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Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction.

Csepe TA, Kalyanasundaram A, Hansen BJ, Zhao J, Fedorov VV - Front Physiol (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center Columbus, OH, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

(A) Example of Tachy-Brady arrhythmia often observed in structurally remodeled hearts with upregulated intranodal fibrosis. Atrial Fibrillation or Tachycardia leads to Bradycardia (long pauses) due to SAN exit block, followed by recovery of sinus rhythm or new Tachycardia event. ECG (black) and Optical Action Potentials (green and blue). Modified from Lou et al. (2013) with permission. (B) Enlarged epicardial view of 3D canine SAN model based on structural and functional data from optical mapping experiments. The SAN is demarcated from the atrium (green) by 3 bifurcating coronary arteries (light blue) and connective tissue (light purple). The yellow bundles show SACPs that electrically connect the SAN to the atrium. (C) Macro-reentry between the SAN and atria that occurred in the structurally remodeled canine heart after cessation of atrial tachypacing. Path of macro-reentry correlated with fibrotic strands within SAN. (D) SAN micro-reentry transformed from the previous macro-reentry is shown. Fibrosis strands were the structural substrates anchoring micro-reentry to this area. (B–D) modified from Glukhov et al. (2013) with permission. Abbreviations as seen in Figure 1.
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Figure 2: (A) Example of Tachy-Brady arrhythmia often observed in structurally remodeled hearts with upregulated intranodal fibrosis. Atrial Fibrillation or Tachycardia leads to Bradycardia (long pauses) due to SAN exit block, followed by recovery of sinus rhythm or new Tachycardia event. ECG (black) and Optical Action Potentials (green and blue). Modified from Lou et al. (2013) with permission. (B) Enlarged epicardial view of 3D canine SAN model based on structural and functional data from optical mapping experiments. The SAN is demarcated from the atrium (green) by 3 bifurcating coronary arteries (light blue) and connective tissue (light purple). The yellow bundles show SACPs that electrically connect the SAN to the atrium. (C) Macro-reentry between the SAN and atria that occurred in the structurally remodeled canine heart after cessation of atrial tachypacing. Path of macro-reentry correlated with fibrotic strands within SAN. (D) SAN micro-reentry transformed from the previous macro-reentry is shown. Fibrosis strands were the structural substrates anchoring micro-reentry to this area. (B–D) modified from Glukhov et al. (2013) with permission. Abbreviations as seen in Figure 1.

Mentions: SND is conceptualized as a spectrum of heart rhythm disturbances including bradycardia, sinus pauses/arrest, exit block, “inappropriate” sinus tachycardia and re-entrant arrhythmias, (Alonso et al., 2014; Jensen et al., 2014). It is largely a disease of the elderly and its incidence increases in an exponential manner with age (Mandel et al., 1999; Adan and Crown, 2003; Dobrzynski et al., 2007). Although human SND can be induced by a number of different pathophysiological mechanisms such as drug effects, autonomic imbalances, cardiomyopathy and electrophysiological alterations, SAN structural abnormalities have been commonly observed in these dysfunctions and are significantly associated with HF, SAN ischemia, and inflammatory conditions (Jordan et al., 1978; Adan and Crown, 2003; Sanders et al., 2004; Kottkamp, 2012). In 1907, Keith and Flack saw a “definite increase in the amount of fibrous tissue” present in the SAN from pathological hearts (Keith and Flack, 1907). Later, Hudson emphasized the association of extensive fibrotic lesions in the human SAN with established arrhythmia, especially AF, and suggested that temporary arrhythmias may be associated with minor fibrotic lesions in the SAN (Hudson, 1960). Thery et al. demonstrated a direct correlation between SAN fibrosis and the occurrence of tachy-brady syndrome (Thery et al., 1977). Tachy-brady syndrome, or tachy-brady arrhythmias, have been explained as “the heart rate alternating between too fast and too slow,” where termination of paroxysmal tachycardia “may be followed by long atrial pauses lasting several seconds, which can provoke another tachyarrhythmia paroxysm” (Figure 2A) (Moss and Davis, 1974; Lou et al., 2013, 2014). While the natural increase in SAN fibrosis observed with aging and heart size is not directly associated with SND, degenerative loss of SAN pacemaker cells and their replacement with fibrosis tissue is frequently evident upon pathologic examination of specimens from patients with SND (Birchfield et al., 1957; Davies and Pomerance, 1972; Thery et al., 1977; Hurle et al., 2006; Yeh et al., 2009).


Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction.

