bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from A First-in-Human Phase I Study of BXQ-350, a First-in-Class Sphingolipid Metabolism Regulator, in Patients with Advanced/Recurrent Solid Tumors or High-Grade Gliomas
Authors: Rixe Olivier , Villano John L. , Wesolowski Robert , Noonan Anne M. , Puduvalli Vinay K. , Wise-Draper Trisha M. , Curry Richard , Yilmaz Emrullah , Cruze Charlie , Ogretmen Besim , Tapolsky Gilles , Takigiku Ray
Published: November 2024

AbstractPurpose:
BXQ-350, a nanovesicle formulation of saposin C, is an allosteric sphingolipid metabolism regulator that increases proapoptotic ceramide and decreases oncogenic sphingosine-1-phosphate levels. We conducted a first-in-human phase I study of BXQ-350.
Patients and Methods:
Adults (≥18 years old) with advanced/recurrent, treatment-refractory solid tumors or high-grade gliomas received BXQ-350 intravenously in five dose cohorts (0.7–2.4 mg/kg) in a 3+3 dose escalation and expansion design. The primary endpoints during dose escalation were dose-limiting toxicities and maximum tolerated dose; the primary objective in expansion parts was assessment of antitumor activity (RECIST v1.1/Response Assessment in Neuro-Oncology criteria).
Results:
Eighty-six patients were enrolled. Dose-limiting toxicities were not observed during dose escalation (n = 18), and a maximum tolerated dose was not identified. An additional 68 patients received the 2.4 mg/kg dose. Nine patients (10%) discontinued due to adverse events. The most common treatment-related adverse events were nausea (24%) and fatigue (23%). Eight patients had a progression-free survival of ≥6 months. Two of these achieved a partial response, and six had stable disease, among whom three had a reduction in ≥1 target lesion. Of those with progression-free survival of ≥6 months, seven remained on study for >12 months, five for >24 months, and after 7 years, two remained on study without disease progression.
Conclusions:
BXQ-350 was well-tolerated as monotherapy at doses up to 2.4 mg/kg. It provided some lasting clinical benefit in patients with recurrent solid malignancies across several tumor types, consistent with a decreased systemic sphingosine-1-phosphate/ceramide metabolic rheostat. BXQ-350 warrants further clinical investigation alone and combined with standard of care for advanced solid tumors.
Data from Chemoradiotherapy and Subsequent Immunochemotherapy as Conversion Therapy in Unresectable Locally Advanced Esophageal Squamous Cell Carcinoma: A Phase II NEXUS-1 Trial
Authors: Wang Xin , Kang Xiaozheng , Zhang Ruixiang , Xue Liyan , Xu Jiaqi , Zhao Xiaotian , Ou Qiuxiang , Yu Nuo , Feng Guojie , Li Jiao , Zheng Ziyu , Chen Xiankai , Wang Zhen , Zheng Qingfeng , Li Yong , Qin Jianjun , Bi Nan , Li Yin
Published: November 2024

AbstractPurpose:
This phase II trial investigated the safety and efficacy of chemoradiotherapy (CRT) followed by immunochemotherapy (iCT) and surgery in unresectable locally advanced esophageal squamous cell carcinoma (ESCC).
Patients and Methods:
Patients with unresectable locally advanced ESCC received radiotherapy (50 Gy/25f, 5 days/week) and nab-paclitaxel (100 mg on day 1/week) plus cisplatin (25 mg/m2 on day 1/week) for 5 weeks, followed by tislelizumab (200 mg on day 1/cycle) plus chemotherapy (nab-paclitaxel 150 mg/m2 and cisplatin 75 mg/m2 on day 2/cycle) for two 21-day cycles. Patients who converted to resectable underwent surgery 2 to 4 weeks afterward. The primary endpoint was a 1-year progression-free survival (PFS) rate.
Results:
Thirty patients were enrolled and underwent CRT (median follow-up: 21 months), of whom 24 received iCT. Twenty (66.7%) patients achieved resectability (R0: 95.2%; pathologic complete response: 65.0%; major pathologic response: 90.0%). One-year PFS and overall survival (OS) rates were 79.4% and 89.6%, respectively. The R0 resection group exhibited longer PFS (median, not reached vs. 8.4 months; HR = 0.28; 95% confidence interval, 0.08–0.84; P = 0.02) and OS (median, not reached vs. 19.2 months; HR = 0.18; 95% confidence interval, 0.04–0.73; P < 0.01) than the nonsurgery group. Grade 3 to 4 adverse events were observed in 11 (11/30, 36.7%) patients, and immune-related pneumonitis was observed in 5 (5/24, 20.8%) patients. Post-CRT minimal residual disease before surgery was associated with unfavorable PFS and OS.
Conclusions:
Our study met the primary endpoint. Conversion CRT and subsequent iCT followed by surgery was a promising treatment strategy for unresectable locally advanced ESCC.
A PSMA-Targeted Tri-Specific Killer Engager Enhances NK Cell Cytotoxicity against Prostate Cancer
Authors: Phung Shee Kwan , Zorko Nicholas A. , Soignier Yvette , Waller Rhett L. , Shackelford Madison , Walker Joshua T. , Nelson Trygve D. , Selleck Carly , Bendzick Laura E. , Kotz Laura E. , Kile Quinlan M. , Bozicevich Asha J. , Miller Sarah E. , Khaw Melissa , Shetty Mihir , Hinderlie Peter , Ehrhardt Michael , Li Yingming , Luo Xianghua , Dehm Scott M. , Antonarakis Emmanuel S. , Kennedy Philippa R. , Miller Jeffrey S. , Felices Martin
Published: November 2024

