tbuckley/cabot-search huggingface dataset:
Abstract 4136716: Frailty and Malnutrition Predict Mortality in Older Adults with Atherosclerotic Cardiovascular Disease
Authors: Sridhar Mangalesh, Emily Fishman, Alexander Ambrosini, Kamil Faridi, Michael Nanna
Journal: Circulation (2024)

Background: Frailty and malnutrition are related geriatric syndromes but it remains unknown if both provide independent prognostic information in older adults with atherosclerotic cardiovascular disease (ASCVD). Aims: We compared the prognostic value of combined frailty and malnutrition assessment with either parameter alone in predicting all-cause mortality. Methods: We analyzed 719 older adults (&gt;70 years old) with prevalent ASCVD from visit-6 of the Atherosclerosis Risk in Communities Study. ASCVD was defined as prevalent coronary heart disease, stroke, or history of MI at visit-6. Malnutrition was assessed using the geriatric nutritional risk index (score &lt;98), and physical frailty was determined using the Fried frailty phenotype. Participants were categorized as high-risk if both frail and malnourished, intermediate-risk if frail or malnourished, and low-risk if neither. Cox regression and model performance metrics were used to assess frailty, malnutrition, and their combination, both alone and in conjunction with a base model. Results: The mean age of the cohort was 80.5±4.5 years and 39.4% were women. A total of 67.2% had frailty, 13.4% had malnutrition and 11.1% had both. Median follow-up was 580 days with 61 mortality events. Compared to low-risk adults, intermediate-risk (2.3 [1.04-5.0], p=0.039) and high-risk (OR 3.1 [95% CI 1.1-8.5], p=0.027) adults had significantly higher adjusted risk of mortality (Figure). In contrast, frailty or malnutrition alone were not statistically significant predictors after multivariable adjustment. Addition of the combined risk to the base model led to a modest increase in the c-index compared to the malnutrition model (0.668 vs. 0.647) but not the frailty model (0.668 vs 0.667). There was no significant improvement in reclassification or integrated discrimination index, but the combined model had superior goodness-of-fit than the frailty and malnutrition models, as demonstrated by a difference &gt;|2.0| in the Akaike information criterion (-3.4&amp;-13.5 respectively). Conclusion: Frailty and malnutrition are highly overlapping syndromes. Incorporation of readily available nutritional risk measures to traditional frailty assessment may improve risk prediction in older adults with ASCVD.
Abstract 4136116: Metformin Therapy for Reperfusion Injury Consolidates Cardioprotection in the High-Risk Elderly Heart
Authors: Nadiyeh Rouhi, Hao Wang, Jennie Nguyen, Lily Slotabec, Blaise Seale, Changhong Wen, Fernanda Filho, Michael Adenawoola, Qun Chen, EDWARD LESNEFSKY, Ji Li
Journal: Circulation (2024)

Introduction: Metformin (MET), a first-line diabetes therapy, exhibits cardioprotective effects during acute ischemia and reperfusion (I/R). Cardiac injury is enhanced in the aging heart in murine and humans. Acute, high dose MET treatment at the onset of reperfusion (R) markedly reduced infarct size (MI) in the high risk aged heart via modulation of mitochondrial complex I. However, the effect of subsequent chronic, standard dose MET to consolidate and possibly enhance cardioprotection and survival following I/R in the aged heart remains unknown. Hypothesis: Administration of chronic standard dose of MET will ameliorate mortality and morbidity following MI through rescuing an impaired adaptive metabolic remodeling. Methods: Aged (22-24 month) C57BL6/J mice were subjected to sham operations or 45 min of ischemia by LAD ligation followed by R. All mice received acute, high dose MET (2 mM, i.v.) at the onset of R followed by randomization to chronic MET (300 mg/kg/day) in drinking water versus vehicle (VEH) administered for 14 days. Cardiac function was determined by echocardiography weekly. IonOptix Myocyte Calcium and Contractility System measured the contractile functions and transient calcium signaling of isolated cardiomyocytes. Results: The Kaplan-Meier survival analysis showed that chronic MET treatment following acute treatment at the onset of R significantly reduced mortality compared to VEH group. Although chronic MET treatment did not further reduce MI size, echo and histology showed that chronic MET preserved diastolic function, prevented left ventricular hypertrophy and reduced collagen deposition following I/R in aging. Moreover, isolated cardiomyocytes from MET treated hearts showed improvements in contractile function, transit calcium signaling, and the coupling between contractility and calcium levels as compared to the cardiomyocytes from VEH group hearts. Immunoblotting results showed that Sens2/AMPK metabolic signaling was significantly upregulated by chronic MET post-MI, indicating the metabolic homeostasis modulated by MET is a critical factor involved in the beneficial effects of chronic MET on limiting I/R-induced myocardial damage that leads to deleterious remodeling in aging. Conclusions: The mortality and morbidity of MI in the high risk aged heart is attenuated with acute, high dose of MET treatment followed by chronic standard dose MET treatment to consolidate protection via rescuing the impaired adaptive metabolic response in aging.
Abstract 4136180: Sex Differences in Cognition Related to Cerebral Small Vessel Disease Associated with Younger Age ofHypertension Diagnosis
Authors: Amanpreet Kaur, Hassan Behlouli, Natasha Rajah, Louise Pilote
Journal: Circulation (2024)

