Tag: Cardiovascular Disease

Study reveals low utilization of PCSK9 inhibitors in high-risk patients
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A new study published in Circulation: Cardiovascular Quality and Outcomes from the Family Heart Foundation -; a patient-centered research and advocacy nonprofit organization dedicated to improving the lives of families impacted by inherited lipid disorders and LDL-cholesterol -; revealed that utilization of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) to reduce low-density lipoprotein cholesterol (LDL-C) remains low among high-risk patients. Despite key developments between 2017 and early 2019 that were expected to increase appropriate utilization, rejection of prescribed PCSK9i by insurance plans remains uncharacteristically high compared to other similar therapies for cardiovascular and metabolic disease. Since 2019, PCSK9i have had a label expansion; positive results from major outcomes trials and large studies showing the use of PCSK9 inhibitors reducing cardiac events; a 60% price reduction on PCSK9i and established clinical practice guidelines all of which were supposed to improve utilization, yet access is still a barrier leaving patients at risk for heart attacks and strokes.

The burden of cardiovascular disease, driven largely by atherosclerosis, is increasing in the United States. High LDL-C is a major modifiable risk factor. A 2019 study by the Family Heart Foundation (formerly known as the FH Foundation) published in Circulation: Cardiovascular Quality and Outcomesfound that compared to individuals who were able to obtain their prescribed PCSK9i, those whose prescription was rejected by insurance plans or abandoned experienced significantly more heart attacks, strokes, and other cardiovascular events within 12 months.

The results from this new Family Heart Foundation study suggest that patients still experience substantial challenges getting the PCSK9i that have been prescribed for them by their medical team, despite guidelines recommending their use and extensive evidence documenting their role in LDL-C reduction and the prevention of heart attack or stroke. As a result, eligible patients remain at higher risk of heart attacks and other major cardiovascular events as demonstrated by the 2019 study.”

Diane E. MacDougall, Vice President of Science and Research at the Family Heart Foundation and co-author of the study

Key findings from the current study showed continued barriers for PCSK9i use:
- Despite improving since 2018, 30.95% of PCSK9i prescriptions are rejected by insurance plans. This is significantly higher compared to other guideline-recommended cardiometabolic therapies with demonstrated cardiovascular benefit (rejection rates range from 3.53% to 14.61%).
- Despite developments that were expected to increase PCSK9i utilization, new PCSK9i prescriptions remained low, at 470,018 during the 2019-2021 timeframe compared with 238,704 during the 2015-2018 timeframe.
- Taking into account both rejections by insurance plans and abandonments, paid prescription rate for PCSK9i coverage was substantially lower (49.93%) than those for other guideline-recommended cardiometabolic therapies (ranging from 68.49% to 84.45%).
While statins are the first line of treatment, they may not lower LDL-C enough for high-risk patients. The 2018 ACC/AHA Multi-society Guidelines on the Management of Blood Cholesterol recommended the use of PCSK9i for appropriate patients. PCSK9i were approved by the U.S. Food & Drug Administration in 2015 as a major advancement to lower elevated LDL-C in patients with ASCVD and familial hypercholesterolemia. After 2017, the label for PCSK9i was expanded to include reduction of cardiovascular events in ASCVD patients and reduction of elevated LDL-C in patients with primary hypercholesterolemia, based on positive data from the FOURIER and ODYSSEY Outcomes trials. In addition, PCSK9i have been similarly priced to other guideline-indicated cardiometabolic drugs since 2018.

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Journal reference:

MacDougall, D. E., et al. (2024) Trends in Patient Access to and Utilization of Prescribed PCSK9 Inhibitors in a Large US Claims Database From 2015 to 2021. Circulation: Cardiovascular Quality and Outcomes. doi.org/10.1161/CIRCOUTCOMES.123.009988.
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February 20, 2024
Study suggests high levels of vitamin B3 breakdown products are linked to higher risk of mortality, heart attacks, and stroke

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In a recent study published in Nature Medicine, researchers utilized an untargeted metabolomics technique to look for new compounds and pathways that may contribute to residual cardiovascular disease (CVD) risk.

Study: A terminal metabolite of niacin promotes vascular inflammation and contributes to cardiovascular disease risk. Image Credit: Dragana Gordic/Shutterstock.com

Background

CVD is a worldwide health problem, with only a tiny proportion of the risk linked to known risk factors. Despite breakthroughs in therapeutics, the risk of CVD remains high, indicating the presence of other unidentified variables.

Niacin, an essential vitamin in dietary staples, is critical in CVD. Treatment groups had mean LDL levels <50 mg/dl but significant cardiovascular event rates. Individuals with high inflammatory markers have an increased chance of developing CVD. However, dietary niacin intake has increased due to the increasing consumption of processed and fast food, raising concerns regarding the efficiency of therapeutic niacin in lowering CVD risk.

About the study

In the present study, researchers used untargeted mass spectrometry technology to identify circulating small molecules that predict incident CVD event risks without established risk factors.

The researchers investigated clinical, genetic, and mechanistic links between the terminal breakdown products of excess niacin and the incidence of major adverse cardiac events (MACE). They conducted untargeted metabolomics analyses on fasting plasma from stable cardiac patients in a prospective discovery cohort and subjects with elective diagnostic cardiac examinations.

The researchers postulated that the putative MACE-related analyte with m/z values of 153 Da may be a combination of two co-eluted structural isomers: the N1-methyl-2-pyridone-5-carboxamide (or 2PY) metabolite and the N1-methyl-4-pyridone-3-carboxamide (or 4PY) metabolite. They chemically synthesized both metabolite standards and conducted several chemical characterization tests.

The team used stable-isotope-dilution liquid chromatography with tandem mass spectrometry (LC-MS/MS) to examine the relationship between structural isomer levels in circulation and new-onset major-type adverse cardiovascular event risk in two validation populations [United States (US) cohort of 2,331 individuals and the European cohort of 832 individuals]. They performed a sensitivity analysis on validation cohort data to account for confounding with known risk variables.

The researchers used a genome-wide association study (GWAS) approach and meta-analyses to investigate the genetic determinants of circulating 2PY and 4PY levels. They combined the study results from the United States validation cohort with publicly available summary statistics for 2PY and 4PY levels from various multi-ancestry datasets. They reduced Acmsd expression in vivo by injecting mice with a liver-tropic adeno-associated virus (AAV) expressing either a short hairpin RNA (shRNA) targeting Acmsd or a scrambled control shRNA to directly test the notion that ACMSD influences 2PY and 4PY levels.

