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Tag: Cardiology

  • Study highlights growing burden of neurological disorders worldwide

    Study highlights growing burden of neurological disorders worldwide

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    Globally, the number of people living with, or dying from, neurological conditions such as stroke, Alzheimer’s disease and other dementias, and meningitis has risen substantially over the past 30 years due to the growth and aging of the global population as well as increased exposure to environmental, metabolic, and lifestyle risk factors. In 2021, 3.4 billion people experienced a nervous system condition, according to a major new analysis from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, published in The Lancet Neurology journal.

    The analysis suggests that worldwide, the overall amount of disability, illness, and premature death-;a measurement known as disability-adjusted life years (DALYs)-;caused by neurological conditions increased by 18% over the past 31 years, rising from around 375 million years of healthy life lost in 1990 to 443 million years in 2021.

    The absolute number of DALYs is increasing in large part due to aging and growing populations worldwide. However, if the impact of demographics is removed through age-standardization, rates of DALYs and deaths caused by neurological conditions have declined by around a third (27% and 34% respectively) worldwide since 1990-;largely due to better awareness, vaccination, and global prevention efforts for some conditions such as tetanus (93% decrease in age-standardized rates of DALYs), meningitis (62% decrease), and stroke (39% decrease). 

    The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy (brain injury), migraine, Alzheimer’s disease and other dementias, diabetic neuropathy (nerve damage), meningitis, epilepsy, neurological complications from preterm birth, autism spectrum disorder, and nervous system cancers. Neurological consequences of COVID-19 (cognitive impairment and Guillain-Barré syndrome) ranked 20th, accounting for 2.48 million years of healthy life lost in 2021. 

    The most prevalent neurological disorders in 2021 were tension-type headaches (around 2 billion cases) and migraines (about 1.1 billion cases). Diabetic neuropathy is the fastest-growing of all neurological conditions.

    The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes.”


    Dr Liane Ong, co-senior author from the Institute for Health Metrics and Evaluation (IHME), University of Washington, USA

    The current study builds on previous GBD analyses [2] to provide the largest and most comprehensive analysis to compare the prevalence and burden (illness and death) of nervous system disorders between countries on a global scale between 1990 and 2021-;expanding the number of studied neurological conditions from 15 to 37 that span from birth to later life.

    To better reflect that neurological disorders can occur at any stage of life, for the first time the GBD 2021 Nervous System Disorders Collaborators studied neurodevelopmental disorders and neurological conditions in children, and found that they were responsible for almost a fifth (18%) of all DALYs in 2021, accounting for 80 million years of healthy life lost worldwide. 

    “Every country now has estimates of their neurological burden based on the best available evidence,” said lead author Dr Jaimie Steinmetz from IHME. “As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies.”

    The study, conducted to inform ongoing advocacy and awareness efforts, will support the WHO’s Intersectoral Global Action Plan on epilepsy and other neurological disorders 2022–2031 (IGAP) that aims to reduce the impact and burden of neurological disorders and improve the quality of life of people with neurological disorders as well as their caregivers and families.

    Over 80% of neurological deaths and health loss occur in low- and middle-income countries (LMICs)

    Overall, estimates reveal striking differences in nervous system burden between world regions and national income levels. In high-income Asia Pacific and Australasia – regions with the best neurological health – the rate of DALYs and deaths were under 3,000 and 65 per 100,000 people, respectively in 2021. In these regions, stroke, migraine, dementia, diabetic neuropathy, and autism spectrum disorders accounted for most health loss. 

    In contrast, in the worst-off regions of western and central sub-Saharan Africa, the rate of DALYs and deaths were up to five times higher (over 7,000 and 198 per 100,000 people respectively) in 2021, with stroke, neonatal encephalopathy (brain injury), dementia, and meningitis the biggest contributors to years of healthy life lost.

    “Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” said Dr. Tarun Dua, Unit Head of WHO’s Brain Health unit and one of the co-senior authors of the study. “Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries.”

    The authors highlight that, as of 2017, only a quarter of countries globally had a separate budget for neurological conditions, and only around half had clinical guidelines. What’s more, the medical personnel who care for people with neurological conditions are unevenly distributed around the world, with high-income countries having 70 times more neurological professionals per 100,000 individuals than LMICs.

    Prevention needs to be a top priority

    “Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” said co-lead author Dr Katrin Seeher, Mental Health Specialist at WHO’s Brain Health Unit. 

    The study quantified the proportion of nervous system burden that was potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability. 

    The analysis suggests that modifying 18 risk factors over a person’s lifetime-;most importantly high systolic blood pressure (57% of DALYs)-;could prevent 84% of global DALYs from stroke. 

    Additionally, estimates suggest that controlling lead exposure could reduce the burden of intellectual disability by 63%, while reducing high fasting plasma glucose to normal levels could reduce the burden of dementia by around 15%. 

    “The worldwide neurological burden is growing very fast and will put even more pressure on health systems in the coming decades,” said co-senior author Dr Valery Feigin, Director of Auckland University’s National Institute for Stroke and Applied Neuroscience in New Zealand. “Yet many current strategies for reducing neurological conditions have low effectiveness or are not sufficiently deployed, as is the case with some of the fastest-growing but largely preventable conditions like diabetic neuropathy and neonatal disorders. For many other conditions, there is no cure, underscoring the importance of greater investment and research into novel interventions and potentially modifiable risk factors.”

    “Nervous system conditions include infectious and vector-borne diseases and injuries as well as non-communicable diseases and injuries, demanding different strategies for prevention and treatment throughout life,” said Steinmetz “We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world.” 

    Despite these important findings, the authors note several limitations, including that, while they have done their best to capture all nervous system health loss, some conditions were left out because they could not isolate the neurological component, including infections such as HIV, which has a large impact in many parts of the world. And while the study uses the best available evidence, estimates are constrained by the quantity and quality of data, especially in LMICs.

    Writing in a linked Comment, Professor Wolfgang Grisold, President of the World Federation of Neurology, London, UK (who was not involved in the study) says, “This important new GBD report highlights that the burden of neurological conditions is greater than previously thought. In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging, because the effects on the individuals vary substantially.”

