Continuum of Preshock to Classic Cardiogenic Shock in the Critical Care Cardiology Trials Network Registry.

BACKGROUND: The prognostic implications of phenotypes along the preshock to cardiogenic shock (CS) continuum remain uncertain. OBJECTIVES: This study sought to better characterize pre- or early shock and normotensive CS phenotypes and examine outcomes compared to those with conventional CS. METHODS: The CCCTN (Critical Care Cardiology Trials Network) is a registry of contemporary cardiac intensive care units. Consecutive admissions (N = 28,703 across 47 sites) meeting specific criteria based on hemodynamic variables, perfusion parameters, and investigator-reported CS were classified into 1 of 4 groups or none: isolated low cardiac output (CO), heart failure with isolated hypotension, normotensive CS, or SCAI (Society of Cardiovascular Angiography and Intervention) stage C CS. Outcomes of interest were in-hospital mortality and incidence of subsequent hypoperfusion among pre- and early shock states. RESULTS: A total of 2,498 admissions were assigned to the 4 groups with the following distribution: 4.8% isolated low CO, 4.4% isolated hypotension, 12.1% normotensive CS, and 78.7% SCAI stage C CS. Overall in-hospital mortality was 21.3% (95% CI: 19.7%-23.0%), with a gradient across phenotypes (isolated low CO 3.6% [95% CI: 1.0%-9.0%]; isolated hypotension 11.0% [95% CI: 6.9%-16.6%]; normotensive CS 17.0% [95% CI 13.0%-21.8%]; SCAI stage C CS 24.0% [95% CI: 22.1%-26.0%]; global P < 0.001). Among those with an isolated low CO and isolated hypotension on admission, 47 (42.3%) and 56 (30.9%) subsequently developed hypoperfusion. CONCLUSIONS: In a large contemporary registry of cardiac critical illness, there exists a gradient of mortality for phenotypes along the preshock to CS continuum with risk for subsequent worsening of preshock states. These data may inform refinement of CS definitions and severity staging.

Obstructive sleep apnea and hypertension; critical overview.

Obstructive sleep apnea (OSA) and hypertension are two important modifiable risk factors for cardiovascular disease and mortality. Numerous studies have highlighted the interplay between these two conditions. We provide a critical review of the current literature on the role of the OSA as a risk factor for hypertension and its effect on blood pressure (BP). We discuss several key topics: the effect of OSA on nocturnal BP, BP response to continuous positive airway pressure (CPAP) treatment, CPAP effect on BP in refractory hypertension, the role of OSA in BP variability (BPV), and maladaptive cardiac remodeling mediated by OSA's effect on BP. Finally, we discuss the unique aspects of ethnicity and social determinants of health on OSA with a focus on Asian populations and the disparity in BP control and cardiovascular outcomes.

Physiological Consequences of Upper Airway Obstruction in Sleep Apnea.

OSA is diagnosed and managed by a metric called the apnea-hypopnea index (AHI). The AHI quantifies the number of respiratory events (apnea or hypopnea), disregarding important information on the characteristics and physiological consequences of respiratory events, including degrees of ventilatory deficit and associated hypoxemia, cardiac autonomic response, and cortical activity. The oversimplification of the disorder by the AHI is considered one of the reasons for divergent findings on the associations of OSA and cardiovascular disease (CVD) in observational and randomized controlled trial studies. Prospective observational cohort studies have demonstrated strong associations of OSA with several cardiovascular diseases, and randomized controlled trials of CPAP intervention have not been able to detect a benefit of CPAP to reduce the risk of CVD. Over the last several years, novel methodologies have been proposed to better quantify the magnitude of OSA-related breathing disturbance and its physiological consequences. As a result, stronger associations with cardiovascular and neurocognitive outcomes have been observed. In this review, we focus on the methods that capture polysomnographic heterogeneity of OSA.

Early Cardiac Evaluation, Abnormal Test Results, and Associations with Outcomes in Patients with Acute Brain Injury Admitted to a Neurocritical Care Unit.

