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In February 2014, a group of scientists convened as part of the University of California Davis Cardiovascular Symposium to bring together experimental and mathematical modelling perspectives and discuss points of consensus and controversy on the topic of sodium in the heart. This paper summarizes the topics of presentation and discussion from the symposium, with a focus on the role of aberrant sodium channels and abnormal sodium homeostasis in cardiac arrhythmias and pharmacotherapy from the subcellular scale to the whole heart. Two following papers focus on Na(+) channel structure, function and regulation, and Na(+)/Ca(2+) exchange and Na(+)/K(+) ATPase. The UC Davis Cardiovascular Symposium is a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The focus on Na(+) in the 2014 symposium stemmed from the multitude of recent studies that point to the importance of maintaining Na(+) homeostasis in the heart, as disruption of homeostatic processes are increasingly identified in cardiac disease states. Understanding how disruption in cardiac Na(+)-based processes leads to derangement in multiple cardiac components at the level of the cell and to then connect these perturbations to emergent behaviour in the heart to cause disease is a critical area of research. The ubiquity of disruption of Na(+) channels and Na(+) homeostasis in cardiac disorders of excitability and mechanics emphasizes the importance of a fundamental understanding of the associated mechanisms and disease processes to ultimately reveal new targets for human therapy.

Introduction: Neuromuscular fatigue causes a transient reduction of muscle force, and alters the mechanisms of motor control. Whether these alterations increase the risk of anterior cruciate ligament (ACL) injury is still debated. Here we compare the biomechanics of single-leg drop jumps before and after the execution of a fatiguing exercise, evaluating whether this exercise causes biomechanical alterations typically associated with an increased risk of ACL lesion. The intensity of the fatiguing protocol was tailored to the aerobic capacity of each participant, minimizing potential differential effects due to inter-individual variability in fitness. Methods: Twenty-four healthy male volunteers performed single leg drop jumps, before and after a single-set fatiguing session on a cycle ergometer until exhaustion (cadence: 65-70 revolutions per minute). For each participant, the intensity of the fatiguing exercise was set to 110% of the power achieved at their anaerobic threshold, previously identified by means of a cardiopulmonary exercise test. Joint angles and moments, as well as ground reaction forces (GRF) before and after the fatiguing exercise were compared for both the dominant and the non-dominant leg. Results: Following the fatiguing exercise, the hip joint was more extended (landing: Δ=-2.17°, p = 0.005; propulsion: Δ=-1.83°, p = 0.032) and more abducted (landing: Δ=-0.72°, p = 0.01; propulsion: Δ=-1.12°, p = 0.009). Similarly, the knee joint was more extended at landing (non-dominant leg: Δ=-2.67°, p < 0.001; dominant: Δ=-1.4°, p = 0.023), and more abducted at propulsion (both legs: Δ=-0.99°, p < 0.001) and stabilization (both legs: Δ=-1.71°, p < 0.001) hence increasing knee valgus. Fatigue also caused a significant reduction of vertical GRF upon landing (Δ=-0.21 N/kg, p = 0.003), but not during propulsion. Fatigue did not affect joint moments significantly. Conclusion: The increased hip and knee extension, as well as the increased knee abduction we observed after the execution of the fatiguing exercise have been previously identified as risk factors for ACL injury. These results therefore suggest an increased risk of ACL injury after the execution of the participant-tailored fatiguing protocol proposed here. However, the reduced vertical GRF upon landing and the preservation of joint moments are intriguing, as they may suggest the adoption of protective strategies in the fatigued condition to be evaluated in future studied. [ABSTRACT FROM AUTHOR]

Aims: The heterozygous phospholamban (PLN) mutation R14del (PLN R14del+/−) is associated with a severe arrhythmogenic cardiomyopathy (ACM) developing in the adult. "Superinhibition" of SERCA2a by PLN R14del is widely assumed to underlie the pathogenesis, but alternative mechanisms such abnormal energy metabolism have also been reported. This work aims to (1) to evaluate Ca2+ dynamics and energy metabolism in a transgenic (TG) mouse model of the mutation prior to cardiomyopathy development; (2) to test whether they are causally connected. Methods: Ca2+ dynamics, energy metabolism parameters, reporters of mitochondrial integrity, energy, and redox homeostasis were measured in ventricular myocytes of 8–12 weeks‐old, phenotypically silent, TG mice. Mutation effects were compared to pharmacological PLN antagonism and analyzed during modulation of sarcoplasmic reticulum (SR) and cytosolic Ca2+ compartments. Transcripts and proteins of relevant signaling pathways were evaluated. Results: The mutation was characterized by hyperdynamic Ca2+ handling, compatible with a loss of SERCA2a inhibition by PLN. All components of energy metabolism were depressed; myocyte energy charge was preserved under quiescence but reduced during stimulation. Cytosolic Ca2+ buffering or SERCA2a blockade reduced O2 consumption with larger effect in the mutant. Signaling changes suggest cellular adaptation to perturbed Ca2+ dynamics and response to stress. Conclusions: (1) PLN R14del+/− loses its ability to inhibit SERCA2a, which argues against SERCA2a superinhibition as a pathogenetic mechanism; (2) depressed energy metabolism, its enhanced dependency on Ca2+ and activation of signaling responses point to an early involvement of metabolic stress in the pathogenesis of this ACM model. [ABSTRACT FROM AUTHOR]