Low-Cost Optical Mapping Systems for Panoramic Imaging of Complex Arrhythmias and Drug-Action in Translational Heart Models

Panoramic optical mapping is the primary method for imaging electrophysiological activity from the entire outer surface of Langendorff-perfused hearts. To date, it is the only method of simultaneously measuring multiple key electrophysiological parameters, such as transmembrane voltage and intracellular free calcium, at high spatial and temporal resolution. Despite the impact it has already had on the fields of cardiac arrhythmias and whole-heart computational modeling, present-day system designs precludes its adoption by the broader cardiovascular research community because of their high costs. Taking advantage of recent technological advances, we developed and validated low-cost optical mapping systems for panoramic imaging using Langendorff-perfused pig hearts, a clinically-relevant model in basic research and bioengineering. By significantly lowering financial thresholds, this powerful cardiac electrophysiology imaging modality may gain wider use in research and, even, teaching laboratories, which we substantiated using the lower-cost Langendorff-perfused rabbit heart model

Orthostatic hypotension: clinical review and case study

Transient loss of consciousness (TLOC) accounts for 3% of all attendance in emergency departments within the UK. More than 90% of TLOC presentations are due to epileptic seizures, psychogenic seizures or syncope. However, in England and Wales in 2002, it was estimated that 92000 patients were incorrectly diagnosed with epilepsy, at an additional annual cost to the NHS of up to £189 million. This article will reflect on the case study of a 54-year-old female patient who presented with a possible TLOC, and had a background of long-term depression. Differential diagnoses will be discussed, but the article will focus on orthostatic hypotension. Being diagnosed with this condition is independently associated with an increased risk of all-cause mortality. Causes of orthostatic hypotension and the pathophysiology behind the condition will be discussed, highlighting the importance of obtaining an accurate clinical history. This is extremely pertinent if a patient collapses in an NHS setting and this is witnessed by nurses because they can contribute to the history of the type of collapse, to aid diagnosis and correct treatment. In addition, nurses have a valuable role to play in highlighting polypharmacy to doctors, and non-medical prescribers, as a contributing factor to orthostatic hypotension is polypharmacy. It is therefore important to accurately distinguish TLOC aetiology, not only to provide appropriate management, but to also identify patients at risk of morbidity/mortality related to underlying disease.N/

In vivo fluorescence reflectance imaging of protease activity in a mouse model of post-traumatic osteoarthritis

ObjectiveJoint injuries initiate a surge of inflammatory cytokines and proteases that contribute to cartilage and subchondral bone degeneration. Detecting these early processes in animal models of post-traumatic osteoarthritis (PTOA) typically involves ex vivo analysis of blood serum or synovial fluid biomarkers, or histological analysis of the joint. In this study, we used in vivo fluorescence reflectance imaging (FRI) to quantify protease, matrix metalloproteinase (MMP), and Cathepsin K activity in mice following anterior cruciate ligament (ACL) rupture. We hypothesized that these processes would be elevated at early time points following joint injury, but would return to control levels at later time points.DesignMice were injured via tibial compression overload, and FRI was performed at time points from 1 to 56 days after injury using commercially available activatable fluorescent tracers to quantify protease, MMP, and cathepsin K activity in injured vs uninjured knees. PTOA was assessed at 56 days post-injury using micro-computed tomography and whole-joint histology.ResultsProtease activity, MMP activity, and cathepsin K activity were all significantly increased in injured knees relative to uninjured knees at all time points, peaking at 1-7 days post-injury, then decreasing at later time points while still remaining elevated relative to controls.ConclusionsThis study establishes FRI as a reliable method for in vivo quantification of early biological processes in a translatable mouse model of PTOA, and provides crucial information about the time course of inflammation and biological activity following joint injury. These data may inform future studies aimed at targeting these early processes to inhibit PTOA development

Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias.

Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias

Targeting protein tyrosine phosphatase σ after myocardial infarction restores cardiac sympathetic innervation and prevents arrhythmias.

Millions of people suffer a myocardial infarction (MI) every year, and those who survive have increased risk of arrhythmias and sudden cardiac death. Recent clinical studies have identified sympathetic denervation as a predictor of increased arrhythmia susceptibility. Chondroitin sulfate proteoglycans present in the cardiac scar after MI prevent sympathetic reinnervation by binding the neuronal protein tyrosine phosphatase receptor σ (PTPσ). Here we show that the absence of PTPσ, or pharmacologic modulation of PTPσ by the novel intracellular sigma peptide (ISP) beginning 3 days after injury, restores sympathetic innervation to the scar and markedly reduces arrhythmia susceptibility. Using optical mapping we observe increased dispersion of action potential duration, supersensitivity to β-adrenergic receptor stimulation and Ca(2+) mishandling following MI. Sympathetic reinnervation prevents these changes and renders hearts remarkably resistant to induced arrhythmias

Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease

The nervous system and cardiovascular system develop in concert and are functionally interconnected in both health and disease. This white paper focuses on the cellular and molecular mechanisms that underlie neural–cardiac interactions during development, during normal physiological function in the mature system, and during pathological remodelling in cardiovascular disease. The content on each subject was contributed by experts, and we hope that this will provide a useful resource for newcomers to neurocardiology as well as aficionados

Molecular and cellular neurocardiology: development, and cellular and molecular adaptations to heart disease

The nervous system and cardiovascular system develop in concert and are functionally interconnected in both health and disease. This white paper focuses on the cellular and molecular mechanisms that underlie neural–cardiac interactions during development, during normal physiological function in the mature system, and during pathological remodelling in cardiovascular disease. The content on each subject was contributed by experts, and we hope that this will provide a useful resource for newcomers to neurocardiology as well as aficionados

Imaging of Ventricular Fibrillation and Defibrillation: The Virtual Electrode Hypothesis

Ventricular fibrillation is the major underlying cause of sudden cardiac death. Understanding the complex activation patterns that give rise to ventricular fibrillation requires high resolution mapping of localized activation. The use of multi-electrode mapping unraveled re-entrant activation patterns that underlie ventricular fibrillation. However, optical mapping contributed critically to understanding the mechanism of defibrillation, where multi-electrode recordings could not measure activation patterns during and immediately after a shock. In addition, optical mapping visualizes the virtual electrodes that are generated during stimulation and defibrillation pulses, which contributed to the formulation of the virtual electrode hypothesis. The generation of virtual electrode induced phase singularities during defibrillation is arrhythmogenic and may lead to the induction of fibrillation subsequent to defibrillation. Defibrillating with low energy may circumvent this problem. Therefore, the current challenge is to use the knowledge provided by optical mapping to develop a low energy approach of defibrillation, which may lead to more successful defibrillation