literature review on cardiovascular disease

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Cardiovascular diseases articles within Nature Reviews Cardiology

Review Article | 28 August 2024

Pathophysiological insights into HFpEF from studies of human cardiac tissue

The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains poorly understood. In this Review, Redfield and colleagues highlight the importance of studying human cardiac tissue in HFpEF, discuss sources, challenges and methods for studying human myocardial samples, summarize pathophysiological insights derived from studies of human myocardium in HFpEF and outline knowledge gaps to guide future research.

• Ahmed U. Fayyaz
• , Muhammad Eltony
•  &  Margaret M. Redfield

Research Highlight | 07 August 2024

Stroke triggers an innate immune memory that drives cardiac dysfunction

Acute ischaemic stroke induces persistent innate immune memory through epigenetic changes in myeloid progenitors in the bone marrow, and this innate immune training contributes to cardiac remodelling and dysfunction in the long term, according to a new study.

• Irene Fernández-Ruiz

Review Article | 07 August 2024

Mechanisms and treatment of pulmonary arterial hypertension

In this Review, Ghofrani and colleagues discuss the mechanisms underlying the development of pulmonary arterial hypertension, provide an overview of approved therapies and describe the predominantly non-vasodilatory drugs that are currently being tested in clinical trials.

• Hossein-Ardeschir Ghofrani
• , Mardi Gomberg-Maitland
•  &  Friedrich Grimminger

Research Highlight | 29 July 2024

Potential new therapeutic target for HFpEF

A new small-molecule inhibitor of vasohibins reduces myocardial stiffness and improves diastolic relaxation in a rat model of HFpEF.

Review Article | 25 July 2024

Epidemiology of cardiometabolic health in Latin America and strategies to address disparities

Cardiovascular diseases are the leading cause of death in Latin America and the Caribbean (LAC), precipitated by the unique milieu of population growth, rapid urbanization, socioeconomic disparities and prevalent cardiometabolic risk factors. Brant and colleagues summarize trends in cardiometabolic health in LAC and discuss tailored, innovative solutions to address the growing burden of disease in the region.

• Luisa C. C. Brant
• , J. Jaime Miranda
•  &  Antonio Luiz P. Ribeiro

Roadmap | 22 July 2024

Standardization and clinical applications of retinal imaging biomarkers for cardiovascular disease: a Roadmap from an NHLBI workshop

In this Roadmap arising from an NHLBI workshop, Chew and colleagues explore the use of retinal imaging biomarkers for the prediction, diagnosis and monitoring of systemic cardiovascular diseases. The authors identify knowledge gaps and research opportunities to translate retinal imaging biomarkers into clinical practice.

• Emily Y. Chew
• , Stephen A. Burns
•  &  Young S. Oh

Review Article | 19 July 2024

Functional control of myosin motors in the cardiac cycle

Contraction of the heart is driven by cyclical interactions between myosin and actin filaments driven by ATP hydrolysis. In this Review, Irving summarizes the basal cardiac cycle of the healthy human heart at the ventricular, cellular, sarcomeric, and molecular levels and the implications for the development of novel therapies for heart disease.

• Malcolm Irving

Review Article | 17 July 2024

Dietary patterns to promote cardiometabolic health

Various dietary patterns have been proposed to improve cardiometabolic health. In this Review, Pagidipati et al. emphasize the commonalities between recommendations on what to eat (Mediterranean, Dietary Approaches to Stop Hypertension and low-carbohydrate or ketogenic diets) and the possible benefits of time-restricted eating and intermittent fasting.

• Neha J. Pagidipati
• , Pam R. Taub
•  &  Carol F. Kirkpatrick

Review Article | 15 July 2024

Cardiac involvement in Chagas disease and African trypanosomiasis

Infection with Trypanosoma spp. can cause Chagas disease or human African trypanosomiasis. In this Review, Sabino and colleagues discuss the effects of these infections on the heart, with particular emphasis on the pathogenesis, diagnosis and treatment of Chagas cardiomyopathy.

• Ester Cerdeira Sabino
• , Maria Carmo P. Nunes

Review Article | 10 July 2024

Consequences of ionizing radiation exposure to the cardiovascular system

In this Review, Wu and co-workers describe the consequences of radiation exposure on the cardiovascular system, drawing insights from individuals exposed to whole-body radiation (including nuclear and medical workers) and from patients with cancer undergoing radiation therapy.

• James W. S. Jahng
• , Mark P. Little
•  &  Joseph C. Wu

Review Article | 05 July 2024

The LDL cumulative exposure hypothesis: evidence and practical applications

In this Review, Catapano and colleagues discuss the evidence supporting the LDL cumulative exposure hypothesis and how measuring cumulative LDL exposure can be used to estimate risk and contribute to the prevention of atherosclerotic cardiovascular disease.

• Brian A. Ference
• , Eugene Braunwald
•  &  Alberico L. Catapano

Review Article | 27 June 2024

Autoimmune diseases and atherosclerotic cardiovascular disease

In this Review, Porsch and Binder discuss the evidence for and mechanisms of the increased and premature risk of atherosclerotic cardiovascular disease in patients with autoimmune disease, with particular focus on systemic lupus erythematosus and rheumatoid arthritis.

• Florentina Porsch
•  &  Christoph J. Binder

Review Article | 26 June 2024

Global epidemiology of heart failure

In this Review, Khan and colleagues explore the evolving global epidemiology of heart failure (HF), focusing on changes in incidence and prevalence across the spectrum of left ventricular ejection fraction. The authors highlight the disparities in our understanding of HF epidemiology in low-income and middle-income countries, affirming the need for improved surveillance and resource allocation in vulnerable areas and populations.

• Muhammad Shahzeb Khan
• , Izza Shahid
•  &  Javed Butler

Clinical Outlook | 25 June 2024

Pulsed-field ablation: a revolution in atrial fibrillation therapy

The advent of pulsed-field ablation — a series of ultra-rapid, high-energy pulses that result in non-thermal cell death via electroporation — is revolutionizing the field of atrial fibrillation ablation. Data on first iterations of the technology indicate that safety and efficacy are at least similar to that of thermal ablation but with meaningfully shorter procedure duration.

• Leonid Maizels
•  &  Jonathan M. Kalman

Tools of the Trade | 19 June 2024

Suture-to-scan: ultrasonography-guided induction of heart injury

In this Tools of the Trade article, Berkeley and Thomson describe the use of a minimally invasive strategy to standardize the induction of myocardial infarction in mice.

• Bronwyn Berkeley
•  &  Adrian Thomson

Research Highlight | 12 June 2024

Epigenetic changes in HSCs contribute to HF and comorbidities

Findings from a new study published in Science Immunology suggest that epigenetic changes in haematopoietic stem cells promote the production of pro-inflammatory macrophages and influence their capacity to generate protective macrophage subsets.

• Karina Huynh

Research Highlight | 07 June 2024

RNA interference lowers triglyceride levels

Data from the phase IIb MUIR and ARCHES-2 trials show that RNA interference approaches that target either apolipoprotein C-III or ANGPTL3 significantly reduce plasma triglyceride levels in patients with mixed hyperlipidaemia.

• Gregory B. Lim

Review Article | 30 May 2024

Metabolic remodelling in atrial fibrillation: manifestations, mechanisms and clinical implications

In this Review, the authors describe the changes in metabolism that predispose individuals to developing atrial fibrillation (AF) and highlight the potential of available and emerging therapeutic strategies that target metabolic remodelling to treat AF.

• , Julius Ryan D. Pronto
•  &  Niels Voigt

Research Highlight | 29 May 2024

A distinct platelet differentiation pathway is involved in age-related thrombocytosis

Poscablo and colleagues identify a distinct haematopoietic platelet differentiation pathway that is enriched in ageing mice, which results in platelets that are hyper-reactive compared with canonical platelet populations.

Research Highlight | 28 May 2024

Bariatric metabolic surgery more effective than GLP1R agonists in preventing congestive HF

In patients with type 2 diabetes mellitus and obesity, bariatric metabolic surgery is associated with a lower risk of the incidence of first-ever congestive heart failure than treatment with glucagon-like peptide 1 receptor agonists, according to a new study.

Aficamten reduces symptoms in obstructive hypertrophic cardiomyopathy

Data from the SEQUOIA-HCM trial show that aficamten, a cardiac myosin inhibitor, increases exercise capacity and improves quality of life in patients with symptomatic obstructive hypertrophic cardiomyopathy.

Research Highlight | 21 May 2024

Artificially transplanted mitochondria in endothelial cells promote mitophagy

A study in Nature describes a single-cell-type strategy for vascular cell therapies that involves the artificial transplantation of mitochondria to endothelial cells, which promotes mitophagy and facilitates the formation of functional vessels in ischaemic tissue without the need for mesenchymal stromal cell support.

Research Highlight | 20 May 2024

Bile acid receptor protects against diabetic cardiomyopathy

Activation of the bile acid receptor TGR5 inhibits CD36-mediated fatty acid uptake in cardiomyocytes and protects against cardiac lipotoxicity and the development of diabetic cardiomyopathy in mice, according to a new study.

Review Article | 15 May 2024

Efferocytosis in atherosclerosis

In this Review, Adkar and Leeper describe the mechanisms of programmed cell death and efferocytosis, discuss how efferocytosis becomes impaired in atherosclerosis and other cardiometabolic diseases, and suggest potential strategies to target these pathways for the treatment of atherosclerotic cardiovascular disease.

• Shaunak S. Adkar
•  &  Nicholas J. Leeper

Perspective | 07 May 2024

Illusion of revascularization: does anyone achieve optimal revascularization during percutaneous coronary intervention?

In 1993, Lincoff and Topol claimed that the thrombolytic treatment of ST-segment elevation myocardial infarction was suboptimal in many patients and gave an ‘illusion of reperfusion’. In this Perspective article, the authors propose that a similar illusion of revascularization exists for contemporary percutaneous revascularization in patients with coronary artery disease and ischaemia, and identify how outcomes might be improved.

• Simone Fezzi
• , Daixin Ding
•  &  William Wijns

Research Highlight | 03 May 2024

No benefit of apoA-I infusion after myocardial infarction

In the AEGIS-II trial, infusion of apolipoprotein A-I to increase cholesterol efflux capacity did not improve outcomes in patients with acute myocardial infarction.

Correspondence | 02 May 2024

Screening for Helicobacter pylori infection in patients with cardiovascular and gastrointestinal disease

• Jonatan Wärme
• , Martin O. Sundqvist
•  &  Robin Hofmann

Reply to ‘Screening for Helicobacter pylori infection in patients with cardiovascular and gastrointestinal disease’

• Azita H. Talasaz
•  &  Behnood Bikdeli

Review Article | 02 May 2024

Stress and cardiovascular disease: an update

Physiological responses to stress are thought to increase the risk of cardiovascular disease via haemodynamic, vascular and immune perturbations. In this Review, Vaccarino and Bremner focus on issues with the measurement of psychological stress and the underlying pathobiology connecting stress to the risk of cardiovascular disease.

• Viola Vaccarino
•  &  J. Douglas Bremner

Research Highlight | 25 April 2024

Periodontal treatment reduces AF recurrence

Treatment for periodontal disease might reduce the recurrence of atrial fibrillation (AF) in patients undergoing ablation, suggesting that periodontitis is a modifiable risk factor for AF.

The coronary sinus reducer improves angina symptoms in patients with stable CAD

Findings from the ORBITA-COSMIC trial show that treatment of patients with stable coronary artery disease using a coronary sinus reducer improves angina symptoms but does not increase transmural myocardial perfusion.

Review Article | 25 April 2024

Targeting immune cell recruitment in atherosclerosis

In this Review, the authors discuss the receptors, ligands and interactors that regulate immune cell recruitment in atherosclerosis, describe mechanisms that promote the resolution of inflammation in atherosclerotic lesions, and highlight potential strategies to target these pathways for the treatment of atherosclerotic cardiovascular disease.

• Yvonne Döring
• , Emiel P. C. van der Vorst
•  &  Christian Weber

Research Highlight | 23 April 2024

Benefits of ninerafaxstat in non-obstructive hypertrophic cardiomyopathy

According to data from the IMPROVE-HCM trial, ninerafaxstat is well tolerated by patients with symptomatic non-obstructive hypertrophic cardiomyopathy and improves exercise performance among those who are most symptomatically limited.

Heart pump increases survival in STEMI-related cardiogenic shock

Data from the DanGer Shock trial demonstrate that implantation of a microaxial flow pump in patients with ST-segment elevation myocardial infarction complicated by cardiogenic shock increases the survival rate compared with standard care alone.

• Jennifer Harman

RNA-based therapies targeting APOC3 lower triglyceride levels in patients with hypertriglyceridaemia

Three randomized clinical trials presented at ACC.24 demonstrate that olezarsen and plozasiran, RNA-based therapies that target APOC3 , can robustly reduce plasma triglyceride levels in patients with moderate to severe hypertriglyceridaemia.

Research Highlight | 22 April 2024

No benefit of β-blockers after myocardial infarction with preserved ejection fraction

In the REDUCE-AMI trial, the use of β-blockers in patients with acute myocardial infarction (MI) who have undergone early coronary angiography and have a preserved left ventricular ejection fraction did not reduce the risk of death or new MI compared with no β-blocker use.

Research Highlight | 19 April 2024

Self-expanding valves more beneficial than balloon-expandable valves in patients with a small aortic annulus

In patients with symptomatic aortic stenosis and a small aortic annulus, a self-expanding valve has similar rates of clinical outcomes at 1 year and lower rates of bioprosthetic dysfunction compared with a balloon-expandable valve.

Research Highlight | 16 April 2024

Gut bacteria can break down cholesterol

A new study identifies a group of gut bacteria that can metabolize cholesterol and are associated with lower plasma cholesterol levels.

