Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models

The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to establish an atrial filtration (AF) model in our laboratory, we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB1 KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined may not reflect human AF well, and raise a cautionary note for use of those murine models to study AF.

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Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models

10.1101/2021.08.17.456655 ◽

2021 ◽

Author(s):

Fumin Fu ◽

Michael Pietropaolo ◽

Lei Cui ◽

Shilpa Pandit ◽

Weiyan Li ◽

...

Keyword(s):

Atrial Fibrillation ◽

Structural Changes ◽

Optical Mapping ◽

Histological Evaluation ◽

Atrial Remodeling ◽

Atrial Tachyarrhythmia ◽

P Waves ◽

Disease Etiology ◽

Preclinical Species ◽

Liver Kinase B1

AbstractThe mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to better characterize atrial fibrillation (AF), we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined are poor representations of human AF, and raise a cautionary note about the use of any murine model to study AF.

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Abstract 18601: Impact of Right and Left Atrial Remodeling on Outcomes From Atrial Fibrillation Rotor Ablation

Circulation ◽

10.1161/circ.132.suppl_3.18601 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Amir Schricker ◽

Tina Baykaner ◽

Junaid Zaman ◽

Gautam Lalani ◽

Kenneth Hopper ◽

...

Keyword(s):

Atrial Fibrillation ◽

Left Atrial ◽

Structural Changes ◽

Unknown Etiology ◽

Atrial Remodeling ◽

Left Atrial Remodeling ◽

Single Procedure ◽

Clinical Indices ◽

The Right

Introduction: Targets for the ablation of atrial fibrillation (AF) are debated. In particular, recent studies questioning fractionated electrograms and lines has increased focus on AF substrates of rotors and focal impulses. These AF sources are seen in both atria, but have unknown etiology. We hypothesized that differential remodeling between the right atrium (RA), whose structural changes are largely undefined, and left atrium (LA) influence the distribution of AF sources and the outcomes from AF source ablation. Methods: In 60 patients at AF ablation (62±10 years, 60% persistent, 5% long-standing persistent), we compared size differences between RA and LA to the number of sources in each chamber and outcomes from AF source-guide ablation. We studied if a 64-pole basket differentially fit the LA or RA, judged by deformation of its splines by the atria (fig. A, B) over multiple cardiac cycles on fluoroscopy. Ablation targeted sources in both atria and was followed by PVI, with follow-up per guidelines. Results: Using baskets in both atria, 205 sources (LA 138; RA 67) were identified and ablated. Notably, the same basket in each patient was dynamically deformed by RA in 51 (85%) of cases but in the LA in only 39 (65%), indicating greater LA remodeling. The number of AF sources was higher in the presence of basket deformation of RA (n=174) than LA (n=130). LA deformation correlated with LVEF (p=0.05). Freedom from AF at 1 year was reduced in patients with no basket deformation (i.e. dilation) in LA (p=0.07) or RA (p=0.06). Notably, single procedure AF freedom was substantially lower in patients with differential remodeling (deformation in only 1 chamber) of 84% vs. 60% (fig C). Conclusions: Structural atrial remodeling influences the number of electrical rotors and focal sources in each chamber. A mismatch between right and left atrial remodeling predicts lower success from rotor ablation. These data also provide novel clinical indices of effective basket positioning.

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Echocardiography in Patients with Atrial Fibrillation - What Should the Internist Doctor Know?

Internal Medicine ◽

10.2478/inmed-2020-0124 ◽

2020 ◽

Vol 17 (4) ◽

pp. 49-60

Author(s):

Maria-Luiza Toplicianu-Dimitriu ◽

Ioan Tiberiu Nanea

Keyword(s):