Background: to examine factors associated with cardiac evaluation and associations between cardiac test abnormalities and clinical outcomes in patients with acute brain injury (ABI) due to acute ischemic stroke (AIS), spontaneous subarachnoid hemorrhage (SAH), spontaneous intracerebral hemorrhage (sICH), and traumatic brain injury (TBI) requiring neurocritical care. Methods: In a cohort of patients ≥18 years, we examined the utilization of electrocardiography (ECG), beta-natriuretic peptide (BNP), cardiac troponin (cTnI), and transthoracic echocardiography (TTE). We investigated the association between cTnI, BNP, sex-adjusted prolonged QTc interval, low ejection fraction (EF < 40%), all-cause mortality, death by neurologic criteria (DNC), transition to comfort measures only (CMO), and hospital discharge to home using univariable and multivariable analysis (adjusted for age, sex, race/ethnicity, insurance carrier, pre-admission cardiac disorder, ABI type, admission Glasgow Coma Scale Score, mechanical ventilation, and intracranial pressure [ICP] monitoring). Results: The final sample comprised 11,822 patients: AIS (46.7%), sICH (18.5%), SAH (14.8%), and TBI (20.0%). A total of 63% (n = 7472) received cardiac workup, which increased over nine years (p < 0.001). A cardiac investigation was associated with increased age, male sex (aOR 1.16 [1.07, 1.27]), non-white ethnicity (aOR), non-commercial insurance (aOR 1.21 [1.09, 1.33]), pre-admission cardiac disorder (aOR 1.21 [1.09, 1.34]), mechanical ventilation (aOR1.78 [1.57, 2.02]) and ICP monitoring (aOR1.68 [1.49, 1.89]). Compared to AIS, sICH (aOR 0.25 [0.22, 0.29]), SAH (aOR 0.36 [0.30, 0.43]), and TBI (aOR 0.19 [0.17, 0.24]) patients were less likely to receive cardiac investigation. Patients with troponin 25th-50th quartile (aOR 1.65 [1.10-2.47]), troponin 50th-75th quartile (aOR 1.79 [1.22-2.63]), troponin >75th quartile (aOR 2.18 [1.49-3.17]), BNP 50th-75th quartile (aOR 2.86 [1.28-6.40]), BNP >75th quartile (aOR 4.54 [2.09-9.85]), prolonged QTc (aOR 3.41 [2.28; 5.30]), and EF < 40% (aOR 2.47 [1.07; 5.14]) were more likely to be DNC. Patients with troponin 50th-75th quartile (aOR 1.77 [1.14-2.73]), troponin >75th quartile (aOR 1.81 [1.18-2.78]), and prolonged QTc (aOR 1.71 [1.39; 2.12]) were more likely to be associated with a transition to CMO. Patients with prolonged QTc (aOR 0.66 [0.58; 0.76]) were less likely to be discharged home. Conclusions: This large, single-center study demonstrates low rates of cardiac evaluations in TBI, SAH, and sICH compared to AIS. However, there are strong associations between electrocardiography, biomarkers of cardiac injury and heart failure, and echocardiography findings on clinical outcomes in patients with ABI. Findings need validation in a multicenter cohort.

Experimental observation of near-wall effects during the puncture of soft solids.

Performing conventional mechanical characterization techniques on soft materials can be challenging due to issues such as limited sample volumes and clamping difficulties. Deep indentation and puncture is a promising alternative as it is an information-rich measurement with the potential to be performed in a high-throughput manner. Despite its promise, the method lacks standardized protocols, and open questions remain about its possible limitations. Addressing these shortcomings is vital to ensure consistent methodology, measurements, and interpretation across samples and labs. To fill this gap, we examine the role of finite sample dimensions (and by extension, volume) on measured forces to determine the sample geometry needed to perform and unambiguously interpret puncture tests. Through measurements of puncture on a well-characterized elastomer using systematically varied sample dimensions, we show that the apparent mechanical response of a material is in fact sensitive to near-wall effects, and that additional properties, such as the sliding friction coefficient, can only be extracted in the larger dimension case where such effects are negligible.

A comparison of various insulin resistance indices and the possibility of hypertension in military adults: CHIEF study.

