A canine model of chronic ischemic heart failure.

Preclinical large animal models of chronic heart failure (HF) are crucial to both understanding pathological remodeling and translating fundamental discoveries into novel therapeutics for HF. Canine models of ischemic cardiomyopathy are historically limited by either high early mortality or failure to develop chronic heart failure. Twenty-nine healthy adult dogs (30 ± 4 kg, 15/29 male) underwent thoracotomy followed by one of three types of left anterior descending (LAD) coronary artery ligation procedures: ( = 4) (simple LAD: proximal and distal LAD ligation); ( = 14) (simple LAD plus lateral wall including ligation of the distal first diagonal and proximal first obtuse marginal); and ( = 11) (total LAD devascularization or TLD: simple LAD plus ligation of proximal LAD branches to both the right and left ventricles).

Protective mitochondrial fission induced by stress-responsive protein GJA1-20k.

The Connexin43 gap junction gene has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection.

Cell-Type-Specific Immune Dysregulation in Severely Ill COVID-19 Patients.

Recent studies have demonstrated immunologic dysfunction in severely ill coronavirus disease 2019 (COVID-19) patients. We use single-cell RNA sequencing (scRNA-seq) to analyze the transcriptome of peripheral blood mononuclear cells (PBMCs) from healthy (n = 3) and COVID-19 patients with moderate disease (n = 5), acute respiratory distress syndrome (ARDS, n = 6), or recovering from ARDS (n = 6). Our data reveal transcriptomic profiles indicative of defective antigen presentation and interferon (IFN) responsiveness in monocytes from ARDS patients, which contrasts with higher responsiveness to IFN signaling in lymphocytes.

Cell type-specific immune dysregulation in severely ill COVID-19 patients.

Coronavirus disease 2019 (COVID-19) has quickly become the most serious pandemic since the 1918 flu pandemic. In extreme situations, patients develop a dysregulated inflammatory lung injury called acute respiratory distress syndrome (ARDS) that causes progressive respiratory failure requiring mechanical ventilatory support. Recent studies have demonstrated immunologic dysfunction in severely ill COVID-19 patients.

Prognostic value of point-of-care ultrasound during cardiac arrest: a systematic review.

Background: Despite significant improvements in cardiopulmonary resuscitation, sudden cardiac arrest is one of the leading causes of mortality in the United States. Ultrasound is a widely available tool that can be used to evaluate the presence of cardiac wall motion during cardiac arrest. Several clinical studies have evaluated the use of ultrasound to visualize cardiac motion as a predictor of mortality in cardiac arrest patients.

Interaction of α Carboxyl Terminus 1 Peptide With the Connexin 43 Carboxyl Terminus Preserves Left Ventricular Function After Ischemia-Reperfusion Injury.

Background α Carboxyl terminus 1 (αCT1) is a 25-amino acid therapeutic peptide incorporating the zonula occludens-1 (ZO-1)-binding domain of connexin 43 (Cx43) that is currently in phase 3 clinical testing on chronic wounds. In mice, we reported that αCT1 reduced arrhythmias after cardiac injury, accompanied by increases in protein kinase Cε phosphorylation of Cx43 at serine 368. Herein, we characterize detailed molecular mode of action of αCT1 in mitigating cardiac ischemia-reperfusion injury.

Diabetes Increases Cryoinjury Size with Associated Effects on Cx43 Gap Junction Function and Phosphorylation in the Mouse Heart.

Diabetic patients develop larger myocardial infarctions and have an increased risk of death following a heart attack. The poor response to myocardial injury in the diabetic heart is likely related to the many metabolic derangements from diabetes that create a poor substrate in general for wound healing, response to injury and infection. Studies in rodents have implicated a role for the gap junction protein connexin 43 (Cx43) in regulating the injury response in diabetic skin wounds.

Your Father and Grandfather's Atrial Fibrillation: A Review of the Genetics of the Most Common Pathologic Cardiac Dysrhythmia.

Atrial fibrillation (AF) remains the most common pathologic dysrhythmia in humans with a prevalence of 1-2% of the total population and as high as 10% of the elderly. AF is an independent risk marker for cardiovascular mortality and morbidity, and given the increasing age of the population, represents an increasing burden of disease. Although age and hypertension are known risk factors for development of AF, the study of families with early onset AF revealed mutations in genes coding for ion channels and other proteins involved in electrotonic coupling as likely culprits for the pathology in select cases.