The researchers also used Mendelian randomization (MR) analysis to determine if genetically higher 2PY and 4PY levels were causally associated with CVD outcomes. They conducted in vitro and in vivo functional studies to investigate whether 2PY or 4PY would induce VCAM-1 expression on endothelial cells. They used in vivo methods to investigate the immediate effects of 2PY or 4PY on arterial VCAM-1 expression and function.

Results

Niacin metabolites were associated with an increase in major adverse CVD events (MACEs). Chemical production of authentic 2PY and 4PY standards and additional chemical characterization tests demonstrated that the MACE-associated blood ‘analyte’ with m/z values of 153 Da was a combination of the co-eluting structural isomers 2PY and 4PY with the same elemental composition.

In the US and European validation cohorts, serological 2PY and 4PY levels showed associations with increased three-year major-type adverse cardiovascular event risk [adjusted hazard ratios (HRs) for 2PY of 1.6 and 2.0, respectively; and for the 4PY metabolite: 1.9 and 2.0, respectively). Elevated 4PY levels were still strongly related to the incidence of major-type adverse cardiovascular event risk in both persons with relatively maintained and compromised renal function.

A phenome-level association study of the rs10496731 genetic variant, strongly correlated with both metabolite levels, found a link to soluble-type vascular adhesion molecule 1 (sVCAM-1). A meta-analysis found a link between rs10496731 and sVCAM-1 in 106,000 individuals, including 53,075 women. The validation group (974 individuals, 333 females) showed a significant correlation between sVCAM-1 expression and the niacin metabolites.

4PY metabolite (but not 2PY) administration in physiological amounts increased VCAM-1 expression and leukocyte adhesion to the vascular endothelial cells in murine animals. Both niacin metabolites were related to residual cardiovascular disease risk. The team also proposed an inflammation-dependent mechanism for the clinical connection between the 4PY metabolite and major adverse CVD events.

The study findings showed that two terminal metabolites of niacin and NAD metabolism, 2PY and 4PY, are associated with CVD regardless of established risk factors. Both metabolites genetically link to vascular inflammation, with a gene variation strongly associated with circulating 2PY and 4PY levels and sVCAM-1 levels. Excess niacin, particularly 4PY, is linked to increased MACE risks and may contribute to residual cardiovascular disease risk via inflammatory pathways. Further research is required to improve understanding of these relationships.

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February 19, 2024
Healthy lifestyles linked to specific metabolic markers, large study finds
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In a recent study published in the journal Med, researchers used a collated dataset comprising four American sample cohorts to identify the metabolomic markers of a healthy lifestyle and, potentially, the mechanisms underlying their production. They used a combination of analytical techniques, particularly liquid chromatography-mass spectrometry, on the 13,056 datasets and observed that the healthy lifestyle metabolomic signature was largely reflective of lipid metabolism pathways.

Shorter and more saturated di—and triacylglycerol metabolite sets were found to be inversely associated with healthy lifestyles, while phosphatidylcholine plasmalogens and cholesteryl esters were directly associated with the condition. Encouragingly, the relative concentrations of these biomarkers accounted for a 17% lower risk of all-cause mortality, a 19% reduced risk of cardiovascular disease-related mortality, a 17% lower risk of cancer-related mortality, and a 25% improved probability of attaining longevity.

Study: Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies

The relationship between lifestyle choices and metabolic health

Chronic, non-transmissible disease prevalence is currently higher than it has ever been and has primarily been attributed to the increased adoption of sub-optimal health behavioral choices, including diets (e.g., the Western-style diet) and physical activity levels (e.g., the sedentary lifestyle). Previous research has highlighted the profound benefits of adopting a healthy lifestyle, with research on American cohorts revealing 55-71% reduced all-cause mortality risk in individuals who maintained their body mass index (BMI) between 18.5-24.9 kg/m², consumed alcohol in moderation, partook in physical activity, and abstained from smoking.

Unfortunately, the mechanisms underpinning these interactions remain largely unknown. Some studies have suggested that individuals’ health behavior components such as body weight, diet, alcohol consumption, physical activity, and smoking may have associated metabolomic signatures indicative of their current and historical health. Still, these hypotheses have rarely been tested within a scientific framework. The limited information in the field, despite being at times confounding, suggests that polyunsaturated fatty acids (PUFAs), phosphatidylcholines (PCs), and glutamate and similar amino acids (AAs) are associated with improved health outcomes, while triacylglycerols (TAG), sphingomyelins (SMs), and carnitines are associated with suboptimal ones.

“However, most studies only examined diet and physical activity factors, with small sample sizes and limited sets of metabolites profiled. Thus, a comprehensive understanding of the metabolic pathways underlying healthy lifestyle behaviors remains to be discovered. By studying several modifiable lifestyle factors simultaneously, a better understanding of the common biological mechanisms as well as the key differences may be acquired.”

About the study

In the present study, researchers used lifestyle, metabolomic, and clinical information from four American cohorts comprising more than 13,000 individuals to compute a metabolomic-based combined healthy lifestyle score during mid-life and further examine the relationship between this score and mortality and longevity outcomes. Outcome follow-up was extensive and had a mean duration of 28 years. The cohorts included the Nurses’ Health Study (NHS; 1976), the second iteration of the same prospective cohort (NHSII; 1989), the Women’s Health Initiative (WHI; 1993), and the Health Professionals Follow-up Study (HPFS; 1986). They comprised primarily middle-aged (mean 54.3 years) women (85.8%) belonging to the White ethnicity (96.7%).

Lifestyle information was participant-reported, clinical information was obtained from the prospective cohort database, and metabolomic information was derived from (fasting) blood plasma samples obtained at the time of study initiation and subsequent follow-up. Individuals lacking data on measured outcomes (BMI, alcohol consumption, metabolomic profiling, diets, physical activity levels, smoking status) were excluded. The WHI cohort was used as an external validation cohort for results obtained from the three remaining cohorts.

Plasma metabolomic profiling was carried out using acetonitrile/methanol/formic acid extraction followed by hydrophilic interaction liquid chromatography (HILIC) and positive ionization mass spectrometry (MS) for polar compounds (e.g., amino acids) and isopropanol extraction followed by octyl high-performance liquid chromatography (HPLC) and positive ionization MS for lipids. The Metabolite Standard Initiative (MSI) database was used to identify obtained metabolites.

