Systemic Delivery of Extracellular Vesicles Attenuates Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Atrial fibrillation (AF) is a common comorbidity in heart failure with preserved ejection fraction (HFpEF) patients. To date, treatments for HFpEF-related AF have been limited to anti-arrhythmic drugs and ablation. Here we examined the effects of immortalized cardiosphere-derived extracellular vesicles (imCDCevs) in rats with HFpEF. OBJECTIVES: This study sought to investigate the mechanisms of AF in HFpEF and probe the potential therapeutic efficacy of imCDCevs in HFpEF-related AF. METHODS: Dahl salt-sensitive rats were fed a high-salt diet for 7 weeks to induce HFpEF and randomized to receive imCDCevs (n = 18) or vehicle intravenously (n = 14). Rats fed a normal-salt diet were used as control animals (n = 26). A comprehensive characterization of atrial remodeling was conducted using functional and molecular techniques. RESULTS: HFpEF-verified animals showed significantly higher AF inducibility (84%) compared with control animals (15%). These changes were associated with prolonged action potential duration, slowed conduction velocity (connexin 43 lateralization), and fibrotic remodeling in the left atrium of HFpEF compared with control animals. ImCDCevs reversed adverse electrical remodeling (restoration of action potential duration to control levels and reorganization of connexin 43) and reduced AF inducibility (33%). In addition, fibrosis, inflammation, and oxidative stress, which are major pathological AF drivers, were markedly attenuated in imCDCevs-treated animals. Importantly, these effects occurred without changes in blood pressure and diastolic function. CONCLUSIONS: Thus, imCDCevs attenuated adverse remodeling, and prevented AF in a rat model of HFpEF.

Experience With SynCardia Total Artificial Heart as a Bridge to Transplantation in 100 Patients.

BACKGROUND: The SynCardia temporary total artificial heart (TAH-t) is an effective bridge to transplantation for patients with severe biventricular failure. However, granular single-center data from high-volume centers are lacking. We report our experience with the first 100 TAH-t recipients. METHODS: A prospective institutional database was used to identify 100 patients who underwent 101 TAH-t implantations between 2012 and 2022. Patients were stratified and compared according to Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 vs 2 or greater. Median follow-up on device support was 94 days (interquartile range, 33-276), and median follow-up after transplantation was 4.6 years (interquartile range, 2.1-6.0). RESULTS: Overall, 61 patients (61%) were successfully bridged to transplantation and 39 (39%) died on TAH-t support. Successful bridge rates between INTERMACS profile 1 and INTERMACS profile 2 or greater patients were similar (55.6% [95% CI, 40.4%-68.3%] vs 67.4% [95% CI, 50.5%-79.6%], respectively; P = .50). The most common adverse events (rates per 100 patient-months) on TAH-t support included infection (15.8), ischemic stroke (4.6), reoperation for mediastinal bleeding (3.5), and gastrointestinal bleeding requiring intervention (4.3). The most common cause of death on TAH-t support was multisystem organ failure (n = 20, 52.6%). Thirty-day survival after transplantation was 96.7%; survival at 6 months, 1 year, and 5 years after transplantation was 95.1% (95% CI, 85.4%-98.4%), 86.6% (95% CI, 74.9%-93.0%), and 77.5% (95% CI, 64.2%-86.3%), respectively. CONCLUSIONS: Acceptable outcomes can be achieved in the highest acuity patients using the TAH-t as a bridge to heart transplantation.

Trends in segmentectomy for the treatment of stage 1A non-small cell lung cancers: Does the robot have an impact?

