Ventricular tachyarrhythmias are the main cause of sudden death in patients after myocardial infarction. Here we show that transplantation of embryonic cardiomyocytes (eCMs) in myocardial infarcts protects against the induction of ventricular tachycardia (VT) in mice. Engraftment of eCMs, but not skeletal myoblasts (SMs), bone marrow cells or cardiac myofibroblasts, markedly decreased the incidence of VT induced by in vivo pacing. eCM engraftment results in improved electrical coupling between the surrounding myocardium and the infarct region, and Ca2+ signals from engrafted eCMs expressing a genetically encoded Ca2+ indicator could be entrained during sinoatrial cardiac activation in vivo. eCM grafts also increased conduction velocity and decreased the incidence of conduction block within the infarct. VT protection is critically dependent on expression of the gap-junction protein connexin 43 (Cx43; also known as Gja1): SMs genetically engineered to express Cx43 conferred a similar protection to that of eCMs against induced VT. Thus, engraftment of Cx43-expressing myocytes has the potential to reduce life-threatening post-infarct arrhythmias through the augmentation of intercellular coupling, suggesting autologous strategies for cardiac cell-based therapy.

Abstract-To study endothelial cell (EC)-specific Ca 2ϩ signaling in vivo we engineered transgenic mice in which the Ca 2ϩ sensor GCaMP2 is placed under control of endogenous connexin40 (Cx40) transcription regulatory elements within a bacterial artificial chromosome (BAC), resulting in high sensor expression in arterial ECs, atrial myocytes, and cardiac Purkinje fibers. High signal/noise Ca 2ϩ signals were obtained in Cx40 BAC -GCaMP2 mice within the ventricular Purkinje cell network in vitro and in ECs of cremaster muscle arterioles in vivo. Microiontophoresis of acetylcholine (ACh) onto arterioles triggered a transient increase in EC Ca 2ϩ fluorescence that propagated along the arteriole with an initial velocity of Ϸ116 m/s (nϭ28) and decayed over distances up to 974 m. The local rise in EC Ca 2ϩ was followed (delay, 830Ϯ60 ms; nϭ8) by vasodilation that conducted rapidly (mm/s), bidirectionally, and into branches for distances exceeding 1 mm. At intermediate distances (300 to 600 m), rapidly-conducted vasodilation occurred without changing EC Ca 2ϩ , and additional dilation occurred after arrival of a Ca 2ϩ wave. In contrast, focal delivery of sodium nitroprusside evoked similar local dilations without Ca 2ϩ signaling or conduction. We conclude that in vivo responses to ACh in arterioles consists of 2 phases: (1) a rapidly-conducted vasodilation initiated by a local rise in EC Ca 2ϩ but independent of EC Ca 2ϩ signaling at remote sites; and (2) a slower complementary dilation associated with a Ca 2ϩ wave that propagates along the endothelium. 2ϩ signaling is implicated in regulating the resistance microvasculature. [1][2][3][4][5] Conducted electrical signals travel for millimeters along the vessel wall, 6 mediate coordinated vasomotor responses to localized stimuli, 7-9 and involve distinct Ca 2ϩ signals within smooth muscle (SM) and ECs. For example, arteriolar dilation in response to the endothelium-dependent vasodilator acetylcholine (ACh) involves an increase in ECs 2 and decrease in SM 10 Ca 2ϩ . Although recent intravital studies have demonstrated a crucial role for the endothelium in conducted vasodilation, 9 the extent to which Ca 2ϩ signals are transmitted along the arteriolar wall and the mechanisms underlying Ca 2ϩ transmission are controversial. Some studies indicate that EC Ca 2ϩ responses to dilatory stimuli are localized, 1,2 whereas others indicate that Ca 2ϩ signals can travel along the endothelium for a millimeter or more. 5,11 The majority of information concerning microvascular Ca 2ϩ signaling has been derived from isolated vessels studied in vitro, 4,5,12 largely because of the difficulty of selectively loading ECs or SM cells with Ca 2ϩ sensitive dyes in vivo. 1,10 A fundamental limitation to isolated arterioles is their disconnection from networks in which they normally reside. The extent to which manipulation of arterioles to obtain dye loading and the loss of physiological parameters (eg, pressure or flow) alter Ca 2ϩ signaling is unknown. Therefore, alternative approaches are necessa...

