Adherent skin barrier drape use is associated with a reduced risk of cardiac implantable device infection: Results from a prospective study of 14,225 procedures.

Background: Cardiac implantable electronic device (CIED) infection is a costly and highly morbid complication. Perioperative interventions, including the use of antibiotic pouches and intensified perioperative antibiotic regimens, have demonstrated marginal efficacy at reducing CIED infection. Additional research is needed to identify additional interventions to reduce infection risk. Objective: We sought to evaluate whether adherent skin barrier drape use is associated with a reduction in CIED infection. Methods: A prospective registry of all CIED implantation procedures was established at our institution in January 2007. The registry was established in collaboration with our hospital infection prevention team with a specific focus on prospectively identifying all potential CIED infections. All potential CIED infections were independently adjudicated by 2 physicians blinded to the use of an adherent skin barrier drape. Results: Over a 13-year period, 14,225 procedures were completed (mean age 72 ± 14 years; female 4,918 (35%); new implants 10,005 (70%); pulse generator changes 2585 (18%); upgrades 1635 (11%). Of those, 2469 procedures (17.4%) were performed using an adherent skin barrier drape. There were 103 adjudicated device infections (0.73%). The infection rate in patients in the barrier use groups was 8 of 2469 (0.32%) as compared with 95 of 11,756 (0.8%) in the nonuse group (P = .0084). In multivariable analysis, the use of an adherent skin barrier drape was independently associated with a reduction in infection (odds ratio 0.32; 95% confidence interval 0.154-0.665; P = .002). Conclusion: The use of an adherent skin barrier drape at the time of cardiac device surgery is associated with a lower risk of subsequent infection.

Do barrier dressings reduce cardiac implantable device infection: Protocol for a randomized controlled trial (BARRIER-PROTECT).

Background: Cardiac implantable electronic device (CIED) procedures can be associated with serious complications, including infection with significant mortality and morbidity, necessitating removal of the device and prolonged hospitalization. One potential pathophysiological mechanism is pocket contamination at the time of device implantation. Therefore, steps taken to prevent contamination at this stage can potentially reduce CIED infections.The barrier dressing, an adhesive material applied to the skin, has the potential to reduce the colonization of the surgical site with host flora that can predispose to infection. There are a limited number of randomized prospective studies on barrier dressing use during various surgeries, but it has never been systematically studied in CIED implantation. Objectives: Do Barrier Dressings Reduce Cardiac Implantable Device Infection? (BARRIER-PROTECT trial; NCT04591366) is a single-centre, prospective, double-armed, single-blinded, randomized controlled trial designed to evaluate the use of an intra-operative adhesive barrier dressing to reduce the risk of end-of-procedure pocket swab positivity. We hypothesize that adhesive draping during implant procedures will reduce the risk of contamination from the skin flora. Also, we aim to investigate if the end-of-procedure pocket swab culture positivity can be used as a potential surrogate marker of CIED infection. Methods and Design: Patients undergoing a second or later procedure on the same device pocket (pulse generator change, lead/pocket revision or upgrade) will be enrolled. Eligible and consenting patients will be equally randomized to the use of barrier dressing or not using an automated web-based system. Patients, but not the operator, will be blinded to the arm. The person performing the pocket swabs will also be blinded. The primary endpoint is the end-of-procedure pocket swab culture positivity. The main secondary endpoint is the CIED infection rate. Discussion: This is the first randomized controlled trial to assess the effectiveness of using a barrier adhesive draping on reducing the end-of-procedure pocket swab culture positivity. In this study, we are exploring a low-cost intervention that may significantly reduce CIED infection. Also, having a valid surrogate marker for CIED infection at the time of implant will facilitate design of future clinical trials.

Combinatorial Effect of Biomaterials and Extracellular Vesicle Therapy for Heart Failure with Reduced Ejection Fraction: A Systematic Review of Preclinical Studies.

Heart failure, a pervasive global health burden, necessitates innovative therapeutic strategies. Extracellular vesicles (EVs) have emerged as promising contenders for cardiac repair, owing to their profound influence on fibrosis and inflammation. Merging EVs with biomaterials holds the potential for a synergistic leap in therapeutic efficacy. In this review, the impact of combining EVs with biomaterials in preclinical heart failure models is scrutinized. Fifteen studies, predominantly employing mesenchymal stromal cell-derived EVs along with hyaluronic acid or peptides in coronary ligation models, meet these stringent criteria. The amalgamation of EVs and biomaterials consistently enhances cardiac ejection fraction (1.39; 95% CI: 0.68, 2.11; p = 0.0001) and fractional shortening (1.46, 95% CI: 0.70, 2.22; p = 0.0002) compared to EV monotherapy. Secondary outcomes similarly showcased improvement in the combined treatment group. Although the number of studies analyzed is modest, no indications of publication bias surface. In summary, combination therapy with EVs and biomaterials enhances therapeutic benefit in preclinical heart failure models. The consistent improvement observed across diverse EV sources, biomaterials, and animal models underscores the exciting potential of this synergistic approach.

