Citations

Abstract Introduction Chronic obstructive pulmonary disease involves an unregulated inflammatory process that leads to the destruction and remodeling of lung architecture, potentially resulting in air-filled lesions known as bullae. We outline a novel technique for transbronchial decompression of a bulla using robotic-assisted bronchoscopy (RAB) in a patient with intraparenchymal emphysematous bullae. Case Description A 74-year-old woman with a medical history significant for COPD, Sjögren's disease, and former smoker, presented to our outpatient clinic with progressively worsening exertional dyspnea over the past two years. The patient underwent a thymectomy for thymic hyperplasia where a right middle bulla was incidentally identified. Posterior bullectomy was not performed intraoperatively due to severe pleural adhesions and the high risk of lung injury during dissection. High-resolution chest computed tomography revealed diffuse subpleural bullous changes, with asymmetric high-attenuation mural foci in several cysts (Figure 1A), with a total volume of 124.11 cm3. Given the high surgical risk, a bronchoscopic approach was decided. Bullae needle aspiration was performed under RAB guidance. Decompression was accomplished using PleurX catheter drainage (Pleur-Evac, Telfex, USA). The connection between the robot and the drainage system utilized a 3-way stopcock (Merit Medical Systems, USA) and a 30 cm vinyl connecting tube (Cook Incorporated, USA). Suction through water seal suction was performed at 20mmHg for 5 min, during which we observed bullae reduction with live intraprocedural mobile CT images. The robot was then retracted, and a 4.0 mm Zephyr endobronchial valve was deployed in the superior segment of the right middle lobe to promote atelectasis, no immediate complications were reported. Post-procedural chest CT demonstrated a significant reduction in bullae size as shown in Figure 1B. At the one-month follow-up, chest X-ray imaging revealed increased atelectasis and persistent collapse in the previously identified area of cystic change. By the two-month follow-up, pulmonary function tests indicated nonspecific ventilatory impairment, with improvements in FEV1% (from 70.5% to 78.2%) and FVC% (from 80.5% to 90.2% of the predicted values). Subsequent follow-ups have demonstrated clinical improvement in the patient's symptoms. Conclusion We contribute to the literature by introducing a novel, non-invasive technique for managing bullae with RAB in patients who are not candidates for surgery. Further studies are warranted to standardize this technique and assess its broader applicability. Figure 1. High-resolution computed tomography showing pre- and post-procedure views of the bullae. (A) Coronal and sagittal views showing the right middle lobe bullae. (66x81mm) (B) Post-procedure view of the chest HRCT (17x29 mm)

Abstract RATIONALE:New-onset atrial fibrillation (NOAF) is a common arrhythmia associated with adverse outcomes in patients with chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA). Both conditions, through shared mechanisms, raise the likelihood of NOAF incidence, emphasizing the importance of epidemiological data and preventive measures to prevent NOAF burden. Therefore, we examined the risk of NOAF in patients with COPD, OSA, and their overlap syndrome (OS). METHODS: We extracted data from the Banner Healthcare Organization, US Collaborative Network in TriNetX, identifying three patient cohorts using ICD-10 codes for COPD (J40-J44) and OSA (G47.3). This included 73,540 patients with OS, 198,880 patients with OSA only, and 337,010 patients with COPD only. Patients with a prior diagnosis of AF before their diagnosis of OSA or COPD were excluded. Propensity matching was conducted based on age, sex, ethnicity, and cardiovascular disease risk factors and prevalence including hypertension, tobacco use, dyslipidemia, obesity, and ischemic heart disease. We calculated the relative risk (RR), hazard ratio (HR), and 95% confidence intervals (CI) for incident AF among propensity score-matched cohorts, comparing OS with OSA alone and OS with COPD alone.RESULTS: In the OS vs. OSA only comparison, 63,070 patients were matched per cohort. Lifetime incidence of new AF was higher in the OS group (13.65%) compared to the OSA-only group (8.24%), with an RR of 1.66 [95% CI: 1.60-1.72]. Kaplan-Meier analysis indicated a lower AF-free probability in the OS group (65.96%) than in the OSA-only group (77.03%), with an HR of 1.56 (p < 0.001). In the OS vs. COPD only comparison, 65,810 patients were matched per cohort. Incidence of new AF in the OS group was 13.76%, compared to 9.86% in the COPD-only group, with an RR of 1.40 [95% CI: 1.35-1.44]. Kaplan-Meier analysis showed a lower AF-free probability for the OS group (66.13%) versus the COPD-only group (78.94%), with an HR of 1.28 (p < 0.001). Sensitivity analyses restricted to the first five years post-diagnosis revealed a persistently higher relative risk of incident AF in OS patients, with an RR of 1.67 [95% CI: 1.60-1.73] compared to OSA alone, and an RR of 1.34 [95% CI: 1.29-1.39] compared to COPD alone. CONCLUSION:We identified that patients with OS have a higher risk of NOAF compared to either condition alone. This emphasizes the need for vigilant monitoring and targeted interventions in patients with OS to decrease arrhythmogenicity risks.