NK cell tumor infiltration is associated with good prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC). NK cells recognize and kill targets by a process called natural cytotoxicity. We hypothesized that promoting an antigen-specific synapse with coactivation may enhance NK cell function in mCRPC. We describe a tri-specific killer engager (TriKE) construct that engages with the activating receptor CD16 on NK cells and prostate-specific membrane antigen (PSMA) on mCRPC cells and has an IL15 moiety that is essential for NK cell survival, proliferation, and priming. We show that the PSMA TriKE specifically binds to PSMA-expressing cells and significantly enhances expansion, degranulation, and cytokine production of NK cells derived from healthy donors or patients with prostate cancer. Bystander killing of PSMA-negative tumor cells was also achieved with PSMA TriKE treatment when cocultured with PSMA-positive cells, suggesting potential PSMA TriKE benefit in controlling tumor antigen escape. When tested under physiologic conditions recapitulating the mCRPC tumor microenvironment, NK cells treated with PSMA TriKE and prolonged exposure to hypoxia or myeloid-derived suppressor cells maintained their potent function whereas IL15-treated NK cells showed greatly impaired cytotoxicity. Finally, in vivo testing of PSMA TriKE showed improved tumor control and survival of mice as compared with IL15-treated and untreated control groups. In conclusion, PSMA TriKE demonstrates potential as a new therapy for advanced prostate cancer by providing additional signals to NK cells to maximize their antitumor potential in prostate cancer, especially in the setting of a hostile tumor microenvironment.
Early Screening and Identification of an Asymptomatic Pheochromocytoma in a Child with Von Hippel-Lindau: A Case Report
Authors: Schmeling Kristine , Schuh Jennifer , Lal Dave , Becktell Kerri
Published: November 2024

Introduction: Von Hippel-Lindau (VHL) is a diagnosis that leads to increased risk of tumor development over the course of a patient’s lifetime. Patients with VHL undergo screening for multiple tumor types, including pheochromocytomas (PCCs). There is variability among the different international guidelines regarding the age to begin PCC screening, with most suggesting 5 years for screening initiation. Case Presentation: Our patient is a 4-year-old female who underwent screening for PCC at the time of her VHL diagnosis while asymptomatic that identified a unilateral PCC. This was amendable to treatment with laparoscopic partial adrenalectomy. Conclusion: This is the first report of an asymptomatic PCC being identified in a patient under the age of 5. With early identification, this was treated surgically before it caused systemic symptoms with preservation of normal adrenal gland tissue. This supports adhering to the pediatric specific guidelines which recommend earlier initiation of PCC screening in pediatric patients with VHL.
Investigation and Analysis of Inhalant Allergens in Patients with Allergic Rhinitis in Yinchuan, China
Authors: Yu Yingjie , Yan Xiaohui , Wang Lixin , Dong Lun , Song Dong , Liu Jing , Gao Xiaoping
Published: November 2024

Introduction: This study aimed to analyze the types and distribution characteristics of major inhalant allergens in patients with allergic rhinitis (AR) in Yinchuan, China. Methods: In this cross-sectional study, 2,000 outpatients suspected of having AR were included from 2022 to 2023 at the Department of Otolaryngology-Head and Neck Surgery, General Hospital of Ningxia Medical University. Skin prick tests were performed on the included individuals using 13 common inhalant allergens: house dust mites, dust mites, tropical mites, Artemisia, dog hair, ragweed, cat hair, grass pollen, tree pollen, mold group I, mold group IV, German cockroach (Blattella germanica), and American cockroach (Periplaneta americana). The results of the skin prick tests were summarized, and patients with positive results were grouped by ethnicity, gender, and age to compare the differences in the positive rates of various inhalant allergens between the groups. The number of patients visiting each month was recorded to analyze the temporal variation in the incidence rate and compare the differences in the main inhalant sensitizers among patients in each quarter. Results: Among the 2,000 included patients, there were 1,060 males and 940 females, with an average age of 18.7 years. Among the 2,000 outpatients who underwent allergen skin prick tests, 1,346 cases (67.30%) had positive results. The inhalant allergens were ranked in descending order of positive rates as follows: Artemisia (53.25%), dust mites (51.10%), house dust mites (49.10%), ragweed (45.70%), tropical mites (43.15%), dog hair (19.20%), cat hair (16.05%), American cockroach (12.10%), German cockroach (11.25%), grass pollen (9.15%), tree pollen (7.10%), mold group I (6.10%), and mold group IV (5.05%). There were no statistically significant differences in positive rates between different ethnicities or genders (all p > 0.05). Compared to patients aged 18 years and above, patients under 18 years old had statistically significant differences in positive rates for dust mites, Artemisia, ragweed, mold group I, and German cockroach (all p < 0.05). The seasonal distribution indicated that autumn had the highest number of patient visits in a year (579 cases, 58.95%). Conclusion: Artemisia and dust mites were the major inhalant allergens in patients with suspected AR in Yinchuan, China. The positive rate of inhalant allergen skin prick tests was not correlated with the ethnicity or gender of the local population. Autumn was the season with the highest frequency of visits by patients with suspected AR.
A new clinical entity bridging the cardiovascular system and the kidney: The Chronic Cardiovascular-Kidney Disorder
Authors: Zoccali Carmine
Published: November 2024