Background: There are sex differences in the effect of age at onset (AO) of hypertension onbrain structural changes later in life. This may differentially affect long-term cognition through cerebral smallvessel disease (CSVD) in females and males. However, whether and how the association between age ofhypertension diagnosis contributes to sex differences in cognitive decline related to CVSD later in life remainsunclear. Objective: Our objective was to examine sex differences in cognition in relation to brain structural changesexacerbated by CSVD caused by younger AO of hypertension. Methods: We used data from the UK Biobank to select participants with a known age of hypertensiondiagnosis who also had neuropsychological test scores for cognitive functions affected by CSVD i.e., memoryand executive function (n= 6095). We stratified data by sex and AO at baseline (2006-2010). Controlparticipants who did not have hypertension were chosen at random using propensity score matching. Principalcomponents analysis (PCA) was used to reduce the number of CSVD related cognitive function tests(measured at 2014 follow-up). We selected participants &gt;65 years of age at the time of cognitive function teststo determine cognitive function later in life. This was followed by a sex disaggregated regression analysis totest for the effect of AO on cognitive functions identified from the PCA in females and males. Results: Our main outcomes were cognitive function tests in the domains of memory (working and visual-spatial) and executive function/processing speed. When compared to normotensive controls, cognitiveoutcomes differed by sex and age of hypertension diagnosis. Whereas females diagnosed at middle age (45-54 years) had worse outcomes in the working memory domain compared to controls, males diagnosed at olderage (&gt;65 years) had worse outcomes compared to controls. Only females diagnosed with hypertension ateither younger age (&lt; 35 years) or older age (&gt;65 years) had worse outcomes in the executive visualdeclarative memory domain. We did not see any differences in the processing speed/executive functiondomain in either males or females. Conclusions: This study demonstrates distinctive characteristics of CSVD-related cognitive decline in malesand females based on the age of hypertension onset. Therefore, CSVD is a critical pathophysiologicalmechanism for sex differences in cognitive decline and may aid in identification of novel sex-specific therapy.
Abstract 4136181: Automated Personalized Modulation of the Sympathetic “fight-or-flight” Reflex <i>In Vivo</i> Using Implantable Microdevices for Enhancing Neurocardiac Function and Reducing Mortality Risk.
Authors: Dibyasankha Kundu, Debapriya Hazra, Shayani Mukherjee, Steven Jones, Swati Dey, Deeptankar DeMazumder
Journal: Circulation (2024)

Background: The sympathetic nervous system (SNS) is a critical regulator of cardiovascular function. Whereas acute SNS activation elicits positive inotropy and confers survival advantage, persistent SNS hyperactivity is maladaptive and can lead to arrhythmias, cardiac arrest and heart failure. Hypothesis: Automated optogenetic modulation of the sympathetic stress response in vivo enhances neurocardiac function while avoiding sympathetic hyperactivity-mediated pathological effects. Methods: In normal guinea pigs, we virally transduced excitatory and/or inhibitory channelrhodopsins to the stellate ganglia (SG), the primary sympathetic input to the heart. We studied in situ effects of graded activation of SG opsins (e.g., phasic vs tonic) on cardiac function (e.g., ECG, heart rate) with and without perfusing agents (e.g., β-blockers, antioxidants). In vivo studies used novel implanted µLED devices for wireless body signal streaming (e.g., ECG) and neurophotonic SG opsin modulation closed-loop to dynamic analyses of physiological demand versus ECG-based cardiac risk prediction. Results: Compared to baseline heart rate (218±16 bpm), pulsed activation of inhibitory opsins reduced heart rate by ~25% (156±12; delta=67±14 bpm; p&lt;0.0003; N=5). Pulsed activation of excitatory opsins increased heart rate by ~30% (285±28; delta=65±19 bpm; p&lt;0.0002; N=5). Interestingly, prolonged (&gt;20 min) tonic excitation of the SG caused desensitization, possibly as an intrinsic safety mechanism. Whereas graded SG excitation or inhibition at different LED intensities elicited prompt changes in heart rate, repeated activation of excitatory opsins led to quick desensitization. Our ongoing studies are aimed at understanding how and when SG modulation can enhance cardiac function, trigger intrinsic cardioprotective mechanisms, or cause pathological effects. Conclusion: Automated neurophotonic optogenetic excitation or inhibition of the SG is a robust personalized strategy for modulating cardiovascular function. The ability to rapidly and accurately modulate the sympathetic stress reflex in a graded manner can lead to more timely, effective, and appropriate physiological responses while avoiding undesired pathophysiological responses.
Abstract 4136280: Inflammation and Cancer Mortality among CVD Individuals: NHANES-Continuous study
Authors: Omar Elsayed, Tochi Okwuosa, Daniel Addison, Jorge Cortes, Susan Dent, Sadeer Al-Kindi, Catherine Hedrick, Neal Weintraub, Xiaoling Wang, Avirup Guha
Journal: Circulation (2024)