Encapsulating therapeutic cells in RGD-modified agarose microcapsules.

Current cell-based strategies for repairing damaged tissue often show limited efficacy due to low cell retention at the site of injury. Encapsulation of cells within hydrogel microcapsules demonstrably increases cell retention but benefits can be limited due to premature cell escape from the hydrogel microcapsules and subsequent clearance from the targeted tissue. We propose a method of encapsulating cells in agarose microcapsules that have been modified to increase cell retention by providing cell attachment domains within the agarose hydrogel allowing cells to adhere to the microcapsules. We covalently modified agarose with the addition of the cell adhesion peptide, RGD (arginine, glycine, aspartic acid). We then used a microfluidic platform to encapsulate single cells within 50 µm agarose microcapsules. We tracked encapsulated cells for cell viability, egress from microcapsules and attachment to microcapsules at 2 h, 24 h, and 48 h after encapsulation. Many encapsulated cells eventually egress their microcapsule. Those that were encapsulated using RGD-modified agarose adhered to the outer surface of the microcapsule following egress. NIH 3T3 cells showed nearly 45% of egressed cells attached to the outside of RGD modified agarose microcapsules, while minimal cellular adhesion was observed when using unmodified agarose. Similarly, human umbilical vein endothelial cells had up to 33% of egressed cells attached and explant-derived cardiac cells showed up to 20% attachment with the presence of RGD binding domains within the agarose microcapsules.

Prevention of atrial fibrillation after open-chest surgery with extracellular vesicle therapy.

Almost half of patients recovering from open-chest surgery experience atrial fibrillation (AF) that results principally from inflammation in the pericardial space surrounding the heart. Given that postoperative AF is associated with increased mortality, effective measures to prevent AF after open-chest surgery are highly desirable. In this study, we tested the concept that extracellular vesicles (EVs) isolated from human atrial explant-derived cells can prevent postoperative AF. Middle-aged female and male rats were randomized to undergo sham operation or induction of sterile pericarditis followed by trans-epicardial injection of human EVs or vehicle into the atrial tissue. Pericarditis increased the probability of inducing AF while EV treatment abrogated this effect in a sex-independent manner. EV treatment reduced infiltration of inflammatory cells and production of pro-inflammatory cytokines. Atrial fibrosis and hypertrophy seen after pericarditis were markedly attenuated by EV pretreatment, an effect attributable to suppression of fibroblast proliferation by EVs. Our study demonstrates that injection of EVs at the time of open-chest surgery shows prominent antiinflammatory effects and prevents AF due to sterile pericarditis. Translation of this finding to patients might provide an effective new strategy to prevent postoperative AF by reducing atrial inflammation and fibrosis.

Inhibition of Wnt/ß-catenin signaling upregulates Nav 1.5 channels in Brugada syndrome iPSC-derived cardiomyocytes.

The voltage-gated Nav 1.5 channels mediate the fast Na+ current (INa ) in cardiomyocytes initiating action potentials and cardiac contraction. Downregulation of INa , as occurs in Brugada syndrome (BrS), causes ventricular arrhythmias. The present study investigated whether the Wnt/ß-catenin signaling regulates Nav 1.5 in human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). In healthy male and female iPSC-CMs, activation of Wnt/ß-catenin signaling by CHIR-99021 reduced (p < 0.01) both Nav 1.5 protein and SCN5A mRNA. In iPSC-CMs from a BrS patient, both Nav 1.5 protein and peak INa were reduced compared to those in healthy iPSC-CMs. Treatment of BrS iPSC-CMs with Wnt-C59, a small-molecule Wnt inhibitor, led to a 2.1-fold increase in Nav 1.5 protein (p = 0.0005) but surprisingly did not affect SCN5A mRNA (p = 0.146). Similarly, inhibition of Wnt signaling using shRNA-mediated ß-catenin knockdown in BrS iPSC-CMs led to a 4.0-fold increase in Nav 1.5, which was associated with a 4.9-fold increase in peak INa but only a 2.1-fold increase in SCN5A mRNA. The upregulation of Nav 1.5 by ß-catenin knockdown was verified in iPSC-CMs from a second BrS patient. This study demonstrated that Wnt/ß-catenin signaling inhibits Nav 1.5 expression in both male and female human iPSC-CMs, and inhibition of Wnt/ß-catenin signaling upregulates Nav 1.5 in BrS iPSC-CMs through both transcriptional and posttranscriptional mechanisms.

