness of the ICD in preventing sudden death, anxiety, depression and post-traumatic stress disorder (PTSD) plays a contributing role in the high 1-year mortality rate observed after ICD implantation. ICD patients are at higher risk of having arrhythmias and therefore of receiving shocks, because of their fear of receiving shocks. Negative emotions lead to an increased incidence of disorders in heart rhythms and in the autonomic nervous system functioning. On the other hand, the positive psychophysiological state, called heart coherence, is associated with high performance, stress reduction and greater emotional stability, and less arrhythmic events. Heart rate variability (HRV) is considered a measure of neurocardiac function that reflects heart-brain interactions and autonomic nervous system (ANS) dynamics. HRV pattern with cardiac coherence (CC) is seen as sine wave highly regular pattern compared to the chaotic pattern seen with anger, frustration and other negative emotions. The HeartMath Institute (California, Boulder Creek) developed a heart rhythm monitoring and feedback system that enables physiological coherence to be objectively monitored and quantified.

Training ICD patients' to self-regulate emotions can produce broad improvements in increasing or strengthening self-regulatory capacity, making them less vulnerable to depletions and fear of and consequently less rhythmic events. Resilience is defined by the HeartMath researchers as the capacity to prepare for, recover from and adapt in the face of stress, adversity, trauma or challenge. It reflects the state of sympathovagal balance where the ion travel across the cellular membrane channels is in true physiological homeostasis. Teaching how to improve self-resilience is especially important for highly potential subjects for PTSD like ICD patients. In view of the role of the effects of negative emotions on induction

**123**

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

**3.4 Earth geomagnetic activity orchestrating autonomic nervous system,** 

New perspective is evident disclosing the scientific background of historical and philosophical dilemmas. The human heart rate variability as a measure of the autonomic nervous system (ANS) functions is in delicate resonance with planetary magnetic field. Statistically significant correlations have been established linking earth's magnetic activity to psychophysiological well-being including arrhythmias and sudden cardiac death. Different pathomechanisms are operating through which ANS induces the fatal heart rhythms. Andrew Armor, the pioneer of neurocardiology, elaborates in this direction as well as heart brain communications [90]. The state of cardiac coherence (CC) where HRV-dominant frequency peak is in the 0.04–0.26 Hz range and more peculiarly around 0.1 Hz carries the secrets of psychophysiological well-being and planetary resonance [91–93]. Daily autonomic nervous system activity not only responds to changes in solar and geomagnetic activity (SGMA), but it is also synchronized with the time-varying magnetic fields associated with geomagnetic field-line resonances and Schumann resonances [94, 95]. The great planetary frequency around 0.1 Hz acts also indirectly toward normal heart rhythm by reducing systemic blood pressure in hypertensive subjects [96, 97]. SCD and cerebral strokes and increase in emergency calls were linked to periods of geomagnetic disturbances (low level) and higher level of cosmic rays. This is suggesting biophysical cause effect relationship between cosmic rays and medical events of elderly humans [98, 99]. Daily autonomic nervous system activity not only responds to changes in solar and geomagnetic activity, but it is also synchronized with the time-varying magnetic fields associated with geomagnetic field-line resonances and

In this direction, the longest record of human heart activity synchronized to solar wind indices as well as Schumann resonances and the cosmic rays has been done by our group. A total of 97,000 hours of records were managed statistically. We have satisfying scientific evidence illustrating daily changes of the ANS in response to solar as well as geomagnetic activity. Those ANS responses are initiated after different times of the changes of the solar and planetary activities and when it occurs and it persists for varying times. Increasing heart rate was correlated to increase in solar wind intensity. This is explained as biological stress response of solar winds on human heart through sophisticated mechanisms. The rise of Schumann resonance power, solar radio flux and cosmic rays are all reflected in the increase of parasympathetic tone and HRV. The degree of effect of those energetic environmental stressors on human cardiovascular system affects different people differently depending on their health, sensitivity and self-regulation capabilities [101]. The scientific community in the field is active to establish the effect of SGMA on heart rhythm at cellular level. Laboratory findings demonstrate the effect of ion cyclotron mechanism on extracted myocardial cell regulation [102]. It seems that Schumann resonance is a major interlayer in the SGMA effect on ion channels and the ion transport in cardiac cells and accordingly in the susceptibility of channelopathic subjects to the fatal rhythms. The influence of extremely weak magnetic field in the Schumann resonances (ScR) on the creatine kinase (CK) release, calcium transients as well as spontaneous contractions of rat cardiac cell