Spatiotemporal wave activities in excitable heart tissues have long been the subject of numerous studies because they underlie different forms of cardiac arrhythmias. In particular, understanding the dynamics and the instabilities of spiral waves have become very important because they can cause reentrant tachycardia and their subsequent transitions to fibrillation. Although many aspects of cardiac spiral waves have been investigated through experiments and model simulations, their complex properties are far from well understood. Here, we show that intriguing complexperiodic (such as period-2, period-3, period-4, or aperiodic) spiral wave states can arise in monolayer tissues of cardiac cell culture in vitro, and demonstrate that these different dynamic states can coexist with abrupt and spontaneous transitions among them without any change in system parameters; in other words, the medium supports multistability. Based on extensive image data analysis, we have confirmed that these spiral waves are driven by their tips tracing complex orbits whose unusual, meandering shapes are formed by delicate interplay between localized conduction blocks and nonlinear properties of the culture medium.arrhythmia ͉ cardiac spiral waves ͉ complex oscillations

Globally, the demand for improved health care delivery while managing escalating costs is a major challenge. Measuring the biomagnetic fields that emanate from the human brain already impacts the treatment of epilepsy, brain tumours and other brain disorders. This roadmap explores how superconducting technologies are poised to impact health care. Biomagnetism is the study of magnetic fields of biological origin. Biomagnetic fields are typically very weak, often in the femtotesla range, making their measurement challenging. The earliest in vivo human measurements were made with room-temperature coils. In 1963, Baule and McFee (1963 Am. Heart J. 55 95−6) reported the magnetic field produced by electric currents in the heart (‘magnetocardiography’), and in 1968, Cohen (1968 Science 161 784−6) described the magnetic field generated by alpha-rhythm currents in the brain (‘magnetoencephalography’). Subsequently, in 1970, Cohen et al (1970 Appl. Phys. Lett. 16 278–80) reported the recording of a magnetocardiogram using a Superconducting QUantum Interference Device (SQUID). Just two years later, in 1972, Cohen (1972 Science 175 664–6) described the use of a SQUID in magnetoencephalography. These last two papers set the scene for applications of SQUIDs in biomagnetism, the subject of this roadmap. The SQUID is a combination of two fundamental properties of superconductors. The first is flux quantization—the fact that the magnetic flux Φ in a closed superconducting loop is quantized in units of the magnetic flux quantum, Φ0 ≡ h/2e, ≈ 2.07 × 10−15 Tm2 (Deaver and Fairbank 1961 Phys. Rev. Lett. 7 43–6, Doll R and Näbauer M 1961 Phys. Rev. Lett. 7 51–2). Here, h is the Planck constant and e the elementary charge. The second property is the Josephson effect, predicted in 1962 by Josephson (1962 Phys. Lett. 1 251–3) and observed by Anderson and Rowell (1963 Phys. Rev. Lett. 10 230–2) in 1963. The Josephson junction consists of two weakly coupled superconductors separated by a tunnel barrier or other weak link. A tiny electric current is able to flow between the superconductors as a supercurrent, without developing a voltage across them. At currents above the ‘critical current’ (maximum supercurrent), however, a voltage is developed. In 1964, Jaklevic et al (1964 Phys. Rev. Lett. 12 159–60) observed quantum interference between two Josephson junctions connected in series on a superconducting loop, giving birth to the dc SQUID. The essential property of the SQUID is that a steady increase in the magnetic flux threading the loop causes the critical current to oscillate with a period of one flux quantum. In today’s SQUIDs, using conventional semiconductor readout electronics, one can typically detect a change in Φ corresponding to 10−6 Φ0 in one second. Although early practical SQUIDs were usually made from bulk superconductors, for example, niobium or Pb-Sn solder blobs, today’s devices are invariably made from thin superconducting films patterned with photolithography or even electron lithography. An extensive descriptio...