Lifestyle factors (treatments) were of five main categories – diet, alcohol consumption, physical activity, smoking, and BMI, and were assessed using questionnaires and the Alternative Healthy Eating Index (AHEI). Mortality and longevity (outcomes) were obtained from family-member reports (for death), State statistics records, and the National Death Index database. Multivariable linear regressions, logistic regression, and elastic linear regressions were used for statistical data analyses. Cox proportional hazard ratios were computed to translate these results into relative disease risk.

Study findings

Results reveal that the metabolomic signature most reflective of healthy lifestyles is the lipid metabolism pathway comprising PC, TAG, CE, and DAG metabolite families. Diet composition and BMI were found to be the best predictors of positive metabolite signatures. Metabolite characterization identified more than 400 metabolites associated with lifestyle choices. Elastic regression analyses identified 187 of these metabolites as descriptive of healthy lifestyle behaviors – 58 were positively associated, while 129 were inversely associated with beneficial mortality and longevity outcomes.

“…the MSEA revealed CEs, mainly of PUFAs, and PCs as the most enriched metabolite sets positively associated with a healthy lifestyle. CEs serve as a mean for the storage and transportation of cholesterol and other lipids in the blood and were shown to be reflective of dietary fat intake. PCs are naturally found in the body but also in foods such as eggs, fatty fish, and soybeans. They are well known for their essential role in cell membranes and membrane signaling.”

Animo acids and metabolites involved in purine metabolism were also highlighted as signatures of healthy lifestyles. Vegetarian diets that are rich in circulating glycine, trigonelline, asparagine, hippurate, and glutamine and poor in valine, isoleucine, and leucine were found beneficial over dietary intakes of red meats, chicken, and energy drinks.

Outcome analyses revealed a surprising fact – the metabolomic signatures identified herein were more accurate predictors of mortality and longevity than patient-reported fitness and health levels.

“Indeed, the metabolomic signature explained 38.0% of the association between the self-reported healthy lifestyle score and mortality, pointing to unique biological pathways captured by metabolomics. Consistent with the literature and with our mortality results, we found an association of the healthy lifestyle metabolomic signature with longevity, and the signature explained 48.6% of the association between self-reported healthy lifestyle score and longevity.”

Conclusion

The present study uses a large combined American cohort comprising more than 13,000 participants to identify metabolomic signatures associated with positive mortality and longevity outcomes as a consequence of healthy lifestyle and dietary choices. Study findings reveal that more than 100 metabolites are associated with (positive or negative) health lifestyle outcomes, most of which are involved in the lipid metabolism pathways.

“…our findings suggest that greater adherence to a healthy lifestyle may lead to alterations in the metabolome that are associated with lower premature mortality risk and higher likelihood of longevity. We identified a metabolomic signature associated with a combined healthy lifestyle in US adults that is strongly reflective of lipid metabolism pathways. We found that those with a higher multimetabolite score had a lower risk of total and cause-specific mortality and a greater likelihood of living longer.”
Journal reference:

Tessier, A.-J., Wang, F., Liang, L., Wittenbecher, C., Haslam, D. E., Eliassen, A. H., Tobias, D. K., Li, J., Zeleznik, O. A., Ascherio, A., Sun, Q., Stampfer, M. J., Grodstein, F., Rexrode, K. M., Manson, J. E., Balasubramanian, R., Clish, C. B., Martínez-González, M. A., Chavarro, J. E., … Guasch-Ferré, M. (2024). Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies. In Med. Elsevier BV, DOI – 10.1016/j.medj.2024.01.010, https://www.cell.com/med/fulltext/S2666-6340(24)00040-0
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February 19, 2024
Pilates lowers blood pressure in hypertensive patients, study finds
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A study published in the Journal of Human Hypertension reveals that Pilates training programs are safe for patients with hypertension and that these programs can be incorporated as a part of their rehabilitation.

Study: The efficacy of Pilates method in patients with hypertension: systematic review and meta-analysis. Image Credit: ESB Professional / Shutterstock

Background

Hypertension or high blood pressure is a major public health concern because of its widespread prevalence. The condition significantly increases the risk of cardiovascular disease and associated disability and mortality. Although medicines can effectively treat hypertension, consistent treatment adherence is the primary requisite for optimal outcomes.

Available evidence indicates that a combination of pharmacological and non-pharmacological interventions is highly effective in managing all risk factors associated with hypertension. In particular, physical exercise is considered to be an excellent intervention to reduce blood pressure in hypertensive patients. This intervention effectively reduces blood pressure even in patients who are low responsive to anti-hypertension medications.

Among various types of physical activities, aerobic exercise is considered the primary option for managing blood pressure. In addition, isometric exercise, dynamic resistance exercise, and high-intensity interval training have shown positive effects in hypertensive patients. However, despite many health benefits, these physical activities are generally associated with a low adherence rate.

In this systematic review and meta-analysis, scientists have explored the effectiveness of Pilates training programs in managing blood pressure in hypertensive patients. They have considered Pilates an alternative physical exercise option because of its adaptability in various conditions, such as rehabilitation and fitness.

Study design

The scientists searched across four electronic databases for randomized clinical trials and comparative studies that investigated the effect of Pilates training on blood pressure in patients with hypertension.

A total of four randomized clinical trials and seven comparative studies were included in the final analysis. All these studies were published between 2015 and 2023. Regarding the methodological quality of selected studies, one was low quality, four were good quality, and six were high quality.

The selected studies included a total of 458 participants with decompensated hypertension, arterial hypertension, or normal tension. All arterial hypertensive participants received anti-hypertensive treatment during the Pilates training.

Nine out of eleven selected studies used Pilates-based Mat as their study intervention; one used Pilates with apparatus, and one used both. In comparative studies, the control groups performed aerobic exercises or daily life activities.

Important observations

A considerable proportion of selected studies described the positive impacts of Pilates training programs in managing blood pressure in hypertensive patients. Data from three randomized controlled trials and two comparative studies was included in the meta-analysis.

The findings revealed that Pilates has significantly higher potency in reducing systolic, diastolic, and mean blood pressure compared to other physical activity interventions employed in control groups.

The meta-analysis of data from four comparative studies indicated that Pilates exerts similar blood pressure-lowering effects in hypertensive and normotensive participants. However, these effects were not statistically significant.

