scholarly journals Circadian Mechanisms: Cardiac Ion Channel Remodeling and Arrhythmias

2021 ◽  
Vol 11 ◽  
Author(s):  
Joyce Bernardi ◽  
Kelly A. Aromolaran ◽  
Hua Zhu ◽  
Ademuyiwa S. Aromolaran
Keyword(s):  
Heart Failure ◽  
Circadian Rhythms ◽  
Molecular Mechanisms ◽  
Normal Sinus Rhythm ◽  
Critical Role ◽  
The United States ◽  
Therapeutic Interventions ◽  
Cellular Mechanisms ◽  
Normal Sinus ◽  
Obesity And Diabetes

Circadian rhythms are involved in many physiological and pathological processes in different tissues, including the heart. Circadian rhythms play a critical role in adverse cardiac function with implications for heart failure and sudden cardiac death, highlighting a significant contribution of circadian mechanisms to normal sinus rhythm in health and disease. Cardiac arrhythmias are a leading cause of morbidity and mortality in patients with heart failure and likely cause ∼250,000 deaths annually in the United States alone; however, the molecular mechanisms are poorly understood. This suggests the need to improve our current understanding of the underlying molecular mechanisms that increase vulnerability to arrhythmias. Obesity and its associated pathologies, including diabetes, have emerged as dangerous disease conditions that predispose to adverse cardiac electrical remodeling leading to fatal arrhythmias. The increasing epidemic of obesity and diabetes suggests vulnerability to arrhythmias will remain high in patients. An important objective would be to identify novel and unappreciated cellular mechanisms or signaling pathways that modulate obesity and/or diabetes. In this review we discuss circadian rhythms control of metabolic and environmental cues, cardiac ion channels, and mechanisms that predispose to supraventricular and ventricular arrhythmias including hormonal signaling and the autonomic nervous system, and how understanding their functional interplay may help to inform the development and optimization of effective clinical and therapeutic interventions with implications for chronotherapy.

scholarly journals ZEB2 regulates a transcriptional network of calcium-handling genes in the injured heart

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Gladka ◽  
A De Leeuw ◽  
A Kohela ◽  
B Molenaar ◽  
D Versteeg ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transcription Factor ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Calcium Handling ◽  
Funding Source ◽  
Post Injury ◽  
Mesenchymal Transition

Abstract   Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable progress in managing the progression of the disease, the development of effective therapies for heart failure (HF) remains challenging. Therefore, it is of great importance to understand the molecular mechanisms that maintain calcium level and contractility in homeostatic conditions. Here we identified a transcription factor ZEB2 that regulates the expression of numerous contractile and calcium-related genes. Zinc finger E-box-binding homeobox2 (ZEB2) is a transcription factor that plays a role during early fetal development and epithelial-to-mesenchymal transition (EMT); however, its function in the heart remains to be determined. Recently, we found that ZEB2 is upregulated in murine cardiomyocytes shortly after an ischemic event, but returns to baseline levels as the disease progresses. Gain- and loss-of-function genetic mouse models revealed the necessity and sufficiency of ZEB2 to maintain proper cardiac function after ischemic injury. We show that cardiomyocyte-specific ZEB2 overexpression (Zeb2 cTG) protected from ischemia-induced diastolic dysfunction and attenuated the structural remodeling of the heart. Moreover, RNA-sequencing of Zeb2 cTG hearts post-injury implicated ZEB2 in the regulation of numerous calcium-handling and contractile-related genes when compared to wildtype mice. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban (PLN) at both serine-16 and threonine-17, implying enhanced activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2A), thereby augmenting contractility. Improved cardiac function in ZEB2-overexpressing hearts correlated with higher expression of several sarcomeric proteins like myosin-binding protein C3 (MYBPC3), desmin (DES) and myosin regulatory light chain 2 (MYL2) further contributing to the observed protective phenotype. Furthermore, we observed a decrease in the activity of Ca2+-depended calcineurin/NFAT signaling, which is the main driver of pathological cardiac remodeling. Conversely to Zeb2 cTg mice, loss of ZEB2 from cardiomyocytes perturbed the expression of calcium- and contractile-related proteins and increased the activity of calcineurin/NFAT pathway, exacerbating cardiac dysfunction. Together, we show that ZEB2 is a central regulator of contractile and calcium-handling components, consequently mediating contractility in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in the regulation of calcium homeostasis in cardiomyocytes is a critical step towards the development of improved therapies for various forms of heart failure. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): DR. E. Dekker from Dutch Heart Foundation

Acute Effects of Biventricular Pacing in Heart Failure Patients with a Normal Ejection Fraction and Mechanical Dyssynchrony