Background The complex relationship between heart and kidney dysfunction has been a subject of medical inquiry since the 19th century. The term "cardio-renal syndrome" (CRS) was introduced in the early 2000s and has since become a focal point of research. CRS is typically categorized into five subtypes based on the sequence of cardiovascular and kidney disease events.
Summary The Cardiovascular-Kidney-Metabolic (CKM) syndrome, as defined by the American Heart Association (AHA), describes a set of interrelated metabolic risk factors and their effects on the kidneys and cardiovascular system. This syndrome emphasizes the complexity of managing patients with combined conditions and identifies several knowledge gaps, including disease mechanisms, clinical phenotype variability, and the impact of social determinants of health. The Chronic Cardiovascular-Kidney Disorder (CCKD) framework proposes a shift from the term "syndrome" to "disorder," focusing on concurrent cardiovascular and kidney problems regardless of their sequence.
Key messages
• The CCKD concept calls for simplification and conceptual clarity, arguing that understanding the bidirectional acceleration of disease progression between heart and kidney dysfunction can lead to more effective treatment strategies.
• Both CKM and CCKD share common pathophysiological mechanisms and risk factors, including hypertension, diabetes, obesity, and dyslipidemia. Managing these conditions requires a comprehensive approach that addresses the underlying risk factors and pathophysiological mechanisms.
• Future directions include embracing precision medicine, public health strategies, interdisciplinary care models, and ongoing research and innovation. Both frameworks underscore the need for comprehensive, interdisciplinary care models and innovative treatment strategies to address the complex interplay between cardiovascular and kidney diseases.
Основні клініко-патогенетичні особливості перебігу хронічного рецидивного афтозного стоматиту в пацієнтів із анемічним синдромом
Authors: Гевкалюк Н. О. , Кутоловський Д. Р.
Published: November 2024

Резюме. Етіологія хронічного рецидивного афтозного стоматиту (ХРАС) невідома, захворювання часто має багатофакторний характер, що свідчить про основну генетичну сприйнятливість із можливими сприяючими факторами. Порушення стану порожнини рота може з’являтися при залізодефіцитній анемії.
Мета дослідження – встановити частоту анемії, показники гемоглобіну, гематокриту, рівня сироваткового феритину та еритроцитарного індексу інтоксикації при рецидивному афтозному стоматиті та виявити їх вплив на клінічну картину ХРАС.
Матеріали і методи. У дослідженні взяли участь 75 пацієнтів віком 20–45 років, серед яких 53 були з клінічною історією рецидивних афтозних виразок (основна група) та 22 здорових осіб, які склали контрольну групу. Ми використали клініко-анамнестичні дані, детальне стоматологічне обстеження, лабораторні дослідження крові.
Результати досліджень та їх обговорення. Оцінка клініко-анамнестичних даних пацієнтів дозволила встановити основні симптоми та можливі фактори, що сприяють рецидивуванню. Обстеження хворих на ХРАС дозволило виявити профіль ураженої популяції із переважанням осіб жіночої статі (60,38 %). Оцінка ділянок уражень показала, що слизова оболонка щік була найбільш часто ураженою анатомічно (77,36 %), наступними були слизова оболонка язика та губ (54,72 та 28,30 % відповідно). У 43,40 % випадків мало місце ураження більш ніж однієї анатомічної ділянки (від 2 до 4). За клінічним аналізом крові хворих виявлено еритроцитопенію різного ступеня, дефіцит гемоглобіну, зниження показника гематокриту, рівня сироваткового феритину, збільшення показника еритроцитарного індексу інтоксикації. Пацієнти з рецидивним афтозним стоматитом частіше, ніж особи контрольної групи, страждають від анемії.
Висновки. У хворих на ХРАС відмічається залізодефіцитний стан із частим та вираженим анемічним синдромом. При залізодефіцитних станах, імовірно, розвивається тканинний дефіцит заліза, що може бути одним з етіологічних факторів ХРАС.
Abstract 4138220: Traditional and HIV-specific Risk Factors Are Associated with Incident Non-valvular Atrial Fibrillation and Atrial Flutter among Underrepresented Racial and Ethnic Minority Groups Living with HIV
Authors: Kobe Elizabeth , Clare Robert , Chiswell Karen , Longenecker Chris , Marsolo Keith , Meissner Eric , Okeke Nwora , Pettit April , Sanders Gretchen , Thomas Kevin , Bloomfield Gerald , Shah Nishant
Published: November 2024

Introduction:
With effective antiretroviral therapy (ART), HIV can now be managed as a chronic disease. Chronic disease and cardiovascular risk factor management is especially important for underrepresented racial and ethnic minority groups (UREG). Non-valvular atrial fibrillation and atrial flutter (NVAF) have not been adequately studied in UREG with HIV.

Research Questions:
Among UREG with HIV, what is the incidence of NVAF? What factors are associated with incident NVAF?

Aims:
To narrow an evidence gap among UREG with HIV by 1) describing the incidence of NVAF and 2) identifying factors associated with incident NVAF.

Methods:
This is an ancillary study of the Pathways to Cardiovascular Disease Prevention and Impact of Specialty Referral in Underrepresented Racial and Ethnic Minorities with HIV (PATHWAYS) study, a retrospective population-based study of HIV care patterns among UREG with HIV. Patients without a known history of NVAF entered our study cohort at the date of their first documented HIV diagnosis. We computed the cumulative incidence of NVAF over five years of follow-up (mean 3.4, SD 1.6), handling death as a competing risk. Cox regression analysis was used to examine the univariate associations between characteristics at HIV diagnosis and incident NVAF, adjusting for site and date of HIV diagnosis.

Results:
From 2015-2019, 10,945 UREG meeting entry criteria were identified. On average, patients were 67.1% male, 94.4% Black, and 8.5% Hispanic. Average CHA2DS2VASc score was 0.92 (SD 1.1) and 63.4% were on ART. Cumulative incidence of NVAF at one and five years after HIV diagnosis were 0.48% (95% CI 0.36-0.63) and 2.16% (95% CI 1.85-2.51), respectively. HIV-related factors associated with incident NVAF included baseline CD4 count <200 (HR 1.84, 95% CI 1.20-2.80) and initial ART including protease inhibitors (HR 1.56, 95% CI 1.14-2.13) and/or integrase strand transfer inhibitors (HR 1.47, 95% CI 1.08-1.99). Additional associated factors included older age, Medicare, cardiology visit(s) in prior year, and co-morbid diseases including hypertension, hyperlipidemia, coronary and peripheral artery disease, prior stroke/transient ischemic attack, heart failure, and chronic kidney disease.