Study significance

The meta-analysis finds that Pilates is safe and effective for managing blood pressure in hypertensive patients. However, it might not necessarily have superior effects compared to other physical exercise interventions.

Most studies included in the systematic review and meta-analysis highlight the significant positive effects of Mat Pilates on blood pressure. This suggests that the incorporation of exercises that require isometric strength could be helpful in lowering blood pressure.

Mat Pilates is a low-to-moderate-intensity exercise. In contrast, Pilates with apparatus is a high-intensity exercise. Studies that employed Pilates with apparatus could not find any significant blood pressure-lowering effects. This indicates that the intensity of Pilates is an important factor to consider while applying this intervention for blood pressure management. In support of this hypothesis, existing literature depicts that light or moderate aerobic exercise is more effective than high-intensity aerobic exercise in reducing blood pressure.

Although the findings of the meta-analysis indicated blood pressure-lowering effects of Pilates, overall, it was found that Pilates does not have greater effects than aerobic exercises. Moreover, a combination of aerobic exercise and Pilates failed to demonstrate greater benefits.

Based on these observations, scientists advise incorporating Pilates as a part of the rehabilitation approach to manage blood pressure in hypertensive patients. However, it should be noted that Pilates may not necessarily offer greater benefits than aerobic exercises and that it may not necessarily help improve adherence to training programs.
Journal reference:

Daniel González-Devesa. 2024. The efficacy of Pilates method in patients with hypertension: systematic review and meta-analysis. Journal of Human Hypertension. DOI: 10.1038/s41371-024-00899-110.10, https://www.nature.com/articles/s41371-024-00899-1
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February 18, 2024
Risk of non-alcoholic fatty liver disease for cardiovascular disease and all cause death in patients with type 2 diabetes mellitus

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In a recent study published in the British Medical Journal, researchers investigated the link between non-alcoholic fatty liver disease (NAFLD) in individuals with type 2 diabetes mellitus (T2DM) and all-cause death and cardiovascular disease. They found that individuals with NAFLD and T2DM show an increased risk of cardiovascular disease (CVD) and all-cause death.

Study: Association of non-alcoholic fatty liver disease with cardiovascular disease and all cause death in patients with type 2 diabetes mellitus: nationwide population based study. Image Credit: Explode/Shutterstock.com

Background

The prevalence of NAFLD is on the rise globally and is often associated with metabolic disorders involving insulin resistance. It poses a significant health concern due to its potential to lead to liver complications and CVD, which is a leading cause of mortality, especially among NAFLD patients.

T2DM is a major risk factor for CVD and is closely linked to higher NAFLD prevalence and severity. The complex relationship between NAFLD and T2DM suggests a synergistic effect on cardiovascular risk, with a substantial proportion of T2DM patients also having NAFLD. However, studies examining their association with CVD have yielded mixed results. While some found no correlation, others demonstrated a doubled risk of CVD in T2DM patients with NAFLD compared to those without. Additionally, previous studies were limited by their cross-sectional designs and small sample sizes.

To address this gap, researchers in the present study aimed to assess the risk of CVD and all-cause mortality associated with NAFLD in T2DM patients using a large-scale, population-based longitudinal approach.

About the study

This nationwide cohort study utilized data from the National Health Information Database linked t the National Health Screening Program. The exclusion criteria were age ≤ 20 years, consumption of ≥30 g/day alcohol, missing data, or a history of type 1 diabetes mellitus, chronic hepatitis B, and C, liver cirrhosis, hepatocellular carcinoma, or CVD. Additionally, patients who developed CVD within one year were also excluded.

A total of 7,796,763 participants were selected, and the endpoint was the occurrence of all-cause death, CVD, or until 31 December 2018. CVD included myocardial infarction or ischemic stroke, confirmed through hospital admissions with corresponding claims for brain magnetic resonance imaging or computed tomography. The patients were followed-up for a median of 8.13 years.

Data on anthropometric measurements and laboratory parameters were collected. Blood pressure was measured in a seated position, and fasting venous blood samples were taken to assess various parameters, including glucose, liver enzymes, lipid profile, and creatinine levels. Additionally, the estimated glomerular filtration rate was determined.

Information on lifestyle factors such as smoking, alcohol consumption, regular exercise, and socioeconomic status was obtained through a standardized self-assessment questionnaire. Statistical methods included Cox proportional hazards models adjusted for various factors, Kaplan-Meier survival curves, and subgroup analyses.

Results and discussion

Among the participants, 6.49% of the participants had T2DM. Grade 1 and 2 NAFLD were found in 22.04% and 11.11% of participants, respectively. A higher proportion of T2DM patients had grade 2 NAFLD (26.73%) and grade 1 NAFLD (34.06%) compared to those without T2DM. Among participants with T2DM, 6.77% had CVD, and about 8.38% of participants died. In contrast, among those without T2DM, 2.24% had CVD, and about 2.71% of participants died.

Incidence rates for CVD, myocardial infarction, ischemic stroke, and all-cause mortality increased with the severity of NAFLD and were higher in patients with T2DM than in those without. Hazard ratios for these outcomes were also higher with grade 1 and grade 2 NAFLD compared to no NAFLD, regardless of T2DM status. Moreover, the five-year absolute risk for these outcomes increased with NAFLD severity, particularly in patients with T2DM. Risk differences for CVD, myocardial infarction, ischemic stroke, and all-cause death were higher between no NAFLD and grade 2 NAFLD than between no NAFLD and grade 1 NAFLD. Additionally, these risk differences were higher in patients with T2DM compared to those without T2DM.

NAFLD was linked to an increased risk of cardiovascular disease, myocardial infarction, ischemic stroke, and all-cause death in both T2DM and non-T2DM patients (p<0.001). Among NAFLD patients, those with grade 2 NAFLD exhibited the highest risk, followed by grade 1 NAFLD.

Further, the incidence rates of CVD, myocardial infarction, ischemic stroke, and all-cause death increased sequentially from no NAFLD to grade 1 NAFLD and to grade 2 NAFLD across all age groups, with higher rates observed in T2DM patients.

The study’s limitations include the use of the fatty liver index for NAFLD definition, lack of assessment of glycated hemoglobin variability and changes in diabetes drugs, limited generalizability to other ethnicities, and the inability to evaluate hepatic fibrosis.