Mechanisms of Cardiac Repair in Cell Therapy.

Heart failure is an important cause of morbidity and mortality. More than 20 years ago, special interest was drawn to cell therapy as a means of restoring damaged hearts to working condition. But progress has not been straightforward as many of our initial assumptions turned out to be wrong. In this review, we critically examine the last 20 years of progress in cardiac cell therapy and focus on several of the popular beliefs surrounding cell therapy to illustrate the mechanisms involved in restoring heart function after cardiac injury. Are they true or false?

Extracellular vesicle microRNA and protein cargo profiling in three clinical-grade stem cell products reveals key functional pathways.

The cell origin-specific payloads within extracellular vesicles (EVs) mediate therapeutic bioactivity for a wide variety of stem cell types. In this study, we profiled the microRNA (miRNA) and protein cargos found within EVs produced by three clinical-grade stem cell products of different ontogenies being considered for clinical application, namely bone marrow-derived mesenchymal stromal cells (BM-MSCs), heart-derived cells (HDCs), and umbilical cord-derived MSCs (UC-MSCs). Although several miRNAs (757) and proteins (420) were found in common, each producer cell type expressed unique miRNA profiles when the most highly expressed transcripts were compared. Differential expression analysis revealed that BM-MSCs and HDCs were quite similar, while UC-MSCs had the greatest number of unique miRNAs and proteins. Despite these differences, all three EVs promoted cell adhesion/migration, immune response, platelet aggregation, protein translation/stabilization, and RNA processing. EVs from BM-MSCs were implicated in apoptosis, cell-cycle progression, collagen formation, heme pigment synthesis, and smooth muscle differentiation, while HDC and UC-MSC EVs were found to regulate complement activation, endopeptidase activity, and matrix metallopeptidases. Overall, miRNA and protein profiling reveal functional differences between three leading stem cell products. These findings provide a framework for mechanistic exploration of candidate therapeutic molecules driving the salutary effects of EVs.

Viral Transgene Expression in Rodent Hearts and the Assessment of Cardiac Arrhythmia Risk.

Heart disease is the leading cause of morbidity and mortality worldwide. Due to their low cost, ease of handling, and abundance of transgenic strains, rodents have become essential models for cardiovascular research. However, spontaneous lethal cardiac arrhythmias that often cause mortality in heart disease patients are rare in rodent models of heart disease. This is primarily due to the species differences in cardiac electrical properties between human and rodents and poses a challenge to the study of cardiac arrhythmias using rodents. This protocol describes an approach to enable efficient transgene expression in mouse and rat ventricular myocardium using echocardiography-guided intramuscular injections of recombinant virus (adenovirus and adeno-associated virus). This work also outlines a method to enable reliable assessment of cardiac susceptibility to arrhythmias using isolated, Langendorff-perfused mouse and rat hearts with both adrenergic and programmed electrical stimulations. These techniques are critical for studying heart rhythm disorders associated with adverse cardiac remodeling after injuries, such as myocardial infarction.

Should they stay, or should they go: Do we need to remove the old cardiac implantable electronic device if a new system is required on the contralateral side?

Background: Ipsilateral approach in patients requiring cardiac implantable electronic device (CIED) revision or upgrade may not be feasible, primarily due to vascular occlusion. If a new CIED is implanted on the contralateral side, a common practice is to explant the old CIED to avoid device interaction. Objective: The purpose of this study was to assess a conservative approach of abandoning the old CIED after implanting a new contralateral device. Methods: We used an artificial intelligence algorithm to analyze postimplant chest radiographs to identify those with multiple CIEDs. Outcomes of interest included device interaction, abandoned CIED elective replacement indicator (ERI) behavior, subsequent programming changes, and explant of abandoned CIED. Theoretical risk of infection with removal of abandoned CIED was estimated using a validated scoring system. Results: Among 12,045 patients, we identified 40 patients with multiple CIEDs. Occluded veins were the most common indication for contralateral implantation (n = 27 [67.5%]). Fifteen abandoned CIEDs reached ERI, with 4 reverting to VVI 65. One patient underwent explant due to device interaction, and 2 required device reprogramming. Of 32 patients with an implantable cardioverter-defibrillator, 8 (25%) had treated ventricular arrhythmia. There were no failed or inappropriate therapies due to interaction. Eighteen patients (45%) had hypothetical >1% annual risk of hospitalization for device infection if the abandoned CIED had been explanted. Conclusion: In patients requiring new CIED implant on the contralateral side, abandoning the old device is feasible. This approach may reduce the risk of infection and concerns regarding abandoned leads and magnetic resonance imaging scans. Knowledge of ERI behavior is essential to avoid device interactions.