BACKGROUND: Insulin resistance is associated with the development of hypertension, whereas there were rare studies comparing various non-insulin based insulin resistance (NI-IR) indices for the possibility of hypertension among young and middle-aged adults. METHODS: This cross-sectional study included a total of 4,080 military personnel, aged 18-50 years, without antihypertensive medications therapy in 2014. All subjects received annual health examinations for blood pressure (BP) measurements. Stage I isolated diastolic hypertension (IDH) and isolated systolic hypertension (ISH) and combined hypertension were respectively defined as systolic BP (SBP) < 130 mmHg/diastolic BP (DBP) 80-89 mmHg, SBP 130-139 mmHg/DBP < 80 mmHg, and SBP 130-139 mmHg/DBP 80-89 mmHg. The cut-off values of stage II hypertension for SBP and DBP were 140-159 mmHg and 90-99 mmHg, respectively. Four NI-IR indices included the serum triglycerides (TG) to high-density lipoprotein cholesterol (HDL-C) ratio, TyG index, Metabolic Score for IR (METS-IR) and ZJU index which were defined according to their specific formula. Multiple logistic regression analysis with adjustments for age, sex, anthropometrics, substance use, kidney function, serum uric acid, atherogenic cholesterols and physical activity was performed to determine the associations. RESULTS: There were 1,024 subjects with hypertension (25.1%) in which 739 were stage I hypertension, and 285 were stage II hypertension. For total hypertension, there were an association with TyG and METS-IR indices [odds ratios (ORs) and 95% confidence intervals: 1.432 (1.215-1.688) and 1.553 (1.040-2.321), respectively]. For hypertension subtypes, TyG index was positively associated with overall, stage I, and stage II ISH [ORs: 1.447 (1.149-1.823), 1.317 (1.029-1.687), and 2.011 (1.351-2.994), respectively], while TG/HDL-C, METS-IR and ZJU indices were merely associated with stage II ISH [ORs: 1.053 (1.006-1.103), 3.001 (1.171-7.696) and 1.009 (1.000-1.017), respectively]. In addition, TyG and METS-IR indices were positively associated with stage II IDH [ORs: 1.813 (1.207-2.721) and 2.85 (1.080-7.520), respectively], and TyG index was also associated with combined hypertension [OR: 1.425 (1.007-1.833)]. CONCLUSION: Among young and middle-aged adults, insulin resistance assessed by the four NI-IR indices was positively associated with stage II ISH, while only TyG index had a significant association for both stage II IDH and combined hypertension.

Characterizing advanced heart failure risk and hemodynamic phenotypes using interpretable machine learning.

BACKGROUND: Although previous risk models exist for advanced heart failure with reduced ejection fraction (HFrEF), few integrate invasive hemodynamics or support missing data. This study developed and validated a heart failure (HF) hemodynamic risk and phenotyping score for HFrEF, using Machine Learning (ML). METHODS: Prior to modeling, patients in training and validation HF cohorts were assigned to 1 of 5 risk categories based on the composite endpoint of death, left ventricular assist device (LVAD) implantation or transplantation (DeLvTx), and rehospitalization in 6 months of follow-up using unsupervised clustering. The goal of our novel interpretable ML modeling approach, which is robust to missing data, was to predict this risk category (1, 2, 3, 4, or 5) using either invasive hemodynamics alone or a rich and inclusive feature set that included noninvasive hemodynamics (all features). The models were trained using the ESCAPE trial and validated using 4 advanced HF patient cohorts collected from previous trials, then compared with traditional ML models. Prediction accuracy for each of these 5 categories was determined separately for each risk category to generate 5 areas under the curve (AUCs, or C-statistics) for belonging to risk category 1, 2, 3, 4, or 5, respectively. RESULTS: Across all outcomes, our models performed well for predicting the risk category for each patient. Accuracies of 5 separate models predicting a patient's risk category ranged from 0.896 +/- 0.074 to 0.969 +/- 0.081 for the invasive hemodynamics feature set and 0.858 +/- 0.067 to 0.997 +/- 0.070 for the all features feature set. CONCLUSION: Novel interpretable ML models predicted risk categories with a high degree of accuracy. This approach offers a new paradigm for risk stratification that differs from prediction of a binary outcome. Prospective clinical evaluation of this approach is indicated to determine utility for selecting the best treatment approach for patients based on risk and prognosis.

Central Sleep Apnea in Patients With Coronary Heart Disease Taking P2Y12 Inhibitors.

