Associations of Hypertension and Orthostatic Hypotension with Subclinical Cardiovascular Disease.

BACKGROUND: Orthostatic hypotension is associated with cardiovascular disease. It remains unclear if low standing blood pressure or high seated blood pressure is responsible for this association. We compared associations of orthostatic hypotension and hypertension with high-sensitivity cardiac troponin I and N-terminal pro-B-type natriuretic peptide. METHODS: We performed a secondary analysis of the Study to Understand Fall Reduction and Vitamin D in You (STURDY), a randomized controlled trial funded by the National Institute on Aging, between July 2015 and May 2019. Participants were community-dwelling adults, 70 years or older. Blood tests for high-sensitivity cardiac troponin I and N-terminal pro-B-type natriuretic peptide were drawn at visits concurrent with blood pressure measurements. Secondary analysis occurred in 2023. We determined associations between blood pressure phenotypes and cardiac biomarkers. RESULTS: Of 674 participants (mean age 76.5 ± 5.4 years, 43% female, 17.2% Black race), 29.1% had prior cardiovascular disease. Participants with seated hypertension had 10.1% greater high-sensitivity cardiac troponin I (95% CI = 3.8, 16.9) and 11.0% greater N-terminal pro-B-type natriuretic peptide (4.0, 18.6) than those without seated hypertension. Participants with standing hypertension had 8.6% (2.7, 14.9) greater high-sensitivity cardiac troponin I and 11.8% greater N-terminal pro-B-type natriuretic peptide (5.1, 18.9) than those without standing hypertension. Hypotensive phenotypes were not associated with either biomarker. CONCLUSIONS: Both seated and standing hypertension were associated with greater high-sensitivity cardiac troponin I and N-terminal pro-B-type natriuretic peptide, but hypotensive phenotypes were not. Hypoperfusion may not be the principal mechanism behind subclinical cardiac injury among older adults with orthostatic hypotension.

Associations of Adipokine Levels With Levels of Remnant Cholesterol: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: The metabolic syndrome phenotype of individuals with obesity is characterized by elevated levels of triglyceride-rich lipoproteins and remnant particles, which have been shown to be significantly atherogenic. Understanding the association between adipokines, endogenous hormones produced by adipose tissue, and remnant cholesterol (RC) would give insight into the link between obesity and atherosclerotic cardiovascular disease. METHODS AND RESULTS: We studied 1791 MESA (Multi-Ethnic Study of Atherosclerosis) participants who took part in an ancillary study on body composition with adipokine levels measured (leptin, adiponectin, and resistin) at either visit 2 or visit 3. RC was calculated as non-high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol, measured at the same visit as the adipokines, as well as subsequent visits 4 through 6. Multivariable-adjusted linear mixed-effects models were used to assess the cross-sectional and longitudinal associations between adipokines and log-transformed levels of RC. Mean±SD age was 64.5±9.6 years; mean±SD body mass index was 29.9±5.0 kg/m2; and 52.0% were women. In fully adjusted cross-sectional models that included body mass index, diabetes, low-density lipoprotein cholesterol, and lipid-lowering therapy, for each 1-unit increment in adiponectin, there was 14.6% (95% CI, 12.2-16.9) lower RC. With each 1-unit increment in leptin and resistin, there was 4.8% (95% CI, 2.7-7.0) and 4.0% (95% CI, 0.2-8.1) higher RC, respectively. Lower adiponectin and higher leptin were also associated with longitudinal increases in RC levels over median follow-up of 5 (interquartile range, 4-8) years. CONCLUSIONS: Lower adiponectin and higher leptin levels were independently associated with higher levels of RC at baseline and longitudinal RC increase, even after accounting for body mass index and low-density lipoprotein cholesterol.

Weight Loss Differentially Impacts Sex Hormones in Women and Men with Type 2 Diabetes: Look AHEAD Sex Hormone Study.

