Medina‐Inojosa, Betsy J.

Background A subset of individuals with major depressive disorder (MDD) have a high burden of cardiovascular risk factors and cerebral small‐vessel disease, implicating vascular disease in the development of depression. Cross‐sectional studies demonstrate a link between endothelial dysfunction and MDD, but the prospective association between peripheral endothelial dysfunction (PED) and an incident diagnosis of MDD is unknown. Methods and Results Patients undergoing a baseline assessment of cardiovascular risk were evaluated for PED using reactive hyperemia–peripheral arterial tonometry (≤1.8 consistent with PED). Patient medical records were reviewed to identify those who underwent a formal clinical evaluation of MDD after the index PED evaluation. The frequency of PED was compared in those with and without MDD. Logistic regression analyses were performed to assess the association between baseline PED and incident MDD. Between January 2006 and December 2020, 1614 patients underwent testing for PED. Four hundred eighty‐four (30.1%) patients underwent a formal evaluation for MDD after (0–15 years) the index procedure (mean±SD age, 52.8±13.8 years; 65.2% women). Of these, 157 (32.4%) had PED and 108 (31.0%) were diagnosed with MDD. Individuals with MDD had a higher frequency of PED (40.2% versus 30.2%; P =0.034) compared with those without MDD. In multivariable analyses, PED was significantly associated with MDD (odds ratio, 2.3 [95% CI, 1.4–3.8]; P <0.001). Conclusions PED is significantly associated with incident MDD. Thus, PED may be a useful marker to identify individuals at increased risk of depression who may benefit from more frequent and earlier management strategies.

Abstract Background Cardiovascular disease remains the leading cause of death and burden globally, warranting the need to explore novel predictors of major adverse cardiovascular events (MACE) using new technologies. Artificial Intelligence (AI)-enhanced ECG (AI-ECG) algorithms can provide information on cardiovascular health of individuals, independent of conventional risk factors. Purpose The current study aimed to understand whether a previously described AI-ECG sex estimation algorithm could be applied for risk stratification of major adverse cardiovascular events (MACE), with a focus on a population without previous history of MACE. Methods Patients having 12-lead ECGs between 2018-2019 were included and followed up until August 2023. Exclusion criterion was a prior history of MACE. AI-ECG sex estimation was determined using a previously described algorithm predicting sex based on 12-lead ECGs. The algorithm generates outputs ranging from 0 to 1, representing the estimated probability of being male. Outputs above 0.5 were considered as AI-ECG-estimated male, and below as AI-ECG-estimated female. This was compared with biological sex to determine whether the two matched. Inconsistency between AI-ECG estimated sex and biological sex was defined as discordance. MACE was defined as myocardial infarction, coronary revascularization, non-fatal stroke, and all-cause death. Results Among 80,578 subjects (mean age 59.1 ± 16.1 years, 52.4% female), 9.7% exhibited sex discordance in AI-ECG estimation. Discordance was associated with a 56% higher risk of MACE (HR, 1.56, 95% CI 1.46-1.65, p &lt;0.001), and remained significant in multivariable analysis with traditional risk factors (HR 1.35, 95% CI 1.27-1.43, p &lt;0.001) (Figure 1). Sex-specific analysis showed increased MACE risk in both discordant males and females (Figure 2). Conclusion In patients with no history of MACE, discordance in AI-ECG sex estimation is associated with increased risk of MACE. These findings suggest the potential of AI-ECG sex estimation algorithm for risk assessment, especially in patients with no history of MACE.Figure 1.Cox proportional hazard modelFigure 2.Kaplan-Meier of MACE by sex