Abstract Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. They are also associated with life-threatening immune-related adverse events (irAEs), including the rare, poorly understood, and potentially fatal triad of myasthenia gravis, myocarditis, and myositis(triple M syndrome). We aimed to describe the management, intensive care unit (ICU)utilization, and outcomes of patients with irAEs with a specific focus on triple M syndrome. Methods: We conducted a retrospective chart review of patients with irAEs admitted to three quaternary care hospitals between December 2018 and 2023. We aimed to collect data on demographics, cancer type, treatment, ICU resource utilization, and outcomes including mortality. Results: Over this 5-year period, 140 patients were admitted for irAEs. Forty-nine percent were male, median age was 73 (IQR 64-80) years, 7% were of African American or Asian descent, and 32%required ICU admission. Median ICU and hospital length of stay (LOS) were 1.5 (IQR 0.7-2.9)and 7.2 (IQR 4.1-13.4) days, respectively. Among ICU patients, 14/140 (10%) had myositis,22/140 (16%) myocarditis, and 9/140 (6.4%) myasthenia gravis. Triple-M syndrome was diagnosed in 7/140 (5%) patients, including 3 with metastatic melanoma, 2 with genitourinary malignancies, 1 with metastatic lung and 1 with colon cancer. Four had received pembrolizumab and 3 nivolumab. Median ICU and hospital LOS were 3 (IQR 1-6) and 10 (IQR 8-21) days in this group. Three patients required mechanical ventilation, one required tracheostomy, and one required vasopressor support. Triple-M management included corticosteroids, IVIG, pyridostigmine, mycophenolate mofetil, and rituximab. Patients with triple-M syndrome were significantly older than other patients with ICI toxicity (P <0.009) and had higher mortality (57%vs 25%, p = 0.07). Patients discharged from the ICU had a median survival of 67 (IQR 26-201)days. Conclusions: Patients with irAEs frequently require ICU level of support with significant morbidity and mortality, especially with triple M syndrome. Clinicians should always consider the possibility of triple-M syndrome in patients with multiple irAEs as symptoms can be subtle and easily overlooked. Corticosteroids remain the primary treatment of irAEs and can be combined with other immunosuppressive agents such as infliximab, anti-thymocyte globulin, or pyridostigmine. Unfortunately, mortality due to triple-M syndrome remains high underscoring the importance of early recognition and prompt multidisciplinary management of these toxicities.