Outcomes of a comprehensive strategy during repeat atrial fibrillation ablation.

BACKGROUND/PURPOSE: Atrial fibrillation (AF) recurs post-ablation in 30-40% of patients. The approach to a repeat ablation, beyond isolation of reconnected pulmonary veins (PVs), is not well established. We sought to prospectively assess outcomes and predictors of recurrence among consecutive patients who underwent repeat AF ablation with a standardized approach. METHODS: This was a single-center prospective study of consecutive patients who underwent repeat AF ablation. Our protocol consisted of six steps: PV re-isolation, ablation of left atrial low-voltage areas (LVAs), ablation of isoproterenol-induced non-PV triggers, electrophysiology study (EPS) and ablation of induced AVNRT/AVRT, ablation of induced clinical atrial flutters, and lastly empiric ablation as per operator discretion if no other ablation was performed. RESULTS: Among 725 AF ablations performed during the study period, 74 were repeat ablations. Of those undergoing repeat ablation, 53 (72%) had PV reconnection, 30 (41%) had LVAs, seven (10%) had non-PV triggers, five (7%) had AVNRT, and 15 (20%) had typical atrial flutter. Following repeat ablation, arrhythmia-free survival was 65% at 1 year. The absence of PV reconnection was the only factor independently associated with recurrence after repeat ablation (recurrence rate 71%, adjusted OR 7.91, 95% CI 2.31-27.16, p = 0.001). CONCLUSIONS: A comprehensive approach to repeat AF ablation including PV re-isolation, LVA ablation, non-PV trigger ablation, EPS, and flutter ablation was associated with a 65% 1-year arrhythmia-free survival. The absence of PV reconnection was the only independent predictor of arrhythmia recurrence. Further research is needed to identify therapies beyond PV isolation for patients undergoing repeat ablation.

Nanoengineered Sprayable Therapy for Treating Myocardial Infarction.

We report the development, as well as the in vitro and in vivo testing, of a sprayable nanotherapeutic that uses surface engineered custom-designed multiarmed peptide grafted nanogold for on-the-spot coating of an infarcted myocardial surface. When applied to mouse hearts, 1 week after infarction, the spray-on treatment resulted in an increase in cardiac function (2.4-fold), muscle contractility, and myocardial electrical conductivity. The applied nanogold remained at the treatment site 28 days postapplication with no off-target organ infiltration. Further, the infarct size in the mice that received treatment was found to be <10% of the total left ventricle area, while the number of blood vessels, prohealing macrophages, and cardiomyocytes increased to levels comparable to that of a healthy animal. Our cumulative data suggest that the therapeutic action of our spray-on nanotherapeutic is highly effective, and in practice, its application is simpler than other regenerative approaches for treating an infarcted heart.

Direct comparison of different therapeutic cell types susceptibility to inflammatory cytokines associated with COVID-19 acute lung injury.

BACKGROUND: Although 90% of infections with the novel coronavirus 2 (COVID-19) are mild, many patients progress to acute respiratory distress syndrome (ARDS) which carries a high risk of mortality. Given that this dysregulated immune response plays a key role in the pathology of COVID-19, several clinical trials are underway to evaluate the effect of immunomodulatory cell therapy on disease progression. However, little is known about the effect of ARDS associated pro-inflammatory mediators on transplanted stem cell function and survival, and any deleterious effects could undermine therapeutic efficacy. As such, we assessed the impact of inflammatory cytokines on the viability, and paracrine profile (extracellular vesicles) of bone marrow-derived mesenchymal stromal cells, heart-derived cells, and umbilical cord-derived mesenchymal stromal cells. METHODS: All cell products were manufactured and characterized to established clinical release standards by an accredited clinical cell manufacturing facility. Cytokines and Extracellular vesicles in the cell conditioned media were profiled using proteomic array and nanoparticle tracking analysis. Using a survey of the clinical literature, 6 cytotoxic cytokines implicated in the progression of COVID-19 ARDS. Flow cytometry was employed to determine receptor expression of these 6 cytokines in three cell products. Based on clinical survey and flow cytometry data, a cytokine cocktail that mimics cytokine storm seen in COVID-19 ARDS patients was designed and the impact on cytokine cocktail on viability and paracrine secretory ability of cell products were assessed using cell viability and nanoparticle tracking analysis. RESULTS: Flow cytometry revealed the presence of receptors for all cytokines but IL-6, which was subsequently excluded from further experimentation. Despite this widespread expression, exposure of each cell type to individual cytokines at doses tenfold greater than observed clinically or in combination at doses associated with severe ARDS did not alter cell viability or extracellular vesicle character/production in any of the 3 cell products. CONCLUSIONS: The paracrine production and viability of the three leading cell products under clinical evaluation for the treatment of severe COVID-19 ARDS are not altered by inflammatory mediators implicated in disease progression.