Background: Both cancer and cardiovascular disease (CVD) are the leading causes of death worldwide. While previous research showed a relationship between CVD and cancer incidence, limited evidence is available regarding the relationship between inflammation and cancer mortality in CVD patients. Methods: A prospective cohort study using data from the continuous National Health and Nutrition Examination Survey (NHANES) (1999-2016) merged with Medicare and National Death Index (NDI) mortality data until December 31, 2018. We included CVD individuals with no history of cancer at baseline to investigate the relationship between inflammatory markers, including Neutrophil-to-Lymphocyte ratio (NLR), as the main exposure and cancer mortality as the main outcome. Results: We included 4,089 adult individuals representing 127,809,316 individuals (47% females, 72% non-Hispanic Whites, and 5% Hispanics). The risk factor analysis (Table) using the competing risk modeling showed that while inflammatory markers did not show significant associations with cancer mortality in the overall analysis, upon stratification by race/ethnicity, NH-Blacks showed higher cancer mortality with higher WBC count (aHR 5.61, 95% CI 1.66-18.91, p=0.007) and NLR (aHR 2.97, 95% CI 1.19-7.42, p=0.02), but lower cancer mortality with higher neutrophil (aHR 0.08, 95% CI 0.01-0.60, p=0.02) and lymphocyte (aHR 0.34, 95% CI 0.15-0.80, p=0.02) counts. Notably, our NH-Blacks showed lower neutrophils at baseline than others which could be explained by a phenomenon called “Benign Ethnic Neutropenia -BEN-” that still brings more complexity when interpreting NLR. Conclusions: Our study highlights the close relationship between cardiovascular health, inflammation, and cancer mortality. The findings also suggest that race/ethnicity may play a significant role in the relationship between inflammation and cancer mortality among individuals with CVD. Yet, further research is still needed to underpin the biological pathways influencing this relationship.
Abstract 4136776: Prognostic Value of Resting Heart Rate and Heart Rate Variability in the 12-lead Electrocardiogram: Mortality Data From the CODE Nationwide Database
Authors: Diego Moraes, Bruno Nascimento, Gabriela Paixao, Paulo Rodrigues Gomes, Magda Pires, Antonio Ribeiro
Journal: Circulation (2024)