    Source:

    Journal reference:

    GBD 2021 Nervous System Disorders Collaborators. (2024). Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Neurology. doi.org/10.1016/s1474-4422(24)00038-3.

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  • New insights into cardiac structure and disease repair

    New insights into cardiac structure and disease repair

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    In a recent study published in the journal Nature, a large team of researchers from the United States (U.S.) used single-cell ribonucleic acid (RNA) sequencing combined with high-resolution fluorescence in situ hybridization to determine the identities of the various cell types that coordinate spatially to give rise to the complex morphological structure of the heart.

    Study: Spatially organized cellular communities form the developing human heart. Image Credit: beerkoff / ShutterstockStudy: Spatially organized cellular communities form the developing human heart. Image Credit: beerkoff / Shutterstock

    Background

    Each complex structure of the human heart has specific roles that contribute to efficient cardiac function, and the interruption of any of these functions can lead to congenital disabilities such as congenital heart disease in children and cardiac diseases such as valvulopathies and cardiomyopathies in adults. However, despite the critical role of the heart in the human body, the organization and function of the cardiac structures and how they interact with one another remain poorly understood.

    About the study

    In the present study, the researchers used a single-cell RNA sequencing (scRNAseq) approach along with multiplexed error-robust fluorescence in situ hybridization (MER-FISH). This strategy allowed them to combine single-cell transcriptomes and spatial biology and visualize, analyze, and quantify the RNA transcripts of a large number of genes from a single cell.

    They began by identifying the cell lineages that were part of the developing heart, which helped determine how the various cardiac cell types assemble into complex structures and coordinate to regulate the function of the human heart. The scRNAseq was conducted in replicates and analyzed for human hearts in various stages of growth, starting from nine weeks and going up to 16 weeks post-conception.

    The obtained single cells, over 140 million in number, were transcriptionally categorized into five cell compartments: cardiomyocytes, endothelial, mesenchymal, neuronal, and blood. Within these cell compartments, analysis of gene markers helped identify 12 cell classes, with subsequent clustering analyses identifying 39 populations and 75 subpopulations of cells.

    MER-FISH was then used to spatially map the heart cells and explore the cellular mechanisms through which the remodeling and morphogenesis of the heart, including the ventricular wall development, were directed. The organization of the cells identified using scRNAseq, especially during developmental periods such as the compaction of the myocardial wall, was explored using MER-FISH imaging.

    The study then aimed to decipher the assembly of these specific cardiovascular cells into the cellular neighborhoods that come together to form the multi-cell structures that contribute to heart function. The scientists also explored the organizational and cellular complexity of specific regions, such as the ventricles, by exploring the cells within the ventricles that were identified, isolated, and mapped using MER-FISH. Additionally, mouse models were used to interrogate the interactions between cells through in vivo experiments, and pluripotent stem cells from humans were used to evaluate the same in in vitro experiments.

    a, Left, schematic of experiment. Right, scRNA-seq identifies a diverse range of distinct cardiac cells that create the developing human heart as displayed by uniform manifold approximation and projection (UMAP) of ~143,000 cells. b, Schematic shows how 238 cardiac-cell-specific genes were spatially identified using MERFISH. Pseudo-coloured dots mark the location of individual molecules of ten specific RNA transcripts. c, Approximately 250,000 MERFISH-identified cardiac cells were clustered into specific cell populations as shown by UMAP and coloured accordingly in d. d, Identified MERFISH cells were spatially mapped across a frontal section of a 13 p.c.w. heart (left) and shown according to major cell classes (right). e, Joint embedding between MERFISH and age-matched scRNA-seq datasets enabled cell label transfer and MERFISH gene imputation. f, Co-occurrence heatmap shows the correspondence of cell annotations of MERFISH cells to those transferred from the 13 p.c.w. scRNA-seq dataset. g, Gene imputation performance was validated spatially by comparing normalized gene expression profiles of marker genes measured by MERFISH with the corresponding imputed gene expression profiles. Epi, epicardial; MV, mitral valve; P–RBC, platelet–red blood cell; TV, tricuspid valve. Scale bar, 250 µm (g). Illustration in a was created using BioRender (https://www.biorender.com).a, Left, schematic of experiment. Right, scRNA-seq identifies a diverse range of distinct cardiac cells that create the developing human heart as displayed by uniform manifold approximation and projection (UMAP) of ~143,000 cells. b, Schematic shows how 238 cardiac-cell-specific genes were spatially identified using MERFISH. Pseudo-coloured dots mark the location of individual molecules of ten specific RNA transcripts. c, Approximately 250,000 MERFISH-identified cardiac cells were clustered into specific cell populations as shown by UMAP and coloured accordingly in d. d, Identified MERFISH cells were spatially mapped across a frontal section of a 13 p.c.w. heart (left) and shown according to major cell classes (right). e, Joint embedding between MERFISH and age-matched scRNA-seq datasets enabled cell label transfer and MERFISH gene imputation. f, Co-occurrence heatmap shows the correspondence of cell annotations of MERFISH cells to those transferred from the 13 p.c.w. scRNA-seq dataset. g, Gene imputation performance was validated spatially by comparing normalized gene expression profiles of marker genes measured by MERFISH with the corresponding imputed gene expression profiles. Epi, epicardial; MV, mitral valve; P–RBC, platelet–red blood cell; TV, tricuspid valve. Scale bar, 250 µm (g). Illustration in a was created using BioRender (https://www.biorender.com).

    Results

    The findings revealed that various cardiac cell types belonged to specific subpopulations that were part of specific communities, with the functional specialization defined according to the anatomical region in which they were present and the cellular ecosystem. The cardiomyocyte lineages were the largest cell compartment identified using MER-FISH. The study also found that cells that belonged to non-cardiomyocyte cell compartments also underwent segregation into populations and subpopulations and contributed to the formation of specific structures and regions of the heart.

    Cardiomyocyte subpopulations in the ventricular regions exhibited an ability to construct complex laminal structures in the ventricular wall and form cellular communities with other subpopulations of cardiac cells. Furthermore, the in vivo and in vitro experiments conducted to understand the interactions between cells revealed that the spatial organization of subpopulations of cardiac cells during the morphogenesis of the ventricular wall was conducted through various signaling pathways.