BACKGROUND: Despite sex differences in T2D, few studies have examined the role of sex hormones. We sought to assess the impact of weight loss, the cornerstone of T2D management, on sex hormone levels. METHODS: This was an ancillary study to the Look AHEAD (Action for Health In Diabetes) Study (n=850 postmenopausal females, n=890 males, with T2D and BMI ≥25 kg/m2). We measured total testosterone (T), estradiol (E2) and sex hormone binding globulin (SHBG) and calculated bioavailable T (bioT). We examined the effect of the intensive lifestyle intervention (ILI) on hormone changes, whether changes were mediated by waist circumference and sex differences in treatment effect. RESULTS: The baseline mean age was 60 years with a higher proportion of Black females (21%) vs. males (9%) and higher mean BMI in females vs. males (36.3 vs. 34.8 kg/m2). At year 1 in females, ILI decreased E2 by 15% and bioT by 13% and increased SHBG by 21%. At year 1 in males, ILI did not change E2 levels, but increased T by 14% and increased SHBG by 18%. The effect was attenuated over 4 years, there were statistically significant sex differences in treatment effect and change in waist circumference due to ILI at year 1 was a significant mediator of sex hormone changes. CONCLUSION: Weight loss in T2D resulted in sex hormone changes, which varied by sex and were mediated by changes in WC. Changes in sex hormone due to weight loss in T2D should be considered in the context of an individual's health risks, including cardiovascular, bone health, menopausal symptoms and cognition.

Association of Gestational Diabetes With Subclinical Cardiovascular Disease.

Background: Gestational diabetes mellitus (GDM) is associated with increased long-term risk of cardiovascular disease but the cardiovascular structural and functional changes that contribute to risk are not well understood. Objectives: The purpose of this study was to determine whether GDM is associated with adverse cardiac remodeling and endothelial dysfunction a decade after delivery, independent of type 2 diabetes. Methods: Women with deliveries between 2008 and 2009 were initially selected from a prospective clinical cohort. Pregnancy history was chart abstracted and a follow-up study visit was conducted at 8 to 10 years postpartum. Cardiac structure and function were assessed with echocardiography. Endothelial function was measured with peripheral arterial tonometry and glycocalyx analysis. Results: Among 254 women assessed at an average age of 38 years, 53 (21%) had prior GDM. At follow-up, women with GDM had more incident prediabetes or diabetes (58% vs 20% without GDM), more impairment in peripheral arterial tonometry (reactive hyperemia 1.58 vs 1.95; P = 0.01) and reduced perfusion, a marker of glycocalyx assessment (red blood cell filling 0.70 ± 0.04 vs 0.72 ± 0.05; P < 0.01). Despite adjustment for demographic and reproductive characteristics, women with GDM had great septal wall thickness by 8% (95% CI: 2.3%-14.7%) and worse diastology with higher E/E' by 11% (95% CI: 1.1%-21.5%). After additional adjustment for diabetes and prediabetes, several parameters remained significantly impaired. Conclusions: Having GDM within the past decade was associated with more adverse cardiac structure/function and vascular endothelial function. Some, but not all, risks may be mediated through the development of prediabetes or type 2 diabetes. Enhanced preventive efforts are needed to mitigate cardiovascular risk among women with GDM.

PARCCS: A Machine Learning Risk-Prediction Model for Acute Peripartum Cardiovascular Complications During Delivery Admissions.

Background: Maternal mortality in the United States remains high, with cardiovascular (CV) complications being a leading cause. Objectives: The purpose of this paper was to develop the PARCCS (Prediction of Acute Risk for Cardiovascular Complications in the Peripartum Period Score) for acute CV complications during delivery. Methods: Data from the National Inpatient Sample (2016-2020) and International Classification of Diseases, Tenth Revision codes to identify delivery admissions were used. Acute CV/renal complications were defined as a composite of pre-eclampsia/eclampsia, peripartum cardiomyopathy, renal complications, venous thromboembolism, arrhythmias, and pulmonary edema. A risk prediction model, PARCCS, was developed using machine learning consisting of 14 variables and scored out of 100 points. Results: Of the 2,371,661 pregnant patients analyzed, 7.0% had acute CV complications during delivery hospitalization. Patients with CV complications had a higher prevalence of comorbidities and were more likely to be of Black race and lower income. The PARCCS variables included electrolyte imbalances (13 points [p]), age (3p for age <20 years), cesarean delivery (4p), obesity (5p), pre-existing heart failure (28p), multiple gestations (4p), Black race (2p), gestational hypertension (3p), low income (1p), gestational diabetes (2p), chronic diabetes (6p), prior stroke (22p), coagulopathy (5p), and nonelective admission (2p). Using the validation set, the performance of the model was evaluated with an area under the receiver-operating characteristic curve of 0.68 and a 95% CI of 0.67 to 0.68. Conclusions: PARCCS has the potential to be an important tool for identifying pregnant individuals at risk of acute peripartum CV complications at the time of delivery. Future studies should further validate this score and determine whether it can improve patient outcomes.