Abstract Background The concept of ideal cardiovascular health (CVH) was developed by the American Heart Association (AHA) as a composite of seven health factors and behaviors labeled as the Life’s Simple 7 (LS7). Ideal CVH has been associated with complex measures of cardiovascular aging. We hypothesized that physiologic aging, as determined by a simple, routinely used tool such as the electrocardiogram (ECG) enabled by an artificial intelligence algorithm to predict an individual’s physiologic age (ECG age), will be associated with poor CVH as defined by an adapted version of the AHA LS7. Methods We conducted an observational retrospective study of consecutive patients aged ≥18 years who sought care between June 2019 and March 2022, self-reported behavioral history through a validated intake questionnaire in clinical outpatient visits, had a clinically indicated ECG within one year, and provided research authorization. We applied a previously developed AI-ECG convolutional neural network to derive the ECG-Age. We excluded patients with missing data, those with body mass index (BMI) &lt;18.5 kg/m2, previous history of left-bundle branch block, atherosclerotic cardiovascular disease events, atrial fibrillation, heart failure, and non-skin cancer. An adapted version of the LS7 was used to define CVH, which includes anthropometrics (e.g., BMI), behavioral history (e.g., smoking, physical activity, and diet), vital signs (e.g., blood pressure), and laboratory values (e.g., total cholesterol, and fasting glucose). CVH was stratified as ideal, intermediate, and poor if the LS7 score had values of 9-14, 7-8, and 0-6, respectively, constructed by adding 2,1 or 0 points to each metric that met each category criteria, respectively. Accelerated aging was defined as having a Delta-Age ≥1SD above the mean, whereas Delta-age was defined as ECG minus chronological age. Logistic regression models tested the association between CVH categories and positive Delta-Age while adjusting for chronological age and sex. Results We included 114,214 individuals (53.3% females, 86.9% Caucasian). Mean chronological age was 57.7±14 years and mean AI-ECG- Age was 58 ± 12.44 years (R2 0.80, p-value &lt;0.001). Mean Delta-Age was 0.28 ±8.8 years. LS7 average score was 8.3 ± 2.23; 46.8% had ideal, 31.5% intermediate, and 21.7% had poor CVH (Figure A). Compared to those with ideal CVH, those with poor CVH were more than 50% more likely to have Delta-Age ≥1SD (OR 1.61, CI 95% 1.54-1.69, p-value: &lt;0.001), independent of chronological age and sex. (Figure B). Conclusion Poor CVH, defined by the AHA LS7, is linked with biological aging as determined by AI-enabled ECG, highlighting the importance of promoting CVH in adults as a strategy to decelerate biological aging and reduce its associated mortality.

Abstract Aims To test whether an index based on the combination of demographics and body volumes obtained with a multisensor 3D body volume (3D-BV) scanner and biplane imaging using a mobile application (myBVI®) will reliably predict the severity and presence of metabolic syndrome (MS). Methods and results We enrolled 1280 consecutive subjects who completed study protocol measurements, including 3D-BV and myBVI®. Body volumes and demographics were screened using the least absolute shrinkage and selection operator to select features associated with an MS severity score and prevalence. We randomly selected 80% of the subjects to train the models, and performance was assessed in 20% of the remaining observations and externally validated on 133 volunteers who prospectively underwent myBVI® measurements. The mean ± SD age was 43.7 ± 12.2 years, 63.7% were women, body mass index (BMI) was 28.2 ± 6.2 kg/m2, and 30.2% had MS and an MS severity z-score of −0.2 ± 0.9. Features β coefficients equal to zero were removed from the model, and 14 were included in the final model and used to calculate the body volume index (BVI), demonstrating an area under the receiving operating curve (AUC) of 0.83 in the validation set. The myBVI® cohort had a mean age of 33 ± 10.3 years, 61% of whom were women, 10.5% MS, an average MS severity z-score of −0.8, and an AUC of 0.88. Conclusion The described BVI model was associated with an increased severity and prevalence of MS compared with BMI and waist-to-hip ratio. Validation of the BVI had excellent performance when using myBVI®. This model could serve as a powerful screening tool for identifying MS.

Background Extended sedentary behavior is a risk factor for chronic disease and mortality, even among those who exercise regularly. Given the time constraints of incorporating physical activity into daily schedules, and the high likelihood of sitting during office work, this environment may serve as a potentially feasible setting for interventions to reduce sedentary behavior. Methods and Results A randomized cross‐over clinical trial was conducted at an employee wellness center. Four office settings were evaluated on 4 consecutive days: stationary or sitting station on day 1 (referent), and 3 subsequent active workstations (standing, walking, or stepper) in randomized order. Neurocognitive function (Selective Attention, Grammatical Reasoning, Odd One Out, Object Reasoning, Visuospatial Intelligence, Limited‐Hold Memory, Paired Associates Learning, and Digit Span) and fine motor skills (typing speed and accuracy) were tested using validated tools. Average scores were compared among stations using linear regression with generalized estimating equations to adjust standard errors. Bonferroni method adjusted for multiple comparisons. Healthy subjects were enrolled (n=44), 28 (64%) women, mean±SD age 35±11 years, weight 75.5±17.1 kg, height 168.5±10.0 cm, and body mass index 26.5±5.2 kg/m 2 . When comparing active stations to sitting, neurocognitive test either improved or remained unchanged, while typing speed decreased without affecting typing errors. Overall results improved after day 1, suggesting habituation. We observed no major differences across active stations, except decrease in average typing speed 42.5 versus 39.7 words per minute with standing versus stepping ( P =0.003). Conclusions Active workstations improved cognitive performance, suggesting that these workstations can help decrease sedentary time without work performance impairment. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06240286.