Cardiology ◽  
2015 ◽  
Vol 130 (2) ◽  
pp. 112-119 ◽  
Author(s):  
Yi-Chih Wang ◽  
Chih-Chieh Yu ◽  
Fu-Chun Chiu ◽  
Vincent Splett ◽  
Ruth Klepfer ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Sinus Rhythm ◽  
Normal Sinus Rhythm ◽  
Biventricular Pacing ◽  
Mechanical Dyssynchrony ◽  
Left Ventricular ◽  
Acute Effects ◽  
Heart Failure Patients ◽  
Normal Sinus

Objectives: We tested the acute effects of resynchronization in heart failure patients with a normal (>50%) left ventricular (LV) ejection fraction (HFNEF) and mechanical dyssynchrony. Methods: Twenty-four HFNEF patients (72 ± 6 years, 5 male) with mechanical dyssynchrony (standard deviation of electromechanical time delay among 12 LV segments >35 ms) were studied with temporary pacing catheters in the right atrium, LV, and right ventricle (RV), and high-fidelity catheters for pressure recording. Using selected atrioventricular (AV) intervals of 60, 90, 120, 150, and 180 ms to optimize transmitral flow during simultaneous biventricular pacing, the RV-LV (VV) interval was then evaluated at RV30, RV15, 0, LV15, LV30, and LV45 (RV or LV indicates which ventricle was paced first, the number indicates by how many ms). Results: During simultaneous pacing, longer AV intervals were associated with improved LV pressure-derivative minimums and increased aortic pressures (p < 0.05 vs. normal sinus rhythm). In the VV interval from RV30 to LV45, there was a graded increase in the aortic velocity time integral and a decrease in dyssynchrony during simultaneous or LV-first pacing (p < 0.05 vs. normal sinus rhythm). Conclusions: For HFNEF patients with mechanical dyssynchrony, acute simultaneous biventricular or LV-first pacing with longer AV intervals reduced mechanical dyssynchrony and improved diastolic and systolic hemodynamics.

Nonlinear Characterization of Heart Rate Variability in Normal Sinus Rhythm, Atrial Fibrillation and Congestive Heart Failure

2016 ◽  
Author(s):  
Syed Hassan Zaidi ◽  
Imran Akhtar ◽  
Syed Imran Majeed ◽  
Tahir Zaidi ◽  
Muhammad Saif Ullah Khalid
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Heart Rate ◽  
Congestive Heart Failure ◽  
Heart Rate Variability ◽  
Sinus Rhythm ◽  
Time Series Data ◽  
Normal Sinus Rhythm ◽  
Series Data ◽  
Normal Sinus

This paper highlights the application of methods and techniques from nonlinear analysis to illustrate their far superior capability in revealing complex cardiac dynamics under various physiological and pathological states. The purpose is to augment conventional (time and frequency based) heart rate variability analysis, and to extract significant prognostic and clinically relevant information for risk stratification and improved diagnosis. In this work, several nonlinear indices are estimated for RR intervals based time series data acquired for Healthy Sinus Rhythm (HSR) and Congestive Heart Failure (CHF), as the two groups represent different cases of Normal Sinus Rhythm (NSR). In addition to this, nonlinear algorithms are also applied to investigate the internal dynamics of Atrial Fibrillation (AFib). Application of nonlinear tools in normal and diseased cardiovascular states manifest their strong ability to support clinical decision support systems and highlights the internal complex properties of physiological time series data such as complexity, irregularity, determinism and recurrence trends in cardiovascular regulation mechanisms.

scholarly journals Evolving Concepts of Food Safety: The Need for Understanding Mechanisms of Food Toxicology for Public Policy

2018 ◽  
Vol 3 (2) ◽  
Keyword(s):  
Public Policy ◽  
Food Safety ◽  
Chronic Diseases ◽  
Metabolic Diseases ◽  
Critical Role ◽  
The United States ◽  
Microbial Pathogens ◽  
Cellular Mechanisms ◽  
Nutrition And Diet