Deep Diving Into the Cardiovascular Health Paradox: A Journey Towards Personalized Prevention.

Objectives: The Life's Simple 7 score (LS7) promotes cardiovascular health (CVH). Despite this, some with optimal LS7 develop cardiovascular disease (CVD), while others with poor CVH do not, termed the "CVH paradox." This paper explores pathways explaining this paradox. Methods: We examined methodological aspects: 1) misclassification bias in self-reported lifestyle factors (smoking, physical activity, diet); 2) cumulative exposure to risk factors over a lifetime, impacting the CVH paradox. Punctual risk factor assessments are suboptimal for predicting outcomes. We proposed personalized prevention using "novel" elements to refine CVH assessment: 1) subclinical vascular disease markers, 2) metabolic biomarkers in blood and urine, 3) emerging risk factors, 4) polygenic risk scores (PRS), 5) epigenetics, and 6) the exposome. Results: Addressing the CVH paradox requires a multifaceted approach, reducing misclassification bias, considering cumulative risk exposure, and incorporating novel personalized prevention elements. Conclusion: A holistic, individualized approach to CVH assessment and CVD prevention can better reduce cardiovascular outcomes and improve population health. Collaboration among researchers, healthcare providers, policymakers, and communities is essential for effective implementation and realization of these strategies.

Disparities by sex, race, and region in acute myocardial infarction-related outcomes during the early COVID-19 pandemic: the national inpatient sample analysis.

BACKGROUND: Disparities in acute myocardial infarction (AMI)-related outcomes have been reported before the COVID-19 pandemic. We studied in-hospital outcomes of AMI across demographic groups in the United States during the early COVID-19 pandemic. METHODS: The National Inpatient Sample (NIS) database was queried for 2020 to identify AMI-related hospitalizations based on appropriate ICD-10-CM codes categorized by sex, race, and hospital region categories. The primary outcome was in-hospital mortality in females, racial and ethnic minority groups, and Northeast hospital region compared with males, White patients, and Midwest hospital region, respectively. Multivariable regression analysis was used to calculate the adjusted odds ratio and mean difference. RESULTS: A total of 820,893 AMI-related hospitalizations were identified during the study period. On adjusted analysis, during the early COVID-19 pandemic, females had lower odds of in-hospital mortality [aOR 0.89 (0.85-0.92); P < 0.01] and revascularization [aOR 0.68 (0.66-0.69); P < 0.01] than males. Racial and ethnic based analysis showed that Asian/Pacific Islander patients had higher odds of in-hospital mortality [aOR 1.13 (1.03-1.25); P < 0.01] than White patients. During the early COVID-19 pandemic, Northeast and Western region hospitals had higher odds of in-hospital mortality, lower odds of revascularization, longer length of stay, and higher total hospitalization costs than Midwest region hospitals. CONCLUSIONS: Our study disclosed disparities in AMI-related mortality and revascularization by sex, race and ethnic, and region during the early COVID-19 pandemic. Special attention should be given to at-risk populations. Whether these disparities continue in the post-vaccination era warrants further study.

Early Onset Atherosclerotic Cardiovascular Disease.