Background: Our team has previously developed convolutional neural networks (CNNs) to estimate age and sex from a 10-second, 12-lead ECG as indicators of patient wellness. Here, we develop an additional wellness network to estimate body mass index (BMI) from the ECG input signal. Aims: To evaluate the performance of neural networks trained to classify and directly estimate BMI. Methods: We identified all adult patients in the Mayo Clinic system who had a 10-second, 12-lead ECG within 15 days of a BMI measurement. Of the&nbsp;174,863 patients in the cohort, 2,895 were underweight (BMI < 18.5), 42,387 were of normal weight (BMI 18.5-24.9), and 57,939 were overweight only (BMI 25.0-29.9). Among patients categorized as obese, 39,788 had class I obesity (BMI 30.0-34.9), 18,978 had class II obesity (BMI 35.0-39.9), and 12,876 had class III obesity (BMI ≥ 40.0). The cohort was split into training, validation, and testing datasets in an 8:1:1 ratio to develop networks for BMI classification and a direct&nbsp;estimation of BMI. Results: In detecting overweight in the testing set, the model achieved an AUC of 0.86 (95% CI 0.85, 0.87). In detecting class I, class II, and class III obesity, the model yielded AUCs of 0.84 (95% CI 0.83, 0.85), 0.84 (95% CI 0.83, 0.85), and 0.85 (95% CI 0.85, 0.86), respectively. The model to estimate BMI achieved a mean absolute error of 3.70. Conclusions: AI-enabled ECGs demonstrate efficient detection of overweight patients and all classes of obesity. Further research is needed to determine if discrepancies between the traditionally measured BMI and the AI-ECG BMI reflect the presence or lack of metabolic abnormalities.

Introduction: Artificial Intelligence-enabled electrocardiogram (AI-ECG) can estimate the probability of having atrial fibrillation (AFib) while in sinus rhythm. Recurrent stroke in subjects without known AFib may be due to undiagnosed AFib. We evaluated the association between AI-ECG AFib and recurrent ischemic stroke and with incident AFib Methods: Consecutive adults admitted to a Mayo Clinic or Mayo Clinic Health System hospital or to Olmsted Community Hospital for ischemic stroke between January,1,2000 and June,30,2022 were identified using the Rochester Epidemiology Project. Recurrent ischemic strokes were identified after reviewing medical records and imaging studies. We excluded those with known AFib or without ECGs within 3 years prior to the first ischemic stroke. The AI-ECG network was previously developed using 649,931 ECGs from > 180,000 subjects. The primary endpoint was recurrent ischemic stroke; secondary endpoint was incident AFib. Cox model adjusted for age, sex, and CHA2DS2-VASc2 score variables. Results: We included 4,816 subjects, mean age 70±15 yr, 54% male, 92% white, median CHA2DS2-VASc2 score 4 [3-5], median follow-up 3 [1-7] yr. 280 subjects (6%) had a second stroke and 366 (8%) were diagnosed with incident AFib over follow-up. Those with a positive AI-ECG AFib had an increased risk for recurrent ischemic stroke(HR 1.54, 95% CI 1.21-1.96, P<0.001 Figure A) This association remained significant after adjustment for CHA2DS2-VASc2 score(HR 1.37 95% CI 1.07-1.76, P=0.01). These associations were not affected by anticoagulation use over follow-up. AI-ECG AFib was also associated with incident AFib(HR 2.42 95% CI 1.96-2.98, P<0.001 Figure B) Conclusions: AI-ECG AFib predicts recurrent ischemic stroke in the community, possibly reflecting undiagnosed AFib that can be detected by AI-ECG, as it also predicts incident AFib. These results underscore the potential utility of AI-ECG for risk stratification of patients with ischemic stroke.

