The Anatomy of the Atrioventricular Node.

© Springer-Verlag London 2014. It is axiomatic that understanding of abnormal anatomy requires a thorough knowledge of normal findings. Nowadays, this knowledge should be based on the appreciation of the location of the heart within the chest, since the basic rule of anatomy is that all structures should be described relative to the anatomical position. The discrepancy between the planes of the heart and the planes of the body should not detract from the importance of abiding by this rule. Having understood the discrepancies between the axes, it is then important to appreciate that the so-called right chambers are anterior to their allegedly left-sided counterparts, with the left atrium being the most posterior of the cardiac chambers. The atriums possess venous components, appendages, and vestibules, being separated by the septum. The left atrium also has an obvious body. The ventricles are best assessed on the basis of possessing inlet, apical trabecular, and outlet components. The arterial trunks spiral as they extend from the base of the heart into the mediastinum. The cardiac valves are best considered in terms of atrioventricular and arterial complexes, with the leaflets being the working units of all the valves. The atrioventricular valves also have a well-formed tension apparatus, while the arterial valvar leaflets are supported by the valvar sinuses. There are atrial, atrioventricular, and ventricular septal structures. Accounts of the fibrous skeleton are markedly exaggerated, with the so-called central fibrous body being the best formed fibrous element within the heart. This part is perforated by the atrioventricular conduction axis, with the cardiac impulse being generated by the sinus node and slowed in the atrioventricular node. The major coronary arteries and veins occupy the atrioventricular and interventricular grooves, with two coronary arteries arising from the aortic root and most of the veins draining to the coronary sinus located within the left atrioventricular groove.

Knowledge of cardiac development can provide the basis for understanding the morphogenesis of congenital cardiac malformations. Only recently, however, has the quality of information regarding cardiac embryology been sufficient to justify this approach. In this review, we show how such knowledge of development of the normal atrial and ventricular septal structures underscores the interpretation of the lesions that provide the basis for interatrial and interventricular shunting of blood. We show that current concepts of atrial septation, which frequently depend on a suggested formation of an extensive secondary septum, are simplistic. There are additional contributions beyond growth of the primary septum, but the new tissue is added to form the ventral buttress of the definitive atrial septum, rather than its cranial margin, as is usually depicted. We show that the ventricular septum possesses muscular and membranous components, with the entirety of the muscular septum produced concomitant with the so-called ballooning of the apical ventricular component. It is expansion of the atrioventricular canal that creates the inlet of the right ventricle, with no separate formation of an "inlet" septum. The proximal parts of the outflow cushions initially form a septal structure between the developing ventricular outlets, but this becomes converted into the free-standing muscular subpulmonary infundibulum as the aortic outlet is transferred to the left ventricle. These features of normal development are then shown to provide the basis for understanding of the channels that provide the means for interatrial and interventricular shunting.

The isolation of ventricular cardiac myocytes from animal and human hearts is a fundamental method in cardiac research. Animal cardiomyocytes are commonly isolated by coronary perfusion with digestive enzymes. However, isolating human cardiomyocytes is challenging because human myocardial specimens usually do not allow for coronary perfusion, and alternative isolation protocols result in poor yields of viable cells. In addition, human myocardial specimens are rare and only regularly available at institutions with on-site cardiac surgery. This hampers the translation of findings from animal to human cardiomyocytes. Described here is a reliable protocol that enables efficient isolation of ventricular myocytes from human and animal myocardium. To increase the surface-to-volume ratio while minimizing cell damage, myocardial tissue slices 300 µm thick are generated from myocardial specimens with a vibratome. Tissue slices are then digested with protease and collagenase. Rat myocardium was used to establish the protocol and quantify yields of viable, calcium-tolerant myocytes by flow-cytometric cell counting. Comparison with the commonly used tissue-chunk method showed significantly higher yields of rod-shaped cardiomyocytes (41.5 ± 11.9 vs. 7.89 ± 3.6%, p < 0.05). The protocol was translated to failing and non-failing human myocardium, where yields were similar as in rat myocardium and, again, markedly higher than with the tissue-chunk method (45.0 ± 15.0 vs. 6.87 ± 5.23 cells/mg, p < 0.05). Notably, with the protocol presented it is possible to isolate reasonable numbers of viable human cardiomyocytes (9-200 cells/mg) from minimal amounts of tissue (<50 mg). Thus, the method is applicable to healthy and failing myocardium from both human and animal hearts. Furthermore, it is possible to isolate excitable and contractile myocytes from human tissue specimens stored for up to 36 h in cold cardioplegic solution, rendering the method particularly useful for laboratories at institutions without on-site cardiac surgery.

