Nadim Nasrallah, Mark Atallah, Tarek Harb, Gary Gerstenblith, Thorsten M. Leucker
Background
Lipoprotein(a) [Lp(a)] is a primarily genetically determined, causal and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) levels are stable, unaffected by lifestyle, and best measured using isoform-insensitive, molar-based assays. Current guidelines from the European Atherosclerosis Society and U.S. National Lipid Association recommend a one-time Lp(a) measurement in all adults. Cascade testing is advised in affected families.
Results
Elevated Lp(a) levels are associated with increased risk of coronary artery disease, myocardial infarction incidence and recurrence, and aortic stenosis onset and progression. In cerebrovascular disease, high Lp(a) is linked to large artery ischemic stroke incidence and recurrence, as well as poor functional outcomes. Associations with venous thromboembolism are limited to prothrombotic states and extreme Lp(a) concentrations. Elevated levels (≥50 mg/dL or ≥125 nmol/L) should prompt intensified risk factor modification.
Conclusion
There are no currently approved lipid-lowering therapies that substantially reduce Lp(a) levels. Novel agents to lower Lp(a) include antisense oligonucleotides, small interfering ribonucleic acid and small molecules, all of which have shown promising results in phase 2 trials. Ongoing phase 3 trials will evaluate the causal relationship between Lp(a) and ASCVD, and whether lowering Lp(a) reduces cardiovascular outcomes.
{"title":"Lipoprotein(a) in clinical practice: Risk stratification and therapeutic strategies","authors":"Nadim Nasrallah, Mark Atallah, Tarek Harb, Gary Gerstenblith, Thorsten M. Leucker","doi":"10.1111/eci.70127","DOIUrl":"10.1111/eci.70127","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lipoprotein(a) [Lp(a)] is a primarily genetically determined, causal and independent risk factor for atherosclerotic cardiovascular disease (ASCVD). Lp(a) levels are stable, unaffected by lifestyle, and best measured using isoform-insensitive, molar-based assays. Current guidelines from the European Atherosclerosis Society and U.S. National Lipid Association recommend a one-time Lp(a) measurement in all adults. Cascade testing is advised in affected families.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Elevated Lp(a) levels are associated with increased risk of coronary artery disease, myocardial infarction incidence and recurrence, and aortic stenosis onset and progression. In cerebrovascular disease, high Lp(a) is linked to large artery ischemic stroke incidence and recurrence, as well as poor functional outcomes. Associations with venous thromboembolism are limited to prothrombotic states and extreme Lp(a) concentrations. Elevated levels (≥50 mg/dL or ≥125 nmol/L) should prompt intensified risk factor modification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>There are no currently approved lipid-lowering therapies that substantially reduce Lp(a) levels. Novel agents to lower Lp(a) include antisense oligonucleotides, small interfering ribonucleic acid and small molecules, all of which have shown promising results in phase 2 trials. Ongoing phase 3 trials will evaluate the causal relationship between Lp(a) and ASCVD, and whether lowering Lp(a) reduces cardiovascular outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mark Atallah, Nadim Nasrallah, Tarek Harb, Gary Gerstenblith, Thorsten M. Leucker
Background
Lipoprotein(a) [Lp(a)] is a primarily genetically determined, low-density lipoprotein-like particle that plays an important role in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Despite optimal control of traditional lipid levels, elevated lipoprotein(a) [Lp(a)] remains a significant contributor to residual cardiovascular risk, affecting up to 20% of the global population.
Methods
We performed a literature search of PubMed/Medline and Google Scholar until July 2025 to provide a comprehensive overview of the genetics, structure, metabolism, and molecular mechanisms underlying Lp(a)'s pathogenicity.
Results
Structurally, Lp(a) consists of an LDL-like core covalently bound to apolipoprotein(a) [apo(a)], a polymorphic glycoprotein characterized by kringle IV type 2 (KIV-2) repeat variability. This copy number variation is the primary determinant of apo(a) isoform size and plasma Lp(a) levels. Small isoforms are produced more efficiently, resulting in higher concentrations. Lp(a) is synthesized in hepatocytes, and its plasma levels are predominantly governed by production rather than clearance. It carries a high burden of oxidized phospholipids (OxPLs), which confer pro-inflammatory and pro-atherogenic properties. Lp(a) promotes arterial inflammation, endothelial dysfunction, monocyte activation and impaired fibrinolysis via competition with plasminogen. It also plays a direct pathogenic role in valvular calcification by delivering OxPLs and autotaxin to valve interstitial cells, triggering osteogenic signaling cascades.
Conclusion
While environmental factors such as inflammation and hormonal status can transiently modulate levels, genetic variation overwhelmingly dictates lifelong Lp(a) burden. As novel agents targeting Lp(a) enter late-stage clinical trials, mechanistic insights into Lp(a) biology will be essential to risk stratification and future clinical management.