Conclusions:
In a large cohort of UREG living with HIV, both traditional and HIV-specific risk factors are associated with increased risk of incident NVAF. Interventions to mitigate NVAF risk in this population will require interdisciplinary, team-based approaches.
Abstract 4138221: Ezetimibe plus statin combination vs. double dose statin for patients with dyslipidemia and ASCVD risk: A Systematic Review and Meta-Analysis
Authors: Mahmoud Abdelrahman , Almohtasib Yazan , Naeem Ahmed , Ahmed Ali Ashraf Salah , Ramadan Mohamed , A. Ibrahim Ahmed , Amin Ahmed Mazen , Mohammed Yasmine Adel , Abusuilik Husam , Abdelwahab Omar , Rezq Hazem Salah , M. AlBarakat Majd , Salamah Hazem Mohamed , Elshenawy Salem , Abdelazeem Basel
Published: November 2024

Background:
Dyslipidemia is a major risk factor for Atherosclerotic Cardiovascular Disease (ASCVD). Statin is a crucial intervention to fix dyslipidemia and reduce the ASCVD risk. Still, there are several regimens to achieve blood lipid level targets, including increasing the statin dose or adding ezetimibe to the statin used. However, the best option between the two regimens is still a matter of debate.

Research Question:
We aim to evaluate the efficacy and safety of Ezetimibe plus any type of statin versus a double dose of the same statin in patients with ASCVD risk.

Methods:
A systematic review and meta-analysis based on randomized controlled trials (RCTs) obtained from PubMed, Embase Cochrane, Scopus, and WOS till December 2023. We used the random-effects model to report dichotomous outcomes using odds ratio (OR) and continuous outcomes using mean difference (MD), with a 95% confidence interval (CI).

Results:
Forty-seven studies with a total of 18592 patients were included. Ezetimibe plus statin was associated with a decrease in low-density lipoprotein (LDL) levels [MD: -13.69 with 95% CI (-15.64, -11.74), P <0.01], and more patients achieving their targeted LDL levels [OR: 2.89 with 95% CI (2.40, 3.47), P <0.01]. However, there was no significant difference between the two groups regarding any adverse events [OR: 0.98 with 95% CI (0.89, 1.08), P =0.62], and the composite endpoint of cardiovascular death, major coronary events, or nonfatal stroke [OR: 0.72 with 95% CI (0.39, 1.32), P = 0.29], although there was a trend towards better results for patients with the combination regimen.

Conclusion:
Ezetimibe plus statin combination led to more reduced LDL levels and more patients achieving their goal levels than double dose statin, without a significant difference in the rate of any adverse events occurrence. More RCTs are mandatory to assess the effect of both regimens on major clinical events such as stroke, coronary events, and death.
Abstract 4138225: In-Hospital Outcomes of Percutaneous Coronary Intervention (PCI) in patients primarily admitted with ST-Elevation Myocardial Infarction (STEMI) at PCI centers versus patients transferred from non-PCI centers, a retrospective study involving the National Inpatient Sample (NIS 2016-2021) database.
Authors: Ntow Mark Anthony , Agyeman Walter , Aryal Binit , Patel Neel
Published: November 2024

Background:
Timely transfer for PCI is paramount in the management of STEMI. This has been shown to reduce myocardial damage, optimize reperfusion therapy and mitigate the post procedural complications associated with PCI. This study's aim was to describe the in-hospital outcomes associated with acute inter-hospital transfer of patients with STEMI for PCI in comparison with patients directly admitted to a primary PCI center.

Methods:
The National Inpatient Sample (NIS) was used to identify patients who underwent PCI for STEMI between the years 2016-2021. Based on several transfer indicators, primarily admitted patients and patients with acute inter-hospital transfer were identified. Logistic and linear regression models were used to analyze the primary outcome of in-hospital mortality and secondary outcomes of length of hospital stay, hospital charge, and occurrences of post-procedure complications.

Results:
Observations were weighted to obtain a national estimate of 748,430 patients with known transfer status who underwent PCI for STEMI. Of these, 625,520 patients were primarily admitted at PCI centers and 122, 910 patients were transferred from non-PCI centers. The mean age of patients with STEMI undergoing PCI was 62 years, and 72 % of the patients were male. There was no significant difference in mortality between patients transferred and patients primarily admitted for PCI due to STEMI. However, patients transferred had longer hospital stay and significantly higher healthcare cost, with a mean difference of 0.72 days (95% CI: 0.65 - 0.81 days, p-value <0.000) and $3,354 (95% CI: $339 - $6371, p-value <0.029), respectively. Patients transferred also had significantly higher odds of post procedure complications, including cardiogenic shock (Odds ratio: 1.49, 95% CI: 1.08 - 2.06, p-value <0.014), cerebrovascular accident (Odds ratio: 3.64 , 95% CI: 1.15 - 11.45, p-value <0.014) and kidney failure (Odds ratio: 2.10 , 95% CI: 1.09 - 4.02, p-value <0.026).

Conclusion:
Patients with STEMI who were transferred for PCI experienced longer hospital stay and incurred higher healthcare costs. These patients had significantly higher odds of post procedure complications including cardiogenic shock, cerebrovascular accidents and kidney failure.
Abstract 4138252: Association between Pressure-Adjusted Heart Rate and Mortality in Cardiogenic Shock
Authors: Ginder Curtis , Jentzer Jacob , Guo Jianping , Van Diepen Sean , Katz Jason , Morrow David , Berg David
Published: November 2024

Introduction:
Among patients with cardiogenic shock (CS), high right atrial pressure (RAP) and low mean arterial pressure (MAP) are associated with in-hospital mortality. Pressure-adjusted heart rate (PAHR), defined as heart rate * RAP-to-MAP ratio (HR * [RAP/MAP]), integrates these parameters and has been used to identify cardiovascular dysfunction in critical illness. Higher PAHR values associate with higher surgical ICU mortality, but the prognostic significance of PAHR has not been assessed in cardiac intensive care unit (CICU) patients with CS.