    The study also found cardiac regions composed of spatially organized combinations of cell populations that segregated together, called cellular communities. These cellular communities varied in the number and types of cell populations, and within these communities, neighbors of each cardiac cell within a 150-micrometer radius were defined. These interacting populations of cells also had distinct cellular signaling pathways.

    Conclusions

    Overall, the study found that cardiomyocytes were the largest compartment of cell types in the developing heart, and all the cell types exhibited distinct structural and regional distributions in the heart. Specific cell populations also formed cellular communities in various combinations, with signaling pathways between the cell populations within the community defining their structure and function. The study helped in understanding the development of the complex structure of the human heart, providing potential avenues to treat structural heart diseases.

    Journal reference:

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  • Novel tool to predict a person’s risk for cardiovascular complications after bone marrow transplant

    Novel tool to predict a person’s risk for cardiovascular complications after bone marrow transplant

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    For thousands of Americans each year, a bone marrow transplant has the potential to cure diseases such as leukemias, lymphomas and immune deficiency disorders. While lifesaving, bone marrow transplants are taxing procedures that can affect various organs, including the cardiovascular system.

    With advances in medical science and improvement in protocols, more bone marrow transplants, also known as hematopoietic stem cell transplantation, are being offered to older patients, a population at greater risk of cardiovascular disease. 

    Researchers led by Michigan Medicine have not only determined the contemporary prevalence of cardiovascular complications after bone marrow transplant -; they developed a novel tool to predict a person’s risk for such problems following the procedure and help guide the pre-transplant process.

    “In the early era of bone marrow transplant, patients with heart disease were often excluded due to the cardiotoxicity of the conditioning regimens used at the time,” said Salim Hayek, M.D., adjunct professor of internal medicine-cardiology at U-M Medical School who specializes in cardio-oncology. 

    “Understanding the cardiovascular risks of modern bone marrow transplantation is crucial for selecting the right patients and to ensure that none are excluded unnecessarily. This is the first contemporary evidence that shows the risks associated with bone marrow transplant and how to assess a patient’s risk for cardiovascular complications-; which, taken together, can guide clinicians to ensure better outcomes for this procedure.”

    Cardiovascular risks after transplant 

    Hayek and his team built the Cardiovascular Registry in Bone Marrow Transplantation, known as CARE-BMT, which compiles data of patients who underwent transplant from both University of Michigan Health and Rush University. 

    In a study of over 3,300 people who had a bone marrow transplant between 2008 and 2019, 4.1% of patients experienced cardiovascular events within 100 days after the procedure, and 13.9% did so after 5 years. 

    The results are published in JACC Cardio-Oncology. 

    Rare complications

    Overall, cardiovascular complications during the hospitalization for bone marrow transplant were rare. The most common short and long term condition was atrial fibrillation, with 6.8% of patients diagnosed at the five-year mark, followed by 5.4% of patients experiencing heart failure. Severe cardiovascular complications, such as heart attack and stroke, were uncommon.

    Investigators also found that 16.4% of allogenic transplant recipients, those who received bone marrow from another donor, developed long term cardiovascular events after five years, compared to 12.1% of autologous recipients who had damaged bone marrow replaced with their own healthy blood stem cells.

    The landscape of bone marrow transplant has rapidly evolved over the last 20 years, with many improvements in the way patients are selected for and treated during bone marrow transplantation.


    Our cohort allowed us to re-evaluate the incidence of cardiovascular complications in patients who received more modern treatment.”


    Salim Hayek, M.D., adjunct professor of internal medicine-cardiology at U-M Medical School

    Patients with preexisting cardiovascular conditions, such as diabetes and coronary artery disease, were more likely to have complications in the long term but not during the transplant process. 

    “Determining who is at high and low risk of cardiovascular outcomes is crucial to help guide both the pre-transplant evaluation as well as the post-transplant management -; which is why we invested so much in creating a simple risk score that health care providers can use to identify these patients,” said first author Alexi Vasbinder, Ph.D., R.N., a post-doctoral fellow at the U-M Frankel Cardiovascular Center at the time the research was conducted. 

    Pre-bone marrow transplant risk cardiovascular score

    To develop such a tool, researchers used data from the CARE-BMT cohort. They created a simple points based risk score using clinical information that is easily accessible, including age and race, history of coronary artery disease or heart failure, and prior doses of cardiotoxic chemotherapy medications. 

    In an analysis of just over 2,400 adult patients, the final risk model, now known as the CARE-BMT risk score, identified a high risk group that accounted for over 30% of the patients. The five year cardiovascular complication rate was 31.9%; that rose to 55% at 10 years.

    The score performed equally well in allogeneic and autologous bone marrow transplant recipients, as well as in a separate cohort of over 900 patients from Rush University.

    Results are published in the Journal of the American Heart Association.

    “It’s a very simple score that can be easily calculated and implemented in any health care record,” Hayek said. 

    “This will be easy to replicate and use during evaluations before bone marrow transplant to guide referrals of high risk patients to cardiovascular specialists who can then optimize medical and lifestyle management of their conditions.”

    AHA scientific statement

    The two reports formed the basis of a scientific statement published by the American Health Association geared towards the cardiovascular management of patients undergoing bone marrow transplant. 

    The statement covers considerations during the four steps of hematopoietic stem cell transplantation : evaluation before transplant, conditioning therapy and transplant, immediate post-transplant period and long term survivorship. 

    “This innovative cardiac risk assessment tool significantly improves our ability to provide a safer path throughout treatment to our cell therapy recipients possessing cardiovascular comorbidities, which in turn will have a positive effect on long term recovery and quality of life,” said co-author John Maciejewski, M.D., Ph.D., bone marrow transplant physician at U-M Health and clinical assistant professor of internal medicine at U-M Medical School.

    Source:

    Michigan Medicine – University of Michigan

    Journal reference:

    Vasbinder, A., et al. (2023). Cardiovascular Events After Hematopoietic Stem Cell Transplant: Incidence and Risk Factors. JACC: CardioOncology. doi.org/10.1016/j.jaccao.2023.07.007.

