Cardiac Sarcoidosis and a Likely Pathogenic TTN Variant in a Patient Presenting With Ventricular Tachycardia.

Rare variants in TTN are the most common monogenic cause of early-onset atrial fibrillation and dilated cardiomyopathy. Whereas cardiac sarcoidosis is very underdiagnosed, a common presentation can be ventricular arrhythmias. This report presents a patient with a likely pathogenic TTN variant and cardiac sarcoidosis. (Level of Difficulty: Intermediate.).

Injectable conductive hydrogel restores conduction through ablated myocardium.

INTRODUCTION: Therapies for substrate-related arrhythmias include ablation or drugs targeted at altering conductive properties or disruption of slow zones in heterogeneous myocardium. Conductive compounds such as carbon nanotubes may provide a novel personalizable therapy for arrhythmia treatment by allowing tissue homogenization. METHODS: A nanocellulose carbon nanotube-conductive hydrogel was developed to have conduction properties similar to normal myocardium. Ex vivo perfused canine hearts were studied. Electroanatomic activation mapping of the epicardial surface was performed at baseline, after radiofrequency ablation, and after uniform needle injections of the conductive hydrogel through the injured tissue. Gross histology was used to assess distribution of conductive hydrogel in the tissue. RESULTS: The conductive hydrogel viscosity was optimized to decrease with increasing shear rate to allow expression through a syringe. The direct current conductivity under aqueous conduction was 4.3 × 10-1 S/cm. In four canine hearts, when compared with the homogeneous baseline conduction, isochronal maps demonstrated sequential myocardial activation with a shift in direction of activation to surround the edges of the ablated region. After injection of the conductive hydrogel, isochrones demonstrated conduction through the ablated tissue with activation restored through the ablated tissue. Gross specimen examination demonstrated retention of the hydrogel within the tissue. CONCLUSIONS: This proof-of-concept study demonstrates that conductive hydrogel can be injected into acutely disrupted myocardium to restore conduction. Future experiments should focus on evaluating long-term retention and biocompatibility of the hydrogel through in vivo experimentation.

Reversible cardiac dysfunction in severe COVID-19 infection, mechanisms and case report.

A previously healthy 49-year-old male patient presented with COVID-19 infection and required mechanical ventilation and extracorporeal membrane oxygenation due to severe hypoxemia. Echocardiography showed cardiac dysfunction with an apical sparing strain pattern, which rapidly normalized within a week. Apical sparing myocardial strain in patients with COVID-19 infection may suggest reverse-type stress cardiomyopathy.

Three-Dimensional Printed Biopatches With Conductive Ink Facilitate Cardiac Conduction When Applied to Disrupted Myocardium.

BACKGROUND: Reentrant ventricular arrhythmias are a major cause of sudden death in patients with structural heart disease. Current treatments focus on electrically homogenizing regions of scar contributing to ventricular arrhythmia with ablation or altering conductive properties using antiarrhythmic drugs. The high conductivity of carbon nanotubes may allow restoration of conduction in regions where impaired electrical conduction results in functional abnormalities. We propose a new concept for arrhythmia treatment using a stretchable, flexible biopatch with conductive properties to attempt to restore conduction across regions in which activation is disrupted. METHODS: Carbon nanotube patches composed of nanofibrillated cellulose/single-walled carbon nanotube ink 3-dimensionally printed in conductive patterns onto bacterial nanocellulose were developed and evaluated for conductivity, flexibility, and mechanical properties. The patches were applied on 6 canines to epicardium before and after surgical disruption. Electroanatomic mapping was performed on normal epicardium, then repeated over surgically disrupted epicardium, and then finally with the patch applied passively. RESULTS: We developed a 3-dimensional printable carbon nanotube ink complexed on bacterial nanocellulose that was (1) expressable through 3-dimensional printer nozzles, (2) electrically conductive, (3) flexible, and (4) stretchable. Six canines underwent thoracotomy, and, during epicardial ventricular pacing, mapping was performed. We demonstrated disruption of conduction after surgical incision in all 6 canines based on activation mapping. The patch resulted in restored conduction based on mapping and assessment of conduction direction and velocities in all canines. CONCLUSIONS: We have demonstrated 3-dimensional custom-printed electrically conductive carbon nanotube patches can be surgically manipulated to improve cardiac conduction when passively applied to surgically disrupted epicardial myocardium in canines.

Management of ventricular arrhythmias in patients with ventricular assist devices.