Hypothesis:
We hypothesized that higher PAHR values are associated with higher risk of in-hospital mortality in patients with CS.

Methods:
The Critical Care Cardiology Trials Network (CCCTN) is a multinational registry of CICUs coordinated by the TIMI Study Group. Among CS admissions (2018-2023) undergoing invasive hemodynamic assessment within 24h of CICU admission, we calculated PAHR (in bpm) and assessed its relationship with in-hospital mortality. Patients on temporary mechanical circulatory support were excluded. Odds ratios were adjusted for age, sex, vasoactive-inotropic score (VIS), SCAI stage, and preceding cardiac arrest. Subgroup analyses stratifying by CS subtype were performed.

Results:
Among the 1411 CS admissions in the analysis cohort (mean age 61 years, 31% women), 18% had AMI-CS, 75% had HF-CS, and 7% had secondary CS. At the time of assessment (median 1.4h after CICU admission), 75% were on vasoactive support (median VIS 3.8). Median HR was 92 (Q1-Q3 77-109) bpm, RAP 15 (Q1-Q3 10-19) mmHg, MAP 75 (Q1-Q3 67-87) mmHg, and PAHR 17 (Q1-Q3 11-24) bpm. A stepwise gradient of higher in-hospital mortality with increasing PAHR values (p-trend <0.001;
Fig
) was observed. In adjusted models, a higher PAHR was associated with higher in-hospital mortality (aOR per 10-bpm, 1.35 [95% CI, 1.15-1.58]), and had stronger prognostic associations with mortality than its individual hemodynamic components
(Fig)
.

Conclusion:
Higher PAHR is strongly associated with in-hospital mortality in CS patients. PAHR, a simple parameter which is readily calculable without needing a pulmonary artery catheter, may aid in identifying CS patients at higher risk of death.
Abstract 4138272: CMR Quantification of Myocardial Oxygenation Extraction Fraction Maps Using a Model-based Self-supervised Learning Network: Initial Experience in Patients with Cardiomyopathies
Authors: Huang Qi , Tang Haoteng , Wang Keyang , Li Ran , Zhan Marcus , Yang Yang , Woodard Pamela , Zheng Jie
Published: November 2024

Background:
Measurements of myocardial oxygenation extraction fraction (mOEF) maps with cardiovascular magnetic resonance (CMR) has been recently developed to assess myocardial oxygen metabolism in healthy. Recent studies focus on developing supervised machine learning methods to improve the quantification of mOEF. However, these supervised learning methods may be limited by the lack of ground-truth mOEF maps because MRI cannot directly measure mOEF with the same precision as PET.

Hypothesis:
Model-based self-supervised learning neural networks maybe feasible to generate mOEF maps accurately.

Aims:
To develop a physical model-based self-supervised learning neural network to accurately estimate mOEF for the patients with a variety of cardiomyopathies.

Methods:
An ECG triggered, two-dimensional asymmetric spin-echo (ASE) prepared sequence was employed to scan 71 patients with dilated, hypertrophic, or ischemic cardiomyopathies. At least 3 slices were scanned for each patient and each ASE scan was performed free-breathing with a spatial resolution of 1.7 × 1.7 × 8
mm
3
and scan time of 18 RR-interval. Acquisition of late gadolinium enhancement (LGE) was performed in each patient after the administration of 0.15
mmol/kg
gadolinium agent for the visualization of myocardial infarction regions.

A fully convolutional neural network with U-Net architecture was optimized with a physical model-based signal loss function (see Figure 1) on the ASE training dataset from 67 patients to generate mOEF maps. To evaluate if the method can accurately quantify abnormal mOEF, four patients with myocardial infarction were selected as the test set.

Results:
A previous publication reported normal mOEF levels at approximately 0.6-0.7 in healthy subjects. Figure 2 shows our proposed method generated mOEF maps from two representative patients and their LGE images for comparisons. In comparison with the remote region (mOEF = 0.70±0.10), the mOEF of myocardial regions with infarction was significantly lower (mOEF = 0.36±0.12, p < 0.001). The infarction areas predicted by the network overlapped well with the LGE.

Conclusion:
Quantification of mOEF using the proposed model-based self-supervised U-Net is feasible to detect abnormalities in regional myocardial oxygenation. Current study is ongoing to evaluate the proposed technique in a large cardiac patient dataset.
Abstract 4138282: Effect of cardiopulmonary exercise testing parameters and global longitudinal strain on survival after surgery for severe primary mitral regurgitation
Authors: Afoke Jonathan , Tsai Chieh-Mei , Schaff Hartzell , Daly Richard , Dearani Joseph , Crestanello Juan , Shrestha Malakh , Bagameri Gabor , Rowse Phillip , Chopko Trevor , Briggs Casey , martinez aguilar myriam , Todd Austin , Michelena Hector , Nkomo Vuyisile , Allison Thomas
Published: November 2024

Background:
Optimum timing of surgery for severe primary mitral regurgitation (MR) particularly in the absence of significant symptoms or echo evidence of LV impairment remains unclear. Other modalities of assessment include cardiopulmonary exercise testing (CPET) and novel echo measurements, such as LV global longitudinal strain (LVGLS). We sought to evaluate whether pre-op CPET or LVGLS are associated with survival after surgery.

Methods:
We identified consecutive patients who had surgery for severe primary MR between 2007 and 2017 and had pre-op CPET. Clinical and mortality data were collected from chart review and our institutional database. LVGLS was retrospectively collected by a single person blinded to patient outcomes. Primary outcome was post surgery all cause death, and we used univariable analysis to identify variables associated with all cause death.