{"title":"The biology of lipoprotein(a): From genetics to molecular mechanisms","authors":"Mark Atallah, Nadim Nasrallah, Tarek Harb, Gary Gerstenblith, Thorsten M. Leucker","doi":"10.1111/eci.70133","DOIUrl":"10.1111/eci.70133","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lipoprotein(a) [Lp(a)] is a primarily genetically determined, low-density lipoprotein-like particle that plays an important role in atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Despite optimal control of traditional lipid levels, elevated lipoprotein(a) [Lp(a)] remains a significant contributor to residual cardiovascular risk, affecting up to 20% of the global population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We performed a literature search of PubMed/Medline and Google Scholar until July 2025 to provide a comprehensive overview of the genetics, structure, metabolism, and molecular mechanisms underlying Lp(a)'s pathogenicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Structurally, Lp(a) consists of an LDL-like core covalently bound to apolipoprotein(a) [apo(a)], a polymorphic glycoprotein characterized by kringle IV type 2 (KIV-2) repeat variability. This copy number variation is the primary determinant of apo(a) isoform size and plasma Lp(a) levels. Small isoforms are produced more efficiently, resulting in higher concentrations. Lp(a) is synthesized in hepatocytes, and its plasma levels are predominantly governed by production rather than clearance. It carries a high burden of oxidized phospholipids (OxPLs), which confer pro-inflammatory and pro-atherogenic properties. Lp(a) promotes arterial inflammation, endothelial dysfunction, monocyte activation and impaired fibrinolysis via competition with plasminogen. It also plays a direct pathogenic role in valvular calcification by delivering OxPLs and autotaxin to valve interstitial cells, triggering osteogenic signaling cascades.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>While environmental factors such as inflammation and hormonal status can transiently modulate levels, genetic variation overwhelmingly dictates lifelong Lp(a) burden. As novel agents targeting Lp(a) enter late-stage clinical trials, mechanistic insights into Lp(a) biology will be essential to risk stratification and future clinical management.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yang Chen, Ying Gue, Gregory Y. H. Lip, David S. Gardner, Mark A. J. Devonald
Background
Acute kidney injury (AKI) is common and linked to poor outcomes, but early detection remains challenging. Previous research identified urinary trace elements (TE) as early AKI biomarkers in intensive care unit (ICU) or cardiac surgery patients. We aimed to explore whether urinary TE enhance machine learning (ML) models for AKI prediction.
Methods
We constructed ML models using the ICU cohort. We filtered the variables and optimized hyperparameters before predicting Kidney Disease: Improving Global Outcomes stage 2–3 AKI using eight ML classifiers: light gradient boosting machine (LightGBM), random forest (RF), ML logistic regression, support vector machine, multilayer perceptron, eXtreme gradient boosting (XGBoost), Gaussian Naive Bayes and k-nearest neighbors. External validation was performed in the cardiac surgery cohort.
Results
Among 149 ICU patients (median age 56.0 [interquartile range (IQR): 43.5–67.0], 63.1% male), 25 developed stage 2–3 AKI; among 144 cardiac surgery patients (median age 70.0 [IQR: 62.0–76.0], 72.9% male), 12 developed stage 2–3 AKI. Each ML in the internal validation had area under the curve (AUC) above .7, with XGBoost having the highest (.813); LightGBM had the second highest AUC (.799), highest G-mean (.567) and F1-score (.545). In external validation, RF had the highest AUC (.740), XGBoost had the highest G-mean (.289) and F1-score (.286). Age, strontium and boron were consistently ranked among the top five most important features in LightGBM, RF and XGBoost.
Conclusion
ML models primarily based on urinary TE can identify AKI risk in both clinical groups (ICU and cardiac surgery), with LightGBM, RF and XGBoost serving as high-performance models for early prediction of stage 2–3 AKI.