Review Article | 10 April 2024

Canonical and non-canonical roles of complement in atherosclerosis

In this Review, Kemper and colleagues discuss the canonical and non-canonical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential new therapeutic strategies targeting the complement system for the prevention and treatment of atherosclerotic cardiovascular disease.

• Pasquale Maffia
• , Claudio Mauro
•  &  Claudia Kemper

Cardiovascular disease and cancer: shared risk factors and mechanisms

Patients with cardiovascular disease (CVD) have an increased risk of cancer, and patients with cancer have an increased risk of CVD. In this Review, the authors discuss the shared modifiable risk factors and the shared pathophysiological mechanisms underlying the bidirectional relationship between these two prevalent diseases.

• Nicholas S. Wilcox
•  &  Bonnie Ky

Review Article | 04 April 2024

Uncovering atherosclerotic cardiovascular disease by PET imaging

In this Review, van Leent and colleagues provide an overview of current PET imaging approaches for assessment of atherosclerotic cardiovascular disease, as well as of whole-body PET applications; discuss the link between imaging readouts and atherosclerotic plaque pathology; and highlight promising developments in PET systems and radiotracer synthesis.

• Alexander Maier
• , Abraham J. P. Teunissen
•  &  Mandy M. T. van Leent

Obituary | 03 April 2024

Alain Cribier (1945–2024)

Gilard and Wijns reflect on the life of Alain Cribier, who revolutionized the management of patients with valvular disease.

• Martine Gilard

Research Highlight | 02 April 2024

Small extracellular vesicles from the infarcted heart can promote tumour growth

After myocardial infarction, the heart secretes small extracellular vesicles with pro-neoplastic properties that can accelerate tumour growth when taken up by cancer cells.

Clinical Outlook | 02 April 2024

Interventional thrombus modification in STEMI

In ST-segment elevation myocardial infarction, the role of interventional modification of thrombi in the coronary arteries before stenting is controversial. However, innovations in stroke intervention have sparked renewed interest in thrombus modification approaches. We discuss current and emerging techniques to extract or disperse thrombi, aiming to reduce downstream embolization, microvascular obstruction and myocardial injury.

• Jason L. Walsh
• , Rafail A. Kotronias
•  &  Giovanni Luigi De Maria

Research Highlight | 28 March 2024

A newly identified gut hormone suppresses cholesterol production in the liver

A new study identifies a hormone that is secreted by the gut in response to cholesterol absorption and can inhibit cholesterol synthesis in the liver, which prevents an increase in circulating cholesterol levels.

Review Article | 26 March 2024

Contemporary pharmacological treatment and management of heart failure

In this Review, Bozkurt provides an overview of the management of patients with heart failure across the full range of left ventricular ejection fraction, derived from the recommendations in the latest US and European guidelines.

• Biykem Bozkurt

Review Article | 20 March 2024

Optimizing antithrombotic therapy in patients with coexisting cardiovascular and gastrointestinal disease

In this Review, the authors address considerations for enteral antithrombotic therapy in patients with cardiovascular disease and gastrointestinal comorbidities, who often have an increased risk of gastrointestinal bleeding. Approaches include tailoring of antithrombotic regimens and gastrointestinal-protection strategies.

• , Parham Sadeghipour

Research Highlight | 18 March 2024

Presence of microplastics in carotid plaques linked to cardiovascular events

In patients with carotid artery disease, the presence of microplastics and nanoplastics in the carotid plaque is associated with an increased risk of death or major cardiovascular events compared with patients in whom microplastics and nanoplastics were not detected.

Tools of the Trade | 18 March 2024

Long-read sequencing provides insights into genetic influence

In this Tools of the Trade article, Trivett discusses the potential of long-read sequencing in generating high-quality reference genomes of animal models of cardiovascular disease.

• Cara Trivett

Review Article | 18 March 2024

Protein glycosylation in cardiovascular health and disease

Protein glycosylation is vital to the regulation of cell function, and changes in this post-translational modification underlie many disease processes. In this Review, Chatham and Patel discuss how protein glycosylation contributes to normal cardiovascular function and its role in cardiovascular disease, identifying important knowledge gaps and areas for future research.

• John C. Chatham
•  &  Rakesh P. Patel

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• Volume 107, Issue 5
• Impact of cardiovascular disease and risk factors on fatal outcomes in patients with COVID-19 according to age: a systematic review and meta-analysis
• Article Text
• Article info
• Citation Tools
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• http://orcid.org/0000-0003-1484-4645 SungA Bae ,
• http://orcid.org/0000-0002-3164-3258 So Ree Kim ,
• http://orcid.org/0000-0001-6589-5122 Mi-Na Kim ,
• http://orcid.org/0000-0002-2467-3336 Wan Joo Shim ,
• http://orcid.org/0000-0002-6710-685X Seong-Mi Park
• Division of Cardiology , Korea University Anam Hospital , Seoul , Korea (the Republic of)
• Correspondence to Professor Seong-Mi Park, Division of Cardiology, Korea University Anam Hospital, Seoul, Korea (the Republic of); smparkmd{at}korea.ac.kr

Objective Previous studies that evaluated cardiovascular risk factors considered age as a potential confounder. We aimed to investigate the impact of cardiovascular disease (CVD) and its risk factors on fatal outcomes according to age in patients with COVID-19.

Methods A systematic literature review and meta-analysis was performed on data collected from PubMed and Embase databases up to 11 June 2020. All observational studies (case series or cohort studies) that assessed in-hospital patients were included, except those involving the paediatric population. Prevalence rates of comorbid diseases and clinical outcomes were stratified by mean patient age in each study (ranges: <50 years, 50–60 years and ≥60 years). The primary outcome measure was a composite fatal outcome of severe COVID-19 or death.

Results We included 51 studies with a total of 48 317 patients with confirmed COVID-19 infection. Overall, the relative risk of developing severe COVID-19 or death was significantly higher in patients with risk factors for CVD (hypertension: OR 2.50, 95% CI 2.15 to 2.90; diabetes: 2.25, 95% CI 1.89 to 2.69) and CVD (3.11, 95% 2.55 to 3.79). Younger patients had a lower prevalence of hypertension, diabetes and CVD compared with older patients; however, the relative risk of fatal outcomes was higher among the former.

Conclusions The results of the meta-analysis suggest that CVD and its risk factors (hypertension and diabetes) were closely related to fatal outcomes in COVID-19 for patients across all ages. Although young patients had lower prevalence rates of cardiovascular comorbidities than elderly patients, relative risk of fatal outcome in young patients with hypertension, diabetes and CVD was higher than in elderly patients.

Prospero registration number CRD42020198152.

• meta-analysis
• cardiac risk factors and prevention
• quality and outcomes of care

This article is made freely available for use in accordance with BMJ’s website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.

https://doi.org/10.1136/heartjnl-2020-317901

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Contributors SAB, SRK, M-NK and S-MP conceived the idea of the study. SAB and S-MP screened the studies and performed data extraction. SAB performed the statistical analysis, and S-MP supervised the analysis. SAB, S-MP, SRK, M-NK and WJS interpreted the findings. SAB drafted the manuscript; S-MP critically reviewed the manuscript, and SAB revised the manuscript for final submission. All authors have approved the final draft of the manuscript. S-MP and SAB are guarantors. S-MP accepts full responsibility for the work and conduct of the study, has access to the data and controls the decision to publish. The corresponding author attests that all listed authors meet the authorship criteria and that no others meeting the criteria have been omitted.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Patient consent for publication Not required.

Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Additional data are available from the corresponding author on reasonable request.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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A Thorough Literature Review of the Potential Benefits and Drawbacks of Long-Term Aspirin Use for the Primary Prevention of Cardiovascular Disease

Shubietah, Abdalhakim R. M. MD *,† ; Marin, Monica Pernia MD ‡ ; Rajab, Islam M. MD § ; Oweidat, Majd H. BSc ¶ ; Zayed, Alaa BSc † ; Hmeedan, Alaa MD *,†

* From the Department of Internal Medicine, An-Najah National University Hospital, Nablus, Palestine

† Department of Medicine, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine

‡ Neuro-Oncology Department, Columbia University, Irving Medical Center, New York, NY

§ Columbia University, Irving Medical Center, New York, NY

¶ Department of Medicine, Hebron University, College of Medicine, Hebron, Palestine.

Disclosure: The authors declare no conflict of interest.

Concept and design: A.R.M.S. and I.M.R. A.R.M.S., M.P.M., I.M.R., M.H.O., A.Z., and A.H. contributed to the composition of the original draft and participated in the literature search. Writing—review and editing: A.R.M.S. and M.P.M. Figures and tables design: A.R.M.S.

Correspondence: Abdalhakim R. M. Shubietah, MD, Department of Internal Medicine, An-Najah National University Hospital, 00970. PO Box 7, Nablus, Palestine. E-mail address: [email protected] .

This article examines the role of aspirin in the primary prevention of cardiovascular disease. It highlights findings from major studies such as ASPREE (ASPirin in Reducing Events in the Elderly), ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events), and ASPREE-XT (ASPirin in Reducing Events in the Elderly - eXTension) , among others. The review focuses on aspirin’s role in primary prevention for specific populations including older adults, diabetics, hypertension patients, rheumatoid arthritis patients, kidney transplant recipients, and those with specific lipoprotein(a) genotypes, among other groups. We review these studies, noting aspirin’s role in reducing events such as myocardial infarctions and its potential for increasing bleeding risks. The review also considers the implications for patients with kidney disease, referencing the Chronic Renal Insufficiency Cohort (CRIC) study and the International Polycap Study-3 (TIPS-3) trial. Additionally, it addresses the shifting paradigms in guidelines from the US Preventive Services Task Force and other entities, underscoring the importance of individualized aspirin use by balancing benefits against bleeding risks. The article further explores the concept of platelet reactivity, discusses strategies for improving adherence to aspirin therapy, and identifies existing research gaps, such as the phenomenon of aspirin resistance. It concludes by suggesting potential areas for future investigation to enhance understanding and application of aspirin in cardiovascular disease prevention.

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Gestational diabetes mellitus and development of intergenerational overall and subtypes of cardiovascular diseases: a systematic review and meta-analysis

• Ashley Chen 1 ,
• Breanna Tan 1 ,
• Ruochen Du 2 ,
• Yap Seng Chong 3 ,
• Cuilin Zhang 3 , 4 , 5 ,
• Angela S. Koh 6 , 7 &
• Ling-Jun Li 3 , 4 , 5 , 8  

Cardiovascular Diabetology volume  23 , Article number:  320 ( 2024 ) Cite this article

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We aimed to summarize the association between gestational diabetes mellitus (GDM) and its intergenerational cardiovascular diseases (CVDs) impacts in both mothers and offspring post-delivery in existing literature.

PubMed, Embase, Web of Science, and Scopus were utilized for searching publications between January 1980 and June 2024, with data extraction and meta-analysis continuing until 31 July 2024. Based on a predefined PROSPERO protocol, studies published as full-length, English-language journal articles that reported the presence of GDM during pregnancy and its association with any CVD development post-delivery were selected. All studies were evaluated using the Newcastle-Ottawa Scale. Maximally adjusted risk estimates were pooled using random-effects meta-analysis to assess the risk ratio (RR) of GDM, and overall and subtypes of CVDs in both mothers and offspring post-delivery.

The meta-analysis was based on 38 studies with a total of 77,678,684 participants. The results showed a 46% increased risk (RR 1.46, 95% CI 1.34–1.59) for mothers and a 23% increased risk (1.23, 1.05–1.45) for offspring of developing overall CVDs after delivery, following a GDM-complicated pregnancy. Our subgroup analysis revealed that mothers with a history of GDM faced various risks (20% to 2-fold) of developing different subtypes of CVDs, including cerebrovascular disease, coronary artery disease, heart failure, and venous thromboembolism.

Conclusions

These findings underscore the heightened risk of developing various CVDs for mothers and offspring affected by GDM, emphasizing the importance of preventive measures even right after birth to mitigate the burden of CVDs in these populations.

Gestational Diabetes Mellitus (GDM) is characterized by elevated blood sugar levels. It is primarily diagnosed during the second or third trimester of pregnancy in women who do not have a pre-existing diabetic condition [ 1 ]. It is a prevalent metabolic disorder, affecting approximately 1% to over 30% of pregnancies [ 2 ]. In the year 2021, the American Heart Association (AHA) issued a statement underscoring the importance of considering adverse outcomes during pregnancy, such as hypertensive disorders, gestational diabetes, preterm delivery, small-for-gestational-age delivery, pregnancy loss, and placental abruption, when evaluating the risk of cardiovascular diseases (CVDs) in individuals with a history of pregnancy [ 3 ]. Notably, the risk remains elevated up to 25 years after pregnancy, particularly in the window of 8 to 15 years after delivery [ 4 ].

Emerging evidence suggests that offspring born to pregnancies complicated by GDM are at elevated risk of developing cardiovascular disorders later in life [ 5 , 6 ]. Exposure to GDM in utero has been linked to cardiovascular risks, including elevated levels of total cholesterol and systolic blood pressure in offspring from mid-childhood to adolescence [ 5 , 7 ]. However, data on the intergenerational impact of GDM on CVDs remains scarce, let alone a notable absence of a comprehensive systematic review and meta-analysis examining these impacts on overall and various subtypes of CVDs among mother-offspring pairs affected by GDM-complicated pregnancies.

Our review sought to explore the connections between GDM and the subsequent occurrence of overall CVDs as well as distinct types of CVDs in both mothers and offspring following childbirth. Specifically, considering that the existing body of literature primarily originates from Western populations, our objective is to evaluate the potential differences in outcomes for the Asian demographic. We put forth the hypothesis that women with a history of GDM and their offspring might be confronted with an elevated risk of CVD development. Due to the intimate interplay between maternal and offspring health throughout the pregnancy period, our findings could offer valuable insights into the underlying pathophysiology linking GDM and the emergence of intergenerational CVDs, and subsequently raise public awareness regarding postnatal care, particularly emphasizing early intervention, to enhance cardiovascular well-being for both mothers and offspring.

