Fibrosis, Electrics and Genetics

Morris, Gwilym M.; Kalman, Jonathan M.

doi:10.1253/circj.cj-14-0419

Cited by 24 publications

(14 citation statements)

References 98 publications

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“…Studies in human and canine SAN have highlighted the importance of structural remodeling in SND (2, 29). These studies suggest that region-specific SAN disease remodeling, such as fibrotic infiltration (13, 37), could contribute to the intrinsic region-specific SAN conduction abnormalities and arrhythmias. Disease-induced structural remodeling may exacerbate region-specific conduction abnormalities induced by adenosine and incapacitate the fail-safe mechanisms of robust heart rhythm protection, and predispose to SND.…”

Section: Discussionmentioning

confidence: 89%

“…Intrinsic mechanisms of SAN function and dysfunctions, such as fibrosis and molecular remodeling, have been extensively studied in animal models, which established a foundation of theories on heart rate regulation and possible mechanisms of SAN arrhythmias (13, 29, 37, 38). However, these animal model studies have also highlighted interspecies variations that affect SAN function, including how the SAN excites the atrium, dynamic changes in the leading pacemaker site (39), fibrotic content and architecture (29), and protein expression profiles (1).…”

Section: Discussionmentioning

confidence: 99%

“…Most current understanding is inferred from animal models, which may not reproduce the human clinical phenomena (3, 13), or clinical electrogram recordings restricted to the atrial surface (5, 14–17). Consequently, studies of the ex vivo human heart (7, 18) provide an opportunity to study human cardiac disease by applying state-of-the-art intramural mapping techniques consisting of near-infrared optical mapping, 3D structural imaging (2), and molecular mapping (19) to resolve mechanisms of human SAN robustness, which are not possible in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure

et al. 2017

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The human sinoatrial node (SAN) efficiently maintains heart rhythm even under adverse conditions. However, the specific mechanisms involved in the human SAN’s ability to prevent rhythm failure, also referred to as its robustness, are unknown. Challenges exist because the three-dimensional (3D) intramural structure of the human SAN differs from well-studied animal models, and clinical electrode recordings are limited to only surface atrial activation. Hence, to innovate the translational study of human SAN structural and functional robustness, we integrated intramural optical mapping, 3D histology reconstruction, and molecular mapping of the ex vivo human heart. When challenged with adenosine or atrial pacing, redundant intranodal pacemakers within the human SAN maintained automaticity and delivered electrical impulses to the atria through sinoatrial conduction pathways (SACPs), thereby ensuring a fail-safe mechanism for robust maintenance of sinus rhythm. During adenosine perturbation, the primary central SAN pacemaker was suppressed, whereas previously inactive superior or inferior intra-nodal pacemakers took over automaticity maintenance. Sinus rhythm was also rescued by activation of another SACP when the preferential SACP was suppressed, suggesting two independent fail-safe mechanisms for automaticity and conduction. The fail-safe mechanism in response to adenosine challenge is orchestrated by heterogeneous differences in adenosine A1 receptors and downstream GIRK4 channel protein expressions across the SAN complex. Only failure of all pacemakers and/or SACPs resulted in SAN arrest or conduction block. Our results unmasked reserve mechanisms that protect the human SAN pacemaker and conduction complex from rhythm failure, which may contribute to treatment of SAN arrhythmias.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure

et al. 2017

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“…This fibrotic matrix provides mechanical protection (Alings et al, 1995 ) of the SAN and electrically insulates the SAN pacemaker cells from the surrounding atrial myocardium, thereby efficiently regulating normal sinus rhythm. This review will take a more in depth look at the role of fibrosis in normal SAN function, as well as factors involved in unfavorable fibrosis production observed in patients and animal models with cardiac diseases and SND (Liu et al, 2007 ; de Jong et al, 2011 ; Nakao et al, 2012 ; Glukhov et al, 2013 , 2015 ; Alonso et al, 2014 ; Jensen et al, 2014 ; Morris and Kalman, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction

et al. 2015

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Heart rhythm is initialized and controlled by the Sinoatrial Node (SAN), the primary pacemaker of the heart. The SAN is a heterogeneous multi-compartment structure characterized by clusters of specialized cardiomyocytes enmeshed within strands of connective tissue or fibrosis. Intranodal fibrosis is emerging as an important modulator of structural and functional integrity of the SAN pacemaker complex. In adult human hearts, fatty tissue and fibrosis insulate the SAN from the hyperpolarizing effect of the surrounding atria while electrical communication between the SAN and right atrium is restricted to discrete SAN conduction pathways. The amount of fibrosis within the SAN is inversely correlated with heart rate, while age and heart size are positively correlated with fibrosis. Pathological upregulation of fibrosis within the SAN may lead to tachycardia-bradycardia arrhythmias and cardiac arrest, possibly due to SAN reentry and exit block, and is associated with atrial fibrillation, ventricular arrhythmias, heart failure and myocardial infarction. In this review, we will discuss current literature on the role of fibrosis in normal SAN structure and function, as well as the causes and consequences of SAN fibrosis upregulation in disease conditions.

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“…[16] Loss of PCs through chronic injury, fibrosis, or apoptosis causes sinus node dysfunction , as does loss of normal SAN architecture. [17] These findings have important implications for development of biological pacemakers, since cellular material may have to adopt particular architectural features in order to achieve robust pacing.…”

Section: San Structure and Function: Basic Principlesmentioning

confidence: 99%

New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development

Vedantham

2015

Trends in Molecular Medicine

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Irreversible degeneration of the cardiac conduction system is a common disease that can cause activity intolerance, fainting, and death. While electronic pacemakers provide effective treatment, alternative approaches are needed when long-term indwelling hardware is undesirable. Biological pacemakers are composed of electrically active cells that functionally integrate with the heart. Recent findings on cardiac pacemaker cells (PCs) within the sinoatrial node (SAN), along with developments in stem cell technology, have opened a new era in biological pacing. Recent experiments that have derived PC-like cells from non-PCs have brought the field closer than ever before to biological pacemakers that can faithfully recapitulate SAN activity. This review discusses these approaches in the context of SAN biology and addresses the potential for clinical translation.

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Fibrosis, Electrics and Genetics

Cited by 24 publications

References 98 publications

Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure

Redundant and diverse intranodal pacemakers and conduction pathways protect the human sinoatrial node from failure

Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction

New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development

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