Recent trends indicate a concerning increase in early-onset atherosclerotic cardiovascular disease (ASCVD) among younger individuals (age < 55 in men and <65 in women). These findings highlight the pathobiology of ASCVD as a disease process that begins early in life and underscores the need for more tailored screening methods and preventive strategies. Increasing attention has been placed on the growing burden of traditional cardiometabolic risk factors in young individuals while also recognizing unique factors that mediate risk of premature atherosclerosis in this demographic such as substance use, socioeconomic disparities, adverse pregnancy outcomes, and chronic inflammatory states that contribute to the increasing incidence of early ASCVD. Additionally, mounting evidence has pointed out significant disparities in the diagnosis and management of early ASCVD and cardiovascular outcomes based on sex and race. Moving toward a more personalized approach, emerging data and technological developments using diverse tools such as polygenic risk scores and coronary artery calcium scans have shown potential in earlier detection of ASCVD risk. Thus, we review current evidence on causal risk factors that drive the increase in early ASCVD and highlight emerging tools to improve ASCVD risk assessment in young individuals.

Expanded genetic testing in familial hypercholesterolemia-A single center's experience.

Objective: Assess the yield of genetic testing for pathogenic variants in ABCG5, ABCG8, LIPA, and APOE in individuals with personal and family histories suggestive of familial hypercholesterolemia. Methods: Retrospective review of patients seen in the Advanced Lipid Disorders Clinic at Johns Hopkins. Results: In the lipid clinic at a single center during the years 2015-2023, 607 patients underwent genetic testing for familial hypercholesterolemia, of which 263 underwent the expanded genetic testing for sitosterolemia. Eighty-eight patients had genetic testing which included APOE, and 22 patients had testing which included LIPA. Among these, one patient was identified to have a pathogenic variant in APOE and another patient with a pathogenic variant in ABCG5 (0.7 % yield). The frequency of a positive result was double that of a variant of uncertain significance. Conclusion: These data suggest in rare cases expanded testing can provide answers for patients and families with a minimal likelihood of a variant of uncertain significance.

Dyslipidemia management in women of reproductive potential: An expert clinical consensus from the national lipid association.

Cardiovascular disease (CVD) is the leading cause of death among women and its incidence has been increasing recently, particularly among younger women. Across major professional society guidelines, dyslipidemia management remains a central tenet for atherosclerotic CVD prevention for both women and men. Despite this, women, particularly young women, who are candidates for statin therapy are less likely to be treated and less likely to achieve their recommended therapeutic objectives for low-density lipoprotein cholesterol (LDL-C) levels. Elevated LDL-C and triglycerides are the two most common dyslipidemias that should be addressed during pregnancy due to the increased risk for adverse pregnancy outcomes, such as preeclampsia, gestational diabetes mellitus, and pre-term delivery, as well as pancreatitis in the presence of severe hypertriglyceridemia. In this National Lipid Association Expert Clinical Consensus, we review the roles of nutrition, physical activity, and pharmacotherapy as strategies to address elevated levels of LDL-C and/or triglycerides among women of reproductive age. We include a special focus on points to consider during the shared decision-making discussion regarding pharmacotherapy for dyslipidemia during preconception planning, pregnancy, and lactation.

Nontraditional Risk Markers for Incident Coronary Artery Calcium Among Persons ≥65 Years of Age.

Background: The initiation of coronary artery calcium (CAC) is an important physiologic milestone associated with increased cardiovascular disease risk. However, traditional risk factors (RF) do not perform well for predicting incident CAC among the 54 million older U.S. adults. Objectives: The authors sought to assess the association between nontraditional cardiovascular disease RF and incident CAC in older persons. Methods: There were 815 MESA (Multi-Ethnic Study of Atherosclerosis) participants ≥65 years of age who had CAC = 0 at Visit 1 and a follow-up CAC scan. Multivariable adjusted Cox hazards ratios (aHR) and C-statistics were calculated to examine the association of nontraditional RF with incident CAC. Results: The mean age was 70.2 years and 67% were women. The median follow-up time to repeat CAC scan was 3.6 years (IQR: 2.6-9.2 years) and 45% of participants developed incident CAC. Albuminuria (aHR: 1.50, 95% CI: 1.07-2.09), carotid plaque (aHR: 1.32, 95% CI: 1.04-1.66), and thoracic aortic calcification (TAC) (aHR: 1.38, 95% CI: 1.10-1.75) were significantly associated with incident CAC, while higher levels of nontraditional RF including apolipoprotein-B, lipoprotein(a), high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide were not. When added to demographics, albuminuria, carotid plaque, and TAC provided a greater C-statistic improvement (+0.047, P = 0.004) vs all traditional RF combined (+0.033, P = 0.05). Conclusions: Among nontraditional RF and measures of subclinical atherosclerosis, only albuminuria, carotid plaque, and TAC were significantly associated with incident CAC in persons ≥65 years of age. Identification of albuminuria or extracoronary atherosclerosis may help guide the timing of repeat CAC scoring in older persons with baseline CAC = 0.

DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases.

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.

Association of aortic valve calcium with dementia and stroke: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Calcific aortic valve disease is associated with increased thrombin formation, platelet activation, decreased fibrinolysis, and subclinical brain infarcts. We examined the long-term association of aortic valve calcification (AVC) with newly diagnosed dementia and incident stroke in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: AVC was measured using non-contrast cardiac CT at Visit 1. We examined AVC as a continuous (log-transformed) and categorical variable (0, 1-99, 100-299, ≥300). Newly diagnosed dementia was adjudicated using International Classification of Disease codes. Stroke was adjudicated from medical records. We calculated absolute event rates (per 1000 person-years) and multivariable adjusted Cox proportional hazards ratios (HR). RESULTS: Overall, 6812 participants had AVC quantified with a mean age of 62.1 years old, 52.9 % were women, and the median 10-year estimated atherosclerotic cardiovascular disease (ASCVD) risk was 13.5 %. Participants with AVC >0 were older and less likely to be women compared to those with AVC=0. Over a median 16-year follow-up, there were 535 cases of dementia and 376 cases of stroke. The absolute risk of newly diagnosed dementia increased in a stepwise pattern with higher AVC scores, and stroke increased in a logarithmic pattern. In multivariable analyses, AVC was significantly associated with newly diagnosed dementia as a log-transformed continuous variable (HR 1.09; 95 % CI 1.04-1.14) and persons with AVC ≥300 had nearly a two-fold higher risk (HR 1.77; 95 % CI 1.14-2.76) compared to those with AVC=0. AVC was associated with an increased risk of stroke after adjustment for age, sex, and race/ethnicity, but not after adjustment for ASCVD risk factors. CONCLUSIONS: After multivariable adjustment, AVC >0 was significantly associated with an increased risk of newly diagnosed dementia, but not incident stroke. This suggests that AVC may be an important risk factor for the long-term risk of dementia beyond traditional ASCVD risk factors.

Association of endogenous sex hormone levels with tooth loss due to periodontitis in men and post-menopausal women: The multi-ethnic study of atherosclerosis.

AIM: To investigate the association between endogenous sex hormone levels and history of tooth loss related to periodontitis in healthy middle-aged to older men and post-menopausal women. METHODS: This cross-sectional study included 5649 participants aged 45-84 (mean age, 63 ± 10 years) from the Multi-Ethnic Study of Atherosclerosis cohort who had sex hormone levels measured and answered a questionnaire regarding perceived periodontal status at exam 1. Multivariable logistic regression was used to examine the association of sex hormones (exposure) with history of tooth loss (outcome), stratified by sex. RESULTS: Among post-menopausal women, higher free testosterone (per 1SD) was associated with a greater prevalence of tooth loss [OR 1.49 (95% CI, 1.08-2.05)], whereas higher sex hormone binding globulin (SHBG) was associated with a lower prevalence of tooth loss [OR 0.74 (0.58-0.94)], after adjustment for cardiometabolic risk factors and reproductive factors. In men, higher free testosterone and lower SHBG were associated with a lower prevalent probability of tooth loss in unadjusted analysis, but these associations lost significance after covariate adjustment. CONCLUSION: A higher androgenic sex hormone profile in post-menopausal women (i.e., increased free testosterone, lower SHBG) was associated with an increased prevalence of tooth loss, after adjusting cardiometabolic risk factors. No such association was found in men. These findings suggest that sex hormones may influence or serve as a marker for periodontal health.

Forecasting the Burden of Cardiovascular Disease and Stroke in the United States Through 2050-Prevalence of Risk Factors and Disease: A Presidential Advisory From the American Heart Association.