ABSTRACT: Central sleep apnea (CSA) is common in patients with heart failure. Recent studies link ticagrelor use with CSA. We aimed to evaluate CSA prevalence in patients with coronary heart disease (CHD) and whether ticagrelor use is associated with CSA. We reviewed consecutive patients with CHD who underwent a polysomnography (PSG) test over a 5-year period from 3 sleep centers. We sampled patients who were on ticagrelor or clopidogrel during a PSG test at a 1:4 ticagrelor:clopidogrel ratio. Patients with an active opioid prescription during PSG test were excluded. Age, left ventricle (LV) dysfunction, and P2Y12 inhibitor use were included in a multivariate logistic regression. A total of 135 patients were included with 26 on ticagrelor and 109 on clopidogrel (age 64.1 ± 11.4, 32% male). High CSA burden (12%) and strict CSA (4.4%) were more common in patients on ticagrelor than in those on clopidogrel (27% vs. 8.3% and 10.0% vs. 1.8%). Ticagrelor use (vs. clopidogrel) was associated with high CSA burden (OR 3.53, 95% CI 1.04-12.9, P = 0.039) and trended toward significance for strict CSA (OR 6.32, 95% CI 1.03-51.4, P = 0.052) when adjusting for age and LV dysfunction. In an additional analysis also adjusting for history of atrial fibrillation, ticagrelor use and strict CSA became significantly associated (OR 10.0, 95% CI 1.32-117, P = 0.035). CSA was uncommon in patients with CHD undergoing sleep studies. Ticagrelor use (vs. clopidogrel) was associated with high CSA burden and trended toward significance for strict CSA.

Development of a novel PLDLA/ß-TCP composite-based biodegradable anterior cervical plate and screw system.

We investigated the effectiveness and safety of a new composite-based biodegradable anterior cervical plate/screw (ACPS) system for the anterior cervical discectomy and fusion (ACDF) fixation. A biocomposite in combination with 30 wt% ß-tricalcium phosphate (ß-TCP; a biodegradable ceramic having osteoconductive ability) and 70 wt% poly-l/d-lactide copolymer (PLDLA; a biodegradable polymer) was developed and used in the ACPS device, comprising one plate and four screws for fixation. Based on a literature review, a clinically required period of performance maintenance was set as 16 weeks, and to verify the performance for a period of 16 weeks or more, the test was conducted for 26 weeks. Following ISO 13781:2017 testing protocols, an in vitro degradation test was performed to verify the performance and evaluate the decomposition characteristics of the biodegradable ACPS system. Using an animal model as a preclinical investigation, the prepared ACPS device was implanted into five mongrel dogs weighing over 30 kg to evaluate the detachment prevention effect of the ACPS system on polyether ether ketone (PEEK) cage after ACDF. By week 26, the molecular weight was decreased by 45.35% for the plate and 52.56% for the screw; the bending strength of the plate was decreased by approximately 26.2% when compared with the initial stage. The torsional yield strength and pullout strength of the screw was increased by 52.31% and 5.3%, respectively by week 2 and then subsequently decreased until week 26. No detachment or dislocation of the inserted PEEK cage was observed for 26 weeks in vivo study. These findings recommend that the ACPS system might be a promising biodegradable tool for the fixation of interbody implants and supporting the fusion in an ACDF model. Furthermore, additional clinical trials are planned for the future.

Echocardiographic derived pulmonary artery wedge pressure is associated with mortality, heart hospitalizations, and functional capacity in chronic systolic heart failure: insights from the HF-ACTION trial.

BACKGROUND: Heart Failure (HF) is associated with increased morbidity and mortality. Identification of patients at risk for adverse events could lead to improved outcomes. Few studies address the association of echocardiographic-derived PAWP with exercise capacity, readmissions, and mortality in HF. METHODS: HF-ACTION enrolled 2331 outpatients with HF with reduced ejection fraction (HFrEF) who were randomized to aerobic exercise training versus usual care. All patients underwent baseline echocardiography. Echocardiographic-derived PAWP (ePAWP) was assessed using the Nagueh formula. We evaluated the relationship between ePAWP to clinical outcomes. RESULTS: Among the 2331 patients in the HF-ACTION trial, 2125 patients consented and completed follow-up with available data. 807 of these patients had complete echocardiographic data that allowed the calculation of ePAWP. Of this cohort, mean age (SD) was 58 years (12.7), and 255 (31.6%) were female. The median ePAWP was 14.06 mmHg. ePAWP was significantly associated with cardiovascular death or HF hospitalization (Hazard ratio [HR] 1.02, coefficient 0.016, CI 1.002-1.030, p = 0.022) and all-cause death or HF hospitalization (HR 1.01, coefficient 0.010, CI 1.001-1.020, p = 0.04). Increased ePAWP was also associated with decreased exercise capacity leading to lower peak VO2 (p = < 0.001), high Ve/VCO2 slope (p = < 0.001), lower exercise duration (p = < 0.001), oxygen uptake efficiency (p = < 0.001), and shorter 6-MWT distance (p = < 0.001). CONCLUSIONS: Among HFrEF patients, echocardiographic-derived PAWP was associated with increased mortality, reduced functional capacity and heart failure hospitalization. ePAWP may be a viable noninvasive marker to risk stratify HFrEF patients.