Conclusion

In conclusion, patients with T2DM and even mild NAFLD have a higher risk of cardiovascular disease and all-cause death. The risk gap between no NAFLD and grade 1 or grade 2 NAFLD is more significant in T2DM patients than in those without. The findings emphasize the need for NAFLD screening and prevention in T2DM patients to reduce subsequent cardiovascular risk and mortality.

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February 16, 2024
Impact of diet on health outcomes among United Kingdom Biobank participants

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In a recent study published in Nutrients, researchers assessed the association between diet and health outcomes among United Kingdom Biobank (UKBB) participants.

Study: Associations of Diet with Health Outcomes in the UK Biobank: A Systematic Review. Image Credit: Yulia Furman/Shutterstock/com

Background

Diet is crucial in preventing and controlling chronic diseases, with dietary patterns associated with cardiovascular diseases and cancer. Understanding the association between nutrition and disease necessitates a comprehensive approach considering environmental, genetic, psychological, and behavioral aspects.

Large epidemiological studies, like the UKBB, which leverage big data, can provide valuable insights into the association between diet and disease. However, qualitative and quantitative reviews of previous research are required to acquire a comprehensive overview of the progress made with these data.

About the study

In the present systematic review, researchers evaluated the impact of diet on health outcomes among UK Biobank participants aged between 40 and 69 years, focusing on the relationship between diet and non-communicable disease (NCD) incidence.

The team searched the Web of Science and PubMed databases for relevant studies published from 2018 to 2022.

Eligible studies evaluated the diet of UKBB participants using 24-hour Oxford WebQ dietary recalls, food frequency questionnaires (FFQs), and food preference questionnaires (FPQs).

The studies assessed individual food components, dietary patterns, a priori-determined diets and health indices, and specific nutrients as estimation variables and the relationship between food and non-communicable diseases, with known risk factors as environmental variables (e.g., diabetes, cancer, hypertension, and cardiovascular disease).

The team excluded studies focusing on dietary intake for deficiencies, exploring dietary influence on cognitive function-related NCDs (such as Alzheimer’s disease and dementia), or individual studies examining a particular disease.

They used the Newcastle-Ottawa scale (NOS) to assess study quality. The effect estimate summary was gathered from multiple studies using hazard ratio (HR) values of models maximally adjusted for identical dietary exposures.

The team used risk estimates to compare the most and least adherence categories for healthy diets, focusing on healthy patterns and comparing their risk estimates to unhealthy ones.

For studies recording varying food proportions, they obtained risk estimates from the most to the least intake and converted odds ratios (OR) as HR values.

They used bubble plots to visually depict effect distribution, while descriptive statistics and box-and-whisker plots assessed effect distribution by disease types.

Results

Initially, the team identified 346 records, of which they considered only 36 for the systematic review, including 11 studies on cardiovascular diseases (CVDs), eight on T2DM, ten on cancer, and seven on other non-communicable diseases.

The number of participants in the included studies ranged between 5,000 and 400,000. Almost all (except one of medium quality) studies were high quality.

Most studies focused on specific macronutrients or food categories, with only a handful examining dietary patterns. Several studies found that eating more processed and red meat increases the chance of developing colorectal and lung cancer.

Fish-eating and vegetarian diets can reduce cancer incidence. A well-balanced diet with high diet quality scores could lower diabetes risk. A study reported that eating dried fruit reduced the risk of breast and lung cancer.

The study findings indicated that higher adherence to healthy diets (eating a variety of foods with a minimum of three servings of whole grains, vegetables, and fruits per day and limiting processed meat intake to once a week) modestly lowers the incidence of cardiovascular disease, T2DM, and colorectal cancer.

Healthy diets include a higher intake of plant-based foods and a lower intake of processed meats, refined grains, sugar-sweetened beverages, and foods rich in saturated fat, added sugars, and sodium.

Studies found a favorable relationship between processed foods and CVD incidence but not death. Consuming raw vegetables reduces the risk of CVD, whereas cooked vegetables do not. High fiber, sugar, and saturated fat consumption may impact their effects.

However, genetics may be more significant than nutrition in avoiding colorectal cancer. A healthy diet, red meat consumption, and processed meat consumption all produced consistent findings for CVD, T2DM, and some cancer types. A healthy diet had median HRs of 0.9 for colorectal cancer, 0.8 for CVD, and 0.9 for T2DM.

Conclusion

Overall, the study findings showed that a healthy eating pattern considerably lowers the risk of cardiovascular disease, colon cancer, and type 2 diabetes.

The UK Biobank cohort data confirms these findings, with high consumption of whole grains, fruits, vegetables, and meat marginally decreasing the incidence of type 2 diabetes, cardiovascular disease, and colorectal cancer.

Future research should use multi-omics data and machine learning algorithms to account for the intricate interactions between dietary components and their impact on disease risk.

Focusing on healthy dietary patterns that include a range of foods can strengthen correlations with CVD and T2DM.

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February 16, 2024
Managing migraines and menopausal symptoms to reduce cardiovascular risks in middle-aged women

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For middle-aged women plagued by migraines, or hot flashes and night sweats, another worry may linger in the backs of their minds: whether these experiences have set them up for a heart attack, a stroke or another cardiovascular crisis.

After all, past research suggesting such a link during and after menopause has gotten a lot of attention.

But a pair of new studies in the journal Menopause suggest that most of them don’t need to worry as much, especially if they don’t have both migraines and long-term hot flashes and night sweats.

Instead, they should focus on tackling the other factors that can raise their cardiovascular risk by getting more sleep, exercise and healthy foods, quitting tobacco, and minding their blood pressure, blood sugar, cholesterol and weight.

For women who have experienced both migraines and hot flashes or night sweats over many years, one of the new studies does suggest an extra level of cardiovascular risk. That makes heart disease and stroke prevention even more important in this group, says study leader Catherine Kim, M.D., M.P.H., of the University of Michigan.

And for women currently in their 20s and 30s who experience migraines, the new research suggests that they might be heading for a higher risk of long-term menopause-related symptoms when they get older.

Long-term study yields important insights

Kim and her colleagues at Michigan Medicine, U-M’s academic medical center, published the new pair of studies based on an in-depth analysis of data from a long-term study of more than 1,900 women who volunteered to have regular physical exams and blood tests, and to take yearly health surveys, when they were in their late teens to early 30s.

Those women, now in their 50s and 60s, have provided researchers with a priceless view of what factors shape health in the years leading up to menopause and beyond, through their continued participation in the CARDIA study.