BACKGROUND: Cardiovascular disease and stroke are common and costly, and their prevalence is rising. Forecasts on the prevalence of risk factors and clinical events are crucial. METHODS: Using the 2015 to March 2020 National Health and Nutrition Examination Survey and 2015 to 2019 Medical Expenditure Panel Survey, we estimated trends in prevalence for cardiovascular risk factors based on adverse levels of Life's Essential 8 and clinical cardiovascular disease and stroke. We projected through 2050, overall and by age and race and ethnicity, accounting for changes in disease prevalence and demographics. RESULTS: We estimate that among adults, prevalence of hypertension will increase from 51.2% in 2020 to 61.0% in 2050. Diabetes (16.3% to 26.8%) and obesity (43.1% to 60.6%) will increase, whereas hypercholesterolemia will decline (45.8% to 24.0%). The prevalences of poor diet, inadequate physical activity, and smoking are estimated to improve over time, whereas inadequate sleep will worsen. Prevalences of coronary disease (7.8% to 9.2%), heart failure (2.7% to 3.8%), stroke (3.9% to 6.4%), atrial fibrillation (1.7% to 2.4%), and total cardiovascular disease (11.3% to 15.0%) will rise. Clinical CVD will affect 45 million adults, and CVD including hypertension will affect more than 184 million adults by 2050 (>61%). Similar trends are projected in children. Most adverse trends are projected to be worse among people identifying as American Indian/Alaska Native or multiracial, Black, or Hispanic. CONCLUSIONS: The prevalence of many cardiovascular risk factors and most established diseases will increase over the next 30 years. Clinical and public health interventions are needed to effectively manage, stem, and even reverse these adverse trends.

Regional Differences in the US in Outcomes with Preeclampsia.

This study explores preeclampsia outcomes across US regions and examines regional differences in specific preeclampsia-associated pregnancy complications and disease management. Patient-reported measures were obtained from The Preeclampsia Registry, an open-access database composed of women with at least one pregnancy diagnosed with a hypertensive disorder of pregnancy. Pregnancies and associated outcomes were stratified by US region (Northeast, Midwest, South and West). Among 2,667 pregnancies of which 92% were in White women, maximum systolic blood pressure at any time in pregnancy was highest among women in the South and Midwest (p=0.039). Furthermore, more women in the South received pre-pregnancy antihypertensives (p=0.026) and antenatal steroids (p=0.025) and delivered at an earlier gestational age (p=0.014) compared to women in other regions. Pregnancy complications such as elevated liver enzymes were higher in women in the South (p=0.019), and women in the South and West had additional end-organ damage such as renal complications (p<0.001) and hemolysis (p=0.008) as compared to women in other regions. Further investigation is needed to assess whether healthcare access or policy could be contributing to these regional discrepancies.

Has mortality in the United States returned to pre-pandemic levels? An analysis of provisional 2023 data.

BACKGROUND: The COVID-19 pandemic, which started in 2020, resulted in greater all-cause mortality in 2020 and in subsequent years. Whether all-cause mortality remains elevated in 2023 compared to pre-pandemic numbers is unknown. METHODS AND RESULTS: The United States (US) Center for Disease Control Wide-Ranging, Online Data for Epidemiologic Research database was used to compare mortality rates between 2019 and provisional data for 2022 and 2023. Age-adjusted mortality rates (AAMRs) for all-cause as well as top causes of mortality were collected. Mortality based on subgroups by sex, age, and ethnicity was also collected. All-cause AAMRs between 2018 and 2023 per 100,000 individuals were 723.6, 715.2, 835.4, 879.7, (provisionally) 798.8, and (provisionally) 738.3, respectively, with AAMRs in 2023 remaining above 2019 pre-pandemic levels. Similar trends were noted in subgroups based on sex, ethnicity, and most age groups. Mortality attributed directly to COVID-19 peaked in 2021 as the 3rd leading cause of death and dropped to the 10th leading cause in 2023. Provisional mortality rate trends for 2023 suggest that rates for diseases of the heart increased during the pandemic but appear to have returned to or dipped below pre-pandemic levels. CONCLUSION: Provisional 2023 all-cause mortality rates in the US have decreased from the 2021 peak associated with the COVID-19 pandemic but remain above the pre-pandemic baseline. Mortality from some conditions, including diseases of the heart, appears to have recovered from the impact of the COVID-19 pandemic.

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.