cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells.

It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node.

Fibrosis independent atrial fibrillation in older patients is driven by substrate leukocyte infiltration: diagnostic and prognostic implications to patients undergoing cardiac surgery.

BACKGROUND: The objectives of the study were to characterize and quantify cellular inflammation and structural remodeling of human atria and correlate findings with molecular markers of inflammation and patient surrogate outcome. METHODS: Voluntary participants undergoing heart surgery were enrolled in the study and blood samples were collected prior to surgery, and right atrium samples were harvested intraoperatively. Blood samples were analyzed by flow cytometry and complete blood counts. Atrial samples were divided for fixed fibrosis analysis, homogenized for cytokine analysis and digested for single cell suspension flow cytometry. RESULTS: A total of 18 patients were enrolled and samples assessed. Isolated cells from the atria revealed a CD45+ population of ~ 20%, confirming a large number of leukocytes. Further characterization revealed this population as 57% lymphocytes and 26% monocyte/macrophages (MoΦ), with the majority of the latter cells being classical (CD14++/CD16-). Interstitial fibrosis was present in 87% of samples and correlated significantly with patient age. Older patients (> 65) had significantly more atrial fibrosis and cellular inflammation. AFib patients had no distinguishing feature of atrial fibrosis and had significantly greater CD45+ MoΦ, increased expression of MMP9 and presented with a significant correlation in length of stay to CCL-2/MCP-1 and NLR (neutrophil-to-lymphocyte ratio). CONCLUSION: Atrial fibrosis is correlated with age and not determinate to AFib. However, severity of atrial leukocyte infiltration and markers of matrix degradation are determinant to AFib. This also correlated with CCL2 (or MCP-1) and NLR-indicative of marked inflammation. These data show the potential importance of diagnostic and prognostic assessments that could inform clinical decision making in regard to the intensity of AFib patient management.

Interleukin-10 treatment attenuates sinus node dysfunction caused by streptozotocin-induced hyperglycaemia in mice.

Aims: Diabetes, characterized by hyperglycaemia, causes sinus node dysfunction (SND) in several rodent models. Interleukin (IL)-10, which is a potent anti-inflammatory cytokine, has been reported to decrease in obese and diabetic patients. We tested the hypothesis that administration of IL-10 inhibits the development of SND caused by hyperglycaemia in streptozotocin (STZ)-induced diabetic mice. Methods and results: Six-week old CL57/B6 (WT) mice were divided into the following groups: control, STZ injection, and STZ injection with systemic administration of IL-10. IL-10 knockout mice were similarly treated. STZ-induced hyperglycaemia for 8 weeks significantly depressed serum levels of IL-10, but increased several proinflammatory cytokines in WT mice. STZ-induced hyperglycaemia-reduced resting heart rate (HR), and attenuated HR response to isoproterenol in WT mice. In isolated perfused heart experiments, corrected-sinus node recovery time was prolonged in WT mice with STZ injection. Sinus node tissue isolated from the WT-STZ group showed fibrosis, abundant infiltration of macrophages, increased production of reactive oxygen species (ROS), and depressed hyperpolarization activated cyclic nucleotide-gated potassium channel 4 (HCN4). However, the changes observed in the WT-STZ group were significantly attenuated by IL-10 administration and were further exaggerated in IL-10 knockout mice. In cultured cells, preincubation of IL-10 suppressed hyperglycaemia-induced apoptotic and profibrotic signals, and overproduction of ROS. IL-10 markedly inhibited the high glucose-induced p38 activation, and activated signal transducer and activator of transcription (STAT) 3 phosphorylation. Conclusions: Our results suggest that IL-10 attenuates ROS production, inflammation and fibrosis, and plays an important role in the inhibition of hyperglycaemia-induced SND by suppression of HCN4 downregulation. In addition, IL-10-mediated inhibition of p38 is dependent on STAT3 phosphorylation.

Scarce Occurrence of Calcification in Human Sinoatrial Nodal Arteries in Old Age.