Csepe TA, Kalyanasundaram A, Hansen BJ, Zhao J, Fedorov VV - Front Physiol (2015)

(A) Example of Tachy-Brady arrhythmia often observed in structurally remodeled hearts with upregulated intranodal fibrosis. Atrial Fibrillation or Tachycardia leads to Bradycardia (long pauses) due to SAN exit block, followed by recovery of sinus rhythm or new Tachycardia event. ECG (black) and Optical Action Potentials (green and blue). Modified from Lou et al. (2013) with permission. (B) Enlarged epicardial view of 3D canine SAN model based on structural and functional data from optical mapping experiments. The SAN is demarcated from the atrium (green) by 3 bifurcating coronary arteries (light blue) and connective tissue (light purple). The yellow bundles show SACPs that electrically connect the SAN to the atrium. (C) Macro-reentry between the SAN and atria that occurred in the structurally remodeled canine heart after cessation of atrial tachypacing. Path of macro-reentry correlated with fibrotic strands within SAN. (D) SAN micro-reentry transformed from the previous macro-reentry is shown. Fibrosis strands were the structural substrates anchoring micro-reentry to this area. (B–D) modified from Glukhov et al. (2013) with permission. Abbreviations as seen in Figure 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 2: (A) Example of Tachy-Brady arrhythmia often observed in structurally remodeled hearts with upregulated intranodal fibrosis. Atrial Fibrillation or Tachycardia leads to Bradycardia (long pauses) due to SAN exit block, followed by recovery of sinus rhythm or new Tachycardia event. ECG (black) and Optical Action Potentials (green and blue). Modified from Lou et al. (2013) with permission. (B) Enlarged epicardial view of 3D canine SAN model based on structural and functional data from optical mapping experiments. The SAN is demarcated from the atrium (green) by 3 bifurcating coronary arteries (light blue) and connective tissue (light purple). The yellow bundles show SACPs that electrically connect the SAN to the atrium. (C) Macro-reentry between the SAN and atria that occurred in the structurally remodeled canine heart after cessation of atrial tachypacing. Path of macro-reentry correlated with fibrotic strands within SAN. (D) SAN micro-reentry transformed from the previous macro-reentry is shown. Fibrosis strands were the structural substrates anchoring micro-reentry to this area. (B–D) modified from Glukhov et al. (2013) with permission. Abbreviations as seen in Figure 1.
Mentions: SND is conceptualized as a spectrum of heart rhythm disturbances including bradycardia, sinus pauses/arrest, exit block, “inappropriate” sinus tachycardia and re-entrant arrhythmias, (Alonso et al., 2014; Jensen et al., 2014). It is largely a disease of the elderly and its incidence increases in an exponential manner with age (Mandel et al., 1999; Adan and Crown, 2003; Dobrzynski et al., 2007). Although human SND can be induced by a number of different pathophysiological mechanisms such as drug effects, autonomic imbalances, cardiomyopathy and electrophysiological alterations, SAN structural abnormalities have been commonly observed in these dysfunctions and are significantly associated with HF, SAN ischemia, and inflammatory conditions (Jordan et al., 1978; Adan and Crown, 2003; Sanders et al., 2004; Kottkamp, 2012). In 1907, Keith and Flack saw a “definite increase in the amount of fibrous tissue” present in the SAN from pathological hearts (Keith and Flack, 1907). Later, Hudson emphasized the association of extensive fibrotic lesions in the human SAN with established arrhythmia, especially AF, and suggested that temporary arrhythmias may be associated with minor fibrotic lesions in the SAN (Hudson, 1960). Thery et al. demonstrated a direct correlation between SAN fibrosis and the occurrence of tachy-brady syndrome (Thery et al., 1977). Tachy-brady syndrome, or tachy-brady arrhythmias, have been explained as “the heart rate alternating between too fast and too slow,” where termination of paroxysmal tachycardia “may be followed by long atrial pauses lasting several seconds, which can provoke another tachyarrhythmia paroxysm” (Figure 2A) (Moss and Davis, 1974; Lou et al., 2013, 2014). While the natural increase in SAN fibrosis observed with aging and heart size is not directly associated with SND, degenerative loss of SAN pacemaker cells and their replacement with fibrosis tissue is frequently evident upon pathologic examination of specimens from patients with SND (Birchfield et al., 1957; Davies and Pomerance, 1972; Thery et al., 1977; Hurle et al., 2006; Yeh et al., 2009).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology and Cell Biology, Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center Columbus, OH, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus