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Identifying the role of crosstalk signaling between energy and electrical activities in the atria
In tissues with high and rapidly fluctuating metabolic rates such as cardiac tissue, the mitochondria are the powerhouses of the cell. The mechanisms that match ATP supply to demand have been investigated since the early 50’s. However, the identity and the specific targets of the control mechanisms for matching ATP supply and demand, even under normal conditions, are still the subject of controversy.
Recently, the mitochondria have come to be viewed not only as the organelles that receive signals from ATP consumers, but because mitochondrial dysfunction have been implicated in cardiovascular diseases, the mitochondria can also affect ATP consumer activity. It is also well documented that cardiovascular diseases are associated with electrical disorders in the atria. However, current experimental and numerical methods do not allow us to determine which defect (electric or energetic) is the upstream, causative event and which is the downstream consequence and whether the two are inter-related.
Therefore, it is not surprising that there is no effective drug treatment for a cardiac disease such as atrial fibrillation, the most common sustained arrhythmia, and one which increases the risk of stroke and heart failure.
The goal of this project is to investigate the dynamics and localization of the crosstalk between cardiac ionic channels and energy metabolism under different working regimes of the atrial cells. Investigating the role of perturbations in energetic metabolism on electrical activity in the atria has the potential to improve patient care and assist in developing new, safer, and more successful therapies.
The ultrastructural remodeling of Ca2+ and PKA signaling in failing heart pacemaker cells
Cells within the sinoatrial node, the heart’s pacemaker, initiate each normal heartbeat. In pacemaker cells from the sinoatrial node, Ca2+ activates adenylate cyclase to generate a high basal level of cAMP-mediated/protein kinase A (PKA)-dependent phosphorylation of different proteins on the surface membrane and on the sarcoplasmic reticulum (SR). The SR, acting as a Ca2+ clock, rhythmically discharges diastolic local Ca2+ releases (LCRs) beneath the cell surface membrane; LCRs activate an inward Na+-Ca2+ exchanger current that accelerates the rate of diastolic membrane depolarization together with the f channel current. In response to diastolic membrane depolarization, L-type Ca2+
channels (LCCs) are open and activate the ryanodine receptor (RyR) to further release Ca2+ from the SR,via the Ca2+-induced Ca2+ release mechanism. To avoid regenerative self-excitation, RyRs and LCCs are found to cluster into discrete units to form the Ca2+ release unit (CRU). The beat-to-beat LCR period therefore may depend on the stochastic properties of both the Ca2+ release from the RyR and the individual LCC opening. However, proof of such a concept on a beat-to-beat basis has not been established even under normal conditions in pacemaker cells.
Moreover, the CRU configuration and its geometrical dimensions are not known. LCR characteristics (e.g., size, amplitude, duration) are not fixed but can be modulated by the phosphorylation level and the CRU geometry. Heart failure induces remodeling of the CRU structural features and phosphorylation activities in the ventricular myocytes. Moreover, heart failure is associated with LCC-RyR signaling defective in this cell type. However, whether such changes occur in pacemaker cells and affect fundamental properties that determine pacemaker cell function, specifically Ca2+ and PKA signaling, in animals suffering from heart failure are not known.
The goal of this project is to investigate the role of Ca2+ activated AC-cAMP/PKA and CaMKII as master regulators that control pacemaker cell automaticity and LCR period in a beat-to-beat manner under healthy and cardiac disease conditions. Research into such a role is novel and will help us to understand whether ultrastructural remodeling of Ca2+ and PKA signaling affects heart function in patients with cardiac disease. Investigating the perturbations in temporal and spatial dynamics of Ca2+ and PKA activity has the potential to improve patient care and assist in developing new, safer, and more successful therapies.
Age-dependent deterioration arising from changes in extrinsic neural input versus intrinsic mechanisms in heart pacemaker cells
The U.S. Administration on Aging estimates that by the year 2050, 20% of the population will be 65 and older. In parallel, the incidence of chronic cardiovascular disease and risk of disability grow exponentially with increasing age. Although the basal heart rate in humans does not change in advanced age, heart-rate variability (HRV) decreases with age and has been correlated with increased morbidity andmortality in patients with cardiovascular diseases. However, the pathological mechanisms behind these changes have not been conclusively delineated. The brain controls the heart rate via discharged parasympathetic and sympathetic nerve neurotransmitters that bind to pacemaker cell receptors within the sinoatrial node tissue. Because neurotransmitters and intrinsic pacemaker cell mechanisms activate similar signaling cascades, the heart rate and heart rate variability readout may reflect both reduced extrinsic neural input and diminished intrinsic pacemaker cell functionin aging hearts. The project has two main goals: (i) to establish how changes in the molecular properties intrinsic to pacemaker cells and their responses to autonomic neural input determine the reduction in HRV in vivo in advanced age; (ii) to test whether the intrinsic-basal heart rate and HRV reflect the activity of intrinsic pacemaker cells pathways only, thereby constituting a means of diagnosing heart diseases. The project’s success depends mainly on expert knowledge of pacemaker function, HRV analysis, and the generation of relevant aging models. The Yaniv lab brings expertise in characterizing coupled-clock pacemaker function and producing reliable aging models, and has the know-how to apply nonlinear analysis of heart rate and rhythm. By dissecting mechanisms defining HRV at different hierarchical levels (intact heart, denervated heart, and isolated sinoatrial node), and by using nonlinear techniques to quantify HRV of adult and aged mice, a better understanding of the mechanisms that regulate HRV in health and old age and/or disease will be gained. The expected results will set the ground for development of a non-invasive diagnostic tool as well as future hypotheses relating to adaptation of mechanisms controlling intrinsic pacemaker clocks in advanced age. Detection ofbeat-to-beat variability of intrinsic pacemaker cell mechanisms as a means of diagnosing heart function is novel and has yet to be thoroughly examined. Early detection of age-associated cardiac disease and, particularly, identificationof the failing mechanism using noninvasive methods, may prevent deterioration of heart function and reduce the severity of the associated symptoms and the need for artificial, implantable pacemakers.
Mechano-signal transduction by calcium and phosphorylation in healthy and dysfunctional heart pacemaker tissue
Cardiovascular diseases are the leading cause of death worldwide. Among them, rhythmic disorders are a central cause of sudden cardiac death and a considerable economic burden. The sinoatrial node (SAN) is the primary heart pacemaker which controls heart rate and rhythm. Normal automaticity of SAN pacemaker cells is regulated by integrated functions within a system of two coupled-clocks. The so-called membrane clock is dependent on the funny current (If), and the denominated calcium (Ca2+) clock is activated by Ca2+ release from intracellular stores, via the ryanodine receptor (RyR) channel.Heart failure associated increased mechanical load has been documented together with RyR phosphorylation and its subsequent increased activity. In heart cells, the kinetics of Ca2+ binding to thecontractile engines and their phosphorylation level determine the degree of mechanical activity.However, the relationship between Ca2+ and phosphorylative signaling and transduction of mechanical cues in the SAN is not clear. The mechanism may involve production of reactive oxygen species (ROS) in response to mechanical load, activating Ca2+/calmodulin-dependent protein kinase II (CaMKII), which is coupled to PKA signaling. We hypothesize that mechanical overload can modulate SAN function, through mechanisms involving intracellular Ca2+ and post-translational modifications.
The project has two main goals: (i) to characterize the role of Ca2+
and phosphorylative signaling on transduction of mechanical cues in the SAN, by utilizing and developing state-of-the-art, multidisciplinary experimental approaches (e.g.,biophysical, electrophysiological, optical, image processing, and signal processing); (ii) to test whether increased mechanical loads contribute to SAN dysfunction in heart disease.
By combining the multi-disciplinary approaches, the applied project will promote the development of new methods to simultaneously measure electrical, mechanical and local Ca2+ signaling on a beat-to-beat basis in SAN tissue. Meeting the objectives of this innovative and highly competitive project will shed light on the relative contribution of disturbed mechanical signaling to SAN dysfunction and on how increased mechanical loads in certain heart diseases can lead to arrhythmogenic events.
Smart implantable cardiac defibrillator
Cardiac fibrillation is one of the primary causes of morbidity and mortality in the developed world, where ventricular fibrillation (i.e., also known as arrhythmia) is the most dangerous type. Specifically,cardiac fibrillation is the leading cause of sudden cardiac death, which claims almost half a million lives annually in the US alone. Prevention of sudden death in high-risk patients has been the focus of much attention and has resulted in the development of medications and technologies for this purpose. To date, the usefulness of antiarrhythmic medications has been unsatisfactory. One technological solution that reduces the probability of sudden death is the implantable cardiac defibrillator. In general, the ICD consists of a pulse generator that can send an electrical impulse or a mechanical shock to the heart, a set of electrodes that can sense the electrical rhythm (ECG) and measure the mechanical function of the heart (flow, pressure, saturated oxygen, etc.), a computer chip that tells the ICD when to deliver the shock, and a battery. Although the ICD does reduce the probability of sudden death, the current technology, due to unnecessary shocks, still falls short of completely improving a person’s quality of life and psychological state. One main shortcoming is that the ICD can only detect when arrhythmogenic events happen, but cannot predict them (i.e., the shock is generated only after the arrhythmogenic event started, which might already be too late). In this project we aim to design an autonomous control system for the ICD that can predict and detect arrhythmogenic events using efficient transmission operations and advanced, cloud-based analytics.
Investigating the dynamics of intrinsic molecular clock-like mechanisms in human cardiac pacemakers
The heart rate and rhythm are controlled by the level of synchronization of molecular clock-like mechanisms intrinsic to pacemaker cells. However, little is known about the dynamics of these mechanisms and how their mutual interactions affect the pacing machinery. Human induced pluripotent stem cells (iPSCs) have the capacity to differentiate into any specialized cell type, including pacemaker cells. These cells offer an innovative and relevant approach to the study of inherited human cardiac pathologies (e.g., Long QT Syndrome), as well as to the exploration of novel specific drug targets. The purpose of our joint project is to decipher the main control mechanisms that synchronize the dynamics of intrinsic clock-like mechanisms in iPSC-derived pacemaker cardiomyocytes. We anticipate that this project will lead to the identification of the mechanisms underlying the failing pacemaker in certain cardiac pathologies.