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  • More women experience cardiovascular disease following a depression diagnosis than men

    More women experience cardiovascular disease following a depression diagnosis than men

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    People with depression face an increased risk of cardiovascular disease (CVD); however, more women experience CVD following a depression diagnosis than men, according to a new study published today in JACC: Asia. The study investigates the connection between depression and CVD, shedding light on potential mechanisms that contribute to its sex-based differences and underscoring the importance of tailoring CVD prevention and management strategies according to sex-specific factors. 

    Depression is the third leading cause of morbidity worldwide. Prior research shows that it is associated with a heightened risk of cardiovascular events, including myocardial infarction (MI), angina, stroke and CV mortality. Women with depression are at greater relative risk of developing heart-related negative health outcomes than men, but there is still controversy over the evidence on sex differences in the impact of depression on heart health and the mechanisms underlying this are not well understood. 

    The identification of sex-specific factors in the adverse effects of depression on cardiovascular outcomes may help in the development of targeted prevention and treatment strategies that address the specific CVD risks faced by depressed patients. A better understanding will allow healthcare providers to optimize care for both men and women with depression, leading to improved CVD outcomes for these populations.” 


    Hidehiro Kaneko, MD, assistant professor at the University of Tokyo in Japan and a corresponding author of the study

    Researchers in this study evaluated the association between depression and subsequent CVD events by conducting an observational cohort study using the JMDC Claims Database between 2005 and 2022. They identified 4,125,720 participants who met the study’s criteria. The median age was 44 (36-52) years, and 2,370,986 participants were men. Depression was defined as those clinically diagnosed before their initial health checkup. 

    Using standardized protocols, the study collected participant’s body mass index (BMI), blood pressure and fasting laboratory values at their initial health checkup. The primary outcome was a composite endpoint including MI, angina pectoris, stroke, heart failure (HF) and atrial fibrillation (AF). 

    Researchers analyzed the statistical significance of differences in clinical characteristics between participants with and without depression. Results indicate that the hazard ratio of depression for CVD was 1.39 in men and 1.64 in women compared with participants without depression. Models also indicate that hazard ratios of depression for MI, angina pectoris, stroke, HF, and AF were higher for women than for men. 

    Study authors highlight an important discussion regarding the potential mechanisms that may contribute to why depression impacts women’s heart health more than men’s. One explanation is that women may experience more severe and persistent symptoms of depression compared to men, and they may be more likely to have depression during critical periods of hormonal changes, such as pregnancy or menopause. 

    Other mechanisms include women’s greater susceptibility to traditional risk factors when depressed, such as hypertension, diabetes and obesity, which may contribute to the development of CVD. Differences in healthcare utilization and treatment between men and women and sex-specific differences in biological factors, such as genetics and hormonal profiles, may also increase women’s CVD risk. 

    “Our study found that the impact of sex differences on the association between depression and cardiovascular outcomes was consistent,” Kaneko said. “Healthcare professionals must recognize the important role of depression in the development of CVD and emphasize the importance of a comprehensive, patient-centered approach to its prevention and management. Assessing the risk of CVD in depressed patients and treating and preventing depression may lead to a decrease of CVD cases.” 

    Limitations of the study include the inability to establish direct causality between depression and cardiovascular events and the inability to accurately reflect the severity or duration of depressive symptoms. Potential confounding factors that may influence the association between depression and CVD were not accounted for, such as socioeconomic status. Researchers also acknowledge that COVID-19 may have been a confounder. 

    Source:

    American College of Cardiology

    Journal reference:

    Senoo, K., et al. (2024) Sex Differences in the Association Between Depression and Incident Cardiovascular Disease. JACC: Asia. doi.org/10.1016/j.jacasi.2023.11.015.

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  • Drug-coated balloon shows superiority in coronary in-stent restenosis treatment

    Drug-coated balloon shows superiority in coronary in-stent restenosis treatment

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    In the largest randomized clinical trial and first of its kind to date in the United States, a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) assessed the efficacy and safety of using a drug-coated balloon in patients undergoing coronary angioplasty. In an original investigation presented at the Cardiology Research Technology conference in Washington, D.C. and published simultaneously in JAMA, the team reports that patients treated with a balloon coated with paclitaxel, a drug to prevent restenosis, experienced lower rates of failure compared with patients treated with an uncoated balloon.

    The findings of the trial-;which was designed and conducted in consultation with the U.S. Food and Drug Administration (FDA) and funded by Boston Scientific Corp.-;suggest that the drug-coated balloon offers an effective treatment strategy for the management of coronary in-stent restenosis, or blockages recurring within previously placed stents. On March 1, the FDA approved the paclitaxel-coated balloon evaluated by the BIDMC-led team, representing the first such balloon to be approved for the treatment of coronary disease in the United States.

    Drug-coated balloons have emerged internationally as an alternative treatment option, but despite promising international data, they have not been previously evaluated or approved for use in the United States. Even with advances in stent technology, patients with coronary in-stent restenosis continue to comprise approximately 10 percent of individuals undergoing angioplasty interventions each year. In particular, patients with multiple prior stents have very poor long-term outcomes. There’s growing sentiment that drug-coated balloons could address an unmet clinical need among patients with coronary artery disease in the United States.”


    Robert W. Yeh, MD, MSc, MBA, lead investigator, director of the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology and section chief of Interventional Cardiology at BIDMC

    Each year, millions of people around the world undergo coronary angioplasty, a non-surgical intervention to treat blockages in the arteries that supply blood to the heart. In one variation of the procedure known as balloon angioplasty, a deflated balloon attached to a catheter is inserted into a narrowed artery. Once in position, the balloon is inflated, opening up the narrowed blood vessel and restoring blood flow to the heart. While balloon angioplasty is highly effective, five to ten percent of patients experience in-stent restenosis-;a re-narrowing of the treated artery and recurrence of symptoms that requires additional repair-;within a year of the procedure.

    The multicenter randomized trial, known as AGENT IDE, enrolled participants with in-stent restenosis, all of whom had high rates of coronary risk factors; more than half had diabetes and nearly 80 percent previously had two or more major coronary arteries partially or completely blocked. Among the 600 enrollees, 406 were randomized to receive the paclitaxel-coated balloon catheter and194 to receive an uncoated balloon catheter. Clinical follow-up was performed in hospital at 30 days, six months and 12 months following the procedure and will continue through five years.