Atrial Fibrillation ◽

Left Atrial ◽

Structural Changes ◽

Excess Mortality ◽

Ventricular Dysfunction ◽

Imaging Technique ◽

Left Ventricular ◽

Clinical Impact ◽

Atrial Remodeling ◽

Routine Imaging

AbstractAtrial fibrillation (AF) is the most common cardiac arrhythmia, with an increasing prevalence and an enormous clinical impact due to the high stroke rate, left ventricular dysfunction and excess mortality. The occurrence and maintenance of AF is favored by both the degree of left atrial (LA) dilation and the association of fibrotic lesions of the myocardium. The LA is a marker of adverse cardiovascular events in patients with AF. Atrial remodeling can be electrical (shortening atrial refractory), structural (altering geometry and altering collagen content) and contractile (loss of contractility). Cardiac imaging plays a central role in the clinical management of this arrhythmia. Echocardiography represents the routine imaging technique used in patients with AF, with a role in detecting LA dysfunction and cardiac structural changes that predispose to this arrhythmia, also having the ability to predict the maintenance of sinus rhythm after cardioversion and after ablation.

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Association of Atrial Fibrillation with Morphological and Electrophysiological Changes of the Atrial Myocardium

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2016.88 ◽

2016 ◽

Vol 59 (2) ◽

pp. 43-49 ◽

Cited By ~ 1

Author(s):

Adéla Matějková ◽

Ivo Šteiner

Keyword(s):

Atrial Fibrillation ◽

Structural Changes ◽

Anterior Wall ◽

Atrial Septum ◽

P Wave ◽

Atrial Myocardium ◽

P Waves ◽

Long Time ◽

History Of ◽

Right Atria

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. For long time it was considered as pure functional disorder, but in recent years, there were identified atrial locations, which are involved in the initiation and maintenance of this arrhythmia. These structural changes, so called remodelation, start at electric level and later they affect contractility and morphology. In this study we attempted to find a possible relation between morphological (scarring, amyloidosis, left atrial (LA) enlargement) and electrophysiological (ECG features) changes in patients with AF. We examined grossly and histologically 100 hearts of necropsy patients – 54 with a history of AF and 46 without AF. Premortem ECGs were evaluated. The patients with AF had significantly heavier heart, larger LA, more severely scarred myocardium of the LA and atrial septum, and more severe amyloidosis in both atria. Severity of amyloidosis was higher in LAs vs. right atria (RAs). Distribution of both fibrosis and amyloidosis was irregular. The most affected area was in the LA anterior wall. Patients with a history of AF and with most severe amyloidosis have more often abnormally long P waves. Finding of long P wave may contribute to diagnosis of a hitherto undisclosed atrial fibrillation.

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P322Understanding the multiple P-wave morphologies in paroxysmal atrial fibrillation, during sinus rhythm, using computer simulation

EP Europace ◽

10.1093/europace/euaa162.166 ◽

2020 ◽

Vol 22 (Supplement_1) ◽

Author(s):

D Filos ◽

D Tachmatzidis ◽

C Bakogiannis ◽

D Mouselimis ◽

A Tsarouchas ◽

...

Keyword(s):