Histamine is highly concentrated in the heart of animals and humans. Excessive release in pathophysiological conditions, such as immediate hypersensitivity and septic shock, causes cardiac dysfunction and arrhythmias. Previous pharmacological studies revealed that H(1) and H(2) receptors mediate these effects. Yet, an accurate estimate of the distribution and molecular characteristics of cardiac histamine receptors is missing. Recently, the genes encoding H(1) and H(2) receptors have been cloned, and the amino acid sequence and protein structure have been elucidated. Accordingly, we analyzed gene and protein expression levels of H(1) and H(2) receptors in atria and ventricles of guinea pig, rabbit, rat, and human hearts. With immunocytochemical techniques, we examined the regional expression of H(1) and H(2) receptor proteins in the sinoatrial and atrioventricular nodes and surrounding myocardium of the guinea pig heart. Northern and Western blot studies revealed that cardiac histamine H(1) and H(2) receptors are variably distributed among different mammalian species and different regions of the heart, whereas H(2) receptors are abundantly expressed in human atrial and ventricular myocardium. These findings agree with those of previous pharmacological studies, clearly demonstrating that the responses of the heart to histamine depend on the expression level of H(1) and H(2) receptors. The highly abundant expression of H(2) receptors in the human heart substantiates histamine arrhythmogenicity in various disease states. The new knowledge of a differential distribution of histamine receptor subtypes in the human heart will foster a better understanding of histamine roles in cardiovascular pathophysiology and may contribute to new therapeutic approaches to histamine-induced cardiac dysfunctions.

See Article by Hu et al The PKC (protein kinase C) family consists of ≈13 members within 3 classes. PKCα belongs to the conventional/classical class of PKCs, together with PKCβ1, PKCβ2, and PKCγ. The conventional PKCs are Ca2+ and lipid activated and function downstream of Gq protein-coupled receptor signaling, which, when over activated, causes pathological cardiac remodeling and heart failure.1 PKCα and PKCβ1/II have been identified in the rodent and human heart, and PKCα expression or activity have been reported to increase in the diseased heart.1 Studies in PKCα genetic mouse models, and preclinical studies with PKC inhibitors in rodents and large animal models, have consistently suggested that inhibiting PKCα in the failing heart would be beneficial.2–9 The PKC inhibitors used have not been specific for PKCα alone (eg, ruboxistaurin, Ro-32–0432, and Ro-31–8220 inhibit PKCα/β/γ). However, PKCα is the most abundant isoform in mouse heart (based on protein content)10 and ruboxistaurin was shown to provide benefit in PKCβ/γ−/− mice subjected to pressure overload, the beneficial effects of these inhibitors has been attributed to inhibition of PKCα.2 The development of PKC-specific inhibitors has been of interest for several diseases, including those of cardiac pathogenesis (heart failure and atherosclerosis). However, to date, results from clinical trials have been disappointing.1 In the current issue of Circulation: Genomic and Precision Medicine , Hu et al11 undertook a study to ascertain the effects of reduced PKCα abundance in human left ventricle (LV) tissue. This was of interest because although animal studies had convincingly shown that inhibition of PKCα provided cardiac protection, the impact on the human heart was not clear. The identification of …

Uptake of purine substrates shows major physiological variations in mammalian skin fibroblasts

New Insights Into the Pathophysiology of Coronary Arteries by Epicardial High Frequency Echocardiography

The direct-current magnetocardiogram, which shows the T-Q (baseline) shift, is used to clarify the cause of S-T depression induced by stress testing in the human heart. Measurements are made of the amount of baseline shift associated with the S-T depression. Results are presented of a well-documented patient, with typical coronary artery disease, undergoing a two-step exercise test. Before exercise, there was no S-T or baseline shift. During exercise, the S-T segment became depressed and the baseline segment was simultaneously elevated, at about 70% of the S-T amplitude. After termination of exercise, the baseline elevation disappeared somewhat more rapidly than the S-T depression. These results were consistent in repeated tests of this patient. Because the baseline shift is a reflection of an injury current, these results confirm the belief that exercise-induced S-T depression is mostly due to an injury current which is interrupted during the S-T interval. The baseline shift seen here is the first non-invasive measurement of an injury current in the human heart, and its presence and time-course generally agree with measurements in the animal heart. This work also confirms that the direct-current magnetocardiogram, although not practical for clinical purposes, is useful as a research tool.