Abstract RATIONALE: The diagnosis of Pulmonary Embolism (PE) is associated with high mortality and morbidity. In patients with cancer, high-risk pulmonary emboli further escalate these risks. Ensuring access to the necessary resources for appropriate intervention is crucial for improving patient outcomes. However, the resource-intensive nature of managing multiple life-threatening conditions can create barriers for certain demographic populations, leading to disparities in outcomes. To address this issue, we explored mortality trends among diverse groups based on gender, ethnicity, and geographical background in the United States from 1999-2000. METHODS: We obtained mortality data from death certificate queries in the Centers for Disease Control and Prevention Wide-range Online Data for Epidemiologic Research database. Queries included all decedents with the underlying cause of death being PE (I26) in patients with a diagnosis of cancer (C00 – C97). Age-adjusted mortality rates (AAMR) per 100,000 people were compared across demographic populations, and 95% Confidence Intervals were standardized to the year 2000. Log-linear regression models were utilized to assess temporal mortality shifts and calculate annual percentage change (APC) from 1999 to 2020. RESULTS: A total of 179483 PE-related deaths was reported in patients with cancer. The AAMR increased from 2.14 [2.08-2.19] in 1999 to 3.05 [3.00-3.11] in 2020. The cumulative AAMR was 2.42 [2.41-2.43] with an average APC of +1.56% (p<0.001). The mortality rate accelerated following the year 2016, with the years prior having an APC of +0.69%, (p<0.001) and the years following having an APC +5.33% (p<0.001). A higher mortality was observed in males (AAMR 2.71 [2.69-2.73]) than females (2.20 [2.18-2.21]), in rural communities (AAMR 2.50 [2.47-2.53]) compared to urban communities (AAMR 2.38 [2.37-2.40]), and in non-Hispanic (AAMR 2.48 [2.47-2.49]) populations over Hispanic populations (AAMR 1.45 [1.42-1.48]). Mortality was highest in the Black population (AAMR 3.65 [3.60-3.69]), followed by White population (AAMR 2.33 [2.32-2.34]), American Natives (AAMR 1.43 [1.33-1.54]), and Asian (AAMR 1.04 [1.00-1.08]). Geographically, Midwest (AAMR 2.58 [2.56-2.61]) had the highest mortality while the South (AAMR 2.26 [2.24-2.28]) had the lowest mortality. CONCLUSIONS: We identified significant disparities in mortality related to pulmonary embolism (PE) among cancer patients across different demographic populations. Further investigation into these healthcare inequities is essential for addressing the disparities affecting various groups.

Abstract RATIONALE: Endothelial-to-mesenchymal transition (EndMT) is a cellular process in which endothelial cells (ECs) transition into mesenchymal cells, a mechanism recently linked to pulmonary vascular remodeling in pulmonary hypertension (PH). However, the regulatory mechanisms driving EndMT in PH remain largely undefined. MicroRNA-153 (miR-153), a small non-coding RNA, regulates gene expression by targeting the 3'-untranslated region (3'-UTR) of mRNA, affecting mRNA translation and stability. This study investigates miR-153's role in modulating EndMT in PH. METHODS: Human lung vascular endothelial cells (LVECs) were isolated from healthy individuals and patients with idiopathic pulmonary arterial hypertension (IPAH). In vitro, normal LVECs were exposed to hypoxia (3% O₂) for 72 hours or treated with TGF-β1 (10 ng/mL) for 7 days to induce EndMT. Levels of miR-153 and EndMT markers were quantified by qPCR, Western blotting, or immunostaining. Proliferation and apoptosis of ECs were assessed using EdU and TUNEL assays, respectively. LVECs were transfected with miR-153 inhibitor or mimic, then exposed to normoxic or hypoxic conditions, respectively for 72 hours. In vivo, mice were subjected to either hypoxia (10% O₂ for 6 weeks, Hx-PH) or Sugen5416/hypoxia (20 mg/kg i.p. plus 10% O₂ for 6 weeks, SuHx-PH) to induce PH. The PH phenotype in mice was evaluated by hemodynamic measurements and histological analysis of H&E-stained lung tissues. RESULTS:In silico analysis identified miR-153 as a direct regulator of human SNAI1 and SNAI2 genes via binding to their 3'-UTR. Downregulation of miR-153 in IPAH LVECs was correlated with elevated SNAI1/2 expression, increased EndMT, and higher proliferation compared to normal LVECs. Hypoxia or TGF-β1 treatment reduced miR-153 expression, increased EndMT transcription factors (SNAI1/2), mesenchymal markers (SM-22, vimentin), and reduced EC markers (CD31, VE-cadherin). In normoxic LVECs, miR-153 inhibition significantly upregulated SNAI1/2, increased EndMT and EC proliferation, and reduced apoptosis. Conversely, miR-153 mimic abolished hypoxia- and TGF-β1-induced EndMT. Overexpression of miR-153 attenuated hypoxia-induced EC survival. In PH mouse models, reduced miR-153 levels were associated with activated SNAI1/2, EndMT, and pulmonary vascular remodeling. CONCLUSIONS: Downregulation of miR-153 drives phenotypic transition of LVECs to proliferative mesenchymal cells via SNAI-mediated EndMT, contributing to pulmonary vascular remodeling and PH. Therefore, miR-153 could be a potential therapeutic target for PH treatment.