Search Strategy and Selection Criteria

We conducted the systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement for standard protocols [ 8 ]. An investigator (L.-J.L.) oversaw the search strategy. References for this systematic review were identified through searches of four main databases (i.e., PubMed, Embase, Web of Science, and Scopus) for articles published between January 1, 1980, and June 30, 2024. Grey literature including case reports, working papers, government documents, white papers and evaluations were not included. Since we were interested in the intergenerational impact of maternal GDM on cardiovascular outcomes, we included two topics in our review. They are “Topic 1—maternal GDM and postpartum maternal CVD” and “Topic 2—maternal GDM and offspring CVD”. Search terms for these two topics are described in detail in Supplementary Table 1. Articles resulting from these searches and relevant references cited in those articles were reviewed, among which those reporting non-human subjects, written in non-English language or without full-text available were excluded. Flow charts of detailed literature searching on each topic are shown in Supplementary Fig. 1. This review was registered at PROSPERO International Prospective Register of Systematic Reviews ( https://www.crd.york.ac.uk/PROSPERO/ ) with the registration No. CRD42023438259.

Data Extraction and Assessment of Quality

During the literature searching phase, two investigators (C.S. & B.T.) independently selected eligible studies (based on title and abstract, followed by full-text articles) and extracted the relevant data. Results were verified and discrepancies (if any) were evaluated by a third investigator (L-J.L.). A clear set of pre-specified inclusion criteria and exclusion criteria was established prior to the data extraction. Studies published as full-length and English-language articles in peer-reviewed journals that reported the presence of GDM during pregnancy and its association with any CVD development post-delivery were included. Excluded studies were those published as case reports, reviews, letters, and conference abstracts. Non-full-length articles, non-English publications, and studies conducted on animal models were also excluded. The first phase was conducted in title and abstract screening (C.S., & B.T.), and the second phase was conducted in full-text screening (C.S., & B.T.). Subsequently, two investigators (C.S. & B.T.) performed the quality assessments for all papers based on the Newcastle-Ottawa Scale Criteria (NOSC) [ 9 , 10 ] and a third investigator (L.-J.L.) assessed the findings independently. The maximum score of 9 points in the NOSC is distributed in three aspects based on the study groups, namely selection of study groups (four points), comparability of groups (two points), and ascertainment of exposure and outcomes (three points) for case–control and cohort studies. We used the points to further categorize the publication quality into low risk of bias (between 7 and 9 points), high risk of bias (between 4 and 6 points), and very high risk of bias (between 0 and 3 points) [ 9 , 10 ]. The inter-rater agreement between the two investigators, C.S. and B.T., was 95% for the data extraction phase and 90% for the quality assessment phase. In cases of disagreement, the senior investigator, L.-J.L., reviewed the discrepancies and made the final decision.

Once all papers were identified for both topics, study characteristics such as the name of the first author, country of study conduction, number of participants, mean age, race/ethnicity, years of follow-up, GDM diagnostic guidelines, assessment of CVDs outcomes, effect size, and adjustments model were tabulated. Studies that detailed information on maternal GDM during index pregnancy and intergenerational CVDs diagnosis after delivery were further included in the meta-analysis. Studies that were identified to be at higher risk of bias were assigned a lower weightage in the calculation for overall effect size.

Data synthesis and analysis

Data analysis was conducted between 1st August 2023 and 31 July 2024. Due to the various effect sizes reported in papers, we calculated risk ratio (RR) using random-effects meta-analysis to represent estimates reported from different studies, including hazard ratio (HR), incidence rate ratio (IRR), and odds ratio (OR). For studies’ estimates stratified by comorbidity of type 2 diabetes (T2D) or overweight/obesity, an overall estimate was calculated based on the prevalence of within population T2D or overweight/obesity [ 9 ].

The risk estimate with the greatest degree of statistical adjustment was included in the meta-analysis. Statistical heterogeneity was assessed with the Cochran Q-test [ 10 ] and I 2 statistic, defining levels as mild, moderate, substantial, and high heterogeneity based on I 2 values falling within the ranges of 0–25%, 25–50%, 50–75%, and 75–100%, respectively [ 11 , 12 ]. Publication bias was assessed visually with funnel plots and with the Egger [ 13 , 14 ] (linear regression method) and Begg-Mazumdar [ 15 ] regression tests (rank correction method), and a p-value < 0.05 was considered representative of statistically significant publication bias [ 13 , 15 ]. All analyses were conducted with Stata, version 17.0 (Stata Corporation, College Station, Texas, USA). All P values were from 2-sided tests, and the results were deemed statistically significant at p  < 0.05 unless stated otherwise.

Subgroup Analysis

To comprehensively explore subgroup differences and potential sources of observed heterogeneity, we conducted a series of subgroup analyses based on various study characteristics. Firstly, we presented overall CVDs outcomes, and stratified further based on subtypes of CVDs outcomes based on individual studies. We categorized different CVDs conditions into the following subtypes: coronary artery disease (CAD), angina pectoris, heart failure, arrhythmia, valve disorders, peripheral artery disease, venous thromboembolism (VTE), cardiovascular procedures, cerebrovascular disease (CeVD) and aortic dissection (Supplementary Table 2). Secondly, based on the overall CVDs, we performed stratified meta-analyses based on study characteristics, such as study race/ethnicity (exclusive Asian vs. mixed population yet primarily composed of Caucasians), median duration of follow-up (> 10 years vs. ≤ 10 years), method for ascertaining GDM (medical code vs. self-reporting), and study quality (low risk of bias vs. moderate-to-high risk of bias). To assess the potential mediating role of subsequent development of T2D underlying the association between GDM and overall CVDs, we examined the risk ratio for overall CVDs in women who had T2D comorbidity and those who did not specify. Thirdly, we conducted subgroup analyses in associations of overall CVDs stratified by major covariates, such as BMI, lifestyle factors, socioeconomic status, pregnancy complications, and systemic comorbidities. Q-test based on one-way ANOVA was conducted using the R package (R 4.2.2), and statistical significance for any difference in estimates between subgroups was determined with a two-sided p-value threshold of < 0.10.

Study characteristics and summaries in systematic review

Supplementary Table 3 summarizes the characteristics and quality scores of the 36 studies involving mothers ( n  = 74,890,936, follow-up range: 1 day to 46 years after index pregnancy) and the 6 studies involving offspring ( n  = 14,260,765, follow-up range: at birth to 40 years after index pregnancy) within the context of GDM-related pregnancies. The majority of these studies were cohort studies ( n  = 33), with a small subset being cross-sectional studies ( n  = 7), and two identified as case-control studies. These studies were further analysed to categorize the studied outcomes of interest into overall CVD outcomes and various subtypes of CVDs, as illustrated above.

GDM and overall CVD outcomes in mothers

Among the studies that presented CVDs outcomes in mothers, fourteen out of the 33 studies were conducted in the US [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ], four in Canada [ 4 , 30 , 31 , 32 ], five in Sweden [ 33 , 34 , 35 , 36 , 37 ], two in Iran [ 38 , 39 ], three in the UK [ 40 , 41 , 42 ], while the remaining six were in Denmark [ 43 ], France [ 44 ], Netherlands [ 45 ], South Korea [ 46 ], China [ 47 ], Israel [ 48 ], and New Zealand [ 49 ], respectively. The sample sizes in these studies ranged from 391 to 2,201,352, and the ages of the study populations spanned from under 20 to over 65 years old. The reported incidence rates of overall CVDs varied from 14 to 1,818 cases per 1000 person-years (Supplementary Table 3). GDM was defined based on either medical reports/diagnostic codes or self-reported. Aside from medical reports and self-reported CVDs definition, clinical diagnostic assessments for CVDs included coronary computed tomography angiography [ 34 , 38 ], electrocardiogram findings [ 19 , 24 , 38 ], echocardiogram [ 50 ], and cardiac-specific enzymes [ 19 ]. While the majority of articles reported a positive association between GDM and a 1.04- to 3.18-fold increased risk of maternal overall CVD outcomes post-index pregnancy, five studies reported a null association [ 22 , 27 , 29 , 38 , 45 ].

GDM and overall CVD outcomes in offspring

The six papers that reported CVD outcomes amongst offspring were conducted in the United States [ 51 ], the Czech Republic [ 52 ], Canada [ 53 ], Denmark [ 54 ], Israel [ 55 ], and France [ 56 ], respectively. The sample sizes ranged from 128 to 11,318,691, and the ages of the study populations spanned from birth to 40 years. The reported incidence rates ranged from 22 to 94 cases per 100,000 person-years (Supplementary Table 3). GDM at index pregnancy was all defined via clinical guidelines or diagnostic codes [ 51 , 52 , 53 , 54 , 55 , 56 ], while offspring CVDs outcomes were defined via national registries [ 51 , 53 , 54 ], hospital databases [ 55 ], or clinical diagnostic assessments such as two-dimensional electrocardiography [ 52 ] and neuroimaging or pathohistological examination [ 56 ].

All studies demonstrated a positive association between GDM-complicated pregnancy and a 1.19 to 2.24-fold increased risk of offspring overall CVDs following birth. Notably, Leybovitz-Haleluya et al. [ 55 ] observed a 60% higher risk of CVDs development in offspring born to mothers managed with oral treatment of insulin compared to those managed with diet and exercise alone. Moreover, Darmency-Stamboul et al. [ 56 ] reported a higher incidence of perinatal arterial ischemic stroke among boys compared to girls (59% vs. 41%), while Guillemette et al. [ 53 ] did not find any significant interaction between the sex of offspring and CVDs outcomes.

Meta-analysis of GDM and postpartum CVDs development in mothers

Table  1 ; Fig.  1 A summarizes key study characteristics, including study population details, locations, follow-up periods, pre-pregnancy BMI, sample sizes, methods for defining GDM and CVDs, and effect sizes with 95% confidence intervals. Most studies made statistical adjustments for maternal age, race/ethnicity, and BMI. In a meta-analysis of thirty-three studies, women with GDM were found to have a higher risk of developing overall CVDs (RR 1.46, 95% CI 1.34–1.59) over follow-up periods from one day to 46 years. Among these studies, 19 had low bias risk [ 4 , 16 , 18 , 19 , 23 , 29 , 30 , 31 , 32 , 34 , 36 , 38 , 40 , 41 , 42 , 43 , 45 , 46 , 48 ], while 13 had high bias risk [ 17 , 20 , 21 , 24 , 27 , 28 , 34 , 35 , 37 , 39 , 44 , 47 , 49 ], and one had very high bias risk [ 26 ] (Table  1 ). The analysis showed significant heterogeneity (I 2  = 95.44%), and a p-value less than 0.001 from Cochran’s Q test, indicating significantly substantial variability among all publications (Fig.  1 A). Publication bias assessment using Egger’s and Begg’s tests, along with a funnel plot (Supplementary Fig. 2), indicated no evidence of bias, with Egger’s test result ( p  = 0.76) and Begg’s test result ( p  = 0.61) supporting this conclusion.

Meta-analysis Results. Evidence of risk ratio (RR) and 95% confidence interval (CI) of maternal GDM and maternal postpartum overall CVDs (A) and offspring overall CVDs (B), using unadjusted random-effects model. Heterogeneity was presented in both I 2 (describing the percentage of variation across studies that is due to heterogeneity rather than chance) and T 2 (reflecting the variance of the true effect sizes). Abbreviations: RR: risk ratio; confidence interval; %, percentage

For various CVDs subtypes, women with GDM exhibited significantly elevated risks in different categories: coronary artery disease (1.53; 1.32–1.76), heart failure (1.38; 1.17–1.62), venous thromboembolism (1.18; 1.00-1.39), cardiovascular procedures (2.10; 1.63–2.70), peripheral artery disease (2.00; 1.62–2.48), arrhythmia (1.48; 1.46–1.50), angina pectoris (2.03; 1.44–2.85), as well as overall CeVDs (1.27; 1.11–1.44) including ischemic stroke/TIA (1.52; 1.30–1.78), and haemorrhagic stroke/intracranial haemorrhage (1.44; 1.15–1.78), compared to women without a history of GDM (Fig.  2 ).

Subgroup analyses stratified by subtypes of CVDs. Evidence of risk ratio (RR) and 95% confidence interval (CI) of maternal GDM and subtypes of CVDs in both mothers and offspring using unadjusted random-effects model. Heterogeneity was presented in both I 2 (describing the percentage of variation across studies that is due to heterogeneity rather than chance) and T 2 (reflecting the variance of the true effect sizes)

Subgroup analyses based on study characteristics such as race/ethnicity, sample size, follow-up duration, diagnostic methods for GDM, comorbidities of Type 2 Diabetes (T2D), overweight or obesity, and study quality grading did not show significant differences in pooled risk ratios (Supplementary Fig. 3) (all Q-test p  > 0.10). For instance, studies indicated a similar heightened risk of overall CVDs outcomes in women who are overweight or obese (1.51; 1.27–1.80) compared to the general population of women (1.47; 1.34–1.62) ( p  = 0.44). Additionally, findings revealed that women with T2D did not have an increased risk of overall CVDs outcomes (1.40, 1.13–1.75) in comparison to those without T2D (1.47, 1.34–1.62) ( p  = 0.69).

Further subgroup analyses revealed significant differences between subgroups when adjusting for major confounders. Notably, it showed significant differences if certain key confounders were not adjusted for in the association between GDM and postpartum CVDs in mothers, namely maternal pre-pregnancy BMI at study entry (Yes vs. No: 1.39, 1.32–1.56 vs. 1.63, 1.36–1.94; p  = 0.06), parity (Yes vs. No: 1.36, 1.25–1.48 vs. 1.55, 1.34–1.81; p  = 0.095), and comorbidities (Yes vs. No: 1.37, 1.26–1.49 vs. 1.60, 1.37–1.86; p  = 0.07) (Supplementary Fig. 4).