Nutrition and diet, which are fundamental to human development and health, in the context of food safety, can be major determinants in the prevention and contributor to both acute and chronic diseases. While the predominant and legitimate concern is to detect and eliminate microbial pathogens that can cause acute illnesses and deaths (estimated 3-5 thousand deaths in the United States and millions of various acute disorders), food components (nutrients, pollutants, additives, processing by-products, etc.) are major factors in chronic diseases (e.g., “metabolic diseases” of diabetes, cardiovascular diseases, cancers). They contribute to millions of long-term health problems and deaths, globally. The objective of this “Communication” is to integrate a shared underlying mechanism of toxicity between acute and chronic diseases. The traditional separation of the strategy to understand “causes” of acute and chronic diseases, while for some practical tactics is understandable (i.e. screening for food-associated pathogens), it fails to recognize that these microbial -associated toxins work by exactly the same molecular/biochemical and cellular mechanisms as the toxicants- causing chronic diseases. Since all chemicals work by mutagenic, cytotoxic or “epigenetic” alteration of gene expression at the transcriptional, translational or post-translational levels, understanding characteristics of all three of these toxicological mechanisms is important so that public policy- strategies for prevention of both these classes of food –related diseases can be made and that a solid foundation for the concept of “functional foods” be made. A moral imperative has to be given to the critical role that safe food can make during pregnancy in preventing long-term health effects later in life.

scholarly journals ECG Classification using Machine Learning

2019 ◽  
Vol 8 (4) ◽  
pp. 2492-2494
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Congestive Heart Failure ◽  
Sinus Rhythm ◽  
Normal Sinus Rhythm ◽  
Original Data ◽  
Ecg Signals ◽  
Normal Sinus ◽  
Electrocardiogram Signals

Recently, the obvious increasing number of cardiovascular disease, the automatic classification research of Electrocardiogram signals (ECG) has been playing a important part in the clinical diagnosis of cardiovascular disease. Convolution neural network (CNN) based method is proposed to classify ECG signals. The proposed CNN model consists of five layers in addition to the input layer and the output layer, i.e., two convolution layers, two down sampling layers and one full connection layer, extracting the effective features from the original data and classifying the features using wavelet .The classification of ARR (Arrhythmia), CHF (Congestive Heart Failure), and NSR (Normal Sinus Rhythm) signals. The experimental results contains on ARR signals from the MIT-BIH arrhythmia,CHF signals from the BIDMC Congestive Heart Failure and NSR signals from the MIT-BIH Normal Sinus Rhythm Databases show that the proposed method achieves a promising classification accuracy of 90.63%, significantly outperforming several typical ECG classification methods.

scholarly journals Bucindolol Decreases Atrial Fibrillation Burden in Patients with Heart Failure and the ADRB1 Arg389Arg Genotype

2021 ◽  
Author(s):  
Jonathan P. Piccini ◽  
Christopher Dufton ◽  
Ian A. Carroll ◽  
Jeff S. Healey ◽  
William T. Abraham ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Sinus Rhythm ◽  
Normal Sinus Rhythm ◽  
Left Ventricular ◽  
Rhythm Control ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Normal Sinus

Background - Bucindolol is a genetically targeted β-blocker/mild vasodilator with the unique pharmacologic properties of sympatholysis and ADRB1 Arg389 receptor inverse agonism. In the GENETIC-AF trial conducted in a genetically defined heart failure (HF) population at high risk for recurrent atrial fibrillation (AF), similar results were observed for bucindolol and metoprolol succinate for the primary endpoint of time to first atrial fibrillation (AF) event; however, AF burden and other rhythm control measures were not analyzed. Methods - The prevalence of ECGs in normal sinus rhythm, AF interventions for rhythm control (cardioversion, ablation and antiarrhythmic drugs), and biomarkers were evaluated in the overall population entering efficacy follow-up (N=257). AF burden was evaluated for 24 weeks in the device substudy (N=67). Results - In 257 patients with HF the mean age was 65.6 ± 10.0 years, 18% were female, mean left ventricular ejection fraction (LVEF) was 36%, and 51% had persistent AF. Cumulative 24-week AF burden was 24.4% (95% CI: 18.5, 30.2) for bucindolol and 36.7% (95% CI: 30.0, 43.5) for metoprolol (33% reduction, p < 0.001). Daily AF burden at the end of follow-up was 15.1% (95% CI: 3.2, 27.0) for bucindolol and 34.7% (95% CI: 17.9, 51.2) for metoprolol (55% reduction, p < 0.001). For the metoprolol and bucindolol respective groups the prevalence of ECGs in normal sinus rhythm was 4.20 and 3.03 events per patient (39% increase in the bucindolol group, p < 0.001), while the rate of AF interventions was 0.56 and 0.82 events per patient (32% reduction for bucindolol, p = 0.011). Reductions in plasma norepinephrine (p = 0.038) and NT-proBNP (p = 0.009) were also observed with bucindolol compared to metoprolol. Conclusions - Compared with metoprolol, bucindolol reduced AF burden, improved maintenance of sinus rhythm, and lowered the need for additional rhythm control interventions in patients with HF and the ADRB1 Arg389Arg genotype.

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