Results:
We included 176 patients with median age 63 (IQR 51, 71) years, 63 patients (35.8%) were female and 31 patients (14.8%) had a history of atrial fibrillation. 165 patients (93.8%) had mitral repair, 18 (10.2%) had concomitant CABG, 22 (12.5%) had concomitant ablation procedure and 14 (8.0%) had concomitant tricuspid procedure. 114 patients (64.8%) were in NYHA Class I and 56 (31.8%) were in NYHA Class II. There was no operative mortality. Median % predicted peak VO2 (ppVO2) was 89 (74, 101), median ventilatory equivalent of carbon dioxide (VE/VCO2) was 28.0 (25.7, 31.0) l/min/l/min and median respiratory exchange ratio was 1.2 (1.1, 1.2). 73 patients (41.5%) had abnormal CPET (defined as ppVO2<85%).

Median LVEF was 65 (60, 68) %, median LVESD was 35 (32, 38) mm and median LVGLS was 18.5 (16.6, 20.3) %. 45 patients (25.9%) had abnormal LVEF (defined as ≤ 60%), 11 patients (6.7%) had abnormal LVESD (defined as ≥45mm) and 35 patients (20.8%) had abnormal LVGLS (defined as <16%).

At a median follow up of 10.2 (6.8, 13.2) years, there were 19 (10.8%) deaths. In the univariate analysis, age at surgery (HR 1.12, p<0.001), LVESD (HR 1.11, p=0.009), LVGLS (HR 1.11, p=0.013) and VE/VCO2 (HR 1.08, p=0.044) were associated with all cause mortality.

Conclusion:
A significant proportion of patients with no or mild symptoms exhibit echocardiographic evidence of LV impairment when having surgery for severe primary MR. CPET parameters such as VE/VCO2 and novel echocardiographic measurements such as LVGLS may predict risk of long term mortality and potentially inform timing of surgery in these patients.
Abstract 4138340: Cav-1/FGF2 Axis Mediates Endothelial-Mesenchymal Transition Promoting Aortic Valve Calcification
Authors: Zhu Zhihui , Lai Yongqiang
Published: November 2024

Background:
Calcific Aortic Valve Disease is a common cardiac condition with no effective medication available; severe cases require surgery. Endothelial-to-mesenchymal transition is a key pathological process, yet the genetic regulatory mechanisms involved remain unclear.

Research Questions:
Investigating the mechanism of Cav-1/FGF2 axis-mediated endothelial-mesenchymal transition in aortic valve calcification.

Methods:
Histopathology, immunohistochemical staining, and western blot analysis were performed on 5 non-calcified and 5 calcified aortic valves. Proteomic sequencing was conducted on these samples. Single-cell RNA sequencing on 3 calcified aortic valves focused on valve endothelial and interstitial cells to explore key genes and functions in EndoMT. In vivo and in vitro experiments, along with single-cell multi-omics sequencing, elucidated the role and mechanism of the Cav-1/FGF2 axis in EndoMT using endothelial cell-specific EndoMT knockout mouse models and cell models.

Results:
Proteomics and single-cell sequencing results indicated that Cav-1 is involved in the Endothelial-to-mesenchymal transition process in Calcific Aortic Valve Disease. Cav-1 plays a crucial role in the intermediate transition of EndoMT, interacting significantly with FGF2. Immunohistochemical staining showed high expression of Cav-1 in calcified aortic valves. In vitro experiments demonstrated that Cav-1 mediates Endothelial-to-mesenchymal transition in valve endothelial cells, promoting aortic valve calcification. Molecular docking analysis revealed potential direct interaction between Cav-1 and FGF2 proteins. Elevated Cav-1 gene expression increases the number of cell surface caveolae, enhancing cell surface area, which promotes FGF2 binding to its receptor and activates the TGF-beta receptor, both of which facilitate EndoMT through the Smad pathway.

Conclusion(s):
Activation of the Cav-1/FGF2 axis promotes endothelial-mesenchymal transition, thereby promoting aortic valve calcification.
Abstract 4138345: Incidence and Predictors of Infective Endocarditis in Bacteremic Patients
Authors: Alturki Ahmed , Boulet Jacinthe , Abalhassan Mohammed , Fiorentino Laurie , Fan Yi , Loo Vivian , Huynh Thao
Published: November 2024

Background:
Infective endocarditis (IE) is a serious disease, with a high mortality rate.There has been a shift in the composition of organisms causing infective endocarditis. We aimed to provide a contemporary incidence of IE among bacteremic patients stratified by bacterial pathogens. We also sought to evaluate the predictors of IE in bacteremic patients.

Methods:
We included patients at a large quaternary centre in Canada. All bacteremias during the period from 2014 to 2016 were identified and data was collected on the following variables – patient demographics, organism, comorbidities, pre-disposing factors, clinical findings, pertinent biochemistry, performance of echocardiography, and diagnosis of IE. Diagnosis of IE was made using the modified Duke’s criteria. Logistic regression was used to identify predictors of IE.

Results:
There were 1,708 patients with bacteremia included in this analysis. The mean age was 64.5±17.0 years old; 39.7% were females and 77.4% were community acquired bacteremia. In addition, 47.0% had hypertension, 29.9% had diabetes mellitus, 17.5% had chronic kidney disease and 25.2% were immunosuppressed. There were 102 (6.0%) patients with confirmed infective endocarditis (IE). The proportion of bacteremic patients who developed IE was 13.2% in 281 patients with methicillin-sensitive Staphylococcus aureus, 5.4% in 56 patients with methicillin-resistant S. aureus, 2.4% in 292 patients with S. epidermidis, 9.9% in 121 patients with Streptococcus viridans group, 16.5% in 91 patients with Enterococcus, 1.3% in 303 patients with Escherichia coli, 38.5% in 13 in patients with Streptococcus bovis, and 9.5% in 21 patients with Propionibacterium acnes. Predictors of IE were intravenous drug use (odds ratio [OR]=8.64, 95% confidence interval [CI] 3.50- 21.3; p<0.0001), prosthetic heart valve (OR= 2.10, 95% CI 1.01- 4.39; p=0.049), structural heart disease (OR= 12.2, 95% CI 3.35- 44.67; p= 0.0002) and community acquired bacteremia (OR= 2.06, 95% CI 1.11- 3.82; p=0.02).