The assessment of chemotherapeutic effects of vinca alkaloids by immunofluorescence and flow cytometry

Abnormal myocardial acoustic properties in diabetic patients and their correlation with the severity of disease

Brief optogenetic stimulation of thalamocortical axons evoked a 400 Hz wavelet, 'ripplet,' in the extracellular field potential in cortical layer 4, together with phase-locked spike bursts in fast-spiking inhibitory interneurons and alternating excitatory and inhibitory synaptic currents in excitatory cells.

Expression of innate immune response proteins, including IL-1beta, TNF, and the cytokine-inducible isoform of nitric oxide synthase (iNOS), have been documented in the hearts of humans and experimental animals with heart failure regardless of etiology, although the proximal events leading to their expression are unknown. Noting that expression of a human homologue of Drosophila Toll, a proximal innate immunity transmembrane signaling protein in the fly, now termed human Toll-like receptor 4 (hTLR4), appeared to be relatively high in the heart, we examined TLR4 mRNA and protein abundance in isolated cellular constituents of cardiac muscle and in normal and abnormal murine, rat, and human myocardium. TLR4 expression levels in cardiac myocytes and in coronary microvascular endothelial cells could be enhanced by either LPS or IL-1beta, an effect inhibited by the oxygen radical scavenger PDTC. Transfection of a constitutively active TLR4 construct, CD4/hTLR4, resulted in activation of a nuclear factor-kappaB reporter construct, but not of an AP-1 or an iNOS reporter construct, in cardiac myocytes. In normal murine, rat, and human myocardium, TLR4 expression was diffuse, and presumably cytoplasmic, in cardiac myocytes. However, in remodeling murine myocardium remote from sites of ischemic injury and in heart tissue from patients with idiopathic dilated cardiomyopathy, focal areas of intense TLR4 staining were observed in juxtaposed regions of 2 or more adjacent myocytes; this staining was not observed in control myocardium. Increased expression and signaling by TLR4, and perhaps other Toll homologues, may contribute to the activation of innate immunity in injured myocardium.

Acute myocardial infarction (AMI) is one of the major leading causes of death in humans globally. Recently, increased levels of recruited macrophages and AGE-albumin were observed in the hearts of humans and animals with acute myocardial infarction. Thus, the purposes of this study were to investigate whether the elevated levels of AGE-albumin from activated macrophage cells are implicated in ischemia-induced cardiomyocyte death and to develop therapeutic strategies for AMI based on its underlying molecular mechanisms with respect to AGEs. The present study demonstrated that activated macrophages and AGE-albumin were observed in heart tissues obtained from humans and rats with AMI incidences. In the cellular model of AMI, it was found that increased expression of AGE-albumin was shown to be co-localized with macrophages, and the presence of AGE-albumin led to increased expression of RAGE through the mitogen-activated protein kinase pathway. After revealing cardiomyocyte apoptosis induced by toxicity of the AGE-RAGE system, sRAGE-secreting MSCs were generated using the CRISPR/Cas9 platform to investigate the therapeutic effects of sRAGE-MSCs in an AMI rat model. Gene-edited sRAGE-MSCs showed greater therapeutic effects against AMI pathogenesis in rat models compared to mock MSCs, and promising results of the functional improvement of stem cells could result in significant improvements in the clinical management of cardiovascular diseases.

Myocardial bridging is a frequent anomaly of the heart in humans and other animals. A myocardial bridge is typically characterized by the systolic narrowing seen with traditional catheter angiography, but this abnormality is not by itself a sign of ischemia or the need for intervention. In particular, transient spontaneous angina must be corroborated by reproducible narrowing during acetylcholine testing; this narrowing occurs during resting conditions and is responsive to nitroglycerin administration. Ischemia in myocardial bridging can result from acquired arterial wall disease (coronary artery atherosclerotic disease) or from instances of coronary spasm. Clinical evaluation should seek to identify baseline features such as myocardial bridge thickness (by using computerized axial tomography or intravascular ultrasonography) and the severity of systolic compression or reproducible spasticity (by administering acetylcholine). Nuclear myocardial scintigraphy is usually negative in patients with isolated myocardial bridging. Spastic coronary hyperactivity must be treated initially with antispasmodic medications, such as calcium channel blockers and nitrates, rather than by percutaneous stent placement or bypass surgery. Only exceptionally prolonged and critically severe spasm can induce intraluminal clotting and acute myocardial infarction. Recognizing the exceptionality and variability of ischemic presentations related to myocardial bridging is essential, as is establishing appropriate investigational methods for each of these facets of the condition.

Cardiomyocytes derived from human-induced pluripotent stem cell culture in rod-shaped micropattern