Meta-analysis of GDM and CVDs development in offspring

Table  2 ; Fig.  1 B summarizes key characteristics of the five included studies, detailing study population, location, follow-up years, pre-pregnancy BMI, offspring BMI, ascertainment methods, sample sizes for GDM in mothers and CVDs in offspring, and effect sizes with 95% CI. The meta-analysis revealed that offspring born to mothers with GDM showed a 20% higher risk of developing overall CVDs (1.23; 1.05–1.45) over 0 to 40 years of follow-up period, with high heterogeneity (I 2  = 78.07%) (Fig.  1 B) and high publication bias, which was supported the funnel plot (Supplementary Fig. 5). Due to few publications, subgroup analysis was only successful for CeVD, in which the increased risk of CeVD outcomes in offsprings of mothers with GDM was not statistically significant (1.26; 0.88–1.80) (Fig.  2 ).

This systematic review and meta-analysis synthesized available evidence on GDM and its association with a higher incidence of CVDs in both mothers and offspring post-delivery. Our analysis revealed a 45% increased risk of postpartum CVDs in mothers and a 31% increased risk in offspring over follow-up periods ranging from day 1 to over 40 years after delivery. In mothers, subtypes of CVDs such as coronary artery disease, heart failure, cardiovascular procedures, peripheral artery disease, arrhythmia, and angina pectoris showed increased risks ranging from 45% to 2-fold, while the risk of stroke was enhanced by 20%.

GDM and postpartum CVDs development in mothers

The mechanisms involved in GDM-associated CVDs development among mothers are related to cardiovascular risk factors, endothelial dysfunction, and myocardial remodelling [ 19 , 40 , 57 ]. To begin with, an elevated cardiovascular risk profile that includes conditions such as dyslipidaemia [ 58 ] and metabolic syndrome [ 59 , 60 ], characterizes women with a history of GDM. These predisposing factors heighten their risk of developing CVDs in comparison to their non-GDM counterparts. Additionally, women with GDM have a seven to tenfold higher risk of transitioning to T2D in their later years [ 61 , 62 , 63 ]. This increased risk has been attributed to elevated markers of inflammation and reduced levels of adiponectin present in women with prior GDM [ 64 ].

Secondly, vascular dysfunction is recognized as an independent risk factor for CVDs [ 65 ]. It has been strongly suggested that even though GDM induces a temporary phase of significant glucose intolerance during pregnancy, it might result in substantial and irreversible changes within the endothelium [ 4 ]. Research indicates that women with a history of GDM exhibit decreased coronary flow reserve [ 66 ], which is a marker of potential cardiovascular issues. They also have a higher incidence of impaired endothelial vasodilation [ 30 , 67 ], and increased carotid intima-media thickness (cIMT) [ 30 , 64 ] when compared to their counterparts.

Thirdly, although normal pregnancy brings hemodynamic and physiological changes to the cardiovascular system [ 68 ], these are more pronounced in GDM. Advanced glycation end products in GDM can lead to critical alterations like altered preload, contractility, and heart rate, causing physiological left ventricular (LV) remodelling [ 69 ], endothelial damage, and reduced arterial elasticity [ 70 ]. These changes can persist after delivery, potentially leading to overt CVDs in women with GDM [ 71 ]. Emerging evidence has shown that women with a history of GDM manifested lower LV diastolic and systolic function during late pregnancy [ 72 ], and greater left ventricular mass, impaired LV relaxation, and lower LV systolic function years after delivery [ 73 ], compared with their counterparts.

GDM and CVDs development in offspring

Although research exploring the link between GDM and the subsequent development of CVDs in offspring is relatively limited, our analysis revealed a consistent and strong positive correlation across the five studies included in our review. Notably, some evidence even indicated the early onset of CVDs soon after birth in infants born to mothers with GDM [ 74 ].

Firstly, the intrauterine environment characterized by hyperglycemic level can adversely affect placental morphology and vasculature, leading to conditions such as villous immaturity, villous edema, villous fibrinoid necrosis, and chorangiosis [ 75 ]. These changes could cause fetal hypoxia, which prompts the release of reactive oxygen and nitrogen species, ultimately resulting in an overstimulation of nitrogen oxide [ 76 ]. Such pathological changes can increase inflammation [ 77 ] and lead to vascular endothelial dysfunction [ 78 ] in the fetoplacental unit, culminating in intrauterine growth restriction (IUGR) [ 79 ]. This has been concluded to be the underlying mechanism of the development of hypertension and other types of CVDs [ 65 , 80 ].

Secondly, fetal hyperinsulinemia can occur as a result of constant maternal hyperglycemia experienced in utero [ 81 ]. Over time, this sustained elevation in insulin production within the fetoplacental circulation may harm the fetal pancreatic islet beta cells, diminishing their ability to respond to hyperglycemia by secreting insulin [ 82 ]. This state of hyperinsulinemia could subsequently contribute to cardiac dysfunction in the offspring. For instance, studies indicated that up to 40% of pregnancies complicated by diabetes will result in offspring with myocardial hypertrophy, characterized by a thickened interventricular septum and ventricular walls, along with systolic and diastolic dysfunction [ 83 ].

Thirdly, maternal hyperglycemia may induce fetal hypoxia that results in an increased release of reactive oxygen species in both the fetus and placenta [ 76 ]. This can trigger oxidative damage to membrane lipids and deteriorate mitochondrial DNA [ 84 ]. Research has demonstrated that placentas impacted by GDM exhibit reduced gene and protein expression of markers associated with mitochondrial fusion and proteins related to mitochondrial biogenesis [ 84 ]. Such mitochondrial dysfunction can also extend to the myocardiocytes in the fetal heart, disrupting normal cardiac development [ 85 ].

Clinical implications

As a result of endothelial dysfunction and cardiac remodelling, against a background of CVD risks, women with a history of GDM have elevated risks of developing CVDs in the postpartum period and years after. Our study presents substantial evidence indicating that not only mothers with GDM but also their offspring face a similarly elevated risk of developing CVDs after birth. These findings underscore the importance of developing early prevention strategies that prevent the development of CVDs in GDM-complicated pregnancies. Future public health policies might incorporate these insights, by considering a history of GDM as a unique standalone CVD risk factor for both the mother and the offspring. The inclusion of GDM as a risk factor in CVD risk scoring systems might form the initial steps into public health strategies. Further assessment strategies might include targeted cardiac evaluation via easy-to-use tools such as measures of arterial stiffness, ultrasonography, or cardiac biomarkers.

Strengths and limitations

The primary strength of this systematic review lies in its extensive analysis of research evidence regarding the association of GDM and overall and subtypes of CVDs in both maternal and offspring. The robustness of our study is fortified by a meticulous search strategy, ensuring the thorough identification of all eligible studies, and subgroup analyses. However, the study is not without its limitations. Firstly, our paper exclusively incorporated pertinent papers procured from four distinct search engines, limited to English-language publications. This approach could potentially introduce information bias if pertinent content is present but published in languages other than English or not covered within the predetermined quartet of databases. Secondly, there may be significant heterogeneity observed across studies. This variance stems from divergent follow-up durations, distinct protocols for data collection and screening methodologies, as well as variations in the diagnostic criteria or self-reported definition for GDM and CVDs. Thirdly, reporting risk over such an extended time frame, drawn from various papers without assessing the stability of risk over time, may complicate the contextualization of the reported estimates. Fourthly, pooled risk ratios derived from only two studies in the subgroup analysis should be interpreted with caution. Lastly, while GDM not only heightens the risk of CVDs, it also increases the likelihood of overweight/obesity and type 2 diabetes (T2D) in both mothers and their children, potentially mediating the development of CVDs in both generations. Nonetheless, our subgroup analyses, stratified by overweight/obesity status or T2D comorbidity, did not support these hypotheses. Further investigations utilizing a prospective longitudinal study design with more frequent follow-ups are essential to comprehensively grasp the potential mediating role of metabolic disorders underlying GDM and the development of intergenerational CVDs.

Our systematic review and meta-analysis unveiled increased risks of developing overall and subtypes of CVDs in both mothers and offspring impacted by GDM. These staggering and enduring risks of GDM across two generations highlight an urgent public health need to increase awareness of CVD risks associated with GDM. Future population health strategies that include dedicated CVD risk assessment and cardiac evaluation represent crucial next steps for the field of GDM.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

American Heart Association

Coronary Artery Disease

Cerebrovascular Disease

Confidence Interval

Carotid Intima-media Thickness

Cardiovascular disease

Gestational Diabetes Mellitus

Hazard Ratio

Incidence Rate Ratio

Intrauterine Growth Restriction

Left Ventricular

Preferred Reporting Items for Systematic Reviews and Meta-Analysis

Type 2 Diabetes

Venous Thromboembolism

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Acknowledgements

The research of the authors is supported in part by the Yong Loo Lin School of Medicine, National University of Singapore, and the National University Hospital.

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L.-J.L. conceived the idea of the study; C.A., T.B. & L.-J.L. screened the studies and extracted the data; R.D. carried out the statistical analysis; L.-J.L. supervised the analysis. C.A., T.B. & L.-J.L. interpreted the findings and drafted the manuscript. C.Y.S., C.Z., K.A., and L.-J.L. edited and revised the manuscript. All authors critically revised and revised the manuscript for final submission. All authors have approved the final draft of the manuscript. L.-J.L. is guarantor. L.-J.L accepts full responsibility for the work and the conduct of the study, had access to the data, and controlled the decision to publish. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

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Ashley Chen and Breanna Tan contributed equally to the first authorship.

Supplementary Information

Supplementary figure 1: flow chart of systematic review literature searching scheme for both mothers and offspring, supplementary figure 2: funnel plot regarding meta-analysis of maternal gdm and postpartum overall cvds, 12933_2024_2416_moesm3_esm.jpg.

Supplementary Figure 3: Subgroup analysis stratified by study features. Evidence of risk ratio (RR) and 95% confidence interval (CI) of maternal GDM and maternal postpartum overall CVDs was reported in all subgroups, using unadjusted random-effects model. Heterogeneity was presented in both I 2 (describing the percentage of variation across studies that is due to heterogeneity rather than chance) and T 2 (reflecting the variance of the true effect sizes). Cochran's Q test is used to determine if there are differences of overall CVDs within subgroups or between subgroups. P value < 0.10 for Q-test is considered significant. Abbreviations: CI: confidence interval; GDM, gestational diabetes mellitus; CVDs, cardiovascular diseases; T2D, type 2 diabetes; NOSC, Newcastle-Ottawa Scale

12933_2024_2416_MOESM4_ESM.jpg

Supplementary Figure 4: Subgroup analysis stratified by covariates adjustment. Evidence of risk ratio (RR) and 95% confidence interval (CI) of maternal GDM and maternal postpartum overall CVDs was reported in all subgroups, using unadjusted random-effects model. Heterogeneity was presented in both I 2 (describing the percentage of variation across studies that is due to heterogeneity rather than chance) and T 2 (reflecting the variance of the true effect sizes). Cochran's Q test is used to determine if there are differences of overall CVDs within subgroups or between subgroups. P value < 0.10 for Q-test is considered significant. Abbreviations: CI, confidence interval; BMI, body mass index, HDP, hypertensive disorder during pregnancy; HTN, hypertension; T2D, type 2 diabetes

Supplementary Figure 5: Funnel plot regarding meta-analysis of maternal GDM and offspring overall CVDs

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Chen, A., Tan, B., Du, R. et al. Gestational diabetes mellitus and development of intergenerational overall and subtypes of cardiovascular diseases: a systematic review and meta-analysis. Cardiovasc Diabetol 23 , 320 (2024). https://doi.org/10.1186/s12933-024-02416-7

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• Effects of muscle strength training combined with aerobic training versus aerobic training alone on cardiovascular disease risk indicators in patients with coronary artery disease: a systematic review and meta-analysis of randomised clinical trials
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• http://orcid.org/0000-0002-6623-6994 Tasuku Terada 1 , 2 ,
• Robert Pap 3 ,
• Abby Thomas 4 ,
• Roger Wei 5 ,
• Takumi Noda 6 , 7 ,
• Sarah Visintini 8 ,
• Jennifer L Reed 2 , 9 , 10
• 1 Physiology, Pharmacology and Neuroscience, School of Life Sciences , University of Nottingham , Nottingham , UK
• 2 Exercise Physiology and Cardiovascular Health Lab, Division of Cardiac Prevention and Rehabilitation, University of Ottawa Heart Institute , Ottawa , ON , Canada
• 3 University of Alberta Faculty of Medicine & Dentistry , Edmonton , AB , Canada
• 4 Department of Community Health Sciences , University of Calgary , Calgary , AB , Canada
• 5 Faculty of Medicine , University of Ottawa , Ottawa , ON , Canada
• 6 Graduate School of Medical Sciences, Department of Rehabilitation Sciences , Kitasato University , Sagamihara , Japan
• 7 Department of Cardiovascular Rehabilitation, National Cerebral and Cardiovascular Center , Suita , Japan
• 8 Berkman Library , University of Ottawa Heart Institute , Ottawa , ON , Canada
• 9 School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa , Ottawa , ON , Canada
• 10 School of Human Kinetics, Faculty of Health Sciences, University of Ottawa , Ottawa , ON , Canada
• Correspondence to Dr Tasuku Terada; tasuku.terada{at}nottingham.ac.uk

Objective To compare the effects of aerobic training combined with muscle strength training (hereafter referred to as combined training) to aerobic training alone on cardiovascular disease risk indicators in patients with coronary artery disease (CAD).

Design Systematic review with meta-analysis.

Data sources MEDLINE, Embase, CINAHL, SPORTDiscus, Scopus, trial registries and grey literature sources were searched in February 2024.

Eligibility criteria Randomised clinical trials comparing the effects of ≥4 weeks of combined training and aerobic training alone on at least one of the following outcomes: cardiorespiratory fitness (CRF), anthropometric and haemodynamic measures and cardiometabolic blood biomarkers in patients with CAD.