OBJECTIVES: Lobectomy may unnecessarily resect healthy lung parenchyma in Stage 1A non-small cell lung cancers (NSCLC). Segmentectomies may provide a lung-sparing option. VATS segmentectomies can be technically challenging; robotics may have features that provide advantages in performing segmentectomies. We describe the association of the robot on national trends in segmentectomies. METHODS: The National Cancer Database (2010-2017) was queried for patients with Stage 1A NSCLC who underwent lobectomies and segmentectomies. The proportion of segmentectomies vs. lobectomies and the proportion of robotic vs. VATS segmentectomies was calculated annually. RESULTS: The proportion of segmentectomies increased compared to lobectomies for all surgical approaches but remained constant for minimally-invasive approaches. The proportion of robotic segmentectomies increased over the years compared to VATS segmentectomies. Descriptive statistics are reported as numbers and proportions. Trends in the proportions of lobectomies and segmentectomies were compared using Chi-squared test for categorical variables and unpaired t-test for independent means. A p-value of <0.05 was considered statistically significant. Statistical analysis was performed using SPSS Statistics Software version 24 (IBM Corp, Armonk, NY). CONCLUSIONS: We demonstrate an increasing trend and proportion of robotic segmentectomies being performed in comparison to VATS segmentectomies. The robotic platform may facilitate the performance of more segmentectomies for early-stage NSCLC.

Robotic navigational bronchoscopy in a thoracic surgery practice: Leveraging technology in the management of pulmonary nodules.

Objectives: Robotic navigational bronchoscopy is increasingly used to improve diagnostic yield for pulmonary nodules compared with the 50% to 60% obtained by standard bronchoscopy; however, safety and efficacy data are limited to small series. The aim of this study was to evaluate diagnostic yield and clinical outcomes in a large multisurgeon single-center cohort. Methods: All patients who underwent robotic navigational bronchoscopy and biopsy from September 2020 to October 2022 were identified from a prospective institutional registry. The primary outcome was diagnostic yield. The secondary outcome was diagnostic yield for molecular testing. Results: A total of 503 nodules were biopsied during the study period. Median nodule size was 2.1 cm. Overall diagnostic yield was 87.9%. Factors associated with increased diagnostic yield were decreased time from date of planning computed tomography to procedure date (odds ratio, 0.98; 95% CI, 0.96-0.99; P = .04) and greater nodule size (odds ratio, 1.03; 95% CI, 1.01-1.07; P = .02) per 0.1-cm increment. Molecular analysis was sent in 101 patients and was sufficient in 90% of cases. Complications occurred in 22 (5%) patients, including 13 (3.1%) with pneumothoraxes (7 patients requiring a chest drain), and 5 (1.2%) patients had bleeding requiring intraprocedural bronchial intervention. A total of 41 patients were consented for biopsy and resection during a single anesthetic event. Four of these cases were stopped at robotic navigational bronchoscopy due to an alternative diagnosis. Mean length of stay was 3.4 ± 1.1 days. There were no major complications. Conclusions: This study suggests robotic navigational bronchoscopy has a high diagnostic yield and obtains adequate tissue for molecular analysis critical for selection of targeted therapies. With careful patient selection robotic navigational bronchoscopy can be combined with surgery to treat lung cancer as a single procedure with low complication rates.

MicroRNA-dependent suppression of biological pacemaker activity induced by TBX18.

Chemically modified mRNA (CMmRNA) with selectively altered nucleotides are used to deliver transgenes, but translation efficiency is variable. We have transfected CMmRNA encoding human T-box transcription factor 18 (CMmTBX18) into heart cells or the left ventricle of rats with atrioventricular block. TBX18 protein expression from CMmTBX18 is weak and transient, but Acriflavine, an Argonaute 2 inhibitor, boosts TBX18 levels. Small RNA sequencing identified two upregulated microRNAs (miRs) in CMmTBX18-transfected cells. Co-administration of miR-1-3p and miR-1b antagomiRs with CMmTBX18 prolongs TBX18 expression in vitro and in vivo and is sufficient to generate electrical stimuli capable of pacing the heart. Different suppressive miRs likewise limit the expression of VEGF-A CMmRNA. Cells therefore resist translation of CMmRNA therapeutic transgenes by upregulating suppressive miRs. Blockade of suppressive miRs enhances CMmRNA expression of genes driving biological pacing or angiogenesis. Such counterstrategies constitute an approach to boost the efficacy and efficiency of CMmRNA therapies.

