Citations

Sympathetic control of human blood pressure is mechanistically regulated by α 2 -adrenergic receptors distributed throughout the nervous system and cardiovascular end-targets. Recently, we discovered the sympathoinhibitory effects of central α 2 -adrenergic mechanisms on human sympathetic neuronal emission patterns. However, our knowledge remains incomplete regarding the impact of α 2 -adrenergic mechanisms on beat-by-beat transduction of muscle sympathetic nerve activity (MSNA) bursts to changes in blood pressure and heart rate (HR). Based on evidence of α 2 -adrenergic receptors within central and peripheral sympathetic neural sites and on the vasculature, this study tested the hypothesis that activation of α 2 -adrenergic receptors with dexmedetomidine (DEX) would reduce sympathetic transduction to blood pressure. In eight healthy participants (5 females; 28 ± 7 years), diastolic blood pressure (DBP; brachial arterial catheter), HR (ECG), and MSNA (peroneal microneurography) were recorded during a 5-minute supine baseline (BSL) and an intravenous DEX infusion consisting of a loading dose (10 minutes at 0.225 μg/kg/hr) and a maintenance dose (~0.15 μg/kg/hr). Signal averaging quantified sympathetic transduction to DBP and HR for 12 cardiac cycles following integrated MSNA bursts. We also quantified sympathetic transduction to DBP using a transduction gain estimate derived from the slope of the linear relationship between the peak DBP response and the number of cardiac cycles until peak DBP response. Data (mean ± SD) are reported for the 5-minute BSL and the last 5-minute period during the DEX infusion. Mixed-effects modeling and t -tests were performed. Non-parametric tests were performed for non-normally distributed data. DEX reduced resting MAP (BSL: 92 ± 7, DEX: 82 ± 6 mmHg: p < 0.001) but did not affect resting HR (BSL: 62 ± 14, DEX: 61 ± 14 bpm; p = 0.853). DEX reduced resting integrated MSNA burst frequency (BSL: 14 ± 6, DEX: 4 ± 3 bursts/min; p = 0.001) and total integrated MSNA (BSL: 663 ± 252, DEX: 188 ± 142 AU/min; p < 0.001). DEX attenuated the DBP transduction response, particularly for the cardiac cycle associated with peak DBP during BSL (cardiac cycle 6: BSL: 4.3 ± 3.2, DEX: 3.3 ± 2.0 mmHg; p = 0.025) and prolonged the time to peak DBP transduction (BSL: 6 ±1, DEX: 10 ± 3 cardiac cycles; p = 0.014). Also, DEX reduced DBP transduction gain (BSL: 1.6 ± 2.4, DEX: 0.9 ± 1.3 mmHg/cardiac cycle; p = 0.029). By contrast, DEX did not affect the mean transduction of MSNA bursts to changes in HR (BSL: 3.2 ± 3.1, DEX: 3.9 ± 4.6 mmHg; p = 0.668). These data suggest that α 2 -adrenergic mechanisms distributed among central and peripheral sympathetic neural regions and the cardiovascular system influence moment-to-moment sympathetic regulation of blood pressure homeostasis, but not HR, in humans. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) is an acute separation of coronary artery wall layers that blocks blood flow to the heart and leads to acute coronary syndrome. Patients with SCAD are relatively young females (~40-50 years) who have few cardiovascular risk factors. Sympathoexcitatory stress often precedes SCAD events (i.e. intense physical and/or emotional stress), suggesting that patients with SCAD may have augmented hemodynamic responses to sympathoexcitatory stressors. As such, we aimed to evaluate hemodynamic responses to cold stress in females with a history of SCAD and females without a history of SCAD. We hypothesized that females with a history of SCAD would have augmented hemodynamic responses to cold stress relative to females without a history of SCAD. Methods: Females with a history of SCAD were matched to females without a history of SCAD for age and body mass index. Heart rate (electrocardiogram) and beat-to-beat blood pressure (finger photoplethysmography) were recorded and averaged during two minutes of resting baseline and the minute during the cold pressor test that produced the peak hemodynamic response. Delta (Δ) values of the hemodynamic parameters were calculated. Data are reported as mean ± SD. Unpaired t-tests were used to analyze demographics, anthropometrics, resting hemodynamics, and hemodynamic responses between females with a history of SCAD and females without a history of SCAD. Results: Age (50±9 vs 56±8 years) and body mass index (27±6 vs 24±3 kg/m 2 ) did not differ between females with a history of SCAD (n=20) and females without a history of SCAD (n=12, both p>0.05), respectively. Resting heart rate ([HR], 57±10 vs 59±11 bpm), systolic blood pressure ([SBP], 112±14 vs 110±13 mmHg), diastolic blood pressure ([DBP], 72±10 vs 72±9 mmHg), and mean arterial pressure ([MAP], 86±11 vs 85±9 mmHg) were not different between females with a history of SCAD and females without a history of SCAD, respectively (all p>0.05). Hemodynamic responses to cold stress (ΔHR, 6±5 vs 7±5 bpm; ΔSBP, 20±16 vs 18±7 mmHg; ΔDBP, 7±11 vs 11±6 mmHg; ΔMAP, 10±14 vs 13±5 mmHg; all p>0.05) were not different between females with a history of SCAD and females without a history of SCAD, respectively. Conclusion: Hemodynamic responses to cold stress were not different between females with a history of SCAD and females without a history of SCAD, indicating that an augmented pressor response to this stress is likely not a primary predisposing factor to a SCAD. However, it remains important to assess other forms of stress to inform future care and counseling of patients with history of SCAD. Funding: K23HL155506 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Introduction: Spontaneous coronary artery dissection (SCAD) is one of the most common causes of myocardial infarction in females under the age of 50 and peripartum females. Furthermore, approximately 10% of patients with a history of SCAD have recurrent SCAD within 5 years. In a subset of patients, SCAD events are preceded by sympathoexcitatory stimuli, such as emotional or physical stress. This implicates the sympathetic nervous system in the pathophysiology of SCAD. Thus, we aimed to investigate this relationship through measuring muscle sympathetic nerve activity (MSNA) and quantifying MSNA transduction into diastolic blood pressure (BP) in females with a history of SCAD compared to healthy female controls. We hypothesized that females with a history of SCAD would have both augmented MSNA and MSNA transduction at rest compared to their healthy counterparts. Methods: Females with a history of SCAD and healthy controls (HC) were recruited for the study. MSNA was continuously recorded using microneurography at the peroneal nerve during 10-minute supine rest. Heart rate (HR, 3-lead electrocardiography) and BP (finger photoplethysmography) were continuously recorded during this period. We plotted binned MSNA burst areas against diastolic BP, using linear regression analysis in MATLAB R2023a to quantify the transduction slope. We compared peak bins of transduction slopes between the two groups. Data are presented as mean±SD. Independent samples t-tests were performed for statistical analyses. Results: Seven females with a history of SCAD (49±11 years; BMI: 28.5±7 kg/m 2 ) and six controls (51±8 years; BMI: 26.2±6.3 kg/m 2 ) participated in the study (both p>0.05). Resting systolic BP (SCAD: 121±8 vs. HC: 122±15 mmHg), diastolic BP (SCAD: 78±9 vs. HC: 75±7 mmHg) and HR (SCAD: 59±13 vs. HC: 67±18 bpm) were not different between groups (all p >0.05). MSNA burst frequency (SCAD: 25±12 vs. HC: 27±7 bursts/minute), burst incidence (SCAD: 42±18 vs. HC: 46±15 bursts/100 heartbeats), and total MSNA (SCAD: 820±286 vs. HC: 1050±119 au/minute) did not differ between groups (all p >0.05). MSNA transduction at rest was not different between females with a history of SCAD and healthy controls (0.02±0.03 vs. 0.05±0.05 mmHg(%·s) -1 , p>0.05). Conclusions: These preliminary data suggest that resting MSNA and transduction do not differ between females with a history of SCAD and healthy controls, contrary to our hypothesis. Further investigation is needed to determine if this observation is preserved with exposure to sympathoexcitatory stimuli. Funding: NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Biological sex impacts baroreflex control of integrated muscle sympathetic nerve activity (MSNA), yet our knowledge remains incomplete regarding sex differences in baroreflex regulation of the differently sized APs contributing to variations in MSNA burst frequency and size. We hypothesized that sex differences in baroreflex control of sympathetic action potential (AP) discharge contribute to higher resting AP activity in males compared to females. We measured diastolic blood pressure (DBP; Finometer or brachial arterial catheter) and MSNA (peroneal microneurography and continuous wavelet transform, APs normalized to 10 clusters) in 24 healthy individuals (aged 18-30, 12 females) during a 5-minute supine baseline. Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and DBP. Sympathetic AP baroreflex sensitivity gain was measured as the slope of the linear relationship between AP clusters per burst and DBP. Analyses were performed during DBP rises and falls to explore baroreflex hysteresis. Mixed-effects analyses and t-tests were performed. Data are reported as mean ± SD. In the aggregate cohort, baroreflex control of medium-sized APs exhibited hysteresis. Compared to rises in DBP, DBP falls were associated with greater AP firing probabilities (cluster 3; DBP rise: 20 ± 11, DBP fall: 26 ± 12%; p < 0.01) and greater AP baroreflex gains (cluster 3; DBP rise: -4.36 ± 2.43, DBP fall: -5.32 ± 3.09 %/mmHg; p < 0.01). In the aggregate cohort, baroreflex hysteresis was not detected for small- or large-sized AP clusters (both p ≥ 0.56). Similar observations were detected for medium-sized APs in male (M) and female (F) cohorts when analyses were stratified by sex. Compared to females, males exhibited greater medium-sized AP firing probabilities during DBP rises (cluster 3; M: 23 ± 12, F: 16 ± 8%; p < 0.01) and falls (cluster 3; M: 32 ± 13, F: 20 ± 8%; p < 0.01). However, AP baroreflex gains were not different between sexes during DBP rises (cluster 3; M: -4.87 ± 2.05, F: -3.84 ± 2.75%/mmHg; p = 0.13) and falls (cluster 3; M: -5.87 ± 2.25, F: -4.76 ± 3.77 %/mmHg; p = 0.15). In the aggregate cohort, the number of AP clusters per burst and the AP baroreflex sensitivity gain were not different between rises and falls in DBP. However, compared to females, males demonstrated a greater number of AP clusters per burst during DBP rises (M: 4 ± 0.9, F: 3 ± 0.6 clusters/burst; p < 0.01) and falls (M: 4 ± 0.8, F: 3 ± 0.7 clusters/burst; p < 0.01). No sex differences in AP baroreflex sensitivity gain were detected during DBP rises (M: -0.08 ± 0.09, F: -0.30 ± 0.07 clusters/burst/mmHg; p = 0.14) or falls (M: -0.08 ± 0.08, F: -0.02 ± 0.08 clusters/burst/mmHg; p = 0.09). These data suggest that 1) hysteresis exists in baroreflex regulation of medium-sized but not small or large sympathetic APs firing under baseline conditions and 2) in line with earlier integrated MSNA studies, compared to females, males demonstrate greater resting sympathetic outflow from greater sympathetic AP discharge and more AP clusters firing per burst in periods of rising and falling DBPs. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Importance Monoclonal gammopathy of undetermined significance (MGUS) is associated with an increased risk of cardiovascular disease. Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have demonstrated cardiorenal benefits in patients with type 2 diabetes, but their effectiveness in patients with MGUS remains unexplored. Objective To assess the effectiveness of GLP-1 RAs for primary prevention of major adverse cardiovascular and cerebrovascular events (MACCE) in patients with MGUS and diabetes. Design, Setting, and Participants This retrospective cohort study used a propensity score–matched analysis of data from the TriNetX Global Database, encompassing patients diagnosed with diabetes and MGUS between January 1, 2018, and January 13, 2023. Patients with prior heart failure (HF), ischemic heart disease, coronary revascularization, or stroke or transient ischemic attack before MGUS diagnosis were excluded. The cohort was divided into 2 groups: GLP-1 RA users and nonusers at baseline. After 1:1 propensity score matching, GLP-1 RA users and nonusers were compared up to 5 years from the MGUS diagnosis date. Data analyses were completed January 19, 2025. Exposure GLP-1 RA use within 1 year before MGUS diagnosis. Main Outcomes and Measures The primary end point was MACCE, defined as a composite of all-cause mortality, new-onset HF, acute coronary syndrome, and stroke or transient ischemic attack. Secondary end points included individual MACCE components, decompensated HF, and acute kidney injury or end-stage kidney disease. Results A total of 4871 patients with MGUS (mean [SD] age, 68.9 [10.1] years; 2366 [48.5%] male) were included (473 GLP-1 RA users and 4398 non-users). A total of 460 users were matched to 460 nonusers, with balanced characteristics (mean [SD] age, 65.0 [10.6] vs 65.1 [11.0] years; 229 [49.7%] male vs 234 [50.8%] male), including 14 patients (3.0%) vs 13 patients (2.8%) identifying as Asian, 8 (21.3%) vs 92 (20.0%) as Black or African American, 25 patients (5.4%) vs 20 patients (4.3%) as Hispanic or Latino, and 243 patients (52.8%) vs 250 patients (54.3%) as White. GLP-1 RA use was associated with a significantly lower risk of MACCE (hazard ratio [HR], 0.75; 95% CI, 0.60-0.93). Significant reductions were also observed in all-cause mortality (HR, 0.57; 95% CI, 0.37-0.87), new-onset HF (HR, 0.69; 95% CI, 0.54-0.90), decompensated HF (HR, 0.60; 95% CI, 0.43-0.84), and acute kidney injury or end-stage kidney disease (HR, 0.73; 95% CI, 0.57-0.92). Conclusions and Relevance The findings of this cohort study of GLP-1 RA use vs no use in patients with MGUS and diabetes suggest the potential of GLP-1 RA for primary prevention of MACCE. These findings warrant further investigation in prospective randomized trials.