Abstract Background: Expiratory central airway collapse (ECAC) is defined by excessive inward bulging of either posterior tracheobronchial membrane or anterolateral cartilage. ECAC commonly coexists with COPD, asthma, GERD, and obstructive sleep apnea. ECAC association with bronchiectasis is yet to be documented. Common conditions leading to bronchiectasis are obstructive lung diseases predisposing to recurrent infections, cystic fibrosis, COPD, or idiopathic. This study aims to evaluate the occurrence of bronchiectasis in patients with ECAC as the primary outcome and the correlation between the severity of bronchiectasis and the severity of ECAC as a secondary outcome. Methods: A retrospective single-center study evaluated patients diagnosed with ECAC using dynamic bronchoscopy in Mayo Clinic, Florida, from June 2019 to December 2020. Radiologists analyzed dynamic, or non-contrast chest computed tomography (CT) scans to evaluate the presence of bronchiectatic changes and the prevalence of bronchiectasis in this population. Bronchiectatic changes were documented using the Brody scoring system which recorded the bronchiectasis size, extent and tree in bud appearance in individual lobes. The final score had a range from 0 to 72. The bronchiectasis scores for individual lung lobes were analyzed to interpret distribution of bronchiectasis in ECAC population. The combined bronchiectasis scores of severe ECAC and non-severe ECAC cohorts were compared to assess if severe ECAC had higher bronchiectatic involvement. Results: Out of the 166 patients diagnosed with ECAC through dynamic bronchoscopy, 133 patients (80.1%) presented bronchiectatic changes in their CT scans. Of the 59 patients with severe ECAC, 51 patients (86.4%) were diagnosed with bronchiectasis. Of the 107 patients with non-severe ECAC, 82 (76.6 %) had bronchiectasis. The mean bronchiectasis scores are greater in right and left lower lobes, followed by middle lobes. The median values between severe and non-severe ECAC were 3 and 3 respectively with a p value of 0.34. The inter quartile range was 9 in severe ECAC group and 6 in non-severe ECAC (graph 1). Discussion: The outcomes of this study showed a significant presence of bronchiectatic changes in the ECAC population, implying the importance of evaluating for other pathologies. It can signify a pathological process similar to other pathologies which predispose to recurrent infections except for cystic fibrosis, which has an upper lobe involvement. The correlation of severity between ECAC and bronchiectasis requires more studies with a larger cohort for significant outcomes.

EndMT has been reported to contribute to the pathogenesis of PAH. In this study, we aimed to determine the role of Ca 2+ signaling in the development of EndMT in human lung vascular endothelial cells. Our data suggest that TGF-β 1 requires store-operated Ca 2+ entry through STIM1/Orai channels to induce SNAI-mediated EndMT. For the first time, we demonstrated that TGF-β 1 -induced EndMT is a Ca 2+ -dependent event, whereas inhibition of STIM1/Orai interaction attenuated EndMT in response to TGF-β 1 .