“The anxiety and dread that women with migraines and menopausal symptoms feel about cardiovascular risk is real – but these findings suggest that focusing on prevention, and correcting unhealthy habits and risk factors, could help most women,” said Kim, who is an associate professor of internal medicine at U-M and a primary care physician.

“For the subgroup with both migraines and early persistent hot flashes and night sweats, and for those currently experiencing migraines in their early adulthood, these findings point to an added need to control risks, and address symptoms early,” she adds.

Just over 30% of the middle-aged women in the study reported they had persistent hot flashes and night sweats, which together are called vasomotor symptoms or VMS because they relate to changes in the diameter of blood vessels.

Of them, 23% had reported also having migraines. This was the only group for whom Kim and her colleagues found extra risk of stroke, heart attack or other cardiovascular events that couldn’t be explained by other risk factors that have long been known to be linked to cardiovascular problems.

In addition to those with persistent vasomotor symptoms starting in their 40s or before, 43% of the women in the study had minimal levels of such symptoms in their 50s, and 27% experienced an increase in VMS over time into their 50s and early 60s.

The latter two groups had no excess cardiovascular risk once their other risk factors were taken into account, whether or not they had migraines. Use of hormone-based birth control and estrogen to address medical issues did not affect this risk.

Controlling destiny

In the study of data from the same women in their earlier stages of life, the researchers found that the biggest factors in predicting which ones would go on to have persistent hot flashes and night sweats were having migraines, having depression, and smoking cigarettes, as well as being Black or having less than a high school education.

These two studies, taken together, underscore that not all women have the same experiences as they grow older, and that many can control the risk factors that might raise their chances of heart disease and stroke later in life. In other words, women can do a lot to control their destiny when it comes to both menopause symptoms and cardiovascular diseases.”

Catherine Kim, M.D., M.P.H., University of Michigan

She notes that the American Heart Association calls these risk factors the “Essential 8” and offers guides for what women, men and even children and teens can do to address them.

Evolving knowledge and treatment

The long-term study that the two new findings come from was specifically designed to look at cardiovascular risks when it launched in the mid-1980s. CARDIA stands for Coronary Artery Risk Development in Young Adults.

Back in the 80s, knowledge about the biology of blood vessels, down to the cellular and molecular level, was nowhere near where it is today. Both vasomotor symptoms in menopause and migraines have to do with blood vessel contraction and dilation.

But decades of research has shown the microscopic impacts on blood vessels of years of smoking, poor sleep, poor eating habits and lack of activity, as well as a person’s genetic inheritance, life experiences and hormonal history.

Newer injectable migraine medications called calcitonin gene-related peptide (CGRP) antagonists have reached the market in recent years.

Using monoclonal antibodies, they target a key receptor on the surface of blood vessel cells to prevent migraines and cluster headaches. But they are expensive and not covered by insurance for all people with migraines.

While the new study is based on data from years before these medications became available, Kim said she recommends them to her patients with persistent migraines, as well as working with them to understand what triggers their migraines and how to use other medications including pain relievers and antiseizure medications to prevent them.

She also notes that the paper on future risk of persistent hot flashes and night sweats echoes the recent trend of using antidepressant medications to try to ease these menopause effects.

Kim also says that evidence has grown about the importance of healthy sleep habits for reducing hot flashes, as well the short-term use of estradiol-based hormone therapy patches, which have not been shown to have a link to cardiovascular risk. And, she notes that research has not shown any over-the-counter supplement or herbal remedy to be effective, and that these are far less regulated than medications.

Additional authors:

Kim and Deborah Levine, M.D., M.P.H., senior author of the paper on cardiovascular risk, are both on the faculty in the Division of General Medicine, and members of the U-M Institute for Healthcare Policy and Innovation. Levine heads the Cognitive Health Services Research Program or COG-HSR. Other authors on this paper are Pamela J. Schreiner, Ph.D., of the University of Minnesota, Zhe Yin, M.S., formerly of IHPI, Rachael Whitney, Ph.D., lead statistician at COG-HSR; Stephen Sidney, MD, MPH, of Kaiser Permanente Northern California and Imo Ebong, M.D. of the University of California, Davis.

Schreiner is the senior author of the paper on later persistent VMS risk in younger women. Other authors on that paper are U-M’s Abbi Lane, Ph.D.; Zhe Yin, M.S.; Hui Jiang, Ph.D. and Richard Auchus, M.D., Ph.D.; as well as Thanh-Huyen Vu M.D., Ph.D. of Northwestern University and Cora Lewis, M.D.of the University of Alabama.

The study was funded by the National Heart, Lung and Blood Institute (HL169167), which also sponsors the CARDIA study.

Source:

Michigan Medicine – University of Michigan

Journal reference:

Kim, C., et al. (2024) Migraines, vasomotor symptoms, and cardiovascular disease in the Coronary Artery Risk Development in Young Adults study. Menopause. doi.org/10.1097/GME.0000000000002311.

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February 14, 2024
Flexitarian diet linked to lower cardiovascular risk, study finds
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A new study published in BMC Nutrition examines the cardiovascular risk associated with different dietary patterns.

Study: Plant-based diets and cardiovascular risk factors: a comparison of flexitarians, vegans and omnivores in a cross-sectional study. Image Credit: Antonina Vlasova / Shutterstock.com

How different diets impact cardiovascular health

Omnivorous diets are often rich in meat and meat products, with the average intake in Germany being above the recommended limit of 600 grams each week. High meat intake has been associated with an increased risk of obesity, high blood pressure, insulin resistance, abnormally high blood lipids, and arterial stiffening, all of which are risk factors for cardiovascular disease (CVD).

In contrast, less than 40% of people in Germany are physically active, most of whom spend less than 2.5 hours every week in physical activity. However, moderate activity could reduce the risk of atherosclerosis, a prime risk factor for CVD.

CVD is the leading cause of death around the world, as it accounts for over half of all deaths. Both modifiable and non-modifiable risk factors contribute to the development of CVD, the latter of which include a poor diet and unhealthy lifestyle.

Ecologists claim that a plant-based diet is ideal for the earth’s human population in terms of health, sustainability, animal welfare, and cost-effectiveness. However, rather than an all-or-nothing approach, there could be a happy medium with people mainly eating plant-based food coupled with occasional meat and processed meat intake. In contrast to vegetarians, this type of individual is referred to as a flexitarian.