Results Of 13 246 studies screened, 23 were included (N=916). Combined training was more effective in increasing CRF (standard mean difference (SMD) 0.26, 95% CI 0.02 to 0.49, p=0.03) and lean body mass (mean difference (MD) 0.78 kg, 95% CI 0.39 kg to 1.17 kg, p<0.001), and reducing per cent body fat (MD −2.2%, 95% CI −3.5% to −0.9%, p=0.001) compared with aerobic training alone. There were no differences in the cardiometabolic biomarkers between the groups. Our subgroup analyses showed that combined training increases CRF more than aerobic training alone when muscle strength training was added to aerobic training without compromising aerobic training volume (SMD 0.36, 95% CI 0.05 to 0.68, p=0.02).

Conclusion Combined training had greater effects on CRF and body composition than aerobic training alone in patients with CAD. To promote an increase in CRF in patients with CAD, muscle strength training should be added to aerobic training without reducing aerobic exercise volume.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

https://doi.org/10.1136/bjsports-2024-108530

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Contributors TT is the guarantor. TT drafted the manuscript. TT and SV contributed to the development of the selection and data extraction criteria. SV developed the search strategy. TT, AT, RW, RP and TN screened studies for inclusion. TT, AT, RW, RP and TN extracted information on adherence and adverse events. TT and PR completed the risk of bias assessments. RP and JR critically reviewed the manuscript. All authors read and approved the final manuscript.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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Coronavirus Disease and Cardiovascular Disease: A Literature Review

Affiliations.

• 1 Physician, North Central Bronx Hospital, 3424 Kossuth Ave, Bronx.
• 2 Resident Physician, James J Peter VA Medical center, 130W Kingsbridge Road, Bronx 10468, New York.
• 3 Associate General Dentist, C/O Familia Dental LLC, 3200 Andrews Hwy, Ste 400, Midland Texas, United States.
• 4 Department of Periodontology, Sibar Institute of Dental Sciences, Guntur, Andhra Pradesh, India.
• PMID: 34104818
• PMCID: PMC8177845

Background and aim: Although severe acute respiratory syndrome coronavirus 2 primarily affects the respiratory system, involvement of cardiovascular system is not uncommon and a range of cardiac manifestations among Coronavirus Disease (COVID-19) patients were reported in the literature. Furthermore, it is evident from scientific literature that the incidence of deaths and hospitalizations has been increasingly more among COVID-19 subjects with pre-existing cardiovascular disease (CVD). Various pathophysiological mechanisms have been proposed to explain the cardiovascular involvement in COVID-19. Another emerging significant concern is the varying presentations of COVID-19 and side effects due to the medication used in the management of COVID-19 patients. This review attempts to provide a comprehensive overview of the existing literature on the possible association between CVD and COVID-19 with emphasis on the pathophysiological mechanisms, cardiac manifestations, and impact of medications used for COVID-19 on cardiovascular health. Based on the available literature, we conclude that though CVD could not be reckoned as an independent risk factor for COVID-19 infection, it is evident that pre-existing CVD has an influence on the severity of COVID-19 infection and associated mortality.

Relevance for patients: Literature suggests that people with pre-existing CVD are at increased risk for COVID-19 and associated severity. Consequently, it becomes important to thoroughly gain insights into the possible pathophysiological mechanisms, cardiac manifestations in COVID-19, and the impact of COVID-19 treatment on the cardiovascular system.

Keywords: myocardial injury; severe acute respiratory syndrome coronavirus 2; thromboembolism.

Copyright: © Whioce Publishing Pte. Ltd.

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• Michał Kostro 1 , 2 &
• Tomasz Hrapkowicz 1  

Journal of Cardiothoracic Surgery volume  19 , Article number:  501 ( 2024 ) Cite this article

Metrics details

Transcatheter aortic valve implantation (TAVI) is indicated for elderly patients who often have severe comorbidities and high operative risk. Despite many advantages, it carries the potential for both early and late complications. The literature reports mainly periprocedural problems. This case report describes a rare instance of ascending aortic rupture as a late complication following TAVI.

Case presentation

An 81-year-old male with severe aortic stenosis (AS) was a non-surgical patient due to a high operative risk (EuroSCORE II 14.08%) and comorbidities, including cardiovascular problems, chronic obstructive pulmonary disease, myelodysplastic syndrome. During the TAVI procedure Medtronic CoreValve™ Evolut™ R-26 was implanted via the right femoral artery. Postoperative period elapsed without complications and the patient was discharged home. Six months later, the patient was re-admitted to the hospital on an emergency basis and transferred directly to the operating room due to ascending aortic rupture (EuroSCORE II 53.20%, GERAADA score 64.9%). Computed tomography angiography (CTA) showed aortic rupture with a multiple fresh blood reservoirs and thrombus around the ascending aorta originating from the spot where the nitinol frame of the TAVI valve was attached to the native aorta. Supracoronary excision of the ascending aorta with implantation of a vascular graft (Intergard Woven Graft 34 mm) was performed, preserving the earlier implanted TAVI valve . On the 9th day after surgery the patient’s general condition deteriorated, he suffered from circulatory and respiratory insufficiency. Furthermore, a gastrointestinal bleeding with the need for gastro-, and colonoscopy and multiple blood transfusions occurred. Patient developed urosepsis and acute renal failure with the need for hemodiafiltration . Despite intensive treatment, further deterioration of the medical condition of the patient. and finally the multiple organ failure was observed. Patient died on the 50th postoperative day.

Conclusions

TAVI is a safe method of treating severe AS, especially recommended for non-surgical candidates. Rupture of the ascending aorta is a rare but serious complication of TAVI that usually occur during or shortly after the procedure. This case report highlights the importance of post-procedural monitoring for such TAVI complications , even in the late period following TAVI , and if such complications occur , taking the risk to perform a life-saving operation.

Peer Review reports

According to the European Association for Cardio-Thoracic Surgery (EACTS) 2021 Guidelines, the TAVI procedure is preferred for patients with a higher surgical risk, advanced age, and severe frailty. A Heart-Team is crucial for the success of a TAVI program. Significant considerations are given to the patient’s overall physical health, any existing medical conditions they may have, as well as the specific vascular and cardiac anatomy pertinent to the case [ 1 ].

Currently, there are many TAVI platforms available on the market, supplied by various companies. The most popular are balloon-expandable Edwards Sapien Valve and self-expandable Medtronic CoreValve™ [ 2 ].

Although TAVI is a relatively safe procedure, it may also lead to numerous complications, including atrioventricular block, paravalvular leak (PVL), cerebrovascular events, vascular, annular, or ventricular problems, hypoattenuated leaflet thickening and endocarditis [ 1 , 3 ]. The majority of these complications occur in the periprocedural period, with late complications being very rare with scarce reports in the literature.

Case Presentation

An 81-year-old male patient, 167 cm of height and 61 kg of weight , with severe, symptomatic AS (CCS II , NYHA III) (peak gradient 61 mmHg, mean gradient 35 mmHg, V max 3,9 m/s) was considered as non-surgical due to high operative risk (EuroSCORE II 14.08%) and comorbidities: tricuspid valve regurgitation with concomitant severe pulmonary hypertension, congestive heart failure (ejection fraction (EF) 25%), hypertension, diffuse atherosclerosis, chronic obstructive pulmonary disease and myelodysplastic syndrome.

Considering the patient’s condition and medical history, the Heart Team decided to perform TAVI instead of surgical aortic valve replacement. In the preoperative computed tomography angiography (CTA) , the diameter of the heavily calcified ascending aorta did not exceed 3 cm (Fig.  1 ). In June 2022, Medtronic CoreValve™ Evolut™ R-26 was successfully implanted via the right femoral artery (Fig.  2 ). Follow-up echocardiography confirmed no PVL and well-functioning aortic prosthesis (peak gradient 13 mmHg, mean gradient 7,5 mmHg, V max 1,8 m/s). Postoperative period elapsed without complications and the patient was discharged home on the 3rd post-implantation day.

Preoperative computed tomography angiography (CTA) of the ascending aorta

Image of medtronic CoreValve evolut R-26 after implantation via the right femoral artery

In December 2022, 6 months after TAVI, the patient fainted at home. After regaining consciousness , he reported acute pain in the chest , dyspnoea , exhibited slurred speech and body tremors , which persisted until admitting to the hospital. The patient developed haemorrhagic shock. CTA of the aorta revealed a fresh blood reservoir around the nitinol frame of the TAVI valve − 40 mm x 32 mm on the posterior side of the aorta , and 35 mm x 23 mm on the left side of the aorta. In the pericardium , a thick-walled reservoir containing fresh blood (52 × 53 mm) was visible. The patient was diagnosed with acute ascending aortic rupture (Fig.  3 ). His EuroSCORE II was 53.20% and GERAADA score reached 64.9%. After assessment by the Heart Team and thorough explanation to the patient and patient’s family about severity of the clinical situation and extreme risks involved with the surgery, the consent for surgical approach was provided.

CT image and 3D image reconstruction of ascending aortic rupture

Intraoperatively, 3 intimal tears and rupture of the ascending aorta were found, probably in relation to the contact between the nitinol frame of the implanted valve and the aortic wall . During the procedure ascending aorta was replaced with an Intergard Woven Graft 34 mm. The proximal anastomosis was made at the level of the sinotubular junction , just above the coronary ostia. Distal anastomosis was performed at the point in the upper part of the ascending aorta before the beginning of the aortic arch. The nitinol frame of the TAVI valve was preserved by carefully aligning the graft with the edges of the TAVI cage and tightly suturing it to ensure structural integrity and functionality of the valve. The TAVI valve function was preserved therefore aortic valve replacement was not performed. Additionally, an injury of the anterior mitral leaflet, an aneurysm, was observed (Fig.  4 ); however, it had no influence on mitral valve competency.

Echocardiography image - aneurysm of the anterior mitral leaflet due to mechanical injury probably caused by the nitinol frame of the implanted valve

Haemostasis was very challenging, and the sternum closure was postponed. After successful sternal closure on the next day the patient was quickly extubated and transferred to the regular ward. In the early phase of the postoperative course the patient started active rehabilitation. He was able to walk down the hall on his own. However, because of his general frailty, an unexpected gradual deterioration of the patient’s general condition was observed. He developed a sternal wound infection, which required targeted antibiotic therapy, treatment with vacuum-assisted device and ultimately rewiring of the sternum. In the further postoperative course, left-sided haemothorax occurred, with the need for surgical treatment via left mini-thoracotomy. The patient developed gastrointestinal bleeding despite having been on proton-pump inhibitor. Urosepsis developed. The urine culture, blood culture and bronchoalveolar lavage tests were positive for Klebsiella pneumoniae. The patients’ condition worsened and he required aggressive mechanical ventilation with high oxygen concentration and high positive end-expiratory pressure. Patient’s haemodynamics was supported by noradrenaline and acute kidney injury required hemofiltration .

On the 50th postoperative day due to multi-organ failure , irreversible septic shock, and cardiac arrest, the patient passed away.

Discussion and conclusions

Although TAVI is a relatively safe procedure, potential complications including the possibility of their occurrence long after the operation are possible.

Lange et al. in an analysis of 412 patients undergoing TAVI between 2007 and 2010 reported that only 2 of these patients experienced delayed rupture of the ascending aorta [ 4 ].

The rupture of the aorta is a very rare complication after TAVI (< 1%), but it is a life-threatening condition. It results in a swiftly advancing haemorrhagic shock. Despite immediately performed medical procedures, mortality rate remains considerable [ 5 ].

Also, an aortic dissection occurs very rarely after TAVI procedure, with high mortality and reported incidence between 0.6% and 1.9% [ 6 , 7 ].

In this case , a self-expandable Medtronic CoreValve™ was chosen , which may give a higher risk of aortic rupture due to continuous outward radial force. Balloon-expandable TAVI devices , such as Edwards Sapien Valve , theoretically carry a lower risk of rupture due to one-time radial expansion that reduces mechanical stress on the aortic wall. This may reduce this type of complications. On the other hand , balloon-expandable TAVI devices may pose a bigger risk of other complications , such as annular rupture as a result of overdilatation [ 8 ]. Annular rupture is a very rare TAVI complication (1%) and includes periprocedural injuries in the region of the aortic root and left ventricular outflow tract. This complication , although rare , can be potentially fatal if not recognized and managed promptly. It should be treated surgically as soon as possible [ 8 ].

The most probable mechanism of anterior mitral leaflet aneurysm formation appears to be mechanical injury caused by the nitinol frame of the implanted TAVI valve. Specifically , lower implantation of the TAVI valve could have led to excessive contact between the nitinol frame and the anterior mitral leaflet , resulting in structural damage and the formation of an aneurysm in the leaflet.

This case highlights the critical importance of careful post-procedural monitoring for TAVI complications , such as aortic rupture , even in the late period following TAVI.

Immediate surgical intervention is often the only possible treatment option. The decision to operate was crucial to attempt to save the patient’s life despite the risk associated with the procedure.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

aortic stenosis

computed tomography angiography

European Association for Cardio-Thoracic Surgery

ejection fraction

The European System for Cardiac Operative Risk Evaluation

The German Registry for Acute Aortic Dissection Type A

paravalvular leak

transcatheter aortic valve implantation

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G.H. prepared the concept of the case and wrote the main manuscript text. H.K., D.T. and M.K. prepared figures and helped with the first draft of the manuscript. All authors reviewed and approved the manuscript.

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Hirnle, G., Kubik, H., Tenczyński, D. et al. Rupture of the ascending aorta 6 months after TAVI procedure caused by TAVI prosthesis. J Cardiothorac Surg 19 , 501 (2024). https://doi.org/10.1186/s13019-024-02980-9

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Meditation and Mindfulness: Effectiveness and Safety

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Meditation has a history that goes back thousands of years, and many meditative techniques began in Eastern traditions. The term “meditation” refers to a variety of practices that focus on mind and body integration and are used to calm the mind and enhance overall well-being. Some types of meditation involve maintaining mental focus on a particular sensation, such as breathing, a sound, a visual image, or a mantra, which is a repeated word or phrase. Other forms of meditation include the practice of mindfulness, which involves maintaining attention or awareness on the present moment without making judgments.

