Abstract-Surface electrode recordings cannot delineate the activation within the human or canine sinoatrial node (SAN) because they are intramural structures. Thus, the site of origin of excitation and conduction pathway(s) within the SAN of these mammals remains unknown. Canine right atrial preparations (nϭ7) were optically mapped. The SAN 3D structure and protein expression were mapped using immunohistochemistry. SAN optical action potentials had diastolic depolarization and multiple upstroke components that corresponded to the separate excitations of the node and surface atrial layers. Pacing-induced SAN exit block eliminated atrial optical action potential components but retained SAN optical action potential components. Excitation originated in the SAN (cycle length, 557Ϯ72 ms) and slowly spread (1.2 to 14 cm/sec) within the SAN, failing to directly excite the crista terminalis and intraatrial septum. After a 49Ϯ22 ms conduction delay within the SAN, excitation reached the atrial myocardium via superior and/or inferior sinoatrial exit pathways 8.8Ϯ3.2 mm from the leading pacemaker site. The ellipsoidal 13.7Ϯ2.8/4.9Ϯ0.6 mm SAN structure was functionally insulated from the atrium. This insulation coincided with connexin43-negative regions at the borders of the node, connective tissue, and coronary arteries. During normal sinus rhythm, the canine SAN is functionally insulated from the surrounding atrial myocardium except for 2 (or more) narrow superior and inferior sinoatrial exit pathways separated by 12.8Ϯ4.1 mm. Conduction failure in these sinoatrial exit pathways leads to SAN exit block and is a modulator of heart rate. The clinical signs of SAN dysfunction include bradycardia, sinus pauses, sinus arrest, sinus exit block, and reentrant arrhythmias. 3,4 Although the syndrome may have many causes and commonly affects elderly persons, it usually is idiopathic. 5 Studies of human SAN function are complicated by the inability of epior endocardial mapping to detect the origin and slow propagation of action potentials (APs) within the SAN before it activates adjacent atrial myocardium. 6,7 Sinus rhythm (SR) is physiologically controlled by autonomic modulation of pacemaker ion channels, 8 calcium handling, 9 and shifts of the leading pacemaker site. 10 -12 Anatomic structure and electrophysiological heterogeneity play important roles in SAN excitation under various conditions. 6 Recently, we investigated activation patterns in the rabbit SAN using optical mapping, 13 which is the only available technology that allows the resolution of simultaneous changes in the activation pattern and AP morphology from multiple sites. In that study, we demonstrated that the rabbit SAN is functionally insulated from the atrial septum. 13 However, the rabbit SAN is essentially a 2D structure 14 in contrast to the 3D structure of the canine 7,15,16 and human 17,18 SANs. Bromberg et al 7 suggested that the canine SAN may be functionally insulated from the surrounding atrial myocytes, except for a limited number of exit si...

Traumatic brain injury (TBI) is linked to several pathologies for which there is a lack of understanding of disease mechanisms and therapeutic strategies. To elucidate injury mechanisms, it is important to consider how physical forces are transmitted and transduced across all spatial scales of the brain. Although the mechanical response of the brain is typically characterized by its material properties and biological structure, cellular mechanotransduction mechanisms also exist. Such mechanisms can affect physiological processes by responding to exogenous mechanical forces directed through sub-cellular components, such as extracellular matrix and cell adhesion molecules, to mechanosensitive intracellular structures that regulate mechanochemical signaling pathways. We suggest that cellular mechanotransduction may be an important mechanism underlying the initiation of cell and sub-cellular injuries ultimately responsible for the diffuse pathological damage and clinical symptoms observed in TBI, thereby providing potential therapeutic opportunities not previously explored in TBI.

Microphysiological systems and organs-on-chips promise to accelerate biomedical and pharmaceutical research by providing accurate in vitro replicas of human tissue. Aside from addressing the physiological accuracy of the model tissues, there is a pressing need for improving the throughput of these platforms. To do so, scalable data acquisition strategies must be introduced. To this end, we here present an instrumented 24-well plate platform for higher-throughput studies of engineered human stem cell-derived cardiac muscle tissues that recapitulate the laminar structure of the native ventricle. In each well of the platform, an embedded flexible strain gauge provides continuous and non-invasive readout of the contractile stress and beat rate of an engineered cardiac tissue. The sensors are based on micro-cracked titanium-gold thin films, which ensure that the sensors are highly compliant and robust. We demonstrate the value of the platform for toxicology and drug-testing purposes by performing 12 complete dose-response studies of cardiac and cardiotoxic drugs. Additionally, we showcase the ability to couple the cardiac tissues with endothelial barriers. In these studies, which mimic the passage of drugs through the blood vessels to the musculature of the heart, we regulate the temporal onset of cardiac drug responses by modulating endothelial barrier permeability in vitro.