While the typical omnivore diet has been associated with an increased CVD risk, a plant-based diet appears to reduce the risk of CVDs. However, little research to date has evaluated the impact of a flexitarian diet on CVD risk.

About the study

Study participants between 25 and 45 years old were divided into three groups. The first group comprised long-term flexitarians (FXs) who ingested 50 grams of meat or meat products each day, whereas the second group consisted of vegans who did not eat any foods of animal origin, and the third group included omnivores, whose diet included 170 grams of meat and meat products every day.

The researchers examined blood samples for various markers of CVD, blood pressure, arterial wall compliance, and whether the individual had metabolic syndrome (MetS), characterized by insulin resistance, high blood glucose levels, and an increased weight circumference. These measurements were compared with dietary patterns using multiple tools to characterize diet quality, food intake, and physical activity levels.

What did the study show?

Body mass index (BMI) values were similar for all three groups; however, FX women had lower body fat than omnivore women, with this difference not observed in men. Vegan women had the lowest body fat percentage of all study participants.

Vegetable intake increased from omnivores to vegans, with FXs and vegans consuming twice and three times as much vegetables as omnivores, respectively. Both vegans and FXs consumed twice as many fruits as omnivores.

FXs consumed significantly fewer plant-based milk or dairy alternatives, with neither favored among omnivores. Similar patterns were observed for nuts and legumes.

Meat intake was lowest among vegans and significantly less among FXs as compared to omnivores. Plant-based meat alternatives were primarily consumed among vegans, with some intake reported among FXs. Egg intake was double among omnivores as compared to FXs.

The best diet quality was observed among vegans, followed by FXs, which correlates with previous reports.

All CVD markers were at similar levels in all groups, whereas the lowest fasting glucose levels were observed in vegans. MetS marker scores were significantly better in vegans and FXs than omnivores; however, all groups were associated with low-risk score levels.

Meat and dairy intake were closely associated with total cholesterol levels; however, dairy intake was negatively correlated with fruit and vegetable intake, including legumes and meat substitutes. Soft drinks, sweets, and meat consumption were correlated with increasing low-density lipoprotein (LDL) cholesterol.

MetS scores were related to processed meat and meat consumption and sweets intake but negatively associated with fruit intake. Total inflammation was not correlated with any group.

What are the implications?

Dietary choices are crucial to reducing CVD risk, as confirmed by this pilot study on the flexitarian diet in relation to CVD risk factors. Although not an intervention study, the current study allowed for direct observation of several parameters in three distinctive groups, especially MetS scores and arterial stiffness.

A vegan diet appears to be associated with the best cardiovascular health; however, MetS and arterial stiffness were more favorable in flexitarians than in the other groups. Thus, flexitarian diets also confer significant benefits compared to omnivorous eating patterns.

Reducing meat and processed meat products intake, as in flexitarianism, may contribute to CVD risk factor advantages.”
Journal reference:

Bruns, A., Greupner, T., Nebl, J., & Hahn, A. (2024). Plant-based diets and cardiovascular risk factors: a comparison of flexitarians, vegans and omnivores in a cross-sectional study. BMC Nutrition. doi:10.1186/s40795-024-00839-9.
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February 14, 2024
Mediterranean and vegetarian diets boost heart health by improving novel CVD markers

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In a recent study published in the journal Nutrition & Metabolism, researchers evaluated the impact of the lacto-ovo vegetarian diet (VD) and Mediterranean diet (MD) on apolipoprotein levels and cardiovascular disease (CVD) risk factors among low-moderate-risk individuals.

CVD is the leading cause of global mortality, necessitating the development of novel biomarkers for prevention, early diagnosis, and treatment. Apoproteins, which regulate lipoprotein metabolism, are considered a risk marker for CVD. The European Society of Cardiology (ESC) recommends ApoB as a CVD risk marker. ApoA-I, mainly found in high-density lipoprotein (HDL) lipids, play protective roles in reverse cholesterol transport. However, data on diet’s influence on apolipoproteins is limited.

Study: Effects of a dietary intervention with lacto-ovo-vegetarian and Mediterranean diets on apolipoproteins and inflammatory cytokines: results from the CARDIVEG study. Image Credit: Brian A Jackson / Shutterstock

About the study

In the present study, researchers assessed the influences of MD and VD diets on circulating apolipoproteins and their association with cardiovascular disease risk estimators, such as inflammatory cytokine levels and lipid profiles.

The study included 52 participants (39 women; mean age of 49 years) in the Cardiovascular Prevention with Vegetarian (CARDIVEG) diet randomized, crossover clinical trial. All individuals were at low-moderate CVD risk (<5.0% at ten years, using the ESC guidelines) and selected from the Clinical Nutrition Department of Careggi Hospital, Italy.

Eligibility individuals were overweight or obese with body mass index (BMI) ≥25 kg/m2 and ≥1.0 cardiovascular disease risk factors: low-density lipoprotein (LDL) beyond 115 mg dL^-1; triglyceride levels above 150 mg dL^-1; total cholesterol above 190 g/dL; and fasting blood glucose ranging from 110 to 125.0 mg dL^-1. The researchers excluded individuals with unstable medical conditions, medication prescriptions, expecting or breastfeeding women, and those who consumed poultry, fish, meat, or meat products or participated in weight loss programs in the previous six months.

The participants followed the MD (27 individuals) and VD (25 individuals) diets for three months. Both diets comprised 50% to 55% carbohydrates, 15% to 20% proteins, and 25% to 30% total fats (≤7.0% of saturated fat, less than 300 milligrams of cholesterol). The team provided the participants with one-week menu plans, different recipes, and precise data on foods to consume and avoid.

The primary outcomes were changes in body weight, fat mass, and BMI, and the secondary outcomes included changes in circulating CVD risk markers and apolipoprotein levels. The team obtained medical history, demographics, comorbidities, risk factors, lifestyle, and dietary data at study initiation. They collected blood samples with body composition and BMI data before and after the interventions.

The team used the Medi-Lite and National Health and Nutrition Examination Survey (NHANES) questionnaires to assess adherence to MD and VD diets, respectively. They conducted a primary analysis using general linear modeling, evaluating differences in apolipoprotein levels by sex, age, and CVD risk factors. They used linear regressions to examine the association between these changes and lipid profiles, inflammatory profiles, and dietary components.