    Participants were monitored for three primary endpoints: a relapse necessitating revascularization, or another procedure to restore blood flow in the blocked artery; myocardial infarction, or a heart attack caused by lack of blood flow to the heart; and sudden cardiac death.

    At one year out, Yeh and colleagues demonstrated that the drug-coated ballon was superior to an uncoated balloon with respect to the likelihood of patients experiencing one or more of these endpoints. Eighteen percent of participants in the experimental group experienced one or more of the primary endpoints, versus 29 percent in the control group. Similarly, those who received the drug-coated balloon were statistically significantly less likely to require revascularization (13 percent versus 25 percent) or have a myocardial infarction (6 percent versus 11) than those who received an uncoated balloon. The scientists saw no statistically significant difference in the rates of cardiac death between the two groups (3 percent versus 1.6 percent).

    “The participants in this trial represented a patient group at very high risk for recurrent restenosis,” said Yeh, who is also the Katz Silver Family Professor of Medicine in the Field of Outcomes Research in Cardiology at Harvard Medical School. “More than 40 percent of participants had multiple prior stents. Nevertheless, treatment with the drug-coated balloon had a consistent relative risk reduction and numerically greater absolute risk reduction in events. A drug-coated balloon may be particularly useful in the setting where additional stenting would result in three or more layers of stent which would limit future therapeutic options.”

    Co-authors included Richard Schlofmiz, MD, of Saint Francis Hospital; Jeffrey Moses, MD, and Ajay J. Kirtane, MD, SM, of Columbia University Irving Medical Center/New York Presbyterian Hospital and the Cardiovascular Research Foundation; William Bachinsky, MD, of University of Pittsburgh Medical Center; Suhail Dohad, MD, of Cedars Sinai Medical Center; Steven Rudick, MD, of Lindner Center for Research and Education at Christ Hospital; Robert Stoler, MD, at Baylor Scott & White Heart and Vascular Hospital; Brian K. Jefferson, MD, at HCA Tristar Centennial Medical Center; William Nicholson, MD, at Emory University Hospital; John Altman, MD, at Saint Anthony Hospital; Cinthia Bateman, MD, at South Denver Cardiology; Amar Krishnaswamy, MD, at Cleveland Clinic Foundation; J. Aaron Grantham, MD, at Saint Lukes Hospital of Kansas City; Frank J. Zidar, MD, at Austin Hart; Steven P. Marso, MD, at Overland Park Regional Medical Center; Jennifer A. Tremmel, MD, MS, at Stanford University Medical Center; Cindy Grines at Northside Hospital Cardiovascular Institute; Mustafa I. Ahmed, MD, at University of Alabama at Birmingham; Azeem Latib, MD, at Montefiore Medical Center Albert Einstein College of Medicine; Benham Tehrani, MD, and Wayne Batchelor, MD, at the Innova Schar Heart and Vascular Institute; J. Dawn Abbott, MD, at Lifespan Cardiovascular Institute, Rhode Island Hospital; Paul Underwood, MD, and Dominic J. Allocco, MD, Boston Scientific Corporation. This study was supported by Boston Scientific Corp. Quantitative coronary angiography was conducted by Baim Institute for Clinical Research, Inc, an independent angiographic core laboratory.

    Yeh reported receiving personal fees and grants from Boston Scientific during the conduct of this study; as well as grants and personal fees from Boston Scientific, Abbott, Vascular and Medtronic, and personal fees from the US Food and Drug Administration, Elixir Medical, Shockwave Medical and infrared X outside the submitted work. 

    Source:

    Beth Israel Deaconess Medical Center

    Journal reference:

    Yeh, R. W., et al. (2024). Paclitaxel-Coated Balloon vs Uncoated Balloon for Coronary In-Stent Restenosis: The AGENT IDE Randomized Clinical Trial. JAMA. doi.org/10.1001/jama.2024.1361.

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  • Reevaluating the role of direct oral anticoagulants in cardiovascular treatment

    Reevaluating the role of direct oral anticoagulants in cardiovascular treatment

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    Direct oral anticoagulants (DOACs) are a common treatment for patients with a wide variety of cardiovascular conditions. DOACs are the preferred treatment over vitamin K antagonists (VKAs) for many patients with atrial fibrillation or venous thromboembolism, since the latter would have a higher risk of intracranial bleeding and more complex dosing routine. However, new research suggests that DOACs should not be the first line of treatment for every patient who need to treat or prevent blood clots.

    A systematic overview from researchers at Brigham and Women’s Hospital, a founding member of Mass General Brigham, discusses the efficacy of DOACs compared to other treatment methods. This review utilized data from randomized controlled trials to compare DOACs with other treatment methods for various cardiovascular conditions. Although there is merit to using DOACs in many common conditions, the manuscript provides a robust summary of clinical trials indicating that DOACs fare worse in patients with mechanical heart valves, thrombotic antiphospholipid syndrome, atrial fibrillation associated with rheumatic heart disease, and patients with embolic stroke of unclear source. The authors also highlight clinical scenarios in which there is uncertainty, with a look toward future for better evidence generation.

    The results we reviewed here have significant implications for optimizing anticoagulation therapy and improving patient outcomes in clinical practice. There is a critical need for further research regarding why DOACs are less efficacious or safe than the standard of care in certain scenarios.”


    Behnood Bikdeli, MD, MS, of the Brigham’s Heart and Vascular Center

    Source:

    Brigham and Women’s Hospital

    Journal reference:

    Bejjani, A., et al. (2024). When Direct Oral Anticoagulants Should Not Be Standard Treatment. Journal of the American College of Cardiology. doi.org/10.1016/j.jacc.2023.10.038.

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  • Genetic variants influence blood pressure from early in life

    Genetic variants influence blood pressure from early in life

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    Certain genes associated with hypertension affect blood pressure from early in life, and they increase the risk of cardiovascular disease as you get older. However, you can do something about it.

    We are talking about really small differences, so small that they may fall within what is considered normal blood pressure. The problem is that they tend to last your whole life.” 


    Karsten Øvretveit, PhD Candidate at the Norwegian University of Science and Technology’s (NTNU) Department of Public Health and Nursing

    He is one of the researchers behind a new study that has looked at the relationship between gene variants and blood pressure in the population.