Cardiomyocyte-specific deletion of ß-catenin protects mouse hearts from ventricular arrhythmias after myocardial infarction.

Wnt/ß-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if ß-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific ß-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/ß-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K+ channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific ß-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations.

State-of-play for cellular therapies in cardiac repair and regeneration.

Cardiovascular disease is the primary cause of death around the world. For almost two decades, cell therapy has been proposed as a solution for heart disease. In this article, we report on the "state-of-play" of cellular therapies for cardiac repair and regeneration. We outline the progression of new ideas from the preclinical literature to ongoing clinical trials. Recent data supporting the mechanics and mechanisms of myogenic and paracrine therapies are evaluated in the context of long-term cardiac engraftment. This discussion informs on promising new approaches to indicate future avenues for the field.

Electrophysiological engineering of heart-derived cells with calcium-dependent potassium channels improves cell therapy efficacy for cardioprotection.

We have shown that calcium-activated potassium (KCa)-channels regulate fundamental progenitor-cell functions, including proliferation, but their contribution to cell-therapy effectiveness is unknown. Here, we test the participation of KCa-channels in human heart explant-derived cell (EDC) physiology and therapeutic potential. TRAM34-sensitive KCa3.1-channels, encoded by the KCNN4 gene, are exclusively expressed in therapeutically bioactive EDC subfractions and maintain a strongly polarized resting potential; whereas therapeutically inert EDCs lack KCa3.1 channels and exhibit depolarized resting potentials. Somatic gene transfer of KCNN4 results in membrane hyperpolarization and increases intracellular [Ca2+], which boosts cell-proliferation and the production of pro-healing cytokines/nanoparticles. Intramyocardial injection of EDCs after KCNN4-gene overexpression markedly increases the salutary effects of EDCs on cardiac function, viable myocardium and peri-infarct neovascularization in a well-established murine model of ischemic cardiomyopathy. Thus, electrophysiological engineering provides a potentially valuable strategy to improve the therapeutic value of progenitor cells for cardioprotection and possibly other indications.

High-power, short-duration atrial fibrillation ablation compared with a conventional approach: Outcomes and reconnection patterns.

BACKGROUND: The effectiveness, safety, and pulmonary vein (PV) reconnection patterns of point-by-point high-power, short-duration (HPSD) ablation relative to conventional force-time integral (FTI)-guided strategies for atrial fibrillation (AF) ablation are unknown. OBJECTIVES: To compare 1-year freedom from atrial arrhythmia (AA), complication rates, procedural times, and PV reconnection patterns with HPSD AF AF ablation versus an FTI-guided low-power, long-duration (LPLD) strategy. METHODS: We compared consecutive patients undergoing a first ablation procedure for paroxysmal or persistent AF. The HPSD protocol utilized a power of 50 W and durations of 6-8 s posteriorly and 8-10 s anteriorly. The LPLD protocol was FTI-guided with a power of ≤25 W posteriorly (FTI ≥ 300g·s) and ≤35 W anteriorly (FTI ≥ 400g·s). RESULTS: In total, 214 patients were prospectively included (107 HPSD, 107 LPLD). Freedom from AA at 1 year was achieved in 79% in the HPSD group versus 73% in the LPLD group (p = .339; adjusted hazard ratio with HPSD, 0.67; 95% confidence interval, 0.36-1.23; p < .004 for non-inferiority). Procedure duration was shorter in the HPSD group (229 ± 60 vs. 309 ± 77 min; p < .005). Patients undergoing repeat ablation had a higher propensity for reconnection at the right PV carina in the HPSD group compared with the LPLD group (14/30 = 46.7% vs. 7/34 = 20.6%; p = .035). There were no differences in complication rates. CONCLUSION: HPSD AF ablation resulted in similar freedom from AAs at 1 year, shorter procedure times, and a similar safety profile when compared with an LPLD ablation strategy. Patients undergoing HPSD ablation required more applications at the right carina to achieve isolation, and had a significantly higher rate of right carinal reconnections at redo procedures.