Extracorporeal Membrane Oxygenation Support for Hypokalemia-induced Cardiac Arrest: A Case Report and Review of the Literature.

Background: Hypokalemia is a reversible cause of cardiac arrest in patients presenting to the emergency department (ED). Extracorporeal membrane oxygenation (ECMO) is an established technology for cardiopulmonary support with emerging roles in resuscitation. Here, we review the literature of hypokalemic-induced cardiac arrests and discuss one such case successfully managed with ECMO.

Cryoinjury models of the adult and neonatal mouse heart for studies of scarring and regeneration.

A major limitation in studies of the injured heart is animal-to-animal variability in wound size resulting from commonly used techniques such as left anterior descending coronary artery ligation. This variability can make standard errors sufficiently large that mean separation between treatment and control groups can be difficult without replicating numbers (n) of animals in groups by excessive amounts. Here, we describe the materials and protocol necessary for delivering a standardized non-transmural cryoinjury to the left ventricle of an adult mouse heart that may in part obviate the issue of injury variance between animals.

The connexin43 carboxyl terminus and cardiac gap junction organization.

The precise spatial order of gap junctions at intercalated disks in adult ventricular myocardium is thought vital for maintaining cardiac synchrony. Breakdown or remodeling of this order is a hallmark of arrhythmic disease of the heart. The principal component of gap junction channels between ventricular cardiomyocytes is connexin43 (Cx43).

Enhanced PKCε mediated phosphorylation of connexin43 at serine 368 by a carboxyl-terminal mimetic peptide is dependent on injury.

The gap junction (GJ) protein connexin (Cx43) is important for organized action potential propagation between mammalian cardiomyocytes. Disruption of the highly ordered distribution of Cx43 GJs is characteristic of cardiac tissue after ischemic injury. We recently demonstrated that epicardial administration of a peptide mimetic of the Cx43 carboxyl-terminus reduced pathologic remodeling of Cx43 GJs and protected against induced arrhythmias following ventricular injury.

A peptide mimetic of the connexin43 carboxyl terminus reduces gap junction remodeling and induced arrhythmia following ventricular injury.

Rationale: Remodeling of connexin (Cx)43 gap junctions (GJs) is linked to ventricular arrhythmia.

Objectives: A peptide mimetic of the carboxyl terminal (CT) of Cx43, incorporating a postsynaptic density-95/disks-large/ZO-1 (PDZ)-binding domain, reduces Cx43/ZO-1 interaction and GJ size remodeling in vitro. Here, we determined: (1) whether the Cx43-CT mimetic αCT1 altered GJ remodeling following left ventricular (LV) injury in vivo; (2) whether αCT1 affected arrhythmic propensity; and (3) the mechanism of αCT1 effects on arrhythmogenicity and GJ remodeling.

ZO-1 determines adherens and gap junction localization at intercalated disks.

The disruption of the spatial order of electromechanical junctions at myocyte-intercalated disks (ICDs) is a poorly understood characteristic of many cardiac disease states. Here, in vitro and in vivo evidence is provided that zonula occludens-1 (ZO-1) regulates the organization of gap junctions (GJs) and adherens junctions (AJs) at ICDs. We investigated the contribution of ZO-1 to cell-cell junction localization by expressing a dominant-negative ZO-1 construct (DN-ZO-1) in rat ventricular myocytes (VMs).

Translational lessons from scarless healing of cutaneous wounds and regenerative repair of the myocardium.

Regenerative healing is the process by which injured tissues are restored to their original structure and function. Many species are capable of healing in this manner. However, in mammals the healing response in most tissues is marked by fibroblast proliferation and scar tissue deposition.

Novel therapies for scar reduction and regenerative healing of skin wounds.

Fibrotic scars deposited during skin wound healing can cause disfiguration and loss of dermal function. Scar differentiation involves inputs from multiple cell types in a predictable and overlapping sequence of cellular events that includes inflammation, migration/proliferation and extracellular matrix deposition. Research into the molecular mechanisms underpinning these processes in embryonic and adult wounds has contributed to the development of a growing number of novel therapeutic approaches for improving scar appearance.