    The study shows that high blood pressure occurs in all age groups and that it is related to hereditary factors.

    “We found that genetic factors affect blood pressure from the first years of childhood and throughout your entire life,” says Øvretveit.

    Genetic data from large population studies

    High blood pressure is the main cause of heart attacks and strokes, and cardiovascular disease is the second most common cause of death in Norway, accounting for 23 per cent of all deaths in 2022.

    The direct medical cause of high blood pressure is unknown in many cases, but research shows that our genes play a signifcant role.

    “Lifestyle diseases are often caused by a combination of heredity and environment. Diseases are often the result of not only one, but very many genetic variants,” says Øvretveit.

    In order to find out how much a person is at risk of high blood pressure, researchers have used genetic data from large population studies. This has helped them develop a genetic risk score, which indicates how much your exact genetic makeup puts you at risk.

    Developing genetic risk scores

    Put very simply, a certain value is placed on each gene variant, which reflects the extent to which it can affect blood pressure. The variants are then “weighted”, i.e. some genes weigh more heavily than others, and the genetic risk score is then the sum of the genetic effects.

    “This is how people who are particularly at risk can be identified, and measures can be taken at an early stage before the condition is expressed.

    By keeping their blood pressure alow level, people with a high genetic risk score can achieve a lower risk of disease than people diagnosed with high blood pressure who we consider genetically protected,” says Øvretveit.

    To study the significance of the genetic risk, the researchers have used health data from participants in the HUNT Study from Trøndelag and from the British ‘Children of the 90s’ study. The latter includes health data from nearly 14,000 children from the time they were born until they were in their twenties. The Health Survey in Trøndelag (HUNT) is a large, Norwegian population-based health survey that includes health information and biological material from the inhabitants of Trøndelag. Since the first collection round in 1984, 250,000 people from Trondheim have participated.

    By comparing the blood pressure of the children who had the highest genetic risk with the children who were lowest on the scale, the researchers were able to see how the average blood pressure in the first group was higher from as early as the age of three. The difference lasted throughout their childhood and became more pronounced in adulthood.

    Difference increases with age

    “Although the differences in blood pressure are not very large, the time component is important. If your blood pressure is slightly elevated over many years, it will affect how prone you are to cardiovascular disease and kidney disease,” says Øvretveit.

    When the researchers compared the risk scores and health data of the HUNT Study participants, they saw that the differences in blood pressure between the participants with the highest and those with the lowest risk persisted throughout their whole lives.

    “We have been able to follow the same people from when they were around 37 until they were approximately 70 years old. We found that the differences persisted and resulted in various disease risks, where the differences in disease were quite large.”

    The researchers also found more positive results: if measures are taken, such as lifestyle changes and medications, the risk of disease can be significantly reduced.

    “By keeping their blood pressure at a low level, people with a high genetic risk score can achieve a lower risk of disease than people diagnosed with high blood pressure who we consider genetically protected. It seems that controlling your blood pressure matters more than genetics,” says Øvretveit.

    Large population studies provide good data

    As a basis for the study, Øvretveit and colleagues have used findings from the largest genetic study on blood pressure currently available, which includes data from over a million people. Øvretveit believes the study shows the possibilities that lie in genetic data from large population studies.

    “I don’t think you should start measuring blood pressure in every single child, but the type of data we have used in this study can be used in the future not only to prevent disease, but also to address the risk factors associated with a disease,” says Øvretveit.

    Is it a problem that Europeans are overrepresented in population studies?

    “Yes, it is, but we are now actively working on developing genetic risk scores that are adapted to other populations, and that can be used across many different populations,” says Øvretveit.

    To date, the researchers have identified around 1500 gene variants that have a clear connection with blood pressure, but the biological effect that many of these genes have on blood pressure is not known. In order to find a reliable method, the researchers had to identify high-risk combinations of gene variants and combinations that posed a lower risk through a process of trial and error. 

    “A common method for creating a risk score for genetic disease is to include only those gene variants that are known to have a strong connection with the disease,” says Øvretveit.

    But there are other methods such as including gene variants that produce effects we are more uncertain about. As a result, we get a lot more data in the calculation. 

    “Complex blood pressure traits may be affected by far more gene variants than we have identified so far. The methods we have developed allow this to be taken into account, but we also have to keep in mind that the individual effects of these variants are small,” says Øvretveit.

    The method that gave the most accurate risk score included over a million gene variants.

    “But there are far more that have a known connection with high blood pressure,” says Øvretveit.

    Source:

    Norwegian University of Science and Technology

    Journal reference:

    Øvretveit, K., et al. (2023). Polygenic risk scores associate with blood pressure traits across the lifespan. European Journal of Preventive Cardiology. doi.org/10.1093/eurjpc/zwad365.

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  • Study identifies optimal daily steps for heart failure prevention in older women

    Study identifies optimal daily steps for heart failure prevention in older women

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    The science is clear that movement is good for our bodies as we age. But just how much physical activity is beneficial for people over 60? A new study from the University at Buffalo provides an answer, and it’s not 10,000 steps per day.

    In fact, the study -; published Feb. 21 in JAMA Cardiology -; of nearly 6,000 U.S. women aged 63-99 reports that, on average, 3,600 steps per day at a normal pace was associated with a 26% lower risk of developing heart failure.

    The observational study from the Women’s Health Initiative specifically looked at accelerometer-measured physical activity, sedentary time and heart failure risk. There were 407 heart failure cases -; confirmed by physicians -; identified during a mean follow-up of 7.5 years.

    The risk of developing heart failure was, on average, 12% and 16% lower for each 70 minutes per day spent in light intensity activities and each 30 minutes per day spent in moderate-to-vigorous intensity, respectively. To the contrary, each hour-and-a-half of sedentary time was associated, on average, with a 17% higher risk of experiencing heart failure.

    In ambulatory older women, higher amounts of usual daily light and moderate intensity activities were associated with lower risk of developing heart failure with preserved ejection fraction independent of demographic and clinical factors associated with heart failure risk. Accumulating 3,000 steps per day might be a reasonable target that would be consistent with the amount of daily activity performed by women in this study.”


