Mechanisms of Sinoatrial Node Dysfunction in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The ability to increase heart rate during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiological heart rate response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure with preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. METHODS: Dahl salt-sensitive rats fed a high-salt diet and C57Bl6 mice fed a high-fat diet and an inhibitor of constitutive nitric oxide synthase (Nω-nitro-L-arginine methyl ester [L-NAME]; 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction. Rats and mice fed with a normal diet or those that had a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiologic studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created. RESULTS: Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired ß-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in rats with HF with reduced ejection fraction. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the "membrane clock" (ion channels) and the "Ca2+ clock" (spontaneous Ca2+ release events). The physiologic impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. CONCLUSIONS: Chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.

Molecular Signatures of Sinus Node Dysfunction Induce Structural Remodeling in the Right Atrial Tissue.

The sinus node (SN) is located at the apex of the cardiac conduction system, and SN dysfunction (SND)-characterized by electrical remodeling-is generally attributed to idiopathic fibrosis or ischemic injuries in the SN. SND is associated with increased risk of cardiovascular disorders, including syncope, heart failure, and atrial arrhythmias, particularly atrial fibrillation. One of the histological SND hallmarks is degenerative atrial remodeling that is associated with conduction abnormalities and increased right atrial refractoriness. Although SND is frequently accompanied by increased fibrosis in the right atrium (RA), its molecular basis still remains elusive. Therefore, we investigated whether SND can induce significant molecular changes that account for the structural remodeling of RA. Towards this, we employed a rabbit model of experimental SND, and then compared the genome-wide RNA expression profiles in RA between SND-induced rabbits and sham-operated controls to identify the differentially expressed transcripts. The accompanying gene enrichment analysis revealed extensive pro-fibrotic changes within 7 days after the SN ablation, including activation of transforming growth factor-ß (TGF-ß) signaling and alterations in the levels of extracellular matrix components and their regulators. Importantly, our findings suggest that periostin, a matricellular factor that regulates the development of cardiac tissue, might play a key role in mediating TGF-ß-signaling-induced aberrant atrial remodeling. In conclusion, the present study provides valuable information regarding the molecular signatures underlying SND-induced atrial remodeling, and indicates that periostin can be potentially used in the diagnosis of fibroproliferative cardiac dysfunctions.

Pseudoaneurysm of thoracic aorta presenting as inappropriate sinus tachycardia: a case report.

BACKGROUND: Pseudoaneurysm of thoracic aorta as a complication of blunt trauma to the chest, can present with a variety of symptoms due to mass compression effect. Here we report the first pseudoaneurysm of thoracic aorta presenting with chronic cough and inappropriate sinus tachycardia. The purpose of this case report is to highlight pseudoaneurysm of thoracic aorta as a rare differential diagnosis for inappropriate sinus tachycardia. CASE PRESENTATION: Here we report a case of 29-year-old white woman, a nurse, with history of a motor vehicle accident. She initially presented to medical attention with inappropriate sinus tachycardia 2 years following the motor vehicle accident during her pregnancy. Six years later she underwent sinoatrial node modification after failing a number of medications. Days prior to the ablation she developed a mild cough which became constant within a week following ablation. A computed tomography scan of her chest performed as part of a workup revealed an outpouching of the inferomedial aspect of the aortic arch, which was compressing her left main bronchus. She underwent arch repair surgery and recovered without complications. Four years later she presented with significant symptomatic sinus bradycardia requiring pacemaker placement. CONCLUSIONS: This is the first reported case of thoracic pseudoaneurysm of aorta presenting with inappropriate sinus tachycardia due to compression of the vagal nerve and cough as a result of the left main bronchus compressive effect; it highlights the importance of considering structural abnormalities in a differential diagnosis of inappropriate sinus tachycardia before any interventions.

Sudden fetal death due to dualism of the sino-atrial node.

