In situ assembly of an injectable cardiac stimulator.

Without intervention, cardiac arrhythmias pose a risk of fatality. However, timely intervention can be challenging in environments where transporting a large, heavy defibrillator is impractical, or emergency surgery to implant cardiac stimulation devices is not feasible. Here, we introduce an injectable cardiac stimulator, a syringe loaded with a nanoparticle solution comprising a conductive polymer and a monomer that, upon injection, forms a conductive structure around the heart for cardiac stimulation.

Pharmacological and mechanical properties of isolated pig coronary veins.

Recent successful cardiac transplantation from pig to non-human primates and the first pig-to-human transplantation has put the focus on the properties of the pig heart. In contrast to the coronary arteries, the coronary veins are less well characterized and the aim was to examine the mechanical and pharmacological properties of coronary veins in comparison to the arteries. Vessel segments from the left anterior descending coronary artery (LAD) and the concomitant vein were isolated from pig hearts in cardioplegia and examined .

Resistance to thyroid hormone induced tachycardia in RTHα syndrome.

Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control.

Development and prevention of ischemic contracture ("stone heart") in the pig heart.

Stone heart (ischemic contracture) is a rare and serious condition observed in the heart after periods of warm ischemia. The underlying mechanisms are largely unknown and treatment options are lacking. In view of the possibilities for cardiac donation after circulatory death (DCD), introducing risks for ischemic damage, we have investigated stone heart in pigs.

Excitation and contraction of cardiac muscle and coronary arteries of brain-dead pigs.

Excitability and contraction of cardiac muscle from brain-dead donors critically influence the success of heart transplantation. Membrane physiology, Ca-handling, and force production of cardiac muscle and the contractile properties of coronary arteries were studied in hearts of brain-dead pigs. Cardiac muscle and vascular function after 12 h brain death (decapitation between C2 and C3) were compared with properties of fresh tissue.

A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia-reperfusion in the mouse heart.

The NADPH oxidase enzymes Nox2 and 4, are important generators of Reactive oxygen species (ROS). These enzymes are abundantly expressed in cardiomyocytes and have been implicated in ischemia-reperfusion injury. Previous attempts with full inhibition of their activity using genetically modified animals have shown variable results, suggesting that a selective and graded inhibition could be a more relevant approach.

Longitudinal vibration interferes with cross-bridge attachment and prevents muscle fibre shrinkage under PSE-like conditions.

The impact of longitudinal vibration on cross-bridge attachments between myofilaments was investigated in single fibres and intact muscle. Sinusoidal length vibration (frequency 50 Hz, amplitude 5% of fibre length) reduced active force by 40% when fibres were activated by elevation of [Ca], but did not alter the force when fibres were in rigor state. When vibrated for 30 min in rigor at pH 5.

Electrolyte handling in the isolated perfused rat kidney: demonstration of vasopressin V2-receptor-dependent calcium reabsorption.

Background: The most profound effect of vasopressin on the kidney is to increase water reabsorption through V-receptor (VR) stimulation, but there are also data suggesting effects on calcium transport. To address this issue, we have established an isolated perfused kidney model with accurate pressure control, to directly study the effects of VR stimulation on kidney function, isolated from systemic effects.

Methods: The role of VR in renal calcium handling was studied in isolated rat kidneys using a new pressure control system that uses a calibration curve to compensate for the internal pressure drop up to the tip of the perfusion cannula.

Altered Sarcomeric Structure and Function in Woody Breast Myopathy of Avian Pectoralis Major Muscle.

The "Woody" or "Wooden" breast disease is a severe myopathy of pectoralis major muscle recently identified within rapidly growing broiler lines all around the world with a prevalence rate around 20%, or even higher. Although of significant ethical and economic impact, little is known regarding the structural and functional aspects of the contractile apparatus in the woody breast muscle. The aim of the present study was to determine physiological properties of the contractile system in the morphologically intact muscle fibers of focally damaged woody breast in comparison with normal muscle fibers to gain insight into the muscle function of the animal and possibly mechanisms involved in the disease development.

Lack of PCSK6 Increases Flow-Mediated Outward Arterial Remodeling in Mice.

Proprotein convertases (PCSKs) process matrix metalloproteases and cytokines, but their function in the vasculature is largely unknown. Previously, we demonstrated upregulation of PCSK6 in atherosclerotic plaques from symptomatic patients, localization to smooth muscle cells (SMCs) in the fibrous cap and positive correlations with inflammation, extracellular matrix remodeling and cytokines. Here, we hypothesize that PCSK6 could be involved in flow-mediated vascular remodeling and aim to evaluate its role in the physiology of this process using knockout mice.

De novo mutations in FLNC leading to early-onset restrictive cardiomyopathy and congenital myopathy.

Mutations in FLNC for a long time are known in connection to neuromuscular disorders and only recently were described in association with various cardiomyopathies. Here, we report a new clinical phenotype of filaminopathy in four unrelated patients with early-onset restrictive cardiomyopathy (RCM) in combination with congenital myopathy due to FLNC mutations (NM_001458.4:c.

Rigor bonds cause reduced sarcomeric volume in skinned porcine skeletal muscle under PSE-like conditions.

Effects of rigor cross-bridge attachment on water holding in PSE-like conditions were investigated. A new model using permeabilised/skinned porcine longissimus thoracis et lumborum muscle fibres was established to study effects of varied pH, temperature and the presence of rigor bonds on the muscle fibre structure. Preparations were exposed during 30min to different temperatures (22 and 38°C) and pH (7.

Vascular smooth muscle contraction in hypertension.