Programs that teach meditation or mindfulness may combine the practices with other activities. For example, mindfulness-based stress reduction is a program that teaches mindful meditation, but it also includes discussion sessions and other strategies to help people apply what they have learned to stressful experiences. Mindfulness-based cognitive therapy integrates mindfulness practices with aspects of cognitive behavioral therapy.

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Meditation and mindfulness practices usually are considered to have few risks. However, few studies have examined these practices for potentially harmful effects, so it isn’t possible to make definite statements about safety. 

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} More

A 2020 review examined 83 studies (a total of 6,703 participants) and found that 55 of those studies reported negative experiences related to meditation practices. The researchers concluded that about 8 percent of participants had a negative effect from practicing meditation, which is similar to the percentage reported for psychological therapies. The most commonly reported negative effects were anxiety and depression. In an analysis limited to 3 studies (521 participants) of mindfulness-based stress reduction programs, investigators found that the mindfulness practices were not more harmful than receiving no treatment.

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According to the National Health Interview Survey, an annual nationally representative survey, the percentage of U.S. adults who practiced meditation more than doubled between 2002 and 2022, from 7.5 to 17.3 percent. Of seven complementary health approaches for which data were collected in the 2022 survey, meditation was the most popular, beating out yoga (used by 15.8 percent of adults), chiropractic care (11.0 percent), massage therapy (10.9 percent), guided imagery/progressive muscle relaxation (6.4 percent), acupuncture (2.2 percent), and naturopathy (1.3 percent).

For children aged 4 to 17 years, data are available for 2017; in that year, 5.4 percent of U.S. children used meditation. 

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In a 2012 U.S. survey, 1.9 percent of 34,525 adults reported that they had practiced mindfulness meditation in the past 12 months. Among those responders who practiced mindfulness meditation exclusively, 73 percent reported that they meditated for their general wellness and to prevent diseases, and most of them (approximately 92 percent) reported that they meditated to relax or reduce stress. In more than half of the responses, a desire for better sleep was a reason for practicing mindfulness meditation.

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Meditation and mindfulness practices may have a variety of health benefits and may help people improve the quality of their lives. Recent studies have investigated if meditation or mindfulness helps people manage anxiety, stress, depression, pain, or symptoms related to withdrawal from nicotine, alcohol, or opioids. 

Other studies have looked at the effects of meditation or mindfulness on weight control or sleep quality. 

However, much of the research on these topics has been preliminary or not scientifically rigorous. Because the studies examined many different types of meditation and mindfulness practices, and the effects of those practices are hard to measure, results from the studies have been difficult to analyze and may have been interpreted too optimistically.

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Stress, Anxiety, and Depression

• A 2018 NCCIH-supported analysis of 142 groups of participants with diagnosed psychiatric disorders such as anxiety or depression examined mindfulness meditation approaches compared with no treatment and with established evidence-based treatments such as cognitive behavioral therapy and antidepressant medications. The analysis included more than 12,000 participants, and the researchers found that for treating anxiety and depression, mindfulness-based approaches were better than no treatment at all, and they worked as well as the evidence-based therapies.
• A 2021 analysis of 23 studies (1,815 participants) examined mindfulness-based practices used as treatment for adults with diagnosed anxiety disorders. The studies included in the analysis compared the mindfulness-based interventions (alone or in combination with usual treatments) with other treatments such cognitive behavioral therapy, psychoeducation, and relaxation. The analysis showed mixed results for the short-term effectiveness of the different mindfulness-based approaches. Overall, they were more effective than the usual treatments at reducing the severity of anxiety and depression symptoms, but only some types of mindfulness approaches were as effective as cognitive behavioral therapy. However, these results should be interpreted with caution because the risk of bias for all of the studies was unclear. Also, the few studies that followed up with participants for periods longer than 2 months found no long-term effects of the mindfulness-based practices.
• A 2019 analysis of 23 studies that included a total of 1,373 college and university students looked at the effects of yoga, mindfulness, and meditation practices on symptoms of stress, anxiety, and depression. Although the results showed that all the practices had some effect, most of the studies included in the review were of poor quality and had a high risk of bias.

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Few high-quality studies have examined the effects of meditation and mindfulness on blood pressure. According to a 2017 statement from the American Heart Association, the practice of meditation may have a possible benefit, but its specific effects on blood pressure have not been determined.

• A 2020 review of 14 studies (including more than 1,100 participants) examined the effects of mindfulness practices on the blood pressure of people who had health conditions such as hypertension, diabetes, or cancer. The analysis showed that for people with these health conditions, practicing mindfulness-based stress reduction was associated with a significant reduction in blood pressure.

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Studies examining the effects of mindfulness or meditation on acute and chronic pain have produced mixed results.

• A 2020 report by the Agency for Healthcare Research and Quality concluded that mindfulness-based stress reduction was associated with short-term (less than 6 months) improvement in low-back pain but not fibromyalgia pain.
• A 2020 NCCIH-supported analysis of five studies of adults using opioids for acute or chronic pain (with a total of 514 participants) found that meditation practices were strongly associated with pain reduction.
• Acute pain, such as pain from surgery, traumatic injuries, or childbirth, occurs suddenly and lasts only a short time. A 2020 analysis of 19 studies examined the effects of mindfulness-based therapies for acute pain and found no evidence of reduced pain severity. However, the same analysis found some evidence that the therapies could improve a person’s tolerance for pain.
• A 2017 analysis of 30 studies (2,561 participants) found that mindfulness meditation was more effective at decreasing chronic pain than several other forms of treatment. However, the studies examined were of low quality.
• A 2019 comparison of treatments for chronic pain did an overall analysis of 11 studies (697 participants) that evaluated cognitive behavioral therapy, which is the usual psychological intervention for chronic pain; 4 studies (280 participants) that evaluated mindfulness-based stress reduction; and 1 study (341 participants) of both therapies. The comparison found that both approaches were more effective at reducing pain intensity than no treatment, but there was no evidence of any important difference between the two approaches.
• A 2019 review found that mindfulness-based approaches did not reduce the frequency, length, or pain intensity of headaches. However, the authors of this review noted that their results are likely imprecise because only five studies (a total of 185 participants) were included in the analysis, and any conclusions made from the analysis should be considered preliminary.

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Mindfulness meditation practices may help reduce insomnia and improve sleep quality.

• A 2019 analysis of 18 studies (1,654 total participants) found that mindfulness meditation practices improved sleep quality more than education-based treatments. However, the effects of mindfulness meditation approaches on sleep quality were no different than those of evidence-based treatments such as cognitive behavioral therapy and exercise.

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Several clinical trials have investigated if mindfulness-based approaches such as mindfulness-based relapse prevention (MBRP) might help people recover from substance use disorders. These approaches have been used to help people increase their awareness of the thoughts and feelings that trigger cravings and learn ways to reduce their automatic reactions to those cravings.

• A 2018 review of 37 studies (3,531 total participants) evaluated the effectiveness of several mindfulness-based approaches to substance use disorder treatment and found that they significantly decreased participants’ craving levels. The mindfulness-based practices were slightly better than other therapies at promoting abstinence from substance use.
• A 2017 analysis specifically focused on MBRP examined 9 studies (901 total participants) of this approach. The analysis concluded that MBRP was not more effective at preventing substance use relapses than other treatments such as health education and cognitive behavioral therapy. However, MBRP did slightly reduce cravings and symptoms of withdrawal associated with alcohol use disorders.

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Studies have suggested that meditation and mindfulness may help reduce symptoms of post-traumatic stress disorder (PTSD).

• A 2018 review supported by NCCIH examined the effects of meditation (in 2 studies, 179 total participants) and other mindfulness-based practices (in 6 studies, 332 total participants) on symptoms of PTSD. Study participants included veterans, nurses, and people who experienced interpersonal violence. Six of the eight studies reported that participants had a reduction of PTSD symptoms after receiving some form of mindfulness-based treatment.
• A 2018 clinical trial funded by the U.S. Department of Defense compared the effectiveness of meditation, health education, and prolonged exposure therapy, a widely accepted treatment for PTSD recommended by the American Psychological Association. Prolonged exposure therapy helps people reduce their PTSD symptoms by teaching them to gradually remember traumatic memories, feelings, and situations. The study included 203 veterans with PTSD as a result of their active military service. The results of the study showed that meditation was as effective as prolonged exposure therapy at reducing PTSD symptoms and depression, and it was more effective than PTSD health education. The veterans who used meditation also showed improvement in mood and overall quality of life.

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Mindfulness-based approaches may improve the mental health of people with cancer.

• A 2019 analysis of 29 studies (3,274 total participants) of mindfulness-based practices showed that use of mindfulness practices among people with cancer significantly reduced psychological distress, fatigue, sleep disturbance, pain, and symptoms of anxiety and depression. However, most of the participants were women with breast cancer, so the effects may not be similar for other populations or other types of cancer.

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Studies have suggested possible benefits of meditation and mindfulness programs for losing weight and managing eating behaviors.

• A 2017 review of 15 studies (560 total participants) looked at the effects of mindfulness-based practices on the mental and physical health of adults with obesity or who were overweight. The review found that these practices were very effective methods for managing eating behaviors but less effective at helping people lose weight. Mindfulness-based approaches also helped participants manage symptoms of anxiety and depression.
• A 2018 analysis of 19 studies (1,160 total participants) found that mindfulness programs helped people lose weight and manage eating-related behaviors such as binge, emotional, and restrained eating. The results of the analysis showed that treatment programs, such as mindfulness-based stress reduction and mindfulness-based cognitive therapy, that combine formal meditation and mindfulness practices with informal mindfulness exercises were especially effective methods for losing weight and managing eating.

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Several studies have been done on using meditation and mindfulness practices to improve symptoms of attention-deficit hyperactivity disorder (ADHD). However, the studies have not been of high quality and the results have been mixed, so evidence that meditation or mindfulness approaches will help people manage symptoms of ADHD is not conclusive.

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Some research suggests that meditation and mindfulness practices may affect the functioning or structure of the brain. Studies have used various methods of measuring brain activity to look for measurable differences in the brains of people engaged in mindfulness-based practices. Other studies have theorized that training in meditation and mindfulness practices can change brain activity. However, the results of these studies are difficult to interpret, and the practical implications are not clear.

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NCCIH supports a variety of meditation and mindfulness studies, including:

• An evaluation of how the brain responds to the use of mindfulness meditation as part of a combined treatment for migraine pain.
• A study of the effectiveness of mindfulness therapy and medication (buprenorphine) as a treatment for opioid use disorder.
• A study of a mindfulness training program designed to help law enforcement officers improve their mental health by managing stress and increasing resilience.

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• Don’t use meditation or mindfulness to replace conventional care or as a reason to postpone seeing a health care provider about a medical problem.
• Ask about the training and experience of the instructor of the meditation or mindfulness practice you are considering.
• Take charge of your health—talk with your health care providers about any complementary health approaches you use. Together, you can make shared, well-informed decisions

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Nccih clearinghouse.

The NCCIH Clearinghouse provides information on NCCIH and complementary and integrative health approaches, including publications and searches of Federal databases of scientific and medical literature. The Clearinghouse does not provide medical advice, treatment recommendations, or referrals to practitioners.

Toll-free in the U.S.: 1-888-644-6226

Telecommunications relay service (TRS): 7-1-1

Website: https://www.nccih.nih.gov

Email: [email protected] (link sends email)

Know the Science

NCCIH and the National Institutes of Health (NIH) provide tools to help you understand the basics and terminology of scientific research so you can make well-informed decisions about your health. Know the Science features a variety of materials, including interactive modules, quizzes, and videos, as well as links to informative content from Federal resources designed to help consumers make sense of health information.