{"title":"Machine learning prediction of moderate-to-severe acute kidney injury after ICU admission and cardiac surgery with urine trace elements","authors":"Yang Chen, Ying Gue, Gregory Y. H. Lip, David S. Gardner, Mark A. J. Devonald","doi":"10.1111/eci.70131","DOIUrl":"10.1111/eci.70131","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acute kidney injury (AKI) is common and linked to poor outcomes, but early detection remains challenging. Previous research identified urinary trace elements (TE) as early AKI biomarkers in intensive care unit (ICU) or cardiac surgery patients. We aimed to explore whether urinary TE enhance machine learning (ML) models for AKI prediction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We constructed ML models using the ICU cohort. We filtered the variables and optimized hyperparameters before predicting Kidney Disease: Improving Global Outcomes stage 2–3 AKI using eight ML classifiers: light gradient boosting machine (LightGBM), random forest (RF), ML logistic regression, support vector machine, multilayer perceptron, eXtreme gradient boosting (XGBoost), Gaussian Naive Bayes and k-nearest neighbors. External validation was performed in the cardiac surgery cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among 149 ICU patients (median age 56.0 [interquartile range (IQR): 43.5–67.0], 63.1% male), 25 developed stage 2–3 AKI; among 144 cardiac surgery patients (median age 70.0 [IQR: 62.0–76.0], 72.9% male), 12 developed stage 2–3 AKI. Each ML in the internal validation had area under the curve (AUC) above .7, with XGBoost having the highest (.813); LightGBM had the second highest AUC (.799), highest G-mean (.567) and F1-score (.545). In external validation, RF had the highest AUC (.740), XGBoost had the highest G-mean (.289) and F1-score (.286). Age, strontium and boron were consistently ranked among the top five most important features in LightGBM, RF and XGBoost.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>ML models primarily based on urinary TE can identify AKI risk in both clinical groups (ICU and cardiac surgery), with LightGBM, RF and XGBoost serving as high-performance models for early prediction of stage 2–3 AKI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12817231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alessandro Mandurino-Mirizzi, Luca Raone, Andrea Raffaele Munafò, Fabrizio Gazzoli, Marco Mussardo, Claudio Montalto, Francesco Germinal, Marco Ferlini, Italo Porto, Giuseppe Colonna, Jacopo Oreglia, Gabriele Crimi
Background
Pulmonary hypertension (PH) is frequently observed in patients with functional mitral regurgitation (FMR) and heart failure with reduced ejection fraction (HFrEF) and adversely impacts prognosis. However, limited data exist on the outcomes of transcatheter edge-to-edge mitral valve repair (M-TEER) in patients with PH, particularly regarding hemodynamic subtypes.
Methods
This multicenter, retrospective analysis included 144 HFrEF patients with moderate-to-severe or severe FMR who underwent M-TEER across four Italian centers. Baseline hemodynamic assessment was performed using right heart catheterization (RHC) in conscious patients. Procedural outcomes and clinical follow-up were evaluated at 1 year. The endpoints studied included death from any cause, heart failure hospitalization and a composite endpoint of both.
Results
Among the 144 patients, 84% had PH (64% combined post- and pre-capillary-PH (Cpc-PH), 20% isolated post-capillary-PH (Ipc-PH)). Procedural success was achieved in 92%, with significant improvements in New York Heart Association (NYHA) functional class (p < .001) and echocardiographic parameters. At 1 year, the composite endpoint occurred in 30% of patients, with higher rates in PH patients compared to no PH group (34% vs. 9%, respectively, p = .039). Among PH patients, Cpc-PH patients demonstrated the worst outcomes (for the composite endpoint at 1 year Cpc-PH 37% vs. Ipc-PH 24% vs. no-PH 9%, p = .031). Multivariate analysis confirmed Cpc-PH as a significant predictor of adverse outcomes at 1 year.
Conclusions
M-TEER is an effective therapeutic option for patients with HFrEF and FMR, providing significant procedural success and clinical improvements. However, patients with PH, particularly those with Cpc-PH, exhibit worse long-term clinical outcomes.