Hypertension is a major risk factor for many common chronic diseases, such as heart failure, myocardial infarction, stroke, vascular dementia, and chronic kidney disease. Pathophysiological mechanisms contributing to the development of hypertension include increased vascular resistance, determined in large part by reduced vascular diameter due to increased vascular contraction and arterial remodelling. These processes are regulated by complex-interacting systems such as the renin-angiotensin-aldosterone system, sympathetic nervous system, immune activation, and oxidative stress, which influence vascular smooth muscle function.

Signaling and metabolic properties of fast and slow smooth muscle types from mice.

This study aims to improve the classification of smooth muscle types to better understand their normal and pathological functional phenotypes. Four different smooth muscle tissues (aorta, muscular arteries, intestine, urinary bladder) with a 5-fold difference in maximal shortening velocity were obtained from mice and classified according to expression of the inserted myosin heavy chain (SMHC-B). Western blotting and quantitative PCR analyses were used to determine 15 metabolic and 8 cell signaling key components in each tissue.

In Vivo Function of the Chaperonin TRiC in α-Actin Folding during Sarcomere Assembly.

The TCP-1 ring complex (TRiC) is a multi-subunit group II chaperonin that assists nascent or misfolded proteins to attain their native conformation in an ATP-dependent manner. Functional studies in yeast have suggested that TRiC is an essential and generalized component of the protein-folding machinery of eukaryotic cells. However, TRiC's involvement in specific cellular processes within multicellular organisms is largely unknown because little validation of TRiC function exists in animals.

Long-term cardiovascular reprogramming by short-term perinatal exposure to nicotine's main metabolite cotinine.

Aim: Gather 'proof-of-concept' evidence of the adverse developmental potential of cotinine (a seemingly benign biomarker of recent nicotine/tobacco smoke exposure).

Methods: Pregnant C57 mice drank nicotine- or cotinine-laced water for 6 wks from conception (N = 2% saccharin + 100 μg nicotine/mL; C = 2% saccharin + 10 μg cotinine/mL) or 3 wks after birth (C = 2% saccharin + 30 μg cotinine/mL). Controls drank 2% saccharin (CTRL).

Ion currents of cardiomyocytes in different regions of the Göttingen minipig heart.

Introduction: The Göttingen minipig is a promising model for pharmacological safety assessment and for translational research in cardiology. We have examined the main ion currents in cardiomyocytes of the minipig heart.

Methods: Cardiac cells were isolated from different cardiac regions (endo-, mid- and epicardial left ventricle and right ventricle) from Göttingen minipigs and examined using the whole cell patch clamp technique combined with pharmacological interventions.

Blood pressure regulation by CD4 lymphocytes expressing choline acetyltransferase.

Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been determined. We previously showed that CD4 T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals. Here we show that these CD4CD44CD62L T helper cells by gene expression are a distinct T-cell population defined by ChAT (CD4 T).

On the water-holding of myofibrils: Effect of sarcoplasmic protein denaturation.

The role of heat-denatured sarcoplasmic proteins in water-holding is not well understood. Here we propose a new hypothesis that in PSE-like conditions denatured sarcoplasmic proteins aggregate within and outside myofilaments, improving the water-holding of denatured myofibrils. The process is compartmentalized: 1) within the filaments the denatured sarcoplasmic proteins shrink the lattice space and water is expelled; and 2) between the myofibrils and in the extracellular space, the coagulated sarcoplasmic proteins trap the expelled water from interfilamental space.

Role of Active Contraction and Tropomodulins in Regulating Actin Filament Length and Sarcomere Structure in Developing Zebrafish Skeletal Muscle.

Whilst it is recognized that contraction plays an important part in maintaining the structure and function of mature skeletal muscle, its role during development remains undefined. In this study the role of movement in skeletal muscle maturation was investigated in intact zebrafish embryos using a combination of genetic and pharmacological approaches. An immotile mutant line (cacnb1 (ts25) ) which lacks functional voltage-gated calcium channels (dihydropyridine receptors) in the muscle and pharmacological immobilization of embryos with a reversible anesthetic (Tricaine), allowed the study of paralysis (in mutants and anesthetized fish) and recovery of movement (reversal of anesthetic treatment).

Knockdown of fast skeletal myosin-binding protein C in zebrafish results in a severe skeletal myopathy.

Myosin-binding protein C (MyBPC) in the muscle sarcomere interacts with several contractile and structural proteins. Mutations in the cardiac isoform (MyBPC-3) in humans, or animal knockout, are associated with cardiomyopathy. Function of the fast skeletal isoform (MyBPC-2) in living muscles is less understood.

X-ray phase-contrast tomography for high-spatial-resolution zebrafish muscle imaging.

Imaging of muscular structure with cellular or subcellular detail in whole-body animal models is of key importance for understanding muscular disease and assessing interventions. Classical histological methods for high-resolution imaging methods require excision, fixation and staining. Here we show that the three-dimensional muscular structure of unstained whole zebrafish can be imaged with sub-5 μm detail with X-ray phase-contrast tomography.

Immobilization of Dystrophin and Laminin α2-Chain Deficient Zebrafish Larvae In Vivo Prevents the Development of Muscular Dystrophy.

Muscular dystrophies are often caused by genetic alterations in the dystrophin-dystroglycan complex or its extracellular ligands. These structures are associated with the cell membrane and provide mechanical links between the cytoskeleton and the matrix. Mechanical stress is considered a pathological mechanism and muscle immobilization has been shown to be beneficial in some mouse models of muscular dystrophy.