AbstractDespite advances in acute myeloid leukemia (AML) treatment, significant unmet medical needs remain. Surrogate end points for overall survival can accelerate the approval of novel therapies. Measurable residual disease (MRD) is a promising surrogate end point candidate, providing a sensitive and quantitative assessment of disease burden. Numerous studies have demonstrated that negative MRD status—across diverse methodologies, assessment timepoints and thresholds, patient subgroups, and clinical settings—independently predicts improved survival. Although MRD can inform therapeutic decisions at the patient level, its formal integration as a primary surrogate end point in regulatory frameworks for clinical trials requires rigorous validation. MRD Partnership and Alliance in AML Clinical Treatment (MPAACT) is a research consortium among industry and academic leaders. MPAACT actively engages with regulatory agencies, health technology assessment bodies, technology vendors, and patient groups to establish a pathway for validating MRD as a surrogate end point in AML clinical trials. For the current article, the authors reviewed the status of MRD assessment, its use in recent clinical trials, current MRD assessment methodologies, standardization, regulatory guidance, statistical approaches, and patient access considerations necessary for MRD to become a surrogate clinical trial end point. The extensive collaboration between MPAACT, global industry, and academic partners—including data sharing and resource integration—underscores the collective commitment to advancing AML therapies. Establishing MRD as a surrogate end point could accelerate the development and approval of innovative treatments, ultimately improving patient outcomes.

PURPOSE Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy is used commonly for pediatric Hodgkin lymphoma (pHL) in low- and middle-income countries. The role of radiotherapy (RT) after ABVD in pHL is uncertain. MATERIALS AND METHODS We conducted a systematic review to explore the use of ABVD with or without RT in pHL. Key clinical questions included the number of cycles of ABVD, indications for and dose of RT, and outcomes by risk group. A search was performed in PubMed. Articles reporting survival outcomes by risk group were included. RESULTS Of 97 articles identified in the literature search, nine met inclusion criteria. Chemotherapy consisted of four to six cycles in limited disease and mostly six cycles in advanced disease. Three studies used RT for all patients within a specified risk group. Six studies dictated an adapted RT approach, with 3%-43% of the patients receiving RT for bulky adenopathy, slow early response (SER), and/or incomplete response. Radiation doses ranged between 20 and 36 Gy. The progression-free survival and overall survival at 4-10 years ranged from 84% to 100% and 93%-100% in limited disease and 50%-84.4% and 75%-95.3% in advanced disease, respectively. Studies did not directly assess the impact of certain chemotherapy or RT strategies. Recommendations were made after reviewing outcomes with particular approaches. CONCLUSION Four cycles of ABVD are recommended for limited disease, and six cycles of ABVD are recommended for advanced disease. In both limited and advanced diseases, RT is recommended with a dose of 20-21 Gy only to sites of bulky and/or SER, with a boost of up to 36 Gy to sites of incomplete response. This approach could spare radiation for at least half of the patients with limited disease and one third of advanced disease.

The translation of AI-generated brain metastases (BM) segmentation into clinical practice relies heavily on diverse, high-quality annotated medical imaging datasets. The BraTS-METS 2023 challenge has gained momentum for testing and benchmarking algorithms using rigorously annotated internationally compiled real-world datasets. This study presents the results of the segmentation challenge and characterizes the challenging cases that impacted the performance of the winning algorithms. Untreated brain metastases on standard anatomic MRI sequences (T1, T2, FLAIR, T1PG) from eight contributed international datasets were annotated in stepwise method: published UNET algorithms, student, neuroradiologist, final approver neuroradiologist. Segmentations were ranked based on lesion-wise Dice and Hausdorff distance (HD95) scores. False positives (FP) and false negatives (FN) were rigorously penalized, receiving a score of 0 for Dice and a fixed penalty of 374 for HD95. The mean scores for the teams were calculated. Eight datasets comprising 1303 studies were annotated, with 402 studies (3076 lesions) released on Synapse as publicly available datasets to challenge competitors. Additionally, 31 studies (139 lesions) were held out for validation, and 59 studies (218 lesions) were used for testing. Segmentation accuracy was measured as rank across subjects, with the winning team achieving a LesionWise mean score of 7.9. The Dice score for the winning team was 0.65 ± 0.25. Common errors among the leading teams included false negatives for small lesions and misregistration of masks in space. The Dice scores and lesion detection rates of all algorithms diminished with decreasing tumor size, particularly for tumors smaller than 100 mm3. In conclusion, algorithms for BM segmentation require further refinement to balance high sensitivity in lesion detection with the minimization of false positives and negatives. The BraTS-METS 2023 challenge successfully curated well- annotated, diverse datasets and identified common errors, facilitating the translation of BM segmentation across varied environments and providing the tools for future development of personalized volumetric reports to patients undergoing BM treatment.