PURPOSE OF REVIEW: To summarize the available evidence concerning the occurrence and treatment of ventricular arrhythmias in patients supported with long-term ventricular assist devices (VADs). RECENT FINDINGS: Approximately one-third of left ventricular assist device-supported patients experience significant ventricular arrhythmias, with higher rates in certain patient subsets. Ventricular arrhythmias are associated with both increased mortality and morbidity in VAD-supported patients. Mechanical factors, myocardial fibrosis and alterations in cardiac myocyte physiology because of myocardial unloading are contributors to ventricular arrhythmias in this population. In the absence of definitive trials, current evidence supports implanted cardioverter defibrillators (ICDs) in long-term VAD patients to mitigate the risks associated with ventricular arrhythmias. Though antiarrhythmic therapies have limited efficacy, amelioration of inflow cannula contact with the endocardium and suction events or ablation of specific anatomic origins of ventricular arrhythmias, when present, are also efficacious in VAD-supported hearts. SUMMARY: As the application of long-term VAD support continues to grow, it will be increasingly important to clarify and target the mechanisms contributing to ventricular arrhythmias in this population. Prospective trials assessing the benefits of de-novo ICD placement, ablative strategies and other prophylactic and therapeutic interventions will be increasingly important to further improve the survival and quality of life among VAD-supported patients.

Transcriptomic biomarkers of cardiovascular disease.

Transcriptomics is the study of how our genes are regulated and expressed in different biological settings. Technical advances now enable quantitative assessment of all expressed genes (ie, the entire "transcriptome") in a given tissue at a given time. These approaches provide a powerful tool for understanding complex biological systems and for developing novel biomarkers. This chapter will introduce basic concepts in transcriptomics and available technologies for developing transcriptomic biomarkers. We will then review current and emerging applications in cardiovascular medicine.

Free vascularized fibular grafting preserves athletic activity level in patients with osteonecrosis.

Athletic patients with osteonecrosis of the femoral head have few desirable therapeutic options that preserve athletic ability. Because these patients are usually young and healthy, any procedure that avoids total hip arthroplasty would be most desirable. This study prospectively evaluated 15 patients (19 hips) who presented with an average age of 28.5 (range, 12 to 46) years and stages 2 (6/19), 3 (2/19), 4 (9/19), and 5 (2/19) of osteonecrosis of the femoral head. All patients were treated with free vascularized fibular autografting (FVFG) to the femoral head. Postoperative evaluations of pain symptoms and functional activity showed improvements in all patients. The average follow-up time was 8 years. Harris hip scores significantly increased from an average preoperative score of 75.3 to an average postoperative score of 94.8. Seventy-five percent of patients were able to return to their sport after recovery and all patients reported being satisfied with the procedure and would repeat their decision to have surgery. Three patients' hips were converted to arthroplasty at 3, 11, and 17 years post-FVFG. The results demonstrate that FVFG is a successful therapeutic treatment in athletes with osteonecrosis of the femoral head. It reduces pain, increases activity, and allows most patients to return to their sport, an achievement often not possible with other treatment options.

Cardiac fibroblast paracrine factors alter impulse conduction and ion channel expression of neonatal rat cardiomyocytes.

AIMS: The pathological proliferation of cardiac fibroblasts (CFs) in response to heart injury results in fibrosis, which correlates with arrhythmia generation and heart failure. Here we systematically examined the effect of fibroblast-derived paracrine factors on electrical propagation in cardiomyocytes. METHODS AND RESULTS: Neonatal rat cardiac monolayers were exposed for 24 h to media conditioned by CFs. Optical mapping, sharp microelectrode recordings, quantitative RT-PCR, and immunostaining were used to assess the changes in the propagation and shape of the action potential and underlying changes in gene and protein expression. The fibroblast paracrine factors produced a 52% reduction in cardiac conduction velocity, a 217% prolongation of action potential duration, a 64% decrease of maximum capture rate, a 21% increase in membrane resting potential, and an 80% decrease of action potential upstroke velocity. These effects were dose dependent and partially reversible with removal of the conditioned media. No fibroblast proliferation, cardiomyocyte apoptosis, or decreased connexin-43 expression, phosphorylation, and function were found in conditioned cardiac cultures. In contrast, the expression of the fast sodium, inward rectifying potassium, and transient outward potassium channels were, respectively, reduced 3.8-, 6.6-fold, and to undetectable levels. The expression of beta-myosin heavy chain increased 17.4-fold. No electrophysiological changes were observed from media conditioned by CFs in the presence of cardiomyocytes. CONCLUSION: Paracrine factors from neonatal CFs alone produced significant electrophysiological changes in neonatal rat cardiomyocytes resembling those found in several cardiac pathologies.