To elucidate age-related changes of the sinoatrial (sinuatrial) nodal (SAN) artery, the authors investigated age-related changes of elements in the SAN artery by direct chemical analysis. In addition, the effects of different arterial origins, arterial sizes, and genders on element accumulation were investigated in the SAN artery. Fifty-nine formalin-fixed adult Thai hearts were dissected, and the following three types of the SAN artery were found: The first type was a single SAN artery arising from the right coronary artery (RCA). The second type was a single SAN artery arising from the proximal segment of the left circumflex artery (LCX). The third type was dual SAN artery arising from both the RCA and the LCX. For element analysis, both 41 single SAN arteries arising from the RCA and the LCX and 18 larger branches of dual SAN artery were used. After the arteries were incinerated with nitric acid and perchloric acid, element contents were determined by inductively coupled plasma-atomic emission spectrometry. It was found that seven element contents such as Ca, P, S, Mg, Zn, Fe, and Na did not change significantly in the SAN arteries with aging. Regarding the relationships among seven elements in the SAN arteries, extremely significant direct correlations were found among P, S, Mg, and Fe contents with one exception. However, no significant correlations were found between Ca and either P or Mg contents in the SAN arteries. To examine an effect of the different arterial origins on element accumulation, the SAN arteries were separated into the RCA and the LCX groups by the arterial origin and age-related changes of element contents were compared between two groups. It was found that there were no significant differences between the RCA and the LCX groups in age-related changes of Ca and P contents. No gender differences were found in age-related changes of Ca and P contents in the SAN arteries. To elucidate whether calcification occurred in the SAN arteries in old age, both the mass ratios of Ca/P and Mg/Ca were estimated in the SAN arteries. The mass ratio of Ca/P increased progressively in the SAN arteries with Ca increase, being not constant. The mass ratio of Mg/Ca decreased gradually in the SAN arteries with Ca increase, but the average mass ratio of Mg/Ca was very high, being 49.4 ± 16.5%. These results indicated that calcification scarcely occurred in the SAN arteries in old age, independently of the arterial origin and gender.

Real-time relationship between PKA biochemical signal network dynamics and increased action potential firing rate in heart pacemaker cells: Kinetics of PKA activation in heart pacemaker cells.

cAMP-PKA protein kinase is a key nodal signaling pathway that regulates a wide range of heart pacemaker cell functions. These functions are predicted to be involved in regulation of spontaneous action potential (AP) generation of these cells. Here we investigate if the kinetics and stoichiometry of increase in PKA activity match the increase in AP firing rate in response to ß-adrenergic receptor (ß-AR) stimulation or phosphodiesterase (PDE) inhibition, that alters the AP firing rate of heart sinoatrial pacemaker cells. In cultured adult rabbit pacemaker cells infected with an adenovirus expressing the FRET sensor AKAR3, the EC50 in response to graded increases in the intensity of ß-AR stimulation (by Isoproterenol) the magnitude of the increases in PKA activity and the spontaneous AP firing rate were similar (0.4±0.1nM vs. 0.6±0.15nM, respectively). Moreover, the kinetics (t1/2) of the increases in PKA activity and spontaneous AP firing rate in response to ß-AR stimulation or PDE inhibition were tightly linked. We characterized the system rate-limiting biochemical reactions by integrating these experimentally derived data into a mechanistic-computational model. Model simulations predicted that phospholamban phosphorylation is a potent target of the increase in PKA activity that links to increase in spontaneous AP firing rate. In summary, the kinetics and stoichiometry of increases in PKA activity in response to a physiological (ß-AR stimulation) or pharmacological (PDE inhibitor) stimuli match those of changes in the AP firing rate. Thus Ca(2+)-cAMP/PKA-dependent phosphorylation limits the rate and magnitude of increase in spontaneous AP firing rate.

Sick sinus syndrome and atrial fibrillation in older persons - A view from the sinoatrial nodal myocyte.

Sick sinus syndrome remains a highly relevant clinical entity, being responsible for the implantation of the majority of electronic pacemakers worldwide. It is an infinitely more complex disease than it was believed when first described in the mid part of the 20th century. It not only involves the innate leading pacemaker region of the heart, the sinoatrial node, but also the atrial myocardium, predisposing to atrial tachydysrhythmias. It remains controversial as to whether the dysfunction of the sinoatrial node directly causes the dysfunction of the atrial myocardium, or vice versa, or indeed whether these two aspects of the condition arise through some related underlying pathological mechanism, such as extracellular matrix remodeling, i.e., fibrosis. This review aims to shed new light on the myriad possible contributing factors in the development of sick sinus syndrome, with a particular focus on the sinoatrial nodal myocyte. This article is part of a Special Issue entitled CV Aging.