of T-wave alternans (TWA) and repolarization instability and its relation to future ventricular arrhythmias in patients with ICDs, we postulate that teaching the importance of positive emotional states and building a heart coherent pattern are excellent life choices that can interrupt the negative emotion, fatal rhythm and

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

shock continuum for ICD patients [88, 89].

**arrhythmogenesis and SCD**

Schumann resonances [100].

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

of T-wave alternans (TWA) and repolarization instability and its relation to future ventricular arrhythmias in patients with ICDs, we postulate that teaching the importance of positive emotional states and building a heart coherent pattern are excellent life choices that can interrupt the negative emotion, fatal rhythm and shock continuum for ICD patients [88, 89].

#### **3.4 Earth geomagnetic activity orchestrating autonomic nervous system, arrhythmogenesis and SCD**

New perspective is evident disclosing the scientific background of historical and philosophical dilemmas. The human heart rate variability as a measure of the autonomic nervous system (ANS) functions is in delicate resonance with planetary magnetic field. Statistically significant correlations have been established linking earth's magnetic activity to psychophysiological well-being including arrhythmias and sudden cardiac death. Different pathomechanisms are operating through which ANS induces the fatal heart rhythms. Andrew Armor, the pioneer of neurocardiology, elaborates in this direction as well as heart brain communications [90]. The state of cardiac coherence (CC) where HRV-dominant frequency peak is in the 0.04–0.26 Hz range and more peculiarly around 0.1 Hz carries the secrets of psychophysiological well-being and planetary resonance [91–93]. Daily autonomic nervous system activity not only responds to changes in solar and geomagnetic activity (SGMA), but it is also synchronized with the time-varying magnetic fields associated with geomagnetic field-line resonances and Schumann resonances [94, 95]. The great planetary frequency around 0.1 Hz acts also indirectly toward normal heart rhythm by reducing systemic blood pressure in hypertensive subjects [96, 97]. SCD and cerebral strokes and increase in emergency calls were linked to periods of geomagnetic disturbances (low level) and higher level of cosmic rays. This is suggesting biophysical cause effect relationship between cosmic rays and medical events of elderly humans [98, 99]. Daily autonomic nervous system activity not only responds to changes in solar and geomagnetic activity, but it is also synchronized with the time-varying magnetic fields associated with geomagnetic field-line resonances and Schumann resonances [100].

In this direction, the longest record of human heart activity synchronized to solar wind indices as well as Schumann resonances and the cosmic rays has been done by our group. A total of 97,000 hours of records were managed statistically. We have satisfying scientific evidence illustrating daily changes of the ANS in response to solar as well as geomagnetic activity. Those ANS responses are initiated after different times of the changes of the solar and planetary activities and when it occurs and it persists for varying times. Increasing heart rate was correlated to increase in solar wind intensity. This is explained as biological stress response of solar winds on human heart through sophisticated mechanisms. The rise of Schumann resonance power, solar radio flux and cosmic rays are all reflected in the increase of parasympathetic tone and HRV. The degree of effect of those energetic environmental stressors on human cardiovascular system affects different people differently depending on their health, sensitivity and self-regulation capabilities [101]. The scientific community in the field is active to establish the effect of SGMA on heart rhythm at cellular level. Laboratory findings demonstrate the effect of ion cyclotron mechanism on extracted myocardial cell regulation [102]. It seems that Schumann resonance is a major interlayer in the SGMA effect on ion channels and the ion transport in cardiac cells and accordingly in the susceptibility of channelopathic subjects to the fatal rhythms. The influence of extremely weak magnetic field in the Schumann resonances (ScR) on the creatine kinase (CK) release, calcium transients as well as spontaneous contractions of rat cardiac cell

*Sudden Cardiac Death*

**Figure 1.**

**3.3 Fine-tuning the sympathovagal balance**

*disorders. (illustration credit: Ben smith) [87].*

cal coherence to be objectively monitored and quantified.