    Michael J. LaMonte, PhD, study’s lead author, research professor of epidemiology and environmental health in UB’s School of Public Health and Health Professions

    Study participants wore an accelerometer on their hip for up to seven consecutive days, except for when in water. Light physical activity included usual daily activities like self-care, chores around the house and caregiving, while moderate to vigorous activity involved walking at a normal pace, climbing the stairs or doing yard work.

    The study is unique in that it looked at two subtypes of heart failure, the most common of which is heart failure with preserved ejection fraction, often abbreviated as HFpEF. A similar pattern of lower risk with more light and moderate intensity daily activity, and higher risk with prolonged sedentary time, was seen for HFpEF.

    “This is a major, unique finding of our study because there is very little published data on physical activity and HFpEF, so we are providing new information upon which other studies can build,” LaMonte says.

    “More importantly, HFpEF is the most common form of heart failure seen in older women and among racial and ethnic minority groups, and at present there are few established treatment options, which makes primary prevention all the more relevant for HFpEF. The potential for light intensity activities of daily life to contribute to the prevention of HFpEF in older women is an exciting and promising result for future studies to evaluate in other groups, including older men,” LaMonte adds.

    The team’s evaluation of the number of steps per day as an approach to quantifying and translating the favorable results for physical activity was also novel, says LaMonte.

    Encouraging older adults to be more active as part of healthy aging is sound advice well-supported by scientific evidence.

    “However, conveying how much activity is always a challenge to incorporate as part of clinical and public health recommendations,” says LaMonte. “Steps per day is easily understood and can be measured by a variety of consumer-level wearable devices to help people monitor their physical activity levels.”

    In this study, the risk of heart failure, including HFpEF, became significantly lower at around 2,500 steps per day. When standardized to 3,600 steps per day (1 standard deviation unit), there was a 25-30% lower risk of heart failure and HFpEF.

    The study’s findings come at a time when the U.S. government is examining its physical activity guidelines for older adults, particularly a target number of steps per day. The steps per day associated with lower heart failure risk cited in the study are far fewer than the often recommended 10,000 steps for health and wellness.

    For perspective, the average number of steps per day among women in the study was 3,588. The average among U.S. women of similar age is 2,340.

    “It appeared that intensity of stepping did not influence the lower risk of heart failure as results were comparable for light intensity steps and for more vigorous steps,” says LaMonte.

    “Our results showing heart failure prevention in older women might be enhanced through walking around 3,000 steps or so per day at usual pace is very relevant given the current emphasis at the federal level on identifying an amount of daily physical activity that can be referenced against steps per day for cardiovascular health and resilience to incorporate in future public health guidelines.”

    Researchers from the University of California San Diego, University of North Carolina at Chapel Hill, Fred Hutchinson Cancer Center, Stanford University, and Brown University contributed to the study.

    Source:

    Journal reference:

    LaMonte, M. J., et al. (2024). Accelerometer-Measured Physical Activity, Sedentary Time, and Heart Failure Risk in Women Aged 63 to 99 Years. JAMA Cardiology. doi.org/10.1001/jamacardio.2023.5692.

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  • Women gain more health benefits from exercise than men

    Women gain more health benefits from exercise than men

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    In a recent study published in the Journal of the American College of Cardiology, researchers investigated the sex-specific all-cause and cardiovascular mortality risk reductions derived from physical activity. They used a large (n = 412,313) cohort American cohort to identify this association and found that women derived greater benefits than their male counterparts from equivalent amounts of physical activity.

    Historically, however, women have generally lagged men in exercise engagement. These findings may help inform clinicians and the health-minded of the advantages of physical exercise in combatting chronic cardiovascular disease (CVD) and bridge observed “gender gaps” by encouraging women to take up leisure-time physical activity.

    Study: Sex Differences in Association of Physical Activity With All-Cause and Cardiovascular Mortality.

    Study: Sex Differences in Association of Physical Activity With All-Cause and Cardiovascular Mortality.

    The gender gap and what this means for sex-specific cardiac health

    Cardiovascular mortality remains one of the leading causes of global human loss of life, alarmingly a likely underestimation when considering that cardiovascular disease (CVD) is a commonly reported comorbidity in numerous non-transmissible and transmissible pathologies. Decades of research have revealed that physical activity (PA) can substantially reduce all-cause and cardiovascular mortality, but records reveal that public involvement in leisure time PA is sorely lacking.

    In the United States of America (US) alone, fewer than 25% of citizens meet the minimum PA recommendations of 150 min/wk. of moderate PA or 75 min/wk. of vigorous PA prescribed by the US Centers for Disease Control and Prevention (CDC) and the American College of Cardiology. Significant inter-sex differences in PA engagement further skew these already suboptimal observations – a substantially larger proportion of men are known to engage in leisuretime PA than women, which, when combined with differences in physiological responses, exercise capacities, and activity tolerances between the sexes, might result in significantly different mortality outcomes between these cohorts.

    Unfortunately, the empirical outcomes of these “gender gaps” between men and women have never been tested within a scientific framework, denying clinicians, policymakers, and the health conscious of the information they need to optimize PA-related outcomes. Understanding the role of sex in these associations would allow for improved guidelines aimed at bridging the gender gap, fostering increased female PA engagement, and reducing overall mortality risk.

    About the study

    In the present study, researchers aimed to elucidate if PA-derived health benefits differ depending on the sex of the PA-engaging individual. Their cohort was derived from the National Health Interview Survey (NHIS), a large-scale collaboratory effort carried out by the CDC and the National Center for Health Statistics. Established in 1957, the NHIS is a prospective cohort maintaining health records of Americans across 50 states and the District of Columbia, representing a proxy for America’s health.

    The current study used participant data from 1997 to 2017 and was initially comprised of 646,279 individuals. Excluding participants with severe cardiovascular conditions (e.g., coronary heart disease), cancers, or missing demographic or medical data resulted in a final cohort of 412,413 adults. Data collection included demographic and medical information (from the NHIS database) and a consistent, standardized questionnaire for PA frequency, duration, and type assessment, presented at both baseline and follow-up evaluations.

    Cox proportional hazard regression models corrected from demographic and clinical covariates were used to assess primary outcomes. Likelihood ratio tests were used to compute sex-specific differences in outcome estimates.