El Profesor Doctor Hernán Alessandri: su legado para las nuevas generaciones de / Professor Hernán Alessandri, M.D.: his legacy for the new generations of physicians

Professor Alessandri died in 1980. We started our residency in Internal Medicine about 30 years later. Considering the profound changes our society has witnessed, including medical practice, I would like to approach the meaning of his work for our generation. It is not the Father’s figure nor his Aura what inspires us today. Neither is his personality nor his shape. His universality comes from his transcendent image as a teacher. Today’s teachers live rough times, their social status has changed, their professional requirements have grown exponentially, they have to adapt to social phenomena like the Internet and multiculturalism. Being a teacher nowadays demands to be a multifaceted expert. Things have changed since Professor Alessandri made rounds with his patients. But a deeper look allows us to understand that everything returns to where it started: professional deontology of the teacher, never fading but transcendent. We know that Doctor Alessandri had the natural gift to keep faithful to that code with consistency and perseverance. He excelled with integrity in every aspect including professional betterment, constructive work for his institution, collegiality, a warm relationship with students and a model of social values. Beyond virtues and personal defects he will keep on being the mould in which present teachers should be formed, engraved in their souls and in the subconscious of students that seek to learn.

Upregulation of adenosine A1 receptors facilitates sinoatrial node dysfunction in chronic canine heart failure by exacerbating nodal conduction abnormalities revealed by novel dual-sided intramural optical mapping.

BACKGROUND: Although sinoatrial node (SAN) dysfunction is a hallmark of human heart failure (HF), the underlying mechanisms remain poorly understood. We aimed to examine the role of adenosine in SAN dysfunction and tachy-brady arrhythmias in chronic HF. METHODS AND RESULTS: We applied multiple approaches to characterize SAN structure, SAN function, and adenosine A1 receptor expression in control (n=17) and 4-month tachypacing-induced chronic HF (n=18) dogs. Novel intramural optical mapping of coronary-perfused right atrial preparations revealed that adenosine (10 µmol/L) markedly prolonged postpacing SAN conduction time in HF by 206 ± 99 milliseconds (versus 66 ± 21 milliseconds in controls; P=0.02). Adenosine induced SAN intranodal conduction block or microreentry in 6 of 8 dogs with HF versus 0 of 7 controls (P=0.007). Adenosine-induced SAN conduction abnormalities and automaticity depression caused postpacing atrial pauses in HF versus control dogs (17.1 ± 28.9 versus 1.5 ± 1.3 seconds; P<0.001). Furthermore, 10 µmol/L adenosine shortened atrial repolarization and led to pacing-induced atrial fibrillation in 6 of 7 HF versus 0 of 7 control dogs (P=0.002). Adenosine-induced SAN dysfunction and atrial fibrillation were abolished or prevented by adenosine A1 receptor antagonists (50 µmol/L theophylline/1 µmol/L 8-cyclopentyl-1,3-dipropylxanthine). Adenosine A1 receptor protein expression was significantly upregulated during HF in the SAN (by 47 ± 19%) and surrounding atrial myocardium (by 90 ± 40%). Interstitial fibrosis was significantly increased within the SAN in HF versus control dogs (38 ± 4% versus 23 ± 4%; P<0.001). CONCLUSIONS: In chronic HF, adenosine A1 receptor upregulation in SAN pacemaker and atrial cardiomyocytes may increase cardiac sensitivity to adenosine. This effect may exacerbate conduction abnormalities in the structurally impaired SAN, leading to SAN dysfunction, and potentiate atrial repolarization shortening, thereby facilitating atrial fibrillation. Atrial fibrillation may further depress SAN function and lead to tachy-brady arrhythmias in HF.

Epicardial/endocardial sinus node ablation after failed endocardial ablation for the treatment of inappropriate sinus tachycardia.