Introduction: Resting Heart Rate (HR) and Heart Rate Variability (HRV) reflect autonomic control, and are implicated as prognostic factors. We aimed to evaluate the prognostic value of HR and HRV in a cohort from a nationwide telemedicine network. Methods: We assessed unique ECGs recorded from patients ≥16 years-old, from the tele-ECG database of the Telehealth Network of Minas Gerais, Brazil, between 2010 and 2017. Variables of interest were HR and standard deviation of normal RR intervals (SDNN). Self-informed data were collected: sex, age, risk factors (hypertension, dyslipidemia, diabetes, smoking) and comorbidities (myocardial infarction, Chronic Obstructive Pulmonary Disease, and Chagas disease). Outcomes of interest were all-cause and cardiovascular mortality, assessed by ICD codes reported in death certificates, through linkage with the Mortality Information System. Cox regression was applied to evaluate the association between HR and HRV and the outcomes, in 4 models: 1. Unadjusted; 2. Adjusted for sex and age; 3. Model 2 + risk factors + clinical comorbidities; 4. Model 3 + HRV or HR, respectively. Results: At total 992.611 individuals were included, median age of 55 years, 60% women. In 6 years, there were 33.292 deaths (3,37%), 21% due to cardiovascular causes. Patients who died had higher prevalence of all risk factors and comorbidities, as well as higher HR: 76 (IQR 66-87) vs. 74 (IQR 65-83) bpm, p&lt;0.001 and lower HRV: 84 (IQR 51-127) vs. 114 (IQR 74-153), p&lt;0.001. After adjustments (model 4), all HR quartiles were independently associated a progressively increased risk of all-cause mortality, being 88% higher for the 4 th quartile (HR=1.88 (95%CI 1.77–1.89). Similarly, the 1 st and 2 nd HRV quartiles remained associated with increased all-cause mortality (1 st quartile HR=1.42 (95%CI 1.37–1.47) in the final model. For cardiovascular mortality, HR was also an independent predictor, with a progressively higher risk, with a 77% increase (HR=1.77 95%CI 1.65–1.91) in the 4 th quartile. HRV was also an independent predictor of cardiovascular death, with a 33% risk increase (HR=1.33, 95%CI 1.23–1.44) for the 1 st quartile. Male gender, age, and all risk factors and comorbidities were also independent predictors of all-cause and cardiovascular mortality. Conclusions: In a large cohort of Brazilian adults, baseline HR and HRV were independent predictors of all-cause and cardiovascular mortality, after adjustment for clinical variables and autonomic indexes.
Abstract 4136786: Prediabetes increases platelet activation and thrombotic susceptibility via mitochondrial oxidants
Authors: Azaj Ahmed, melissa jensen, Katharine Geasland, Jagadish Swamy, Douglas Spitz, E. Dale Abel, Diana Jalal, Sanjana Dayal
Journal: Circulation (2024)

Recent studies suggest that prediabetes is not only a prelude to diabetes, but also is an independent risk factor for cardiovascular thrombotic events in young and aged people. However, the mechanisms that may promote platelet activation and thrombosis during prediabetes have not been studied. We hypothesized that in prediabetes, dysregulation of electron transfer and accumulation of mitochondrial oxidants promotes platelet activation and thrombosis, and that aging exacerbates the phenotype. We recruited young (18-50 year) and middle-aged (51-64 year) Veterans with prediabetes and age- and BMI- matched healthy Veterans. Compared to healthy cohort, platelets from prediabetes exhibited enhanced agonist induced platelet activation, mitochondrial oxidants, membrane potential and thrombus formation ex vivo in both young and middle-aged cohorts to a similar extent. Preincubation of platelets with either a mitochondria targetable superoxide dismutase (SOD) mimetic or MitoQ (transfers electrons from Complex I/II to complex III to lower superoxide generation within mitochondria), rescued the prothrombotic phenotype. We confirmed these platelet phenotypes in C57BL6/J mice fed high fat (HF) diet for 2 weeks (model of early diabetes). Importantly, HF-fed mice showed increased susceptibility to carotid artery and pulmonary thrombosis in vivo . Pharmacological treatment of HF-fed mice with SOD-mimetic or MitoQ, or genetic overexpression of catalase within mitochondria, rescued the prothrombotic state. This is the first report showing platelet hyperactivity and enhanced thrombotic susceptibility in prediabetes. Further, our findings suggest that enhanced mitochondrial oxidants due to the premature electron escape contribute to the phenotype. Our data imply a therapeutic potential of SOD-mimetic and MitoQ in lowering thrombotic burden in prediabetes.
Abstract 4136654: Urine Output Response to a Furosemide Infusion is Associated with Acute Kidney Injury in Infants Following Cardiac Surgery
Authors: Alyson Pierick, Kera Luckritz, Ashley Huebschman, Ashley Duimstra, Sunkyung Yu, Nathaniel Sznycer-Taub
Journal: Circulation (2024)