Structural coupling of cardiomyocytes and noncardiomyocytes: quantitative comparisons using a novel micropatterned cell pair assay.

Well-controlled studies of the structural and functional interactions between cardiomyocytes and other cells are essential for understanding heart pathophysiology and for the further development of safe and efficient cell therapies. We established a novel in vitro assay composed of a large number of individual micropatterned cell pairs with reproducible shape, size, and region of cell-cell contact. This assay was applied to quantify and compare the frequency of expression and distribution of electrical (connexin43) and mechanical (N-cadherin) coupling proteins in 5,000 cell pairs made of cardiomyocytes (CMs), cardiac fibroblasts (CFs), skeletal myoblasts (SKMs), and mesenchymal stem cells (MSCs). We found that for all cell pair types, side-side contacts between two cells formed 4.5-14.3 times more often than end-end contacts. Both connexin43 and N-cadherin were expressed in all homotypic CM pairs but in only 13.4-91.6% of pairs containing noncardiomyocytes, where expression was either junctional (at the site of cell-cell contact) or diffuse (inside the cytoplasm). CM expression was exclusively junctional in homotypic pairs but predominantly diffuse in heterotypic pairs. Noncardiomyocyte homotypic pairs exhibited diffuse expression 1.7-8.7 times more often than junctional expression, which was increased 2.6-4.4 times in heterotypic pairs. Junctional connexin43 and N-cadherin expression, respectively, were found in 38.6 +/- 7.3 and 39.6 +/- 6.2% of CM-MSC pairs, 21.9 +/- 5.0 and 13.6 +/- 1.9% of CM-SKM pairs, and in only 3.8-9.6% of CM-CF pairs. Measured frequencies of protein expression and distribution were stable for at least 4 days. Described studies in micropatterned cell pairs shed new light on cellular interactions relevant for cardiac function and cell therapies.

Engineering skeletal myoblasts: roles of three-dimensional culture and electrical stimulation.

Immature skeletal muscle cells, or myoblasts, have been used in cellular cardiomyoplasty in attempts to regenerate cardiac muscle tissue by injection of cells into damaged myocardium. In some studies, muscle tissue within myoblast implant sites may be morphologically similar to cardiac muscle. We hypothesized that identifiable aspects of the cardiac milieu may contribute to growth and development of implanted myoblasts in vivo. To test this hypothesis, we designed a novel in vitro system to mimic some aspects of the electrical and biochemical environment of native myocardium. This system enabled us to separate the three-dimensional (3-D) electrical and biochemical signals that may be involved in myoblast proliferation and plasticity. Myoblasts were grown on 3-D polyglycolic acid mesh scaffolds under control conditions, in the presence of cardiac-like electrical current fluxes, or in the presence of culture medium that had been conditioned by mature cardiomyocytes. Cardiac-like electrical current fluxes caused increased myoblast number in 3-D culture, as determined by DNA assay. The increase in cell number was due to increased cellular proliferation and not differences in apoptosis, as determined by proliferating cell nuclear antigen and TdT-mediated dUTP nick-end labeling. Cardiomyocyte-conditioned medium also significantly increased myoblast proliferation. Expression of transcription factors governing differentiation along skeletal or cardiac lineages was evaluated by immunoblotting. Although these assays are qualitative, no changes in differentiation state along skeletal or cardiac lineages were observed in response to electrical current fluxes. Furthermore, from these experiments, conditioned medium did not appear to alter the differentiation state of skeletal myoblasts. Hence, cardiac milieu appears to stimulate proliferation but does not affect differentiation of skeletal myoblasts.

Angiogenesis therapies for cardiovascular disease.

PURPOSE OF REVIEW: The purpose was to summarize the findings of the proangiogenic clinical trials using protein and gene therapy, with analysis of the problems and an interpretation of the results. RECENT FINDINGS: Recent findings include several new large clinical trials, using both gene and protein therapies. There has been development of new basic science concepts, especially with regard to endothelial activation and stabilization of newly formed microvessels. This review provides a critical analysis of the most recent clinical trials, both in efforts to understand the pitfalls of earlier clinical trials, and also to focus on requirements for future studies. SUMMARY: This article reviews many of the clinical trials utilizing proangiogenic therapy, assesses the pitfalls seen within the current trials, and discusses the conclusions drawn and the future of angiogenesis therapy.