CONCLUSIONS:
Methicillin-sensitive Staphylococcus aureus is the commonest cause overall of IE followed by viridans group streptococcus. Streptococcus bovis and Enterococcus bacteremia have the highest incidence of IE. Knowledge of the incidence rates of IE among various pathogens may guide diagnostic testing such as pursuing more advanced imaging procedures for patients with increased risk of IE.
Abstract 4138348: Mechanical stress-mediated nuclear envelope damage promotes Aortic Valve Calcification through the ZBP1-RIPK3-NF-κB signaling axis
Authors: Duan Xiaolin , Su Shuwen , Li Wenyan , Lin Xiangjie , Xu minhui , Jiang Sijie , Wang Liusheng , Xu Dingli , Qingchun Zeng
Published: November 2024

Methods and Results:
We describe a comprehensive characterization of the AVICs nucleus landscape as determined by transmission electron microscopy (TEM) of samples obtained from CAVD patients. Turbulence led to nuclear envelope integrity lose in AVICs cultured in shear stress experiments, with three different fluid conditions [static (ST), laminar stress (LS), and oscillatory stress (OS)], indicated by Western blot and immunofluorescence (IF). Silencing lamin A/C (LMNA) through small interfering RNA (siRNA), accelerated nuclear envelope damage , as indicated by Western blot, qPCR, and immunofluorescence (IF). The formation of Z-DNA and its co-localization with Z-DNA binding protein (ZBP1) was observed due to the nuclear envelope damage by IF. Western blot, qPCR, IHC and IF confirmed Z-DNA-induced inflammation in AVICs through the ZBP1-RIPK3-NF-κB signaling pathway. ZBP1 and RIPK3 knockdown with siRNA markedly reduced the protein level of osteogenic markers alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), and bone morphogenetic protein 2 (BMP2) in VICs. In vivo, aortic valve disease was constructed by direct wire injury (DWI), and we showed that overexpression of LMNA by adeno-associated virus significantly decelerated the progression of aortic valve lesion induced by DWI in mice.

Conclusion:
Excessive mechanical stress can induce damage to the nuclear envelope of AVICs by causing cytoskeletal remodeling, initiating the formation of Z-DNA, and hastening the calcification process in AVICs and CAVD.
Abstract 4138353: Disparities in coronary artery disease-related mortality among patients with obesity in the United States from 1999-2020
Authors: Ahmed Mushood , Javaid Hira , Nadeem Zain , Nofal Abdullah , Shafiq Aimen , Ahmad Adeel , Rahman Asad , Shahid Farhan , Ahmed Raheel , alam mahboob
Published: November 2024

Introduction:
Coronary artery disease (CAD) is the third leading cause of death in the US for adults aged >35 years. Almost half of the adult US population has obesity, which predisposes to atherosclerosis and may lead to poor prognosis in CAD. We aim to identify CAD-related mortality trends in patients with obesity in the US stratified by age, sex, race, and geographical location.

Methods:
The CDC-WONDER database was used to extract death certificate data for adults aged ≥25 years. Crude mortality rates (CMR) and age-adjusted mortality rates (AAMRs) per 100,000 persons were calculated, and temporal trends were delineated by calculating annual percent change (APC) and the average APC (AAPC) in the rates using JoinPoint regression analysis.

Results:
From 1999 to 2020, a total of 182,436 CAD-related deaths occurred in individuals with obesity. The AAMR increased consistently from 1999 to 2018 (APC: 4.48) and surged thereafter till 2020 (APC: 13.91). The AAMR for males (4.91) was almost double that of females (2.76). Non-Hispanic (NH) American Indians or Alaska Natives displayed the highest AAMR (5.37) while NH Asians or Pacific Islanders displayed the lowest (0.88). NH Blacks or African Americans displayed an AAMR of 5.06, followed by NH Whites (3.88) and Hispanics or Latinos (2.6). AAMRs also varied substantially by region (Midwest: 4.09; West: 4; Northeast: 3.67; South: 3.53). States with the highest AAMRs were Vermont and Oklahoma. Non-metropolitan regions exhibited a higher AAMR (4.42) than metropolitan regions (3.64). The adults aged 65-74 years exhibited the greatest CMR (8.99).

Conclusion:
We observed increasing trends in CAD-related deaths in adults with obesity throughout the study period. The highest mortality was exhibited by males and NH American Indians or Alaska Natives, residents of the Midwest and non-metropolitan areas, and individuals aged 65-74 years. Better healthcare practices and lifestyle modifications should be promoted in these high-risk populations to reduce the CAD-related mortality rates in adults with obesity.
Abstract 4138374: Coronary Endothelial Dysfunction Plays Important Roles on Development of Acute Coronary Syndrome and Fatal Cardiovascular Events During Long-Term Follow-up Over 10 Years
Authors: Murakami Tatsuaki
Published: November 2024

Introduction:
Although coronary endothelial dysfunction is thought to affect coronary atherothrombogenic processes, there has been little practical evidence for the relationship between clinical evolution of fatal or non-fatal acute coronary syndrome and coronary endothelial dysfunction.

Hypothesis:
We assessed hypothesis that coronary endothelial dysfunction has clinical impacts on development of acute coronary syndrome and fatal cardiovascular events.

Methods:
Coronary endothelial dysfunction was practically graded by the flow-mediated endothelium-dependent reactive changes in coronary artery diameter (CFMD) to infusion of adenosine triphosphate (ATP ; 50μg) into the normal left coronary artery using quantitative coronary arteriography in 150 patients with stable coronary artery disease. The enrolled patients were categorized into tertile groups according to the values of CFMD, and we prospectively followed-up major adverse clinical cardiac events including acute coronary syndrome and cardiovascular death.