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• Anheyer D, Leach MJ, Klose P, et al.  Mindfulness-based stress reduction for treating chronic headache: a systematic review and meta-analysis . Cephalalgia . 2019;39(4):544-555.
• Black LI, Barnes PM, Clarke TC, Stussman BA, Nahin RL.  Use of yoga, meditation, and chiropractors among U.S. children aged 4–17 years . NCHS Data Brief, no 324. Hyattsville, MD: National Center for Health Statistics. 2018.
• Breedvelt JJF, Amanvermez Y, Harrer M, et al.  The effects of meditation, yoga, and mindfulness on depression, anxiety, and stress in tertiary education students: a meta-analysis . Frontiers in Psychiatry . 2019;10:193. 
• Burke A, Lam CN, Stussman B, et al.  Prevalence and patterns of use of mantra, mindfulness and spiritual meditation among adults in the United States . BMC Complementary and Alternative Medicine. 2017;17(1):316.
• Carrière K, Khoury B, Günak MM, et al.  Mindfulness‐based interventions for weight loss: a systematic review and meta‐analysis . Obesity Reviews . 2018;19(2):164-177. 
• Cavicchioli M, Movalli M, Maffei C.  The clinical efficacy of mindfulness-based treatments for alcohol and drugs use disorders: a meta-analytic review of randomized and nonrandomized controlled trials . European Addiction Research . 2018;24(3):137-162.
• Cillessen L, Johannsen M, Speckens AEM, et al.  Mindfulness‐based interventions for psychological and physical health outcomes in cancer patients and survivors: a systematic review and meta‐analysis of randomized controlled trials . Psychooncology . 2019;28(12):2257-2269.
• Creswell JD.  Mindfulness interventions . Annual Review of Psychology. 2017;68:491-516.
• Davidson RJ, Kaszniak AW.  Conceptual and methodological issues in research on mindfulness and meditation . American Psychologist. 2015;70(7):581-592.
• Farias M, Maraldi E, Wallenkampf KC, et al.  Adverse events in meditation practices and meditation-based therapies: a systematic review . Acta Psychiatrica Scandinavica. 2020;142(5):374-393. 
• Garland EL, Brintz CE, Hanley AW, et al.  Mind-body therapies for opioid-treated pain: a systematic review and meta-analysis . JAMA Internal Medicine . 2020;180(1):91-105.
• Goldberg SB, Tucker RP, Greene PA, et al. Mindfulness-based interventions for psychiatric disorders: a systematic review and meta-analysis . Clinical Psychology Review . 2018;59:52-60.
• Grant S, Colaiaco B, Motala A, et al.  Mindfulness-based relapse prevention for substance use disorders: a systematic review and meta-analysis . Journal of Addiction Medicine . 2017;11(5):386-396. 
• Haller H, Breilmann P, Schröter M et al.  A systematic review and meta‑analysis of acceptance and mindfulness‑based interventions for DSM‑5 anxiety disorders . Scientific Reports . 2021;11(1):20385.
• Hilton L, Hempel S, Ewing BA, et al.  Mindfulness meditation for chronic pain: systematic review and meta-analysis . Annals of Behavioral Medicine. 2017;51(2):199-213.
• Hirshberg MJ, Goldberg SB, Rosenkranz M, et al.  Prevalence of harm in mindfulness-based stress reduction . Psychological Medicine. August 18, 2020. [Epub ahead of print]. 
• Intarakamhang U, Macaskill A, Prasittichok P.  Mindfulness interventions reduce blood pressure in patients with non-communicable diseases: a systematic review and meta-analysis . Heliyon. 2020;6(4):e03834.
• Khoo E-L, Small R, Cheng W, et al.  Comparative evaluation of group-based mindfulness-based stress reduction and cognitive behavioural therapy for the treatment and management of chronic pain: a systematic review and network meta-analysis . Evidence-Based Mental Health.  2019;22(1):26-35.
• Levine GN, Lange RA, Bairey-Merz CN, et al.  Meditation and cardiovascular risk reduction: a scientific statement from the American Heart Association . Journal of the American Heart Association. 2017;6(10):e002218.
• Nidich S, Mills PJ, Rainforth M, et al.  Non-trauma-focused meditation versus exposure therapy in veterans with post-traumatic stress disorder: a randomised controlled trial . Lancet Psychiatry . 2018;5(12):975-986.
• Niles BL, Mori DL, Polizzi C, et al.  A systematic review of randomized trials of mind-body interventions for PTSD . Journal of Clinical Psychology . 2018;74(9):1485-1508.
• Rogers JM, Ferrari M, Mosely K, et al.  Mindfulness-based interventions for adults who are overweight or obese: a meta-analysis of physical and psychological health outcomes . Obesity Reviews . 2017;18(1):51-67. 
• Rosenkranz MA, Dunne JD, Davidson RJ.  The next generation of mindfulness-based intervention research: what have we learned and where are we headed? Current Opinion in Psychology. 2019;28:179-183.
• Rusch HL, Rosario M, Levison LM, et al.  The effect of mindfulness meditation on sleep quality: a systematic review and meta-analysis of randomized controlled trials . Annals of the New York Academy of Sciences . 2019;1445(1):5-16. 
• Schell LK, Monsef I, Wöckel A, et al. Mindfulness-based stress reduction for women diagnosed with breast cancer. Cochrane Database of Systematic Reviews. 2019;3(3):CD011518. Accessed at cochranelibrary.com on June 3, 2022.
• Semple RJ, Droutman V, Reid BA.  Mindfulness goes to school: things learned (so far) from research and real-world experiences . Psychology in the Schools. 2017;54(1):29-52.
• Shires A, Sharpe L, Davies JN, et al.  The efficacy of mindfulness-based interventions in acute pain: a systematic review and meta-analysis . Pain . 2020;161(8):1698-1707. 
• Van Dam NT, van Vugt MK, Vago DR, et al.  Mind the hype: a critical evaluation and prescriptive agenda for research on mindfulness and meditation . Perspectives on Psychological Science. 2018;13(1):36-61. 

.header_greentext{color:green!important;font-size:24px!important;font-weight:500!important;}.header_bluetext{color:blue!important;font-size:18px!important;font-weight:500!important;}.header_redtext{color:red!important;font-size:28px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;font-size:28px!important;font-weight:500!important;}.header_purpletext{color:purple!important;font-size:31px!important;font-weight:500!important;}.header_yellowtext{color:yellow!important;font-size:20px!important;font-weight:500!important;}.header_blacktext{color:black!important;font-size:22px!important;font-weight:500!important;}.header_whitetext{color:white!important;font-size:22px!important;font-weight:500!important;}.header_darkred{color:#803d2f!important;}.Green_Header{color:green!important;font-size:24px!important;font-weight:500!important;}.Blue_Header{color:blue!important;font-size:18px!important;font-weight:500!important;}.Red_Header{color:red!important;font-size:28px!important;font-weight:500!important;}.Purple_Header{color:purple!important;font-size:31px!important;font-weight:500!important;}.Yellow_Header{color:yellow!important;font-size:20px!important;font-weight:500!important;}.Black_Header{color:black!important;font-size:22px!important;font-weight:500!important;}.White_Header{color:white!important;font-size:22px!important;font-weight:500!important;} Other References

• American Academy of Pediatrics Section on Integrative Medicine. Mind-body therapies in children and youth. Pediatrics . 2016;138(3):e20161896.
• Coronado-Montoya S, Levis AW, Kwakkenbos L, et al. Reporting of positive results in randomized controlled trials of mindfulness-based mental health interventions. PLoS One . 2016;11(4):e0153220.
• Dakwar E, Levin FR. The emerging role of meditation in addressing psychiatric illness, with a focus on substance use disorders. Harvard Review of Psychiatry . 2009;17(4):254-267.
• Goyal M, Singh S, Sibinga EMS, et al. Meditation programs for psychological stress and well-being: a systematic review and meta-analysis. JAMA Internal Medicine. 2014;174(3):357-368.
• Institute of Medicine (US) Committee on Advancing Pain Research, Care, and Education. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research . Washington, DC: National Academies Press; 2011. 
• Kabat-Zinn J, Massion AO, Kristeller J, et al. Effectiveness of a meditation-based stress reduction program in the treatment of anxiety disorders. American Journal of Psychiatry. 1992;149(7):936-943.
• Ludwig DS, Kabat-Zinn J. Mindfulness in medicine. JAMA. 2008;300(11):1350-1352.
• McKeering P, Hwang Y-S. A systematic review of mindfulness-based school interventions with early adolescents. Mindfulness . 2019;10:593-610.
• Muratori P, Conversano C, Levantini V, et al. Exploring the efficacy of a mindfulness program for boys with attention-deficit hyperactivity disorder and oppositional defiant disorder. Journal of Attention Disorders . 2021;25(11):1544-1553.
• Nahin RL, Rhee A, Stussman B. Use of complementary health approaches overall and for pain management by US adults. JAMA. 2024;331(7):613-615.
• Poissant H, Mendrek A, Talbot N, et al. Behavioral and cognitive impacts of mindfulness-based interventions on adults with attention-deficit hyperactivity disorder: a systematic review. Behavioural Neurology . 2019;2019:5682050.
• Skelly AC, Chou R, Dettori JR, et al. Noninvasive Nonpharmacological Treatment for Chronic Pain: A Systematic Review Update. Comparative Effectiveness Review no. 227. Rockville, MD: Agency for Healthcare Research and Quality; 2020. AHRQ publication no. 20-EHC009.
• Stieger JR, Engel S, Jiang H, et al. Mindfulness improves brain–computer interface performance by increasing control over neural activity in the alpha band. Cerebral Cortex . 2021;31(1):426-438.
• Teasdale JD, Segal ZV, Williams JMG, et al. Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. Journal of Consulting and Clinical Psychology . 2000;68(4):615-623.
• Weng HY, Lewis-Peacock JA, Hecht FM, et al. Focus on the breath: brain decoding reveals internal states of attention during meditation. Frontiers in Human Neuroscience . 2020;14:336.
• Yoshida K, Takeda K, Kasai T, et al. Focused attention meditation training modifies neural activity and attention: longitudinal EEG data in non-meditators. Social Cognitive and Affective Neuroscience . 2020;15(2):215-223.
• Yuan JP, Connolly CG, Henje E, et al. Gray matter changes in adolescents participating in a meditation training. Frontiers in Human Neuroscience . 2020;14:319.
• Zhang J, Díaz-Román A, Cortese S. Meditation-based therapies for attention-deficit/hyperactivity disorder in children, adolescents and adults: a systematic review and meta-analysis.  Evidence-Based Mental Health . 2018;21(3):87-94.

Acknowledgments

Thanks to Elizabeth Ginexi, Ph.D., Erin Burke Quinlan, Ph.D., and David Shurtleff, Ph.D., NCCIH, for their review of this 2022 publication.

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COVID-19 and Cardiovascular Diseases: A Literature Review From Pathogenesis to Diagnosis

Aroma naeem.

1 Internal Medicine, Mayo Hospital, Lahore, Lahore, PAK

Shehroze Tabassum

Maleeka z khan, nimra mumtaz, qamoos qaiser.

2 Medicine and Surgery, Lahore General Hospital, Lahore, PAK

Mubashar Karamat

Mashhood arif.

3 Internal Medicine, Aziz Fatimah Medical and Dental College, Faisalabad, PAK

Farhan Naeem

Ahmed afifi.

4 Medicine, Benha University, Benha, EGY

Jawad Basit

5 Medicine, Holy Family Hospital, Rawalpindi, PAK

6 Cardiology, Rawalpindi Medical University, Rawalpindi, PAK

Abdulqadir J Nashwan

7 Nursing, Hamad Medical Corporation, Doha, QAT

The coronavirus disease 2019 (COVID-19) took the world by storm after the first case of COVID-19 emerged in China on December 8, 2019. The disease is generally considered as an infection of the respiratory system, but serious life-threatening myocardial injuries have been reported with this infection. Coronavirus can damage cardiac myocytes by entering the cell through angiotensin-converting enzyme 2 (ACE-2) receptor binding. Myocardial infarction, myocarditis, heart failure, cardiac arrhythmias, and Takotsubo cardiomyopathy are cardiac clinical manifestations commonly seen among patients affected by COVID-19. These cardiac pathologies are seen both during ongoing infection and post-infection. Elevated levels of myoglobin, troponin, creatine kinase-MB, plasma interleukin-6, lactate dehydrogenase (LDH), and N-terminal pro-b-type natriuretic peptide (NT-proBNP) have been found in COVID-19-associated myocardial injuries. The diagnostic modalities used in myocardial injuries due to COVID-19 include electrocardiography (ECG), cardiac magnetic resonance imaging (CMR), endomyocardial biopsy, echocardiography (Echo), and computerized tomography (CT-Scan). This literature review will discuss, in detail, the pathogenesis, clinical manifestations, and diagnosis of myocardial injuries due to COVID-19.

Introduction and background

The emergence of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Distress Syndrome-Coronavirus-2 (SARS-CoV-2), has posed one of the greatest challenges to public health in the past few years. The contagious nature of this virion and high transmissibility, even during the asymptomatic phase, has contributed to making this disease a global pandemic. A province in China called Hubei reported the first victim of COVID-19 on December 8, 2019 [ 1 ]. Within a short span of three months, this infection managed to spread across 177 countries/territories and so forth became a global pandemic [ 1 ]. So far, millions of people have been afflicted by COVID-19, and the spread has not stopped till now. As of January 8th, 2023, the present number of confirmed cases of COVID-19 outbreak equates to 668,580,044, with 6,713,479 deaths worldwide [ 2 ]. In particular, the transmission mode via respiratory droplets has played a vital role in establishing it as a global pandemic. However, the primary system targeted by COVID-19 is the respiratory system. This disease's cardiovascular complications present alarming symptoms and can be life-threatening, especially among populations with co-existent cardiovascular diseases. According to recent data, mortality was higher among populations that developed COVID-19 along with acute myocardial injury as their underlying condition compared to those without any cardiac injury, corresponding to elevation in cardiac troponin (cTn) levels [ 3 - 4 ].

Important cardiovascular manifestations of COVID-19 include myocarditis, ischemic heart disease, and arrhythmias. Patients can present with non-specific symptoms of chest pain and palpitations [ 5 ]. Cardiac complications are common not only with COVID-19 infection, but recent studies have shown that these are reported with some mRNA COVID-19 vaccines as well, with effects ranging from cardiac inflammation to life-threatening thrombosis and myocardial ischemia [ 6 ]. Treatment options depend upon the extent of cardiac insult, ranging from mild therapy to ICU admissions. A better understanding of COVID-19 pathogenesis in causing cardiac clinical manifestations can be helpful in timely diagnosis and prompt therapy to lessen the potential harm, which can reduce cardiovascular mortality rates among individuals affected by COVID-19. Our article aims to provide a comprehensive review regarding pathogenesis, clinical manifestations, and diagnosis of myocardial injuries due to COVID-19.

Pathogenesis of myocardial injuries among COVID-19 patients

Role of Angiotensin-Converting Enzyme 2 (ACE-2)

Expression of ACE-2 is typically seen in cardiac myocytes and the cells of the respiratory system and other organ systems [ 7 ]. Viral glycoprotein spike 1 of SARS-CoV-2 binds ACE2 in the host cells [ 8 ]. It causes myocardial damage and, ultimately, downregulation of ACE2 and starts an inflammatory cascade, myocardial interstitial fibrosis, and coronary plaque destabilization [ 9 - 10 ]. ACE2 is involved in converting angiotensin II to vasodilator compound angiotensin 1. Blocking of the ACE2 enzyme results in the elevation of angiotensin II, which is a pro-inflammatory compound found to be associated with raised inflammatory cytokines in systemic circulation and considered to be associated with extrapulmonary manifestations of coronavirus infection such as cardiovascular disease [ 8 ].