Atrial Fibrillation ◽

Sinus Rhythm ◽

Electrical Activity ◽

Pulmonary Veins ◽

P Wave ◽

Electrical Remodeling ◽

Atrial Remodeling ◽

P Waves ◽

Sa Node ◽

Atrial Activation

Abstract Background Atrial Fibrillation (AF) is the most common atrial arrhythmia. The initiation and perpetuation of AF are related to atrial remodeling affecting the electrical and structural atrial characteristics. The beat-to-beat analysis of the P-wave morphology (PWM), during sinus rhythm (SR), revealed the existence of a secondary PWM, while the proportion of the P-waves which follow the secondary morphology is higher in patients with a history of paroxysmal AF (pAF). This observation has led to the hypothesis that the multiple PWM may be the result of a transient shift in the stimulus origin, possibly within the broader anatomical region of the sinoatrial (SA) node, and it is the atrial electrical remodeling that contributes to more frequent P-waves following a secondary morphology in patients with pAF. Purpose To better understand the pathophysiology of AF there is a need to link different levels of analysis, in order to interpret macroscopic observations, through a surface electrocardiogram, with changes occurring at cell and tissue level. Towards this direction, computational modeling can be used as it is a non-invasive and reproducible method of analyzing the electrical activity of the heart. Methods The CRN atrial model was used, and a two-dimensional geometry of the atrial architecture was considered, including the major anatomical structures, like Crista Terminalis, Pectinate Muscles and Pulmonary Veins. Using existing knowledge, the CRN model was adapted to describe the ionic properties of the atrial structures as well as the electrical remodeling occurring under pAF conditions. Several scenarios were considered related to the extent of the electrical remodeled tissue and Heart Rate (HR) values. The stimulation protocol was designed as 5 stimuli originated at a specific point within the SA node area whereas the sixth stimulus originated either at the same location or 1 mm far from the previous one. The temporal variations of the atrial activation as a result of the transient shift of the sixth stimulus origin were computed. Results In electrically remodeled tissue, the displacement of the excitation site within the SA node resulted in a significant increase of the differences in atrial activation compared to healthy tissue, and the greater the spatial extent of the remodeling the greater the differences in the completion of the electrophysiological processes. In addition, increased HR or HR variability led to the increase of the differences especially when electrical remodeling coexists. Conclusions The observed differences in atrial substrate activation can explain the increased number of P-waves that match a secondary PWM in pAF patients during SR, while a future perspective is to use PWM as a marker to estimate the electrical remodeling extent in the atrial tissue. These results underline the need to link the macroscopic findings to the suspected microscopic electrical activity in order to better understand the pathophysiology of AF.

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Recent Clinical and Experimental Advances in Atrial Fibrillation

ISRN Cardiology ◽

10.5402/2011/958189 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Shigeru Miyagawa ◽

Taichi Sakaguchi ◽

Hiroyuki Nishi ◽

Yasushi Yoshikawa ◽

Satsuki Fukushima ◽

...

Keyword(s):

Atrial Fibrillation ◽

Extracellular Matrix ◽

Structural Changes ◽

Heart Diseases ◽

Atrial Remodeling ◽

Clinical Settings ◽

Atrial Myocytes ◽

General Classification ◽

Surgical Treatments

Atrial fibrillation (AF) is the most common arrhythmia in clinical settings (Fuster et al., 2001), and it is often associated with congestive heart diseases (Issac et al., 2007). Many studies in both laboratory and clinical settings have sought to analyze the mechanisms of AF, develop treatments based on these mechanisms, and examine atrial remodeling in chronic AF. The aim of this paper is to analyze recent findings regarding the atrial remodeling that occurs in AF. In particular, we will describe the electrical and structural changes that involve atrial myocytes and the extracellular matrix. We will also describe the general classification and basic pathophysiology of AF and its surgical treatments.

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Echocardiography-derived total atrial conduction time (PA-TDI duration): risk stratification and guidance in atrial fibrillation management

Clinical Research in Cardiology ◽

10.1007/s00392-021-01917-9 ◽

2021 ◽

Author(s):

Patrick Müller ◽

Bob Weijs ◽

Nadine M. A. A. Bemelmans ◽

Andreas Mügge ◽

Lars Eckardt ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cardiac Imaging ◽

Structural Changes ◽

Clinical Care ◽

Imaging Modalities ◽

Atrial Remodeling ◽

Conduction Time ◽

Cardiovascular Morbidity And Mortality ◽

Atrial Conduction Time ◽

Patients At Risk

AbstractAtrial fibrillation (AF) is a major cause of cardiovascular morbidity and mortality. To early detect and to avoid AF-related complications, several cardiac imaging modalities and approaches aim to quantify the severity of the underlying atrial cardiomyopathy (i.e., the extent of atrial remodeling). However, most established cardiac imaging modalities just incorporate single components of atrial remodeling and do not reflect the complete multifactorial process, which may contribute to their limited predictive value. Echocardiography-derived PA-TDI duration is a sophisticated echocardiographic parameter to assess total atrial conduction time and directly reflects both electrical and structural changes to the atria. Therefore, PA-TDI duration provides a more comprehensive quantification of the extent of atrial remodeling than other imaging modalities. In this article we review the role of PA-TDI duration as a marker of atrial remodeling and summarize the available data on PA-TDI duration to identify patients at risk for AF, as well as to guide AF management. Moreover, we discuss how to assess PA-TDI duration and provide recommendations on the implementation of PA-TDI duration into routine clinical care. Graphic abstract