Background: Depression is prevalent in almost half of patients with cardiovascular disease (CVD) and is associated with CVD and mortality. We used an artificial intelligence algorithm using ECG that predicts physiological age (ECG-Age) that has been linked to increased total and CVD mortality and CVD risk factors. We hypothesized that depressive symptoms would be associated with physiologic aging, as measured by AI-ECG Methods: A previously validated algorithm was applied to determine ECG-Age to 105,732 consecutive ECGs of individuals age ≥18 who sought care at Mayo Clinic between June 2019 and January 2022 and filled the Patient Health Questionnaire-9 (PHQ-9) within a month of ECG. PHQ-9 ascertains severity and frequency of depressive symptoms with values from 0 - 27 and were categorized as (None≤4, Mild 5-9, Moderate 10-14, Moderately severe 15-19 and Severe ≥20). Delta-Age was defined as ECG-Age minus chronological age and accelerated aging was defined as a Delta-Age >1SD above the mean. Logistic regression analyses associated PHQ-9 scores with positive Delta-Age while adjusting for CVD risk factors Results: Mean chronological age was 57±17 yr and mean ECG-Age 58±14 yr (R2 0.85, P < 0.0001), Delta-Age 0.71±9.40 yr, 58% women, average PHQ-9 5±6, 61% had none, 20% mild, 10 % moderate, 5%moderately severe and 4% had severe depressive symptoms. Delta-Age was 2.10 years higher in those with depressive symptoms, reflecting accelerated aging. Compared to those with no depressive symptoms, those with severe symptoms were 1.5 times more likely to have Delta-Age >1SD (OR 1.52 CI 95%1.73-1.33), independently of CV risk factors and the Charlson comorbidity index. Figure. There is significant attenuation of the association once accounting for age, sex and CVD risk factors Conclusions: Depressive symptoms are associated with physiologic aging, highlighting the role of depression in physiologic aging and the potential of preventive strategies in patients with depression and CVD

Introduction: Metabolically obese normal weight (MONW) refers to metabolic abnormalities despite normal body mass index (BMI). Hypothesis: Because obesity is generally defined by BMI, it is assumed that people with MONW do not have excessive adiposity but still have the metabolic dysregulation associated with adiposity. Methods: We included participants aged 20-65 of the National Health and Nutrition Examination Surveys from 1999-2006 and 2011-2018 with normal BMI (18.5-25 kg/m 2 ), fasting blood samples, and DEXA data. According to the AHA criteria, MONW was defined having ≥3 of the following criteria, besides a normal BMI: Hypertriglyceridemia (≥ 150 mg/dL) or treatment for elevated triglycerides; HDL cholesterol level < 40 mg/dL in men or <50 mg/dL in women or treatment for reduced HDL-C; elevated blood pressure (systolic ≥ 130 mmHg and/or diastolic ≥ 85 mmHg) or antihypertensive treatment or history of hypertension; elevated fasting plasma glucose ≥ 100 mg/dL or insulin/oral hypoglycemic treatment and central obesity by waist circumference (≥ 94 cm in men and ≥ 80 cm in women). High fat percentage was defined as ≥25% in men, ≥35% in women. Weighted logistic regression was performed to test the relation between MONW and high fat%, central obesity. Results: Of the 7,887 participants (53.6% men; mean age±SE was 39.23±0.24 years), 2433 (33.4%) had normal BMI included in the analysis. Among these, 148 had MONW (5%). Mean Fat% was 26.08±0.36% in those with MONW versus 21.90±0.17% in those without MONW for men, and 37.02±0.35% versus 33.31±0.21% for women. MONW subjects were 2.21 times more likely to have either central obesity or high fat % (OR 12.09, 95%CI: 6.18-23.67, p<0.01) and 2.18 times more likely to have high fat % (OR=2.84, 95%CI: 1.72-4.67, p<0.01) (see Figure). Conclusions: Most individuals with MONW have either increased fat content, central deposition of fat, or both. That highlights people with normal BMI may still have metabolic complications of adiposity.

Introduction: The effect of obesity on physiologic aging has not been completely established. We previously developed an artificial intelligence-enabled electrocardiogram (AI-ECG) algorithm that predicts age and determines that the difference between AI-ECG age and chronological age (Age-Gap) may reflect accelerated aging, as it is associated with increased total and cardiovascular (CV) mortality. Hypothesis: Obesity is associated with an increased Age-Gap reflecting morbidity and accelerated aging. Methods: We included adults undergoing a wellness evaluation including, body fat percentage (BF%) determination by air displacement plethysmography (Bod-Pod®) and a 12-lead ECG within 2 years. We excluded those with coronary artery disease, congestive heart failure, stroke or being underweight defined as having a BMI<18.5 kg/m2. Logistic regression models tested the association between obesity by BMI (≥30 kg/m2) or BF% quartiles (≥35% for men and ≥25 in women) and being older by AI-ECG. Results: We included 1295 subjects (70% women), mean chronological age 46.7 ± 13.1 years. Mean Age-gap positive difference compared to those with BMI<25 was 1.39, 2.06 and 2.83 for those with BMI 25-29.9, 30-34.9, and >35 respectively (p<0.05). In the BF% group, Age-gap difference compared to those in the 1st quartile was 0.008, 0.37 and 1.52 for those in the 2nd, 3rd, and 4th quartile (p<0.05). Those>3 years older by ECG were more likely to have obesity by BMI and BF%, see figure. Conclusions: Obesity, either by BMI or BF%, is associated with increased physiologic age as measured by AI-ECG, highlighting the importance of obesity as a health threat.