Role of Cytokine Storm

Multiple studies have documented high levels of inflammatory markers and cytokines, including Interferon-gamma, Interleukin-1 beta (IL-1β), monocyte chemoattractant protein (MCP-1), IP-10, and TNF alpha, in patients of COVID-19 [ 11 ]. The potential contribution of cytokine storm in causing myocardial insult in COVID-19 patients can be divided into direct and indirect effects:

Direct effect of cytokine storm: A significant rise in MCP-1 is seen after the COVID-19 outset. It is important in the recruitment of monocytes/macrophages [ 12 ]. Recruitment of macrophages around the viral inclusions poses a major threat to the mechanical functioning of the heart. Histopathology showed abundant lymphocytes and macrophages in COVID-myocarditis patients [ 13 ]. IL-1β is another important cytokine in COVID-19 patients. It stimulates the release of other cytokines, including IL-21, IL-17, and IL-22, and thickens the heart layers, ultimately leading to cardiomyopathy [ 13 - 14 ].

Indirect effect of cytokine storm: Cytokine storm indirectly causes damage to the heart by its effect on the lungs leading to hypoxemia and decreased blood supply to cardiac vasculature [ 15 ].

Role of Coagulopathy

There is a great risk of thromboembolism among COVID-19 patients, which is depicted by higher levels of fibrin degradation products (FDPs) and D-dimers, particularly in seriously ill patients [ 16 - 17 ]. ACE2 expression on endothelial cells is a site of attack for the virus, leading to systemic endothelial damage. This systemic endothelium can lead to the activation of complement and thrombin systems and aggregation of white blood cells and platelets, collectively leading to coagulopathy [ 18 ]. Moreover, immobilization in seriously ill patients is another independent risk factor contributing to coagulopathy. The prothrombotic state can be followed by a blockage of the coronary arteries [ 19 ].

Libby and Lüscher [ 20 ] described COVID-19 as an endothelial illness, especially in its more advanced complex stages. It explains the pivotal role of the endothelium in thrombosis and fibrinolysis. The endothelium has vasodilator/vasoconstrictor balance, endothelial inflammatory balance, and antioxidant/pro-oxidant balance, along with the barrier function. Disturbance of these mechanisms in disease, along with the cytokine storm, has been hypothesized to be the main pathophysiological changes leading to endothelial damage. The pathogenesis of myocardial injuries in patients by COVID-19 is summarized in Figure  1 .

Authors’ original work

ACE-2: Angiotensin-converting enzyme 2; FDPs: Fibrin degradation products.

Cardiac clinical manifestations of COVID-19

Myocardial Infarction

Myocardial infarction (MI) in COVID-19 is attributed to various pathological mechanisms. It is suggested that glycoproteins in the viral envelope can bind to both porphyrin and the β-chain of hemoglobin, leading to hypoxia which ultimately causes type 2 acute myocardial infarction (AMI), characterized by an imbalance in the myocardial oxygen demand due to infection and myocardial oxygen supply [ 9 , 20 - 21 ]. The pro-thrombotic state caused by the pro-inflammatory state can also aggravate Type 1 AMI [ 19 , 22 ].

Arrhythmias

Arrhythmias are another life-threatening complication identified in COVID-19 patients, which can result in both bradyarrhythmia and tachyarrhythmia [ 23 ]. The possible mechanism on top of direct cardiac damage by SARS-CoV-2 is electrolyte imbalances. For instance, hypokalemia due to renin-angiotensin-aldosterone system (RAAS) disturbance increases the risk of tachyarrhythmia [ 15 , 24 ]. Studies exploring the etiology of arrhythmias in COVID-19 patients with myocarditis have stated several causes, including direct cell injury, cell membrane rupture, ischemia, inflammatory cytokines, scarring, and pericarditis. Inflammatory cytokines result in dislodging of a desmosomal protein called plakoglobin and is the potent cause of arrhythmogenic cardiomyopathies [ 25 ].

Heart Failure

Heart failure is another clinical manifestation reported in COVID-19 patients [ 19 ]. Direct cardiac damage and a hyper-inflammatory state lead to necrosis in the myocardium. Moreover, endothelial insult and micro-thrombosis play a role in damaging the endocardium. These can eventually lead to the failure of the systolic and diastolic functioning of the heart, causing cardiogenic shock [ 13 ]. The compromised pulmonary vascular bed can lead to pulmonary hypertension and right heart failure [ 26 ].

Myocarditis

The direct cardiac damage and hyperinflammation caused by cytokine storms can lead to myocarditis. Viral inclusions lead to the recruitment of inflammatory cells, including monocytes, macrophages, neutrophils, and lymphocytes, which are associated with edema. Myocardial edema and necrosis of myocardial cells and connective tissue interstitium represent this viral-induced myocarditis. The cell-mediated auto-immune response caused by the virus can also lead to myocarditis [ 27 ]. Epicardial fat is linked with myocarditis, by acting as a reservoir for the COVID-19 virus and by the release of adipokines. The thickness of epicardial fat is directly associated with the extent of myocardial inflammation in COVID-19 patients [ 28 ].

Takotsubo Cardiomyopathy

Transient systolic and diastolic left ventricular dysfunction is a characteristic feature of this disease [ 29 - 30 ]. The disease is known to be preceded by an emotional and psychological trigger [ 31 ]. The role of catecholamines in its pathogenesis is widely studied and debated [ 32 ]. Studies have reported an increased incidence of this stress cardiomyopathy in COVID-19 patients [ 33 ]. The continuous stress, anxiety, fear, and panic attacks, in addition to the cytokine storm in COVID-19, can give rise to excessive catecholamine release that can trigger Takotsubo cardiomyopathy.

Myocardial Effects due to Post-COVID-19 Syndrome (PCS)

Pathogenesis in post-COVID-19 syndrome (PCS) includes autonomic nervous system (ANS) dysfunction. In the cardiovascular system, it manifests as chest pain, palpitations, orthostatic disorders, blood pressure variations, and rhythm disorders, including inappropriate sinus tachycardia (IST). IST is a prevailing condition among PCS patients and plays a vital role in cardiac symptoms seen in PCS, like palpitations, impaired exercise capacity, and fatigue [ 34 ].

Psychological Effects of COVID-19 on Heart

Both clinical and experimental research has reported the cardiovascular consequences of social distancing. The impact of loneliness and mandatory isolation period on heart diseases are profound. The lack of positive relationships is recognized as an important risk factor for cardiovascular mortality [ 35 - 36 ]. Takotsubo cardiomyopathy due to psychological stress has already been discussed above. The emotional stressors that trigger Takotsubo cardiomyopathy are further increased by the isolation period, which needs to be followed by the patients of COVID-19 [ 33 ]. Cardiac clinical manifestations of COVID-19 are summarized in Figure  2 .

AMI: Acute myocardial infarction; COVID-19: Coronavirus disease of 2019.

Diagnosing cardiac injury among COVID-19 patients

In addition to routine laboratory testing, the role of various biomarkers in diagnosing COVID-19 is being investigated to diagnose COVID-19 with a low probability of misdiagnosis reliably. Biomarkers can assist clinicians in initiating treatment and monitoring COVID-19 patients. Elevated levels of different cardiac biomarkers have been found among COVID-19 patients [ 37 ]. Many reports have shown increased serum lactate dehydrogenase levels (LDH) in most COVID-19 patients. Elevated LDH levels have been linked with increased mortality in COVID-19 patients [ 38 ].

Levels of CK-MB are raised in COVID-19 patients with acute myocardial injury. Especially patients who did not survive the COVID-19 infection were found to have raised CK-MB levels. However, raised myoglobin levels are more specific for cardiac insult in COVID-19 patients [ 39 ].

Plasma concentrations of interleukin-6 are elevated in COVID-19 patients with cardiac insult [ 5 ]. According to one meta-analysis, patients with complicated diseases had 2.9 times higher mean interleukin-6 levels than those with uncomplicated diseases [ 40 ].

Prothrombotic endothelial injury due to COVID-19 increases the likelihood of venous thromboembolism, acute myocardial infarction, and pulmonary embolism. In COVID-19 patients, raised D-dimers and fibrin degradation products indicate the development of disseminated intravascular coagulation and pulmonary embolism, which impact hemodynamic stability. Elevated D-dimer levels in COVID-19 patients have also been associated with higher mortality rates than those without a rise in D-dimers [ 38 ].

Troponin levels are elevated due to myocardial injury and myocarditis, which may be due to an increased workload on the heart, poor oxygen supply, or direct tissue injury. The raised troponin level in COVID-19 patients is a direct risk for severe outcomes such as death. In sepsis, troponin levels were also found to be of prognostic significance. However, a negative troponin profile does not exclude myocardial injury. High-sensitivity Troponin I (hs-TnI) is more reliable for diagnosing myocardial injury [ 38 - 39 ].

Elevated NT‐proBNP levels have been found in cardiac involvement in COVID-19 patients. NT-proBNP or BNP levels may also be elevated in patients who show no signs or symptoms of fluid overload, regardless of myocardial injury [ 41 ].

Other biomarkers of systemic inflammation, such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), glucose, neutrophils, and neutrophil/lymphocyte ratio, are found to be increased in COVID-19 patients with myocardial injury. However, these biomarkers may be non-specific and less sensitive [ 28 ].

Electrocardiography

In COVID-19 patients with myocarditis, electrocardiography (ECG) may show ST elevation and PR depression, indicating pericardial injury. However, QT interval prolongation, arrhythmia, bundle branch block, and premature ventricular complexes may also be depicted on ECG [ 26 ]. Cardiac complications from COVID-19 recorded on ECG may also reveal T wave inversion and non-specific ST segment disruption [ 42 ]. ECG may reveal some patients' de-novo development of fragmented QRS complexes [ 43 ]. ECG can be considered as the screening test for myocardial complications caused by COVID-19.

Echocardiography and Cardiac Magnetic Resonance Imaging

Echocardiography (Echo) and cardiac magnetic resonance imaging (CMR) are recommended by American Heart Association (AHA) to confirm myocarditis in COVID-19 patients [ 44 ]. Although endomyocardial biopsy (EMB), as a diagnostic test, is considered a gold standard for confirmation of myocarditis. However, myocardial involvement in viral myocarditis is focal and patchy, making EMB less sensitive. This necessitates non-invasive imaging tests as an essential part of the workup. Hence, CMR is the most beneficial test for viral myocarditis [ 45 ]. In a study, CMR showed myocardial inflammation, edema, and scarring in individuals with COVID-19-related myocarditis. Although CMR is a better technique than ECHO, it is less recommended because of the need for decontamination after usage and slower output. Echocardiography is recommended as it can indicate myocardial injury due to acute coronary syndrome (ACS) as a wall defect [ 46 ]. The limitations of CMR include limited availability, high cost, extended exam time, and patient-specific issues like arrhythmia, difficulty in holding one's breath, claustrophobia, implanted metallic devices, and contrast hypersensitivity [ 47 ].

CMR is the key diagnostic test for the diagnosis of acute myocarditis in the context of stable patients. Echocardiography, as opposed to CMR, enables us to perform a bedside diagnostic and prognostic assessment, allowing us to circumvent challenges associated with transporting COVID-19 patients who are unstable [ 48 ].

Endomyocardial Biopsy (EMB)

The AHA and the European Society of Cardiology presented endomyocardial biopsy (EMB) as the quintessential diagnostic aid for myocarditis [ 49 ]. EMB is considered the gold standard investigation for confirmation of myocarditis [ 45 ]. In COVID-myocarditis patients, EMB revealed an abundance of lymphocytic infiltrate and macrophages [ 47 ]. EMB can also supply tissues to look for biomarkers for a more accurate diagnosis of COVID-related myocarditis. However, EMB has its limitations, including low sensitivity, required expertise, and risk of COVID-19 spread. Therefore, if invasive right heart catheterization is required, EMB should be undertaken concurrently to reduce the risk of contagious spread [ 25 ].

EMB is an invasive procedure that should only be used in life-threatening clinical scenarios where histological information might direct therapy decisions [ 48 ].

Computerized Tomography (CT-Scan)

In a study by Özer et al. [ 27 ], the computerized tomography (CT-Scan) technique was used to evaluate the thickness of epicardial fat. Epicardial fat acts as a reservoir of coronavirus and contributes to cytokine-mediated myocardial inflammation among patients with COVID-19.

Bihan et al. found that the mean epicardial adipose tissue volume was linked to death or transfer from a non-ICU hospital medical department to an ICU in the selected cohort with a high proportion of obese individuals affected with COVID-19. To accurately predict the prognosis of COVID-19, measuring epicardial fat volume upon hospitalization may be helpful [ 50 ]. Diagnostic modalities used in myocardial injuries due to COVID-19 are summarized in Figure  3 .

COVID-19: Coronavirus disease of 2019; LDH: Lactate dehydrogenase; CK-MB: Creatine kinase-myocardial band; NT-proBNP: N-terminal pro-b-type natriuretic peptide; CK: Creatine kinase; MRI: Magnetic resonance imaging; Echo: Echocardiogram; COVID: Coronavirus disease; CT: Computed tomography.

Conclusions

COVID-19 and its associated injuries have been incriminated with many severe consequences, even death, which makes this concern a public health issue. Myocardial injury remains a significant sequela of COVID-19-induced insults. Scientific investigations are ongoing regarding the underlying pathophysiology and clinical manifestations to ultimately disentangle the complex mechanisms involved. The role of ACE2, cytokine storm, endothelial damage, and coagulopathy are some of the major factors leading to the cardiac manifestations of COVID-19. Several diagnostic modalities such as ECG, Echo, CMR, EMB, and CT scan are used for detecting the pathological changes caused by COVID-19. Several studies have been published on this topic since the pandemic's beginning, but further studies are required to strengthen the evidence.

The authors have declared that no competing interests exist.