Results

MD and VD improved lipid profiles and anthropometric variables, reducing total energy, fats, and cholesterol and increasing total carbohydrates. VD lowered protein and increased dietary fiber, while MD decreased body weight, fat mass, and BMI. VD also reduces fat-free body mass. VD reduced LDL by 5.0%, while MD reduced serum triglycerides by 9.0%. Both diets lowered inflammatory parameters, with MD significantly decreasing interleukin-10 by 37% and interleukin-17 by 49%.

Both diets reduced inflammatory parameters, with significantly higher (24%) ApoC-I levels after VD. Both diets increased ApoA-I (2.7% by VD and 6.1% by MD), ApoC-I (24% by VD and 11% by MD), and ApoD (6.5% by VD and 6.2% by MD) levels. However, ApoB/ApoA-I ratios reduced by 1.9% and 7.4% after VD and MD, respectively. Conversely, the team observed opposite trends for ApoB (+0.7% by VD and −1.6% by MD), ApoC-III (−5.6% by VD and +1.8% by MD), and ApoE (+14% by VD and −1.6% by MD).

The team found negative correlations between apolipoprotein C-III and carbohydrates after MD and between ApoD levels and saturated fats after VD. In contrast, they found positive correlations between HDL and ApoD after VD and between serum triglycerides, ApoCI, and ApoD after MD. IL-17 positively correlated with ApoB and ApoC-III after VD. However, they found significant negative correlations between ApoC-III and carbohydrate percentage after MD and between ApoD and saturated fat percentage after VD. Serum triglycerides showed positive correlations with ApoC-I and ApoD levels after MD.

HDL changes positively correlated with ApoD levels after VD. Linear regressions confirmed the results, adjusted for potential confounders such as weight change and the treatment order. The subgroup analyses showed that both diets positively influenced circulating apolipoproteins, especially in women aged ≥50 years with less than three cardiovascular disease risk factors.

The study findings showed that VD and MD improve cardiovascular disease risk in low-moderate CVD-risk individuals by regulating lipid and inflammatory profiles. MD more positively affects apolipoprotein levels, especially in women, individuals aged >50 years, and those with one or two CVD risk factors. The study also found differences in associations between apolipoprotein levels and specific nutrients, with an unexpected inverse association between carbohydrate intake and ApoC-III after MD.

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February 14, 2024
AI models show promise in predicting heart disease risks, but lack validation
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In a recent review published in BMC Medicine, scientists evaluate artificial intelligence models (AI-Ms) that predict cardiovascular disease (CVD) risks in general and specific populations while also developing an independent validation score (IVS) for AI-Ms.

Study: Artificial intelligence in the risk prediction models of cardiovascular disease and development of an independent validation screening tool: a systematic review. Image Credit: Summit Art Creations / Shutterstock.com

Background

The global prevalence of cardiovascular diseases (CVDs) is increasing rapidly, which has led to the development of several CVD prediction models. CVD prediction models like Framingham and SCORE identify individuals at a greater risk of developing CVDs to ultimately implement preventive measures across the vulnerable population.

Within computer science, the application of AI, machine learning (ML), and deep learning (DL) can be used to develop computational systems with a similar functioning capacity analogous to human intelligence while performing a complex task. This functioning capacity is associated with humans’ reasoning, learning, perception, problem-solving, decision-making, and language comprehension skills.

AI-Ms have been increasingly applied in the healthcare sector for disease risk prediction. However, this application has been subjected to multiple challenges linked to data privacy, security, transparency, legality, and concerns related to ethics. Nevertheless, as compared to traditional risk prediction models, AI-Ms are associated with greater accuracy, data-processing capability, and fewer processing restrictions.

About the study

Extensive data extraction was performed based on predictors, algorithms, bias, and population. A tool to assess the replicability and applicability of AI-Ms, as well as ensure the external validation of AI-Ms, was developed to screen AI-Ms.

For the current review, all relevant articles were obtained from Embase, Web of Science, PubMed, and IEEE Library. The prediction risk of bias assessment tool (PROBAST) was also used.

Key findings

A total of 79 relevant articles published between 2017 and 2021 were obtained, of which 486 AI-Ms were identified. Most of these studies were related to the development of new AI-Ms; however, none of the models underwent independent external validation.

Thus, AI risk prediction researchers appear to be more focused on developing new models than validating existing ones, which is crucial for clinical applications. Since unvalidated AI-Ms would result in the generation of many useless prediction models, researchers must focus on validating AI-Ms to avoid wasting research time.

A key factor that restricts the implementation of external validation is the use of limited data sources for model development. However, this could be addressed by using data from multi-source databases.

Most AI-based models as CVD risk predictors were developed in North America and Europe, very few of which were developed in Asian and South American countries, whereas none were developed in Africa. Since the extent of CVD risks varies among ethnicities, it is important to develop AI-Ms that focus on specific ethnic groups.

The four most common variables used in AI-Ms for CVD risk predictions include total cholesterol, age, sex, and smoking status. Compared to traditional models, AI-Ms evaluate multimodal data, including additional gene- or protein-related information and image data. Other advantages of AI models include data re-input and utility.

Many studies did not provide important research information, which compromised model validation. In the future, studies must provide a Transparent Reporting of a multivariable prediction model for the Individual Prognosis Or Diagnosis (TRIPOD) statement when the manuscript is submitted.

According to PROBAST, all models were at a high risk of bias, primarily because of the inappropriate use of statistical tools. IVS analysis revealed that only 10 models were “recommended” for use, whereas the remaining models were categorized under “not recommended” or “warning.”

The IVS tool has been developed for screening independent external validation models. This scoring system evaluates the suitability for independent external validation based on transparency, risk assessment, performance, and clinical implication.

The newly developed IVS indicated that independent external validation may not be suitable for over 95% of the models, thus implying that these models cannot be used in clinical settings.

Conclusions

Although several AI-Ms for CVD predictions are available, few studies have systematically analyzed the models for their effectiveness. The current review summarized AI-Ms for CVD and discussed current challenges associated with their use.

The current study provided important insights into AI models used for CVD risk predictions, including the geographical imbalance, a high risk of bias, a low standard-reaching rate of report quality, a lack of independent external validation, and an imperfect evaluation system. In this context, the use of a newly developed IVS tool could help assess the replicability of the models.
Journal reference:

Cai, Y., Ca, Y., Tang, L., et al. (2024) Artificial intelligence in the risk prediction models of cardiovascular disease and development of an independent validation screening tool: a systematic review. BMC Medicine 56. doi:10.1186/s12916-024-03273-7
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February 9, 2024