INTRODUCTION: Success of endocardial sinus node (SN) ablation for refractory inappropriate sinus tachycardia (IST) is limited by the epicardial location of the SN and potential damage to the phrenic nerve (PN). An epicardial approach may overcome these limitations. METHODS AND RESULTS: IST patients who failed endocardial ablation underwent an epicardial approach. Percutaneous pericardial access was obtained with a double wire technique for PN protection (i.e., with a balloon catheter), if needed. Earliest sinus activation was mapped and ablated with remapping for changes in P-wave morphology or sinus rate. The endpoint was total SN ablation (patients with atrial pacing [AP]); otherwise the target was a >25% decrease in sinus rate and inversion of P-wave axis. Five patients (all female, age 36 ± 4 years) underwent ablation. Two had prior AP, and 1 elected to have SN ablation and pacemaker during the same procedure. Three had prior endocardial ablation limited by PN proximity. Baseline sinus rate was 119 ± 20 bpm. After 35.2 ± 21.3 lesions (22.4 ± 21.7 epicardial, 12.8 ± 21.3 endocardial), 4 were in junctional rhythm, 1 in atrial rhythm at 90 bpm. This latter patient had symptom recurrence and underwent combined minimally invasive surgical/catheter SN cryoablation. Atrial tachycardia subsequently occurred and was successfully ablated. The only significant complication was pericarditis (3 patients). At last follow-up (30.4 ± 18.4 months), all had symptom resolution. Two were AP >99%, 1 was AP 54%. Two remain in ectopic atrial rhythm with controlled rates. CONCLUSIONS: Combined epicardial/endocardial SN ablation is a viable approach for patients with severely symptomatic IST after a failed endocardial attempt.

Muscarinic stimulation and pinacidil produce similar facilitation of tachyarrhythmia induction in rat isolated atria.

Atrial tachyarrhythmias, the most common type of cardiac arrhythmias, are associated with greater stroke risk. Muscarinic cholinergic agonists have been shown to facilitate atrial tachyarrhythmia maintenance in the absence of cardiac disease. This has been attributed to action potential shortening, which enhances myocardial electrical anisotropy, and thus creates a substrate for reentrant excitation. In this study, we describe a similar effect of the ATP-sensitive K(+) channel (KATP) opener pinacidil on tachyarrhythmia induction in isolated rat atria. Pinacidil, which activates a weakly inwardly-rectifying current in isolated atrial myocytes, enhanced arrhythmia induction in the right and left atria. This effect was abolished by the KATP blocker glibenclamide, but not by atropine, which rules out a possible indirect effect due to stimulation of acetylcholine release. However, pinacidil attenuated carbachol-induced tachyarrhythmia facilitation, which may indicate that the action of these agonists converges to a common cellular mechanism. Both agonists caused marked action potential shortening in isolated atrial myocytes. Moreover, during arrhythmia in the presence of pinacidil and carbachol, the atrial vectorelectrographic patterns were similar and consistent with reentrant propagation of the electrical activity. From these results, we conclude that the KATP channel opening is pro-arrhythmic in atrial tissue, which may pose as an additional risk in the scenario of myocardial hypoxia. Moreover, the similarity of the electrophysiological effects of pinacidil and carbachol is suggestive that the sole increase in background K(+) conductance is sufficient for atrial tachyarrhythmia facilitation.

Diabetes increases mortality after myocardial infarction by oxidizing CaMKII.

Diabetes increases oxidant stress and doubles the risk of dying after myocardial infarction, but the mechanisms underlying increased mortality are unknown. Mice with streptozotocin-induced diabetes developed profound heart rate slowing and doubled mortality compared with controls after myocardial infarction. Oxidized Ca(2+)/calmodulin-dependent protein kinase II (ox-CaMKII) was significantly increased in pacemaker tissues from diabetic patients compared with that in nondiabetic patients after myocardial infarction. Streptozotocin-treated mice had increased pacemaker cell ox-CaMKII and apoptosis, which were further enhanced by myocardial infarction. We developed a knockin mouse model of oxidation-resistant CaMKIIδ (MM-VV), the isoform associated with cardiovascular disease. Streptozotocin-treated MM-VV mice and WT mice infused with MitoTEMPO, a mitochondrial targeted antioxidant, expressed significantly less ox-CaMKII, exhibited increased pacemaker cell survival, maintained normal heart rates, and were resistant to diabetes-attributable mortality after myocardial infarction. Our findings suggest that activation of a mitochondrial/ox-CaMKII pathway contributes to increased sudden death in diabetic patients after myocardial infarction.

Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis.

Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca(2+) channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, whereas defects in Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue. These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue levels that favor the common manifestation of atrial arrhythmias and SAN dysfunction.

Age-related histopathological changes in the cardiac conducting system in the Turkish population: an evaluation of 202 autopsy cases.

BACKGROUND: Histopathological features of the cardiac conducting system (CCS) in the Turkish population have not been investigated previously. MATERIAL AND METHODS: We examined CCS of 202 autopsy heart specimens dissected between the years 2004 and 2005 in Bursa Forensic Medicine Institution. Of the 202 cases from all age groups, 154 were males and 48 were females. RESULTS: In our cases, an increase in fibrous and adipose tissue concordant with age, indicating an age-related nature, were detected. Fibrous and fatty tissue infiltration appeared at the age of 35. Fatty infiltration started between the ages 20 and 34 years at the sinoatrial node (SAN). There was no relationship between obesity and fatty tissue infiltration in SAN and atrioventricular node (AVN). In 4 cases calcification and in 19 cases inflammation was observed. Amyloid accumulation was not present. In 7 cases myocardial infarction not involving CCS was seen. In 1 case fibroelastoma was detected. CONCLUSIONS: In the Turkish population age-related fibrosis and fatty infiltration in CCS appeared at the age of 35 years and increased with age. Fatty infiltration in the SAN started at a younger age than that reported in the literature. In cases where the cause of death could not be determined, we could not detect lethal pathological features. However, we think that examination of the CCS will improve the quality of autopsy diagnosis.

A case of cor triatriatum with an abnormal P wave: the pacemaker action from the specialized tissue in the abnormal septum.

A boy presented with an abnormal P wave shown on an electrocardiogram (ECG) checkup at school. An echocardiogram and contrast-enhanced computed tomography (CT) showed cor triatriatum with a slit-like opening between the accessory chamber and the left atrium located along the interatrial septum. The boy underwent open heart surgery for excision of the anomalous membrane, and a postoperative ECG showed normal P waves. The excised tissue was examined immnunohistopathologically using antihyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) antibody and other staining. The authors confirmed the existence of cells positive to HCN4, indicating that they were sinoatrial node cells or at least cells with electrical automaticity.

Histologic findings of the sinus node and the perinodal area in street heroin addicts, victims of sudden unexpected death.

Sudden unexpected death is frequent in street heroin addicts. We conducted a histologic study of the sinus node (SN) to offer some evidence about the possible arrhythmogenic cause of death. Postmortem coronary angiography and microscopic examination of the SN and the perinodal area were performed in 50 heroin addicts (group 1) and in 50 nonaddicts (group 2), all men (16-40 years old). In heroin addicts, fatty and/or fibrous tissue replaced SN tissue in 21 cases (42%). Perinodal infiltration was found in 15 cases (30%). Fibromuscular dysplasia in branches of the sinus node artery (SNA) was found in eight cases (16%). Inflammation with focal and/or diffuse concentration of round cells was detected in the SN in 22 cases (44%). Old mural thrombi were also found in 13 cases (26%). The histologic changes in the SN and perinodal area offer an explanation about the possible mechanism of arrhythmia and sudden death in this population.

Insights into sick sinus syndrome from an inducible mouse model.