Change in Systemic Arterial Pulsatility Index (SAPi) during Heart Failure Hospitalization is Associated with Improved Outcomes.

Study Objective: To identify Change in Systemic Arterial Pulsatitlity index (ΔSAPi) as a novel hemodynamic marker associated with outcomes in heart failure (HF). Design: The ESCAPE trial was a randomized controlled trial. Setting: The ESCAPE trial was conducted at 26 sites. Participants: 134 patients were analyzed (mean age 56.8 ± 13.4 years, 29% female). Interventions: We evaluated the change in SAPi, ([systemic pulse pressure/pulmonary artery wedge pressure) obtained at baseline and at the final hemodynamic measurement in the ESCAPE trial. Main Outcome Measures: Change in SAPi, (ΔSAPi), was analyzed for the primary outcomes of death, heart transplant, left ventricular assist device (DTxLVAD) or hospitalization, (DTxLVADHF) and secondary outcome of DTxLVAD using Cox proportional hazards regression. Results: Median change in SAPi was 0.81 (IQR 0.20-1.68). ΔSAPi in uppermost quartile was associated with reductions in DTxLVADHF (HR 0.55 [95% CI 0.32, 0.93]). ΔSAPi in the uppermost and lowermost quartiles combined was similarly associated with significant reductions in DTxLVADHF (HR 0.62 [95% CI 0.41, 0.94]). ΔSAPi higher than 1.17 was associated with improved DTxLVADHF. ΔSAPi was also associated with troponin levels at discharge (regression coefficient p = 0.001) and trended with 6-minute walk at discharge (Spearman correlation r = 0.179, p = 0.058). Conclusion: ΔSAPi was strongly associated with improved HF clinical profile and adverse outcomes. These findings support further exploration of Δ SAPi in the risk stratification of HF.

Mechanical resilience of the sessile tunicate Botryllus schlosseri.

We demonstrate that the sessile tunicate Botryllus schlosseri is remarkably resilient to applied loads by attaching the animals to an extensile substrate subjected to quasistatic equiradial loads. Animals can withstand radial extension of the substrate to strain values as high as 20% before they spontaneously detach. In the small to moderate strain regime, we found no relationship between the dynamic size of the external vascular bed and the magnitude of applied stretch, despite known force sensitivities of the vascular tissue at the cellular level. We attribute this resilience to the presence and mechanical properties of the tunic, the cellulose-enriched gel-like substance that encases the animal bodies and surrounding vasculature.

High risk for obstructive sleep apnea and risk of hypertension in military personnel: The CHIEF sleep study.

BACKGROUND: Epidemiological studies have revealed an association between obstructive sleep apnea (OSA) and hypertension in the general population, while the association in military personnel was rarely investigated. AIM: To examine the association between high risk for OSA and hypertension by phenotypes in military young adults. METHODS: A total of 746 military personnel, aged 27.9 years, were included in the cardiorespiratory fitness and health in armed forces (CHIEF)-sleep study in Taiwan in 2020. Antihypertensive medications were not used by the subjects. High risk for OSA was assessed using the Berlin Questionnaire. Hypertension was defined using the 7th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines. The cutoff levels of systolic and diastolic blood pressure (SBP and DBP) for the 2017 ACC/AHA- and JNC 7-based guidelines were 130/140 mmHg and 80/90 mmHg, respectively. Hypertension phenotypes included isolated systolic and diastolic hypertension (ISH, high SBP only and IDH, high DBP only) and combined hypertension (both high SBP and DBP). Multivariable logistic regression analysis with adjustment for demographics, lifestyle and metabolic biomarkers. RESULTS: The prevalence of high risk for OSA, JNC 7-based hypertension and 2017 ACC/AHA-based hypertension were 8.0%, 5.2% and 22.0%, respectively. Those with a high risk for OSA had a higher probability of JNC 7-based overall and combined hypertension (odds ratios (ORs) and 95% confidence intervals: 2.82 (1.07-7.42) and 7.54 (1.10-51.54), although the probabilities of ISH and IDH were unaffected by a high risk for OSA (ORs: 1.96 and 2.35, respectively, both P > 0.05). In contrast, no associations for any hypertension phenotypes were found according to the 2017 ACC/AHA criteria. CONCLUSION: A high risk for OSA was associated with severe hypertension and combined hypertension among Asian military young adults.