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Biomarkers of Atrial Fibrillation in Hypertension

Current Medicinal Chemistry ◽

10.2174/0929867324666171006155516 ◽

2019 ◽

Vol 26 (5) ◽

pp. 888-897 ◽

Cited By ~ 2

Author(s):

Costas Tsioufis ◽

Dimitris Konstantinidis ◽

Ilias Nikolakopoulos ◽

Evi Vemmou ◽

Theodoros Kalos ◽

...

Keyword(s):

Atrial Fibrillation ◽

Left Ventricular ◽

P Wave ◽

Diagnostic Tools ◽

Atrial Remodeling ◽

Hypertensive Patients ◽

Risk Patients ◽

Underlying Mechanisms ◽

Prompt Diagnosis ◽

The Ideal

Background: Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia globally and substantially increases the risk for thromboembolic disease. Albeit, 20% of all cases of AF remain undiagnosed. On the other hand, hypertension amplifies the risk for both AF occurrences through hemodynamic and non-hemodynamic mechanisms and cerebrovascular ischemia. Under this prism, prompt diagnosis of undetected AF in hypertensive patients is of pivotal importance. Method: We conducted a review of the literature for studies with biomarkers that could be used in AF diagnosis as well as in predicting the transition of paroxysmal AF to sustained AF, especially in hypertensive patients. Results: Potential biomarkers for AF can be broadly categorized into electrophysiological, morphological and molecular markers that reflect the underlying mechanisms of adverse atrial remodeling. We focused on P-wave duration and dispersion as electrophysiological markers, and left atrial (LA) and LA appendage size, atrial fibrosis, left ventricular hypertrophy and aortic stiffness as structural biomarkers, respectively. The heterogeneous group of molecular biomarkers of AF encompasses products of the neurohormonal cascade, including NT-pro BNP, BNP, MR-pro ANP, polymorphisms of the ACE and convertases such as corin and furin. In addition, soluble biomarkers of inflammation (i.e. CRP, IL-6) and fibrosis (i.e. TGF-1 and matrix metalloproteinases) were assessed for predicting AF. Conclusion: The reviewed individual biomarkers might be a valuable addition to current diagnostic tools but the ideal candidate is expected to combine multiple indices of atrial remodeling in order to effectively detect both AF and adverse characteristics of high risk patients with hypertension.

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Commonalities between Copper Neurotoxicity and Alzheimer’s Disease

Toxics ◽

10.3390/toxics9010004 ◽

2021 ◽

Vol 9 (1) ◽

pp. 4

Author(s):

Roshni Patel ◽

Michael Aschner

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Structural Changes ◽

Copper Ion ◽

Plaque Formation ◽

Ion Concentration ◽

Medical Community ◽

Disease Etiology ◽

Parent Protein ◽

Lead Zinc

Alzheimer’s disease, a highly prevalent form of dementia, targets neuron function beginning from the hippocampal region and expanding outwards. Alzheimer’s disease is caused by elevated levels of heavy metals, such as lead, zinc, and copper. Copper is found in many areas of daily life, raising a concern as to how this metal and Alzheimer’s disease are related. Previous studies have not identified the common pathways between excess copper and Alzheimer’s disease etiology. Our review corroborates that both copper and Alzheimer’s disease target the hippocampus, cerebral cortex, cerebellum, and brainstem, affecting motor skills and critical thinking. Additionally, Aβ plaque formation was analyzed beginning from synthesis at the APP parent protein site until Aβ plaque formation was completed. Structural changes were also noted. Further analysis revealed a relationship between amyloid-beta plaques and copper ion concentration. As copper ion levels increased, it bound to the Aβ monomer, expediting the plaque formation process, and furthering neurodegeneration. These conclusions can be utilized in the medical community to further research on the etiology of Alzheimer’s disease and its relationships to copper and other metal-induced neurotoxicity.

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