Background: Acute kidney injury (AKI) following cardiac surgery in infants is common and associated with longer mechanical ventilation times and length of stay. Prior studies have shown that a lack of responsiveness to bolus dose furosemide has been associated with increased incidence of AKI. However, these studies have excluded patients on continuous furosemide infusions who are often younger, more hemodynamically unstable, and at higher risk for AKI. Hypothesis: Decreased urine output after initiation of a furosemide infusion predicts development of AKI. Methods: A retrospective cohort study of infants (&lt;1 year of age) was conducted who underwent cardiac surgery requiring cardiopulmonary bypass from 2020-2023 and were on a furosemide infusion post-operatively. The primary outcome was post-operative AKI as defined using KDIGO (Kidney Disease: Improving Global Outcomes) guidelines. A furosemide response score (FRS) was calculated using the total urine output divided by the total dose of furosemide administered over a given time. Univariate and multivariate analyses were performed, and receiver operating characteristic curves used to determine the discriminatory ability of the FRS with regards to the primary outcome. Results: A total of 155 infants (median age at surgery 9 days) were included. Overall, 77% of infants met definition for the primary outcome of AKI; 32% stage 1, 30% stage 2, and 15% stage 3. Lower FRS at 4, 10, and 24 hours after infusion initiation were associated with AKI development (p&lt;0.0001). Younger age, smaller weight at surgery, lack of pre-operative feedings, pre-operative inotropic use and higher surgical complexity were also associated with a higher risk of AKI. An FRS (mL/mg/kg) cutoff of &lt;11.3 at 4 hours, &lt;25.5 at 10 hours, and &lt;55.3 at 24 hours had good discriminatory ability (area under the curve 0.7-0.75) in predicting AKI stage 2 or 3 (p&lt;0.001). Controlling for the significant univariate variables listed above, the FRS cutoffs remained an independent risk factor for the development of AKI stage 2 or 3, (p&lt;0.01) and were significantly associated with longer mechanical ventilation days and length of stay. Conclusion: Lack of responsiveness to a furosemide infusion (as measured by urine output corrected for dose of furosemide) is associated with the development of AKI in a high-risk cohort of infants. These novel findings may be helpful to predict those at risk and allow for further investigations for modifiable risk factors.
Abstract 4135582: Sociodemographic Trends in Diabetes Medications after Metformin: the BESTMED (oBservational Evaluation of Second line Therapy MEdications in Diabetes) Study
Authors: Maria Lansang, Lucia Petito, Indhumathy Chelliah, Emma Hegermiller, Ryan Carnahan, Marie McDonnell, Gosia Sylwestrzak, Elisa Priest, Vincent Wiley, Satyender Goel, Alan Kaul, Alexander Turchin
Journal: Circulation (2024)

Objective: Though updated American Diabetes Association (ADA) guidelines recommend initiating GLP1 receptor agonists (GLP1) or SGLT2 inhibitors (SGLT2i) for persons with type 2 diabetes mellitus (PWT2DM) with high CV risk, metformin was previously recommended as 1st-line treatment. For PWT2DM at moderate CV risk, it is unknown which 2nd-line drug optimizes CV outcomes. Our multicenter observational study describes US-wide trends in 2nd-line T2DM medication use (DPP4 inhibitors [DPP4i], GLP1s, SGLT2i and sulfonylureas [SU]) overall and in key sociodemographic subgroups between 2014-2023. Methods: This is a secondary analysis of the oBservational Evaluation of Second line Therapy Medications in Diabetes (BESTMED) study, which used a new-user design to evaluate associations between 2nd-line medications and CV events in PWT2DM at moderate CV risk. The database comprised EHRs and insurance claims for 75,224 PWT2DM from 10 health systems and 2 insurance plans on metformin who initiated a 2nd medication from 1/2013 to 1/2023. Data were obtained from orders or prescription fills. Prescription class was regressed on calendar time via multinomial logistic regression to model trends in prescribing patterns, adjusted for sociodemographic variables. Subgroup analyses were performed by adjustment factors; CIs and p-values for differences were calculated via nonparametric bootstrap (B=200). Due to large sample size, statistical significance was interpreted at p&lt;0.05 and annual rate of change &gt;0.5%. Results: We included 75,224 T2DM adults (median A1c 7.8%), of whom 18%,17%, 18%, and 47% initiated DPP4i, GLP1, SGLT2i, SU respectively. From 2014 - 2023, SGLT2i and GLP1 increased: 5.7 to 28.8%, and 3.5 to 30.3%, and DPP4i and SUs decreased: 25.3 to 11.6%, and 65.6 to 29.3%, respectively. Annual rate of change for SGLT2i was higher in men(3.0% vs 2.1%/year; p&lt;0.001) and in &gt; 65 y (3.0% vs 2.4%; p&lt;0.001), and for GLP1s was higher in those &lt;65 y (3.6% vs 2.1%; p&lt;0.001), women (3.5% vs 2.5%; p&lt;0.001), Hispanic ethnicity (3.2% vs 2.7%; p=0.005), and with class II/III obesity (4.1% versus 2.6% per year; p&lt;0.001). There was no evidence that these trends differed by race, insurance, or SDI. Conclusion: In this nationwide study of prescribing patterns PWT2DM at moderate CV risk, prevalences of 2nd-line T2DM therapies are approaching current ADA guidelines for initial therapy for those at high CV risk. Differences between sociodemographic groups appear aligned with clinical expectations.