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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) Left: Drawing of the posterior human atrial anatomy from (Keith and Flack, 1907), with SAN outlined in red. Right: Histological cross section of the SAN (red outline) connected to the atria by a SACP (yellow outline). The SAN is seen to be isolated from the atria by sup-epicardial fat and connective tissue. Modified from Fedorov et al. (2010b, 2012) with permission. (B) 1—Scanning electron micrograph of the SAN and nodal artery (NA) of a cross section through the CT after digestion of the nodal cells. The collagenous sheaths of endomysial fibrosis formed a complex network in the gaps between the nodal cells, whereas occasional perimysial septums were seen between them. 2—Scanning electron micrograph of non-macerated SAN cells (N), which are encased in dense and coarse endomysial sheaths (yellow arrows) in a specimen from a 75 year old. 3—Scanning electron micrograph of a cross section through the CT, after digestion, from a specimen of 70 years shows a diffuse notable excess of endomysial sheaths (yellow arrows) indicating focal interstitial reactive fibrosis. Vascular space (V) corresponds to a coronary vein. 4—Scanning electron micrograph of non-macerated cross section through the body of the CT shows mainly longitudinal fibers (H) with intermingling oblique (O) or lateral (L) fibers. From Sanchez-Quintana et al. (2002) with permission. (C) Graph showing percentage of fibrous connective tissue volume to the total SAN volume, mean value, and standard deviation. From Shiraishi et al. (1992); used with permission. (D) Fibrosis in the SAN is increased in HF vs. control dog. Left: A structural model of the control canine SAN complex and SACPs. Middle: histological sections showing upregulated fibrotic and fatty content in SAN complex (black outline) and SACP in HF (bottom, blue box) compared to control (top, green box). Right: A structural model of the heart failure SAN complex and SACPs, showing upregulated intranodal fibrosis (blue fibrotic strands). Modified from Lou et al. (2014) with permission. Abbreviations: CT, crista terminalis; Endo, endocardium; Epi, epicardium; HF, heart failure; IAS, interatrial septum; PV, pulmonary veins; RAA, right atrial appendage; RV, right ventricle; SACP, sinoatrial conduction pathway; SAN, sinoatrial node; SVC and IVC, superior and inferior vena cava.
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Figure 1: (A) Left: Drawing of the posterior human atrial anatomy from (Keith and Flack, 1907), with SAN outlined in red. Right: Histological cross section of the SAN (red outline) connected to the atria by a SACP (yellow outline). The SAN is seen to be isolated from the atria by sup-epicardial fat and connective tissue. Modified from Fedorov et al. (2010b, 2012) with permission. (B) 1—Scanning electron micrograph of the SAN and nodal artery (NA) of a cross section through the CT after digestion of the nodal cells. The collagenous sheaths of endomysial fibrosis formed a complex network in the gaps between the nodal cells, whereas occasional perimysial septums were seen between them. 2—Scanning electron micrograph of non-macerated SAN cells (N), which are encased in dense and coarse endomysial sheaths (yellow arrows) in a specimen from a 75 year old. 3—Scanning electron micrograph of a cross section through the CT, after digestion, from a specimen of 70 years shows a diffuse notable excess of endomysial sheaths (yellow arrows) indicating focal interstitial reactive fibrosis. Vascular space (V) corresponds to a coronary vein. 4—Scanning electron micrograph of non-macerated cross section through the body of the CT shows mainly longitudinal fibers (H) with intermingling oblique (O) or lateral (L) fibers. From Sanchez-Quintana et al. (2002) with permission. (C) Graph showing percentage of fibrous connective tissue volume to the total SAN volume, mean value, and standard deviation. From Shiraishi et al. (1992); used with permission. (D) Fibrosis in the SAN is increased in HF vs. control dog. Left: A structural model of the control canine SAN complex and SACPs. Middle: histological sections showing upregulated fibrotic and fatty content in SAN complex (black outline) and SACP in HF (bottom, blue box) compared to control (top, green box). Right: A structural model of the heart failure SAN complex and SACPs, showing upregulated intranodal fibrosis (blue fibrotic strands). Modified from Lou et al. (2014) with permission. Abbreviations: CT, crista terminalis; Endo, endocardium; Epi, epicardium; HF, heart failure; IAS, interatrial septum; PV, pulmonary veins; RAA, right atrial appendage; RV, right ventricle; SACP, sinoatrial conduction pathway; SAN, sinoatrial node; SVC and IVC, superior and inferior vena cava.

Mentions: The SAN is anatomically located at the junction of the superior vena cava and right atrium in the mammalian heart (Figure 1A). In the normal adult human heart, the SAN is 12–20 mm long and 2–6 mm wide, identified by its ellipsoidal shape that traverses intramurally. The superior part (head) lies about 1 mm beneath the epicardium, separated by a layer of connective tissue and fat (Keith and Flack, 1907; James, 1961; Truex et al., 1967; Matsuyama et al., 2004; Sanchez-Quintana et al., 2005). The SAN spreads from its head inferiorly for 10–20 mm remaining beneath the sulcus terminalis and just above the crista terminalis and has several extensions into the surrounding atrial myocardium, forming the specialized sinoatrial conduction pathways (SACPs) (Lev, 1954; Hudson, 1960; Demoulin and Kulbertus, 1978; Fedorov et al., 2010b) (Figure 1A). Importantly, the SAN consists of small clusters of pacemaker myocytes, arranged in parallel rows that frequently anastomose. Dense connective tissue, nerve fibers, and capillaries are interspersed with the SAN pacemaker clusters, creating the SAN pacemaker complex.