Results:
For a mean follow-up period of 132 months (range; 120 to 144) with complete follow-up, the patients in the lower third with severe coronary endothelial dysfunction (Group-L) more frequently developed acute coronary syndrome than those in the middle third with mild coronary endothelial dysfunction (Group-M) plus those in the higher third without coronary endothelial dysfunction (Group-H) [Group-L versus Group-M plus Group-H: 15(30%) versus 5(10%) plus 0(0%), p<0.001, by Kaplan-Meier analysis]. Majority of the patients who resulted in cardiovascular death belonged to Group-L, [6(12%) versus 1(2%) plus 0(0%), p=0.014, by Kaplan-Meier analysis]. Cox hazard proportional model analyses including clinical and angiographical variables indicated that severe coronary endothelial dysfunction was the strong predictor for future acute coronary syndrome (hazard ratio=7.53, 95%confidential interval; 1.78-12.25, p<0.001) and future cardiovascular death (hazard ratio=13.50, 95%confidential interval; 1.55-25.25, p=0.005).

Conclusions:
This is the novel and longest follow-up investigation that demonstrates coronary endothelial dysfunction plays important roles on development of acute coronary syndrome and fatal cardiovascular events and therefore the strategies based on practical status of coronary endothelial dysfunction are required to prevent major adverse ischemic cardiac events.
Abstract 4138424: Ring of Power: Unraveling a Rare Diagnosis in a Young Male with Palpitations
Authors: Jafry Ali , Silverstein Joshua , Thosani Amit , Farah Victor , Lygouris Georgios , Poornima Indu
Published: November 2024

Case Description:
A 36-year-old male presented for an outpatient treadmill ECG stress test for further evaluation of palpitations exacerbated by exercise. He had no ischemic ECG changes, but developed a sustained episode of polymorphic VT at 13 minutes (Figure 1a). The test was stopped and the VT self-terminated after 43 seconds. The patient was admitted for further workup.

Lab workup was unremarkable; baseline ECG demonstrated no ST-T wave changes and displayed normal QT and QRS duration. TTE showed mild biventricular dysfunction. Coronary CT angiogram showed type 3 subtype of Vieussens’ arterial ring (VAR), with an absent left main and super-dominant RCA supplying both LAD and LCx. FFR-CT showed non-hemodynamically significant stenosis in the mid-distal LAD (Figure 1b). Left heart catheterization confirmed presence of VAR and mild diffuse disease in a small-caliber mid-distal LAD (Figures 1c&d). No malignant course or dynamic coronary compression was present. Cardiac MRI revealed normal biventricular function and the absence of late gadolinium enhancement. An exercise stress test, now with myocardial perfusion, was performed and was entirely normal without evidence of myocardial ischemia. Genetic testing for catecholaminergic polymorphic VT was negative. After a multidisciplinary discussion, it was decided not to pursue CABG in the absence of demonstrable ischemia at peak exercise. He underwent an ICD placement for secondary prevention and was discharged on beta blockers.

Discussion:
Three distinct subtypes of VAR have been described, with type 3 being the rarest. The coronary anomaly was first described by Raymond de Vieussens in 1706, and represents an embryologic remnant of the conotruncal circle. It may be diagnosed incidentally in asymptomatic patients or present with angina especially if underlying CAD, aneurysms or fistulae are present. We report the first case of exercise-induced polymorphic VT in a type 3 VAR patient, theorizing that intermittent myocardial ischemia at peak exercise may induce VT in these patients. Surgical revascularization may be considered if myocardial ischemia is demonstrated on stress testing, although its benefit in patients without such evidence of ischemia is unknown.
Abstract 4138426: Geographic Disparities in Cardiometabolic Health Widened Across US States Between 2011 and 2021
Authors: Gardner Rachel , Tale Archana Pravin , Wadhera Rishi
Published: November 2024

Background:
Geographic inequities in cardiovascular mortality are pervasive in the US. Pandemic-related delays in screening and treatment, economic loss, and worsening social determinants may have widened geographic disparities in cardiometabolic health, particularly in states that were hardest hit by these spillover effects. Understanding changes in state-based inequities could inform targeted public health efforts to advance cardiovascular health.

Questions:
Did the prevalence of cardiometabolic risk factors (diabetes, hypertension, hyperlipidemia, obesity) and lifestyle factors (alcohol consumption, physical inactivity, tobacco use) change between 2011 and 2021? How did between-state differences change over this period?

Methods:
We included adults from the CDC’s Behavioral Risk Factor Surveillance System. Survey-weighted logistic regressions models were used to calculate age and sex-adjusted risk difference between states with the highest and lowest adjusted prevalence rates of each risk factor in 2011 and 2011, respectively. An interaction term for state and year was included to assess for differential changes in between-state disparities.

Results:
From 2011 to 2021, there were increases in the age- and sex-adjusted prevalence of diabetes (10.9% [95% CI, 10.7,11.0] to 12.4% [12.2,12.6]), hypertension (32.4% [32.1,32.7] to 33.7% [33.4,34.0]), and obesity (27.5% [27.2,27.7] to 33.1% [32.8,33.5]). Geographic inequities widened, with increases in the difference between states with the highest vs lowest prevalence of diabetes (5.7% [5.3,6.1] to 7.8% [7.3,8.3]), hypertension (14.2% [13.6,14.8] to 17.2% [16.4,17.9]) and obesity (14.3% [13.6,15.0] to (15.7% [14.7,16.7])
(Table).
The prevalence of alcohol consumption (18.0% [17.7,18.2] to 15.6% [15.3,15.8]), physical inactivity (25.7% [25.4,27.4] to 24.0% [23.6,23.7]), and tobacco use (44.9% [44.5,45.3] to 36.3% [35.8,36.8]) decreased, and between-state differences did not widen.

Conclusion:
In this national study, the prevalence of hypertension, obesity, and diabetes increased from 2011 to 2021, and state-based inequities widened. Our findings highlight the urgent need for public health interventions to address widening state-based disparities in cardiometabolic health.