Longer Lasting Torsade de Pointes Arrhythmias Require Reentry for its Maintenance in the CAVB Dog Model
Marc A. Vos Ph.D.
The mechanism of Torsade de Pointes arrhythmias (TdP) has been under debate for many years. Focal activity as well as reentry have both been mentioned in the intiation as perpetuation of TdP. Therefore, the arrhythmogenic mechanisms responsible for TdP were once more investigated in the CAVB dog model, known for its high susceptibility for TdP. In five TdP-sensitive CAVB dogs, 56 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Nonterminating (NT) episodes were defibrillated after 10s. Software was developed to automatically detect activation times and to create 3D visualisations of the arrhythmia. For each episode ...Read More
Emilia Entcheva Ph.D.
Optical targeting (stimulation or recording) allows distributed parallel access to thousands and even millions of cells and locations at the same time, and within the tissue setting; optical targeting is high-throughput by nature. In this talk, I will discuss and demonstrate the combination of optogenetic stimulation with optical imaging of electrical activity in cardiomyocytes, i.e. the realization of “all-optical electrophysiology” in a high-throughput manner (HTS). Examples will include demonstration of cardiac “wave steering” by light and the use of a new fully-automated all-optical HTS platform (OptoDyCE) for drug screening using patient-derived cardiomyocytes (iPS-CMs).
Saman Nazarian M.D., Ph.D.
Peter J. Mohler Ph.D.
Our research is focused on the mechanisms underlying the targeting and regulation of membrane-associated (ion channels, transporters, receptors) and signaling proteins in cardiac and other excitable cells. In particular, we are interested in the role of membrane-associated ankyrin and spectrin family of polypeptides in the targeting and function of ion channels and transporters as well as kinases and phosphatases. A primary focus of the lab is the role of the ankyrin-G-based pathway for targeting voltage gated sodium channels to the intercalated disc of cardiomyocytes. We have discovered a direct requirement of ankyrin-G for Na channel targeting and have linked human ...Read More
Blanca Rodriguez Ph.D.
Amit Noheria M.B.B.S. (M.D.), S.M.
Andrew D. McCulloch Ph.D.
Mechanical stretch of cardiac muscle affects myocyte electrophysiology is potentially arrhythmogenic. We investigated the effects of stretch in vitro and in the intact heart on action potential conduction. Using optical mapping to measure in isolated mouse hearts and in micropatterned mouse cardiomyocyte we found that conduction velocity decreased rapidly and reversibly with volume loading and stretch. This slowing was not altered by stretch-activated channel inhibition, but was abrogated when caveolae were disrupted by genetic deletion of caveolin-3 or chemical depletion of membrane cholesterol. Electron microscopy showed that stretch in wild-type mouse hearts, causes recruitment of caveolae to the sarcolemma. Stretch ...Read More
Quantitative T-wave Alternans Analysis for Sudden Cardiac Death Risk Assessment and Guiding Therapy: Answered and Unanswered Questions
Richard L. Verrier Ph.D., F.A.C.C., F.H.R.S.
Identification of individuals at risk for sudden cardiac death (SCD), the main cause of adult mortality in developed countries, remains a major challenge. The scope of this public health problem is sizeable, as one million SCDs occur annually worldwide. In 30% to 40% of cases, death is the first indication of underlying heart disease. The main contemporary noninvasive marker, left ventricular ejection fraction (LVEF), has not proved adequately reliable, as the majority of individuals who die suddenly have relatively preserved cardiac mechanical function. Monitoring of T-wave alternans (TWA), a beat-to-beat fluctuation in ST-segment or T-wave morphology, on ambulatory electrocardiogram ECG ...Read More
TingTing Hong M.D.; Ph.D.
The Hong Lab has cloned the cardiac isoform of the membrane deformation protein BIN1, which we refer to as cBIN1. The story of cBIN1 originated as a protein trafficking finding, identifying how calcium channels are delivered to T-tubule membrane. In subsequent studies, they have found that cBIN1 forms membrane microdomains in T-tubule membrane, affecting calcium transients, dyad organization, and membrane excitability. In heart failure, cBIN1 is reduced. cBIN1 is also turned over into blood from viable cardiomyocytes. In clinical studies, they are finding that cBIN1 provides a window into the metabolic health of heart muscle and may help in clinical decision making.
Phillip S. Cuculich M.D. and Clifford G. Robinson M.D.
Regulation of Cardiac Calcium Channels in the Fight-or-Flight Response: From Molecular Mechanisms to Heart Failure
William Catterall Ph.D.
Intracellular calcium transients generated by activation of voltage-gated calcium (CaV) channels generate local signals, which initiate physiological processes such as secretion, synaptic transmission, and excitation-contraction coupling. Regulation of calcium entry through CaV channels is crucial for control of these physiological processes. In this article, I review experimental results that have emerged over several years showing that cardiac CaV1.2 channels form a local signaling complex, in which their proteolytically processed distal C-terminal domain, an A-Kinase Anchoring Protein, and cyclic AMP-dependent protein kinase (PKA) interact directly with the transmembrane core of the ion channel through the proximal C-terminal domain. This signaling complex ...Read More
Scorpions, Snakes, Insecticides and Coffee: Insights into the Genesis of Calcium-Dependent Arrhythmias
Héctor H. Valdivia M.D., Ph.D.