Multi-ancestry epigenome-wide analyses identify methylated sites associated with aortic augmentation index in TOPMed MESA.

Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.

Prognostic significance of haemodynamic parameters in patients with cardiogenic shock.

AIMS: Invasive haemodynamic assessment with a pulmonary artery catheter is often used to guide the management of patients with cardiogenic shock (CS) and may provide important prognostic information. We aimed to assess prognostic associations and relationships to end-organ dysfunction of presenting haemodynamic parameters in CS. METHODS AND RESULTS: The Critical Care Cardiology Trials Network is an investigator-initiated multicenter registry of cardiac intensive care units (CICUs) in North America coordinated by the TIMI Study Group. Patients with CS (2018-2022) who underwent invasive haemodynamic assessment within 24 h of CICU admission were included. Associations of haemodynamic parameters with in-hospital mortality were assessed using logistic regression, and associations with presenting serum lactate were assessed using least squares means regression. Sensitivity analyses were performed excluding patients on temporary mechanical circulatory support and adjusted for vasoactive-inotropic score. Among the 3603 admissions with CS, 1473 had haemodynamic data collected within 24 h of CICU admission. The median cardiac index was 1.9 (25th-75th percentile, 1.6-2.4) L/min/m2 and mean arterial pressure (MAP) was 74 (66-86) mmHg. Parameters associated with mortality included low MAP, low systolic blood pressure, low systemic vascular resistance, elevated right atrial pressure (RAP), elevated RAP/pulmonary capillary wedge pressure ratio, and low pulmonary artery pulsatility index. These associations were generally consistent when controlling for the intensity of background pharmacologic and mechanical haemodynamic support. These parameters were also associated with higher presenting serum lactate. CONCLUSION: In a contemporary CS population, presenting haemodynamic parameters reflecting decreased systemic arterial tone and right ventricular dysfunction are associated with adverse outcomes and systemic hypoperfusion.

Multi-ancestry epigenome-wide analyses identify methylated sites associated with aortic augmentation index in TOPMed MESA.

Despite the prognostic value of arterial stiffness (AS) and pulsatile hemodynamics (PH) for cardiovascular morbidity and mortality, epigenetic modifications that contribute to AS/PH remain unknown. To gain a better understanding of the link between epigenetics (DNA methylation) and AS/PH, we examined the relationship of eight measures of AS/PH with CpG sites and co-methylated regions using multi-ancestry participants from Trans-Omics for Precision Medicine (TOPMed) Multi-Ethnic Study of Atherosclerosis (MESA) with sample sizes ranging from 438 to 874. Epigenome-wide association analysis identified one genome-wide significant CpG (cg20711926-CYP1B1) associated with aortic augmentation index (AIx). Follow-up analyses, including gene set enrichment analysis, expression quantitative trait methylation analysis, and functional enrichment analysis on differentially methylated positions and regions, further prioritized three CpGs and their annotated genes (cg23800023-ETS1, cg08426368-TGFB3, and cg17350632-HLA-DPB1) for AIx. Among these, ETS1 and TGFB3 have been previously prioritized as candidate genes. Furthermore, both ETS1 and HLA-DPB1 have significant tissue correlations between Whole Blood and Aorta in GTEx, which suggests ETS1 and HLA-DPB1 could be potential biomarkers in understanding pathophysiology of AS/PH. Overall, our findings support the possible role of epigenetic regulation via DNA methylation of specific genes associated with AIx as well as identifying potential targets for regulation of AS/PH.