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

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

(A) Left: Drawing of the posterior human atrial anatomy from (Keith and Flack, 1907), with SAN outlined in red. Right: Histological cross section of the SAN (red outline) connected to the atria by a SACP (yellow outline). The SAN is seen to be isolated from the atria by sup-epicardial fat and connective tissue. Modified from Fedorov et al. (2010b, 2012) with permission. (B) 1—Scanning electron micrograph of the SAN and nodal artery (NA) of a cross section through the CT after digestion of the nodal cells. The collagenous sheaths of endomysial fibrosis formed a complex network in the gaps between the nodal cells, whereas occasional perimysial septums were seen between them. 2—Scanning electron micrograph of non-macerated SAN cells (N), which are encased in dense and coarse endomysial sheaths (yellow arrows) in a specimen from a 75 year old. 3—Scanning electron micrograph of a cross section through the CT, after digestion, from a specimen of 70 years shows a diffuse notable excess of endomysial sheaths (yellow arrows) indicating focal interstitial reactive fibrosis. Vascular space (V) corresponds to a coronary vein. 4—Scanning electron micrograph of non-macerated cross section through the body of the CT shows mainly longitudinal fibers (H) with intermingling oblique (O) or lateral (L) fibers. From Sanchez-Quintana et al. (2002) with permission. (C) Graph showing percentage of fibrous connective tissue volume to the total SAN volume, mean value, and standard deviation. From Shiraishi et al. (1992); used with permission. (D) Fibrosis in the SAN is increased in HF vs. control dog. Left: A structural model of the control canine SAN complex and SACPs. Middle: histological sections showing upregulated fibrotic and fatty content in SAN complex (black outline) and SACP in HF (bottom, blue box) compared to control (top, green box). Right: A structural model of the heart failure SAN complex and SACPs, showing upregulated intranodal fibrosis (blue fibrotic strands). Modified from Lou et al. (2014) with permission. Abbreviations: CT, crista terminalis; Endo, endocardium; Epi, epicardium; HF, heart failure; IAS, interatrial septum; PV, pulmonary veins; RAA, right atrial appendage; RV, right ventricle; SACP, sinoatrial conduction pathway; SAN, sinoatrial node; SVC and IVC, superior and inferior vena cava.
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Figure 1: (A) Left: Drawing of the posterior human atrial anatomy from (Keith and Flack, 1907), with SAN outlined in red. Right: Histological cross section of the SAN (red outline) connected to the atria by a SACP (yellow outline). The SAN is seen to be isolated from the atria by sup-epicardial fat and connective tissue. Modified from Fedorov et al. (2010b, 2012) with permission. (B) 1—Scanning electron micrograph of the SAN and nodal artery (NA) of a cross section through the CT after digestion of the nodal cells. The collagenous sheaths of endomysial fibrosis formed a complex network in the gaps between the nodal cells, whereas occasional perimysial septums were seen between them. 2—Scanning electron micrograph of non-macerated SAN cells (N), which are encased in dense and coarse endomysial sheaths (yellow arrows) in a specimen from a 75 year old. 3—Scanning electron micrograph of a cross section through the CT, after digestion, from a specimen of 70 years shows a diffuse notable excess of endomysial sheaths (yellow arrows) indicating focal interstitial reactive fibrosis. Vascular space (V) corresponds to a coronary vein. 4—Scanning electron micrograph of non-macerated cross section through the body of the CT shows mainly longitudinal fibers (H) with intermingling oblique (O) or lateral (L) fibers. From Sanchez-Quintana et al. (2002) with permission. (C) Graph showing percentage of fibrous connective tissue volume to the total SAN volume, mean value, and standard deviation. From Shiraishi et al. (1992); used with permission. (D) Fibrosis in the SAN is increased in HF vs. control dog. Left: A structural model of the control canine SAN complex and SACPs. Middle: histological sections showing upregulated fibrotic and fatty content in SAN complex (black outline) and SACP in HF (bottom, blue box) compared to control (top, green box). Right: A structural model of the heart failure SAN complex and SACPs, showing upregulated intranodal fibrosis (blue fibrotic strands). Modified from Lou et al. (2014) with permission. Abbreviations: CT, crista terminalis; Endo, endocardium; Epi, epicardium; HF, heart failure; IAS, interatrial septum; PV, pulmonary veins; RAA, right atrial appendage; RV, right ventricle; SACP, sinoatrial conduction pathway; SAN, sinoatrial node; SVC and IVC, superior and inferior vena cava.
Mentions: The SAN is anatomically located at the junction of the superior vena cava and right atrium in the mammalian heart (Figure 1A). In the normal adult human heart, the SAN is 12–20 mm long and 2–6 mm wide, identified by its ellipsoidal shape that traverses intramurally. The superior part (head) lies about 1 mm beneath the epicardium, separated by a layer of connective tissue and fat (Keith and Flack, 1907; James, 1961; Truex et al., 1967; Matsuyama et al., 2004; Sanchez-Quintana et al., 2005). The SAN spreads from its head inferiorly for 10–20 mm remaining beneath the sulcus terminalis and just above the crista terminalis and has several extensions into the surrounding atrial myocardium, forming the specialized sinoatrial conduction pathways (SACPs) (Lev, 1954; Hudson, 1960; Demoulin and Kulbertus, 1978; Fedorov et al., 2010b) (Figure 1A). Importantly, the SAN consists of small clusters of pacemaker myocytes, arranged in parallel rows that frequently anastomose. Dense connective tissue, nerve fibers, and capillaries are interspersed with the SAN pacemaker clusters, creating the SAN pacemaker complex.

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