Abstract Aims Aortic regurgitation (AR) arises from leaflet disease and/or dilatation of the functional aortic annulus complex. Understanding the mechanisms of AR informs surgical planning of valve and aorta repair. This study investigates the mechanisms, aetiologies, and outcomes of isolated native severe AR in a consecutive cohort of patients. Methods and results Patients with moderate-to-severe (3+)/severe (4+) native valve AR, identified from our institutional echocardiography database (2014–2018), were included. Exclusions were significant concomitant valve disease, endocarditis, or aortic dissection. AR was classified per the El-Khoury system: Type I (normal leaflet motion: Ia–ascending aorta/sinotubular junction dilatation, Ib–aortic root dilation, Ic–aortic annular dilation), Type II (leaflet prolapse), and Type III (leaflet restriction). Valve anatomy and clinical outcomes, including mortality and surgical intervention, were analyzed. Of 282 patients (77.3% male), 58.5% had multiple AR mechanisms. Type II (leaflet prolapse) was most common (48.6%), followed by Type III (36.2%). Bicuspid aortic valve (BAV) represented 35.5% of the population, with leaflet prolapse observed in 72%. Multiple mechanisms were more frequent in BAV (77% vs. 48%, P < 0.001). After a median follow-up of 4.7 years (available for 97.5% of patients), 158 (57.5%) underwent an intervention with 48.7% having an aortic valve repair or valve-sparing aortic root replacement. Conclusion Although leaflet prolapse (Type II) was the pre-dominant AR mechanism, multiple contributing mechanisms were often present, particularly in BAV patients. Aortic valve repair accounted for nearly half of surgical interventions, underscoring the importance of mechanism identification to optimize repair and avoid valve replacement.

Cardiac cachexia (CC) is a severe complication of advanced heart failure (HF), characterized by involuntary weight loss and muscle wasting, leading to poor outcomes and higher mortality. Despite its severity, CC remains under-recognized and undertreated, lacking targeted therapies specifically addressing its pathophysiology. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), though beneficial in reducing cardiovascular risk in patients with HF, may exacerbate muscle wasting in cachectic patients, necessitating further investigation. Non-pharmacological strategies, including tailored nutritional support and exercise programs, have shown positive effects on body composition and quality of life in patients with CC. However, there remains a gap in recommendations tailored to preventive strategies and pharmacologic therapies for patients with CC and concomitant GLP-1RA use. This review highlights the multifactorial mechanisms underlying CC and current and emerging therapeutic approaches for mitigating HF-related sarcopenia while on GLP-1RAs.

ABSTRACTBackgroundThis study investigates the association between thromboembolic events (TE) and castration‐resistant prostate cancer (CRPC) patients receiving oral androgen receptor pathway inhibitors (ARPi) compared to those undergoing chemotherapy, both with and without a pre‐existing history of cardiovascular disease (CVD).MethodsA total of 2779 men diagnosed with CRPC were identified using the Surveillance, Epidemiology, and End Results (SEER) Medicare Linked Database from 2012 to 2016. Patients were stratified based on their CVD history. Within each CVD stratum (pre‐existing CVD vs. no pre‐existing CVD), patients were further categorized into two treatment groups: those receiving oral ARPi and those undergoing chemotherapy. Unadjusted and inverse probability treatment weight (IPTW)‐adjusted proportional hazards models, using Fine and Gray's method, were applied to evaluate the potential association between ARPi treatment and TE.ResultsPatients with pre‐existing CVD treated with ARPi exhibited a significantly lower crude hazard ratio (HR) for TE compared to chemotherapy (HR 0.39, 95% CI 0.27–0.58, p < 0.001). However, after adjustment using IPTW, this association was no longer significant (adjusted hazard ratio [AHR] 1.00, 95% CI 0.75–1.32, p = 0.99). For patients without CVD, ARPi use was also associated with a reduced risk of TE in the crude analysis (HR 0.53, 95% CI 0.32–0.87, p = 0.01), but this effect was not statistically significant after IPTW adjustment (HR 0.99, 95% CI 0.69–1.41, p = 0.94).ConclusionARPi demonstrated no significant effect on TE risk compared to chemotherapy, regardless of pre‐existing CVD status. Similarly, when excluding patients with a prior history of TE, ARPi use remained non‐significantly associated with new TE in the IPTW‐adjusted competing risk analysis, highlighting the need for further investigation.