    Study findings

    Demographic data collation revealed that 54.7% of included participants were women, more than 68% of whom were of White ethnicity. The average age of the study cohort was 43.9 years, and the study collected a total of 4,911,178 person-years of follow-up data. During the course of the study, 39,935 participants died from all causes, 11,670 of which were cardiovascular.

    Previously observed discrepancies in sex-specific PA engagement were validated in this study, with only 32.5% of women engaging in weekly aerobic PA compared to 43.1% of male participants. Every PA metric measured in the survey revealed greater male engagement than female, with 15.2% of men achieving the prescription weekly PA goal of 150 min/wk. In contrast, only 10.3% of women met this goal.

    However, hazard analyses present that the few women who do engage in physical activity derive far greater relative health benefits than their male counterparts. Compared to inactivity, female PA engagement results in a 24% risk reduction (all-cause mortality), while equivalent PA engagement in men only decreased their mortality risk by 15%.

    “In dose-dependent analyses for the entire cohort, the benefit of PA on all-cause mortality peaked at ∼300 min/wk of MVPA and then plateaued. The greatest mortality benefit in men was achieved at 300 min/wk of MVPA with an 18% lower hazard in all-cause mortality. Women derived a similar magnitude of benefit at 140 min/wk of MVPA, and continued to benefit with increasing min/wk of MVPA until the greatest benefit of 24% lower hazard (HR: 0.76; 95% CI: 0.72-0.80) was achieved at ∼300 min/wk.”

    While these findings do require validation in non-American cohorts, where observed results, especially those pertaining to engagement, might vary drastically from those observed herein, this study highlights the profound benefits of PA engagement for both sexes and may play a crucial role in motivating traditionally hesitant women to take up these activities given the health rewards they provide.

    Journal reference:

    • Ji, H., Gulati, M., Huang, T. Y., Kwan, A. C., Ouyang, D., Ebinger, J. E., Casaletto, K., Moreau, K. L., Skali, H., & Cheng, S. (2024). Sex Differences in Association of Physical Activity With All-Cause and Cardiovascular Mortality. Journal of the American College of Cardiology, 83(8), 783-793, DOI – 10.1016/j.jacc.2023.12.019,  https://www.sciencedirect.com/science/article/pii/S0735109723083134?via%3Dihub

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  • Women reap greater health benefits from exercise than men

    Women reap greater health benefits from exercise than men

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    Women who exercise regularly have a significantly lower risk of an early death or fatal cardiovascular event than men who exercise regularly, even when women put in less effort, according to a National Institutes of Health-supported study. The findings, published in the Journal of the American College of Cardiology, are based on a prospective analysis of data from more than 400,000 U.S. adults ages 27-61 which showed that over two decades, women were 24% less likely than those who do not exercise to experience death from any cause, while men were 15% less likely. Women also had a 36% reduced risk for a fatal heart attack, stroke, or other cardiovascular event, while men had a 14% reduced risk. 

    We hope this study will help everyone, especially women, understand they are poised to gain tremendous benefits from exercise. It is an incredibly powerful way to live healthier and longer. Women on average tend to exercise less than men and hopefully these findings inspire more women to add extra movement to their lives.” 


    Susan Cheng, M.D., cardiologist and the Erika J. Glazer Chair in Women’s Cardiovascular Health and Population Science in the Smidt Heart Institute at Cedars-Sinai, Los Angeles

    The researchers found a link between women experiencing greater reduced risks for death compared to men among all types of exercise. This included moderate aerobic activity, such as brisk walking; vigorous exercise, such as taking a spinning class or jumping rope; and strength training, which could include body-weight exercises.

    Scientists found that for moderate aerobic physical activity, the reduced risk for death plateaued for both men and women at 300 minutes, or five hours, per week. At this level of activity, women and men reduced their risk of premature death by 24% and 18% respectively. Similar trends were seen with 110 minutes of weekly vigorous aerobic exercise, which correlated with a 24% reduced risk of death for women and a 19% reduced risk for men.

    Women also achieved the same benefits as men but in shorter amounts of time. For moderate aerobic exercise, they met the 18% reduced risk mark in half the time needed for men: 140 minutes, or under 2.5 hours, per week, compared to 300 minutes for men. With vigorous aerobic exercise, women met the 19% reduced risk mark with just 57 minutes a week, compared to 110 minutes needed by men.

    This benefit applied to weekly strength training exercises, too. Women and men who participated in strength-based exercises had a 19% and 11% reduced risk for death, respectively, compared to those who did not participate in these exercises. Women who did strength training saw an even greater reduced risk of cardiovascular-related deaths – a 30% reduced risk, compared to 11% for men. 

    For all the health benefits of exercise for both groups, however, only 33% of women and 43% of men in the study met the standard for weekly aerobic exercise, while 20% of women and 28% of men completed a weekly strength training session.

    “Even a limited amount of regular exercise can provide a major benefit, and it turns out this is especially true for women,” said Cheng. “Taking some regular time out for exercise, even if it’s just 20-30 minutes of vigorous exercise a few times each week, can offer a lot more gain than they may realize.”

    “This study emphasizes that there is no singular approach for exercise,” said Eric J. Shiroma, Sc.D., a program director in the Clinical Applications and Prevention branch at the National Heart, Lung, and Blood Institute (NHLBI). “A person’s physical activity needs and goals may change based on their age, health status, and schedule – but the value of any type of exercise is irrefutable.”

    The authors said multiple factors, including variations in anatomy and physiology, may account for the differences in outcomes between the sexes. For example, men often have increased lung capacity, larger hearts, more lean-body mass, and a greater proportion of fast-twitch muscle fibers compared to women. As a result, women may use added respiratory, metabolic, and strength demands to conduct the same movement and in turn reap greater health rewards.

    The Physical Activity Guidelines for Americans recommend adults get at least 2.5-5 hours of moderate-intensity exercise or 1.25-2.5 hours of vigorous exercise each week, or a combination of both, and participate in two or more days a week of strength-based activities.

    Source:

    NIH/National Heart, Lung and Blood Institute

    Journal reference:

    Ji, H., et al. (2024) Sex Differences in Association of Physical Activity With All-Cause and Cardiovascular Mortality. Journal of the American College of Cardiology. doi.org/10.1016/j.jacc.2023.12.019.

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