First, we report a sudden fetal death at 33(+3)weeks due to sino-atrial node dualism. The female stillborn was delivered by induced labor. The postmortem examination of the cardiac conduction system revealed a dualism of the sino-atrial node, associated with fragmentation of the atrio-ventricular node and His bundle. These abnormalities of the cardiac conduction system represent the morphological substrate for the development of malignant arrhythmias. In particular, the dualism of the sino-atrial node can cause the dissociation of the longitudinal nodal impulse into two distinct ways of different pulse generation, resulting in supraventricular tachyarrhythmias. This observation suggests new avenues of research on the pathogenesis of the sudden unexpected fetal death. Moreover, our findings confirm the need for an accurate postmortem examination, including serial sectioning of the cardiac conduction system, in every case of unexplained fetal death, following standardized autoptic protocols.

Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling.

BACKGROUND: Sinus node dysfunction is frequently observed in patients with congenital heart disease (CHD). Variants in the Vascular Endothelial Growth Factor-A (VEGF) pathway are associated with CHD. In Vegf(120/120) mice, over-expressing VEGF120, a reduced sinoatrial node (SAN) volume was suggested. Aim of the study is to assess the effect of VEGF over-expression on SAN development and function. METHODS: Heart rate was measured in Vegf(120/120) and wildtype (WT) embryos during high frequency ultrasound studies at embryonic day (E)12.5, 14.5 and 17.5 and by optical mapping at E12.5. Morphology was studied with several antibodies. SAN volume estimations were performed, and qualitative-PCR was used to quantify expression of genes in SAN tissues of WT and Vegf(120/120) embryos. RESULTS: Heart rate was reduced in Vegf(120/120) compared with WT embryos during embryonic echocardiography (52 ± 17 versus 125 ± 31 beats per minute (bpm) at E12.5, p<0.001; 123 ± 37 vs 160 ± 29 bmp at E14.5, p=0.024; and 177 ± 30 vs 217 ± 34 bmp, at E17.5 p=0.017) and optical mapping (81 ± 5 vs 116 ± 8 bpm at E12.5; p=0.003). The SAN of mutant embryos was smaller and more vascularized, and showed increased expression of the fast conducting gap junction protein, Connexin43. CONCLUSIONS: Over-expression of VEGF120 results in reduced heart rate and a smaller, less compact and hypervascularized SAN with increased expression of Connexin43. This indicates that VEGF is necessary for normal SAN development and function.

Slit-roundabout signaling regulates the development of the cardiac systemic venous return and pericardium.

RATIONALE: The Slit-Roundabout (Robo) signaling pathway has pleiotropic functions during Drosophila heart development. However, its role in mammalian heart development is largely unknown. OBJECTIVE: To analyze the role of Slit-Robo signaling in the formation of the pericardium and the systemic venous return in the murine heart. METHODS AND RESULTS: Expression of genes encoding Robo1 and Robo2 receptors and their ligands Slit2 and Slit3 was found in or around the systemic venous return and pericardium during development. Analysis of embryos lacking Robo1 revealed partial absence of the pericardium, whereas Robo1/2 double mutants additionally showed severely reduced sinus horn myocardium, hypoplastic caval veins, and a persistent left inferior caval vein. Mice lacking Slit3 recapitulated the defects in the myocardialization, alignment, and morphology of the caval veins. Ligand binding assays confirmed Slit3 as the preferred ligand for the Robo1 receptor, whereas Slit2 showed preference for Robo2. Sinus node development was mostly unaffected in all mutants. In addition, we show absence of cross-regulation with previously identified regulators Tbx18 and Wt1. We provide evidence that pericardial defects are created by abnormal localization of the caval veins combined with ectopic pericardial cavity formation. Local increase in neural crest cell death and impaired neural crest adhesive and migratory properties underlie the ectopic pericardium formation. CONCLUSIONS: A novel Slit-Robo signaling pathway is involved in the development of the pericardium, the sinus horn myocardium, and the alignment of the caval veins. Reduced Slit3 binding in the absence of Robo1, causing impaired cardiac neural crest survival, adhesion, and migration, underlies the pericardial defects.

[Polymorphisms of 2B-adrenergic receptor and endothelial NO-Synthase genes in genesis of the hereditary sick sinus node syndrome].