AIMS: Sick sinus syndrome is a generalized abnormality of cardiac impulse formation and is responsible for a large proportion of pacemaker implantations. Although the exact aetiology is not known, it is widely accepted that age-dependent degenerative fibrosis of nodal tissue is the most common cause. Despite its importance, an animal model for sick sinus syndrome is lacking. We attempted to generate a mouse model phenocopying the pathohistological changes as well as the characteristic arrhythmic manifestations of this syndrome. METHODS AND RESULTS: We crossed two genetically engineered mouse lines, ROSA-eGFP-DTA and HCN4-KiT-Cre, to achieve an inducible deletion of cells specifically in the cardiac pacemaking and conduction system. This deletion resulted in a degenerative fibrosis of nodal tissue, which accurately reflects the pathohistological findings in human sick sinus syndrome. The extent of the sino-atrial fibrosis could be controlled by varying the dosage of the inducing substance, tamoxifen. A high-dose protocol resulted in the complete ablation of all sino-atrial cells as demonstrated by histochemical analysis and quantitative reverse transcriptase-polymerase chain reaction. The animals developed a variety of arrhythmias, including progressive bradycardia, sinus pauses, supraventricular and ventricular tachycardia and chronotropic incompetence. Remarkably, the complete destruction of the primary pacemaker centre resulted in only a small increase in mortality. CONCLUSION: This study describes the generation and analysis of an inducible mouse model which closely reflects the pathophysiological characteristics of sick sinus syndrome. The model, with the ability to control the extent of nodal cell ablation and fibrosis, offers new insights into sick sinus syndrome and other cardiac conduction diseases.

Protective effects of adenosine in rabbit sinoatrial node ischemia-reperfusion model in vivo: control of arrhythmia by hyperpolarization-activated cyclic nucleotide-gated (HCN)4 channels.

Disturbance of cardiac rhythm is one of the consequences of myocardial ischemia/reperfusion injury. Many researchers have prompted considerable interests in developing therapeutic approaches for its control. In present study, we want to determine whether that adenosine pre- and postconditioning have protective effects on sinoatrial node ischemia/reperfusion injury on morphology, arrhythmia score, serological markers (CK-MB and cTnT), SOD activities, MDA levels and expression of HCN4 channels in SA node cells. According to the arrhythmia score recorded, whether adenosine used in terms of ischemia or reperfusion, the total number of arrhythmia was significantly reduced, as well as the number of its episodes was also markedly decreased. We have also shown a clear correlation between HCN4 channels expression and the dysfunction of SA node cells. HCN4 immunoreactivity decreased after adenosine pre- and postconditioning, but changes were significantly smaller in the cells of the SA node compared with cells of I/R group. The content of cTnT, CK-MB and MDA in adenosine pre- and postconditioning group reduced significantly; but the level of SOD increased significantly. Histological examination and electron microscopy observations found in adenosine pre- and postconditioning group sinoatrial node injury also mitigated. These findings suggested that adenosine pre- or postconditioning were to reduce the incidence of ischemia/reperfusion arrhythmias, reduce myocardial ischemia reperfusion injury. The mechanism was to stabilize the SA node cells membrane and one possible mechanism involves modulation of HCN4 channels in pacemaker cells of the sinoatrial node.

Capillary supply to the sinus node in subjects with long-term atrial fibrillation.

BACKGROUND: Atrial ischemia, and sinus node ischemia in particular, may be involved in the pathogenesis of atrial fibrillation. In this study we compared the sinus node blood capillary content in normal hearts in sinus rhythm and in pathologic hearts with chronic atrial fibrillation and we analyzed the ultrastructural features of such capillaries. METHODS: Sinus node biopsy specimens were obtained from 16 patients in chronic atrial fibrillation undergoing open heart surgery. Control sinus node specimens of normal hearts were obtained at autopsy from 7 subjects. Specimens were processed for immunohistochemical, light microscopy and transmission electron microscopy analysis and compared grossly and with morphometric techniques. RESULTS: The proportion of sinus node tissue corresponding to capillaries, defined as blood vessel density (or BVD), was estimated as 1.06 +/- 1.47% for the atrial fibrillation group versus 2.12 +/- 2.0% for controls (p < 0001). Internal capillary diameter averaged 21.6 microm in the atrial fibrillation group and 24.2 microm in controls (p = 0.175), whereas external diameter averaged 32.2 microm in the atrial fibrillation group and 38.9 microm in controls (p = 0.052). Ultrastructural analysis demonstrated scarce and interrupted myoendocardial bridges and abnormal deposits of elastic fibers under the endothelial basal membrane at the level of precapillary sphincters and metaarterioles of atrial fibrillation specimens. CONCLUSIONS: There is a significant reduction in the amount of capillaries in the sinus node of hearts in chronic atrial fibrillation. Our findings would support a potential association between sinus node tissue ischemia and chronic atrial fibrillation.