Homeostasis of physiological ionic calcium and calcium signal in the cardio- muscle cell and SA node

Cardiac beating arises from the spontaneous rhythmic excitation of SA node (sinoatrial node/atrioventricular node) cells. Here we report that SA node pacemaker activity is critically dependent on Ca2+/calmodulin-dependent protein kinase II. The human heart faithfully supplies blood to the body by beating more than 3 billion times in a lifetime. The SA node possesses automaticity and serves as the primary physiological pacemaker of the heart. The pacemaker action potential (AP) is initiated in a small group of primary pacemaker cells located in the center of the SA node and then propagates through transitional, peripheral regions to the atrial tissue. A number of ionic currents are involved in the SA node pacemaker activity, including delayed rectifier potassium currents (mainly the rapidly activated component, IKr), L- and T-type Ca2+ currents (ICa, L and ICa, T), hyperpolarization-activated cation current (If), and others. In primary SA node cells, ICa, L plays an obligatory role in the generation of rhythmic spontaneous APs, because ICa, L is an important source of inward current for the AP upstroke and diastolic depolarization.

Atrial Fibrillation (AF) is the most common arrhythmia resulting in 454,000 hospitalizations per year in the U.S. In the U.S. AF has an estimated incidence of 5.5 per 1,000 person-years with a significantly larger incidence in older age. Globally, the current prevalence of AF is estimated at 37.6 million, a 17% increase from 2007 estimates.3 and significantly increases the risk for myocardial infarction, heart failure, stroke and all-cause mortality. Data is limitedregarding the financial impacts of AF, however, costs in the U.S. are estimated at $6.5 billionin direct healthcare costs. Despite the existence of numerous medical therapies, recurrence is common, procedural interventions may be invasive, and therapeutic strategies may be associated with intolerable adverse effects limiting treatment adherence.

Given age is the strongest predictive factor for the development of AF, and although viewed as non-modifiable, recent investigations into the role of epigenetics has challenged this notionhighlighting differences between chronological and biological aging. Epigenetics, which describe the changes in gene expression due to external environmental factors (e.g., dietary habits, physical activity, smoking, etc.) without directly changing DNA code sequences, has been viewed as at least partially influential in the development and treatment of numerous diseases and mortality. The effect of one such epigenetic process, DNA methylation, entails the addition of a methyl group to CpG dinucleotide sites within the genome, directly up or down regulating gene expression and affecting downstream cellular structure and function. Several epigenetic DNA methylation age estimators (also known as “clocks”) have been developed to provide estimates of biological ageing and highly predictive of chronological age or predictive of phenotypic expression. The ability to identify age-related biomarkers and slow the rate of biological aging may confer public health benefits by reducing the risk ofage-related disease and mortality and improve overall quality of life.

Most recently, associations between epigenetic age measures and incident AF across three large cardiovascular cohort studies (n=5,600) have been evaluated using four separate epigenetic clocks.11 Of these four, the DNAm GrimAge and DNAm PhenoAge clocks were independently associated with incident AF per 5-year increment of epigenetic age
acceleration even after adjusting for chronological age, sex, race, smoking status, BMI, bloodpressure, anti-hypertensive medication use, history of congestive heart failure or myocardial infarction, and technical differences amongst epigenetic clocks. Although the causal relationship of the epigenetic modifications represented by these epigenetic clocks in the development of AF is still indeterminate, the utilization of epigenetic clocks can potentially serve as a prognostic indicator or risk modifier of AF.

Furthermore, dysregulation of DNA methylation more specifically has been identified in the pathogenesis and maintenance of a variety of AF subtypes. Notably, DNA methyltraferase (DNMT) such as DNMT-1 is implicated in calcium homeostasis via increasing or decreasing methylation status of sarcoplasmic reticulum Ca-ATPases which influences calcium availability within cardiac myocytes leading to changes in action potential currents. Similarly, DNTM-3A is involved in the development of cardiac fibrosis, a process in which impaired calcium signaling is also involved, impacting the remodeling of atrial tissue further promoting the persistence of atrial fibrillation.

Research- NUNM-CBHI

Evaluating changes in Epigenetic Methylation from Antiorbital Ionic Calcium in Adults with Atrial Fibrillation (AIC-AF)

1. Principal Investigators:
   a. Ryan Bradley ND, MPH, National University of Natural Medicine
2. Co-Investigators:
   a. Paul Lee, PhD, Calcium Bone Health Institute Canada (CBHI)
   b. Jamie Corroon, ND, MPH, National University of Natural Medicine
   c. Adam Sadowski, ND, MS, National University of Natural Medicine
3. Biostatistician: Jamie Corroon, ND, MPH, National University of Natural Medicine
4. Study Coordinator: Anders Gundersen, MS – National University of Natural Medicine