Cell therapy attenuates endothelial dysfunction in hypertensive rats with heart failure and preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is defined by increased left ventricular (LV) stiffness, impaired vascular compliance, and fibrosis. Although systemic inflammation, driven by comorbidities, has been proposed to play a key role, the precise pathogenesis remains elusive. To test the hypothesis that inflammation drives endothelial dysfunction in HFpEF, we used cardiosphere-derived cells (CDCs), which reduce inflammation and fibrosis, improving function, structure, and survival in HFpEF rats. Dahl salt-sensitive rats fed a high-salt diet developed HFpEF, as manifested by diastolic dysfunction, systemic inflammation, and accelerated mortality. Rats were randomly allocated to receive intracoronary infusion of CDCs or vehicle. Two weeks later, inflammation, oxidative stress, and endothelial function were analyzed. Single-cell RNA sequencing of heart tissue was used to assay transcriptomic changes. CDCs improved endothelial-dependent vasodilation while reducing oxidative stress and restoring endothelial nitric oxide synthase (eNOS) expression. RNA sequencing revealed CDC-induced attenuation of pathways underlying endothelial cell leukocyte binding and innate immunity. Exposure of endothelial cells to CDC-secreted extracellular vesicles in vitro reduced VCAM-1 protein expression and attenuated monocyte adhesion and transmigration. Cell therapy with CDCs corrects diastolic dysfunction, reduces oxidative stress, and restores vascular reactivity. These findings lend credence to the hypothesis that inflammatory changes of the vascular endothelium are important, if not central, to HFpEF pathogenesis.NEW & NOTEWORTHY We tested the concept that inflammation of endothelial cells is a major pathogenic factor in HFpEF. CDCs are heart-derived cell products with verified anti-inflammatory therapeutic properties. Infusion of CDCs reduced oxidative stress, restored eNOS abundance, lowered monocyte levels, and rescued the expression of multiple disease-associated genes, thereby restoring vascular reactivity. The salutary effects of CDCs support the hypothesis that inflammation of endothelial cells is a proximate driver of HFpEF.

Extracellular Vesicles, Inflammation, and Cardiovascular Disease.

Cardiovascular disease is a leading cause of death worldwide. The underlying mechanisms of most cardiovascular disorders involve innate and adaptive immune responses, and extracellular vesicles are implicated in both. In this review, we describe the mechanistic role of extracellular vesicles at the intersection of inflammatory processes and cardiovascular disease. Our discussion focuses on atherosclerosis, myocardial ischemia and ischemic heart disease, heart failure, aortic aneurysms, and valvular pathology.

Heart transplantation after total artificial heart bridging-Outcomes over 15 years.

BACKGROUND: Data are limited on outcomes after heart transplantation in patients bridged-to-transplantation (BTT) with a total artificial heart (TAH-t). METHODS: The UNOS database was used to identify 392 adult patients undergoing heart transplantation after TAH-t BTT between 2005 and 2020. They were compared with 11 014 durable left ventricular assist device (LVAD) BTT patients and 22 348 de novo heart transplants (without any durable VAD or TAH-t BTT) during the same period. RESULTS: TAH-t BTT patients had increased dialysis dependence compared to LVAD BTT and de novo transplants (24.7% vs. 2.7% vs. 3.8%) and higher levels of baseline creatinine and total bilirubin (all p < .001). After transplantation, TAH-t BTT patients were more likely to die from multiorgan failure in the first year (25.0% vs. 16.1% vs. 16.1%, p = .04). Ten-year survival was inferior in TAH-t BTT patients (TAH-t BTT 53.1%, LVAD BTT 61.8%, De Novo 62.6%, p < .001), while 10-year survival conditional on 1-year survival was similar (TAH-t BTT 66.8%, LVAD BTT 68.7%, De Novo 69.0%, all p > .20). Among TAH-t BTT patients, predictors of 1-year mortality included higher baseline creatinine and total bilirubin, mechanical ventilation, and cumulative center volume <20 cases of heart transplantation involving TAH-t BTT (all p < .05). CONCLUSION: Survival after TAH-t BTT is acceptable, and patients who survive the early postoperative phase experience similar hazards of mortality over time compared to de novo transplant patients and durable LVAD BTT patients.