Since the early 1990s, ICD have become a standard therapeutic option for VT/ VF in channelopathy subjects and in most of the times the first therapeutic choice to defibrillate the fatal rhythms. As time passed, we gained the knowledge of how to fine-tune our ICD subjects to minimize or abolish shocks without using medications as much as possible. Despite the effectiveness of the ICD in preventing sudden death, anxiety, depression and post-traumatic stress disorder (PTSD) plays a contributing role in the high 1-year mortality rate observed after ICD implantation. ICD patients are at higher risk of having arrhythmias and therefore of receiving shocks, because of their fear of receiving shocks. Negative emotions lead to an increased incidence of disorders in heart rhythms and in the autonomic nervous system functioning. On the other hand, the positive psychophysiological state, called heart coherence, is associated with high performance, stress reduction and greater emotional stability, and less arrhythmic events. Heart rate variability (HRV) is considered a measure of neurocardiac function that reflects heart-brain interactions and autonomic nervous system (ANS) dynamics. HRV pattern with cardiac coherence (CC) is seen as sine wave highly regular pattern compared to the chaotic pattern seen with anger, frustration and other negative emotions. The HeartMath Institute (California, Boulder Creek) developed a heart rhythm monitoring and feedback system that enables physiologi-

*Potential role for iPSC-CMs in the evaluation of patients with known or at risk for arrhythmic disorders. Clinical genetic testing attempts to identify a rare variant in genes commonly associated with arrhythmic* 

Training ICD patients' to self-regulate emotions can produce broad improvements in increasing or strengthening self-regulatory capacity, making them less vulnerable to depletions and fear of and consequently less rhythmic events. Resilience is defined by the HeartMath researchers as the capacity to prepare for, recover from and adapt in the face of stress, adversity, trauma or challenge. It reflects the state of sympathovagal balance where the ion travel across the cellular membrane channels is in true physiological homeostasis. Teaching how to improve self-resilience is especially important for highly potential subjects for PTSD like ICD patients. In view of the role of the effects of negative emotions on induction

**122**

cultures was examined. The application of 7.8 Hz, magnetic field of 90 nT was associated with gradual reduction in the spontaneous Ca++ transient amplitude. After 40 minutes of magnetic field application, 28% of the initial amplitude was reached. This reduction was associated with the calcium transient time gradually reduced. The effect is frequency dependent. The described changes occurred only in the 7.6–8 Hz. The frequency of 7.8 Hz is frequency of both central nervous system and cardiovascular system. It is the basic frequency responsible for the resonance between us humans as well as the biology on one hand and the cosmic environment on the other hand. The application of 7.8 Hz, magnetic field of 90 nT for 90 minutes results in the reduction of creatine kinase (CK) release to the buffer. This result was obtained during normal conditions, hypoxic environment and use of 80 μM H2O2 to induce oxidative stress. It sees that the first range of ScR has an effect on cardiac cell characterized by CK release reduction as a stress response and this effect is of a protective effect [103]. Magnetic field dynamics could add to our future understanding of the SGMA interaction with human heart in health and disease. The known transmembrane pacemaker protein CHN4, present in both sinoatrial and AV nodal cells, could interact with field information to provide specificity in an electronic key-to-lock mechanism interaction [104]. It is conspicuous that the near future is carrying more details to disclose the true pathomechanism of how modulation of HRV with fluctuation of SGMA can trigger the fatal rhythms and sudden death. More intelligent preventive as well as therapeutic strategies will be then available.