In this work we have demonstrated for the first time on the clinico-genetic material association between hereditary sick sinus node syndrome (SSNS) ADRA2B and eNOS genes polymorphisms. We have established predominance of homozygote genotype of more rare DD allele in patients with SSNS (28%) compared with subjects of control group (8.99%). We have found predominance of heterozygote genotype 4a/4b in patients with SSNS compared with subjects of control group (41.8 and 25.39%, respectively). The data obtained allow to suggest that eNOS gene polymorphism might be associated with SSNS.

[Polymorphism of connexin 40 gene-- a novel genetic marker of the sick sinus node syndrome].

In this work we have demonstrated for the first time on the clinico-genetic material association between hereditary sick sinus node syndrome and connexin 40 gene polymorphism. We have revealed that heterozygous variant of connexin 40 gene variant is more frequent among patients with sick sinus node syndrome and their healthy relatives than in persons of control group.

Left ventricular noncompaction associated with a sinoatrial node artery originating from the posterolateral branch of the right coronary artery.

Noncompaction of the ventricular myocardium (NVM) is a rare unclassified cardiomyopathy which is characterized by multiple prominent trabeculations and deep intertrabecular recesses. This cardiomyopathy can be isolated or in combination with other congenital cardiac disorders, including coronary artery abnormalities. A 56-year-old female patient presented to the cardiology department with complaints of exertional dyspnoea and chest pain. Transthoracic echocardiography revealed left ventricular dilatation with diffuse hypokinesis. Multiple prominent trabeculations with deep inter-trabecular recesses were observed at the left ventricular apex. Also, coronary angiography demonstrated a sinoatrial node artery originating from the posterolateral branch of the right coronary artery.

An S-shaped sinoatrial nodal artery coronary artery fistula demonstrated by multidetector CT.

The presented case and discussion illustrate the use of CT coronary angiography to depict coronary artery fistulae. A 41-year-old man presented with an acute myocardial infarction. Invasive angiography revealed an incidental coronary artery fistula but was unable to depict its course. CT coronary angiography was undertaken to define the course and termination of the fistula. This confirmed a fistulous connection between the left circumflex artery and the superior vena cava that followed the typical course of an S-shaped sinoatrial nodal artery. Even in such an unusual anomaly this case highlights the ability of CT coronary angiography to accurately depict the coronary artery anatomy.

Spontaneous resolution of sinoatrial exit block and atrioventricular dissociation in a child with dengue fever.

Cardiac rhythm abnormalities, including ventricular arrhythmia, atrial fibrillation and atrioventricular block, have been observed during the acute stage of dengue haemorrhagic fever. Atrioventricular or complete heart block can be fatal and may require a temporary pacemaker. We report a ten-year-old girl who presented with dengue haemorrhagic fever with sinoatrial block and atrioventricular dissociation that had a spontaneous resolution.

A mouse model of conduction system patterning abnormalities in heterotaxy syndrome.

Duplication or absence of parts of the specialized cardiac conduction system in patients with heterotaxy syndrome causes significant clinical disease, but the mechanistic basis by which embryonic disruption of left-right patterning alters conduction system patterning in these patients is not well understood. We sought to determine whether a mouse model of X-linked human heterotaxy recapitulates conduction system abnormalities identified in patients with heterotaxy. Cardiac structure and conduction system patterning were evaluated in Zic3 null embryos from e9.5 to e16.5 using genetic and molecular methods. Severe structural abnormalities involving atrial, ventricular, and conotruncal development were associated with a spectrum of disorganized and ambiguous arrangements throughout the conduction system, including the appearance of duplicated structures. The severity and location of conduction system abnormalities correlated with the severity and location of associated structural heart disease and were identifiable at the earliest stages examined. The Zic3 mouse model provides a novel tool to dissect the mechanistic underpinnings of conduction system patterning and dysfunction and its relationship to cardiovascular malformations, making it a promising model to improve understanding and risk assessment in the clinical arena.

[Coexistence of anomalous sinus node artery originating from the left anterior descending artery and agenesis of the right coronary artery]. / Sol ön inen arterden çikan sinüs nod arteri ile sag koroner arter agenezisi birlikteligi.

Sinus node artery originates from the proximal segment of the right coronary artery, left circumflex artery, or from both. We present a 55-year-old man who underwent coronary angiography for exercise-induced chest pain localized in the epigastric region that resolved within several minutes of resting. He had an anomalous sinus node artery originating from the left anterior descending artery and right coronary artery agenesis. To our knowledge, this is the first reported case of coexistence of these two rare coronary anomalies.