Engineered Fibroblast Extracellular Vesicles Attenuate Pulmonary Inflammation and Fibrosis in Bleomycin-Induced Lung Injury.

Pulmonary fibrosis is a progressive disease for which no curative treatment exists. We have previously engineered dermal fibroblasts to produce extracellular vesicles with tissue reparative properties dubbed activated specialized tissue effector extracellular vesicles (ASTEX). Here, we investigate the therapeutic utility of ASTEX in vitro and in a mouse model of bleomycin-induced lung injury. RNA sequencing demonstrates that ASTEX are enriched in micro-RNAs (miRs) cargo compared with EVs from untransduced dermal fibroblast EVs (DF-EVs). Treating primary macrophages with ASTEX reduced interleukin (IL)6 expression and increased IL10 expression compared with DF-EV-exposed macrophages. Furthermore, exposure of human lung fibroblasts or vascular endothelial cells to ASTEX reduced expression of smooth muscle actin, a hallmark of myofibroblast differentiation (respectively). In vivo, intratracheal administration of ASTEX in naïve healthy mice demonstrated a favorable safety profile with no changes in body weight, lung weight to body weight, fibrotic burden, or histological score 3 weeks postexposure. In an acute phase (short-term) bleomycin model of lung injury, ASTEX reduced lung weight to body weight, IL6 expression, and circulating monocytes. In a long-term setting, ASTEX improved survival and reduced fibrotic content in lung tissue. These results suggest potential immunomodulatory and antifibrotic properties of ASTEX in lung injury.

Regulatory T cell activation, proliferation, and reprogramming induced by extracellular vesicles.

BACKGROUND: Extracellular vesicles (EVs) from heart stromal/progenitor cells modulate innate immunity, with salutary effects in a variety of cardiac disease models. Little is known, however, about the effects of these EVs on adaptive immunity. METHODS: Ex vivo differentiation of naïve CD4+ T cells was conducted to assess the effect of EVs on cytokine production and proliferation of Th1, Th2, Th17, and regulatory T (Treg) cells. These effects were further tested in vivo using the experimental autoimmune myocarditis (EAM) model. RESULTS: Using differentiated CD4+ T cells, we show that EVs secreted by human-derived heart stromal/progenitor cells selectively influence the phenotype, activity, and proliferation of regulatory T (Treg) cells. Exposure of Treg cells to EVs results in faster proliferation, augmented production of IL-10, and polarization toward an intermediate FOXP3+RORγt+ phenotype. In experimental autoimmune myocarditis, EVs attenuate cardiac inflammation and functional decline, in association with increased numbers of splenic IL10+-Treg cells. CONCLUSIONS: T cell modulation by EVs represents a novel therapeutic approach to inflammation, harnessing endogenous immunosuppressive mechanisms that may be applied in solid organ transplantation, graft-versus-host disease, and autoimmune disorders.

Mechanical Circulatory Support in Right Ventricular Failure.

Right ventricular dysfunction presents unique challenges in patients with cardiopulmonary disease. When optimal medical therapy fails, mechanical circulatory support is considered. Devices can by classified according to whether they are deployed percutaneously or surgically, whether the pump is axial or centrifugal, whether the right ventricle is bypassed directly or indirectly, and whether the support is short term or long term. Each device has advantages and disadvantages. Acute mechanical circulatory support is a suitable temporizing strategy in advanced heart failure. Future research in right ventricular mechanical circulatory support will optimize device management, refine patient selection, and ultimately improve clinical outcomes.

Casein-enhanced uptake and disease-modifying bioactivity of ingested extracellular vesicles.

Extracellular vesicles (EVs) from cardiac stromal cells, developed as therapeutic candidates, improve dystrophic muscle function when administered parenterally, but oral delivery remains untested. We find that casein, the dominant protein in breast milk, enhances the uptake and bioactivity of ingested heart-derived EVs, altering gene expression in blood cells and enhancing muscle function in mdx mice with muscular dystrophy. Thus, EVs, administered orally, are absorbed and exert disease-modifying bioactivity in vivo. Formulating EVs with casein enhances uptake and markedly expands the range of potential therapeutic applications.