Atresia of the coronary sinus ostium to the right atrium with a persistent left superior vena cava / Atresia del ostium del seno coronario en el atrio derecho con una vena cava superior izquierda persistente

The coronary sinus has lately assumed an important role in the cardiologic clinic once it has been widely used in invasive procedures of the heart. Commonly, it is used during the electrodes implants for the epimiocardic monitoring of the cardiac rhythm, through a biventricular pace maker. These invasive procedures are not possible in hearts with an atresic coronary sinus ostium. In the presence of this anomaly, another may occur: the development of the "Marchal" vein which is a remaining of the left superior vena cava (LSVC). This happens so that the venous blood from the heart can drain into the right atrium, by a communication between the LSVC and the left brachiocephalic vein. The presence of a LSVC brings difficulties when performing an invasive procedure in order to access the right atrium through the superior vena cava, usually done in the cardiologic clinic. Moreover, the LSVC crossing over the left atrium is vulnerable to cardiovascular surgical interventions, confirmed by clinical reports. In the present study, 400 formalin fixed hearts from male cadavers, aged between 35 and 80 years, were investigated, particularly for the anatomy of the coronary sinus. The obliterated ostium of the coronary sinus to the right atrium associated with a persistent LSVC was present in only one (0.25 percent). We performed a diameter study of these structures since they were dilated due to the venous blood from the heart draining into the right atrium, by a communication between the LSVC and the left brachiocephalic vein. We also perform a literature review of these cases and discuss our finding in relation to its clinical importance.

El seno coronario recientemente ha asumido un papel importante en la clínica cardiológico, siendo ampliamente utilizado en procedimientos invasivos del corazón. Comúnmente, se utiliza en los implantes de los electrodos para el monitoreo epimiocárdico del ritmo cardiaco, a través de un ritmo biventricular establecido. Estos procedimientos invasivos no son posibles en los corazones con una atresia del ostium del seno coronario. En presencia de esta condición, se puede producir otra anomalía: el desarrollo de la vena de "Marchal" la cual es un vestigio de la vena cava superior izquierda (VCSI). Esto provoca que la sangre venosa del corazón pueda drenar en el atrio derecho, por una comunicación entre la VCSI y la vena braquicefálica izquierda. La presencia de una VCSI trae dificultades a la hora de realizar un procedimiento invasivo con el fin de acceder al atrio derecho a través de la vena cava superior, usualmente hecho en la clínica cardiológica. Por otra parte, el cruzamiento de la VCSI sobre el atrio izquierdo es vulnerable en las intervenciones quirúrgicas cardiovasculares, confirmado por informes clínicos. En el presente estudio, 400 corazones fijados en formalina provenientes a cadáveres de sexo masculino, con edades comprendidas entre los 35 y 80 años, fueron investigados, en particular por la anatomía del seno coronario. El ostium obliterado del seno coronario al atrio derecho asociado con una VCSI persistente estuvo presente en sólo una muestra (0,25 por ciento). Se realizó un estudio del diámetro de estas estructuras dilatadas debido a que la sangre venosa drena desde el corazón hacia el atrio derecho, por una comunicación entre la VCSI y la vena braquicefálica izquierda. También se realiza una revisión de la literatura de estos casos y se discuten nuestros hallazgos en relación con su importancia clínica.

Podoplanin deficient mice show a RhoA-related hypoplasia of the sinus venosus myocardium including the sinoatrial node.

We investigated the role of podoplanin in development of the sinus venosus myocardium comprising the sinoatrial node, dorsal atrial wall, and primary atrial septum as well as the myocardium of the cardinal and pulmonary veins. We analyzed podoplanin wild-type and knockout mouse embryos between embryonic day 9.5-15.5 using immunohistochemical marker podoplanin; sinoatrial-node marker HCN4; myocardial markers MLC-2a, Nkx2.5, as well as Cx43; coelomic marker WT-1; and epithelial-to-mesenchymal transformation markers E-cadherin and RhoA. Three-dimensional reconstructions were made and myocardial morphometry was performed. Podoplanin mutants showed hypoplasia of the sinoatrial node, primary atrial septum, and dorsal atrial wall. Myocardium lining the wall of the cardinal and pulmonary veins was thin and perforated. Impaired myocardial formation is correlated with abnormal epithelial-to-mesenchymal transformation of the coelomic epithelium due to up-regulated E-cadherin and down-regulated RhoA, which are controlled by podoplanin. Our results demonstrate an important role for podoplanin in development of sinus venosus myocardium.

MDCT of the S-shaped sinoatrial node artery.

OBJECTIVE: The purpose of this study was to use 64-MDCT to investigate the anatomic characteristics of the S-shaped variant of the sinoatrial node (SAN) artery and to describe the clinical implications of the findings in ablative procedures involving the left atrium. MATERIALS AND METHODS: Coronary CT angiograms of 250 patients (152 men, 98 women; mean age, 60 +/- 12 [SD] years) were retrospectively analyzed for identification of the origin, number, anatomic course, mode of termination, and S-shaped variant of the SAN artery. RESULTS: At least one SAN artery was detected in 244 patients. The S-shaped variant was seen in 35 (14.3%) of these patients. Thirty-four of the variants (30.6% of all left SAN arteries) arose from the proximal to middle portion of the left circumflex artery (mean distance between the ostium of the left circumflex artery and the origin of S-shaped variant, 28.7 +/- 13.1 mm). The other variant (0.7% of all right SAN arteries) originated from the distal right coronary artery. The S-shaped variant was the only artery supplying the SAN in 28 (11.4%) of the patients. In patients with two arteries supplying the SAN, the right SAN artery and the S-shaped variant of the left SAN artery were seen together in seven patients. The S-shaped SAN artery (mean distance from atrial wall, 2.43 +/- 0.992 mm) had a predictable proximal course, lying in the posterior aspect in a groove between the orifices of the left superior pulmonary vein and the left atrial appendage close to the left atrial wall. The terminal segment of the artery approached the nodal tissue posterior to the superior vena cava in 22 patients, anterior to the vena cava in 10 patients, and through branches surrounding the vena cava in two patients. CONCLUSION: The S-shaped variation of the SAN artery is common and has a characteristic anatomic course. MDCT can be used to plan surgical and catheter-based left atrial interventions in which this artery is at risk of injury.

X-linked nonsyndromic sinus node dysfunction and atrial fibrillation caused by emerin mutation.

INTRODUCTION: Atrial fibrillation (AF) is a heritable disorder with male predilection, suggesting a sex chromosome defect in certain patients. Loss-of-function truncation mutations in EMD, encoding the nuclear membrane protein emerin, cause X-linked Emery-Dreifuss muscular dystrophy (EDMD) characterized by localized contractures and skeletal myopathy in adolescence, sinus node dysfunction (SND) in early adulthood, and atrial fibrillation as a variably associated trait. This study sought to identify the genetic basis for male-restricted, nonsyndromic sinus node dysfunction and AF in a multigenerational family. METHODS AND RESULTS: Genealogical and medical records, and DNA samples, were obtained. Progressive SND and AF occurred in four males related through maternal lineages, consistent with X-linked inheritance. Skeletal myopathy was absent, even at advanced ages. Targeted X chromosome genotyping mapped the disease locus to Xq28, implicating EMD as a positional candidate gene. DNA sequencing revealed hemizygosity for an in-frame 3-bp deletion in EMD (Lys37del) in affected males, disrupting a residue within the LEM binding domain critical for nuclear assembly but leaving the remainder of the protein intact. Buccal epithelial cell staining with emerin antibody demonstrated near-total functional loss of emerin. Female relatives underwent prospective electrocardiographic and genetic testing. Those heterozygous for Lys37del had approximately 50-70% emerin-positive nuclei and variable degrees of paroxysmal supraventricular arrhythmia. CONCLUSIONS: Mutation of EMD can underlie X-linked familial AF. Lys37del is associated with epithelial cell emerin deficiency, as in EDMD, yet it causes electrical atriomyopathy in the absence of skeletal muscle disease. Targeted genetic testing of EMD should be considered in patients with SND-associated AF and/or family history suggesting X-linked inheritance.