{"title":"Clinical outcomes of transcatheter edge-to-edge repair in patients with functional mitral regurgitation and pulmonary hypertension","authors":"Alessandro Mandurino-Mirizzi, Luca Raone, Andrea Raffaele Munafò, Fabrizio Gazzoli, Marco Mussardo, Claudio Montalto, Francesco Germinal, Marco Ferlini, Italo Porto, Giuseppe Colonna, Jacopo Oreglia, Gabriele Crimi","doi":"10.1111/eci.70130","DOIUrl":"10.1111/eci.70130","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pulmonary hypertension (PH) is frequently observed in patients with functional mitral regurgitation (FMR) and heart failure with reduced ejection fraction (HFrEF) and adversely impacts prognosis. However, limited data exist on the outcomes of transcatheter edge-to-edge mitral valve repair (M-TEER) in patients with PH, particularly regarding hemodynamic subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This multicenter, retrospective analysis included 144 HFrEF patients with moderate-to-severe or severe FMR who underwent M-TEER across four Italian centers. Baseline hemodynamic assessment was performed using right heart catheterization (RHC) in conscious patients. Procedural outcomes and clinical follow-up were evaluated at 1 year. The endpoints studied included death from any cause, heart failure hospitalization and a composite endpoint of both.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Among the 144 patients, 84% had PH (64% combined post- and pre-capillary-PH (Cpc-PH), 20% isolated post-capillary-PH (Ipc-PH)). Procedural success was achieved in 92%, with significant improvements in New York Heart Association (NYHA) functional class (<i>p</i> < .001) and echocardiographic parameters. At 1 year, the composite endpoint occurred in 30% of patients, with higher rates in PH patients compared to no PH group (34% vs. 9%, respectively, <i>p</i> = .039). Among PH patients, Cpc-PH patients demonstrated the worst outcomes (for the composite endpoint at 1 year Cpc-PH 37% vs. Ipc-PH 24% vs. no-PH 9%, <i>p</i> = .031). Multivariate analysis confirmed Cpc-PH as a significant predictor of adverse outcomes at 1 year.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>M-TEER is an effective therapeutic option for patients with HFrEF and FMR, providing significant procedural success and clinical improvements. However, patients with PH, particularly those with Cpc-PH, exhibit worse long-term clinical outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12817235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145212164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Office and out-of-office blood pressure in the European guidelines on hypertension: A clinical perspective","authors":"Guido Grassi, Pasquale Ambrosino, Giuseppe Mancia","doi":"10.1111/eci.70129","DOIUrl":"10.1111/eci.70129","url":null,"abstract":"","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"55 12","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Valerie Aponte Ribero, Oliver Baretella, Cinzia Del Giovane, Moa Haller, Martin Feller, Benoît Boland, Antoine Christiaens, Wilma Knol, Denis O'Mahony, Viktoria Gastens, Baris Gencer, Stéphanie Baggio, Nicolas Rodondi
Background
The benefit of statins in multimorbid older adults is controversial. Prior observational studies evaluating statin discontinuation in older adults were retrospective cohorts, did not focus on multimorbidity, or lacked adjustment for geriatric syndromes. We aimed to assess the effect of statin discontinuation on cardiovascular and mortality outcomes using the target trial emulation framework.
Methods
We conducted a prospective cohort study using data from the OPERAM trial in adults aged ≥70 years with ≥3 chronic conditions and ≥5 chronic drugs, comparing statin discontinuation to continuation. The primary composite outcome was cardiovascular events or all-cause mortality at 12 months. We calculated adjusted hazard ratios (HR) using weighted pooled logistic regressions without (model-A) and with adjustment for two geriatric syndromes (falls and weight loss; model-B).
Results
Of 2668 person-trial units (mean age 78.5 years), 2533 (95%) continued and 133 (5%) discontinued statins. Discontinuation was associated with higher composite outcome risk (27% vs. 18%; HR model-A 1.53 [95% CI 1.14–2.06]; model-B 1.49 [1.12–1.99]). This was mainly attributable to increased non-cardiovascular deaths (20% vs. 11%; HR model-A 1.56 [1.08–2.27]; model-B 1.52 [1.06–2.19]); there was no clear evidence for an association with cardiovascular events (7% vs. 8%; HR model-A 1.36 [.86–2.14]; model-B 1.35 [.86–2.12]).
Conclusion
In this first target trial emulation in a multimorbid older population, statin discontinuation was associated with increased risk of the composite of cardiovascular events or all-cause mortality, primarily driven by non-cardiovascular deaths. Geriatric syndromes did not modify these increased risks. Only clinical trials can clarify the safety of statin discontinuation.
背景：他汀类药物对多病老年人的益处是有争议的。先前评估老年人停用他汀类药物的观察性研究是回顾性队列研究，没有关注多病，也缺乏对老年综合征的调整。我们的目的是使用目标试验模拟框架评估他汀类药物停药对心血管和死亡率结果的影响。方法：我们使用来自OPERAM试验的数据进行了一项前瞻性队列研究，研究对象为年龄≥70岁、有≥3种慢性疾病和≥5种慢性药物的成年人，比较他汀类药物停药和继续停药。主要综合结局是心血管事件或12个月时的全因死亡率。我们使用加权合并logistic回归计算调整后的风险比（HR），不考虑（模型a），并对两种老年综合征（跌倒和体重减轻，模型b）进行调整。结果：在2668人试验单位（平均年龄78.5岁）中，2533人（95%）继续服用他汀类药物，133人（5%）停用他汀类药物。停药相关的综合结局风险较高（27%对18%；HR模型a为1.53 [95% CI 1.14-2.06]；模型b为1.49[1.12-1.99]）。这主要是由于非心血管死亡增加（20% vs 11%； HR模型a为1.56[1.08-2.27]；模型b为1.52 [1.06-2.19]）；没有明确的证据表明与心血管事件相关（7%对8%；HR模型a 1.36[.86-2.14]；模型b 1.35[.86-2.12]）。结论：在多病老年人群的第一个目标试验模拟中，他汀类药物停药与心血管事件或全因死亡率的综合风险增加相关，主要由非心血管死亡驱动。老年综合症并没有改变这些增加的风险。只有临床试验才能阐明他汀类药物停药的安全性。
{"title":"Target trial emulation of statin discontinuation in multimorbid older adults with polypharmacy","authors":"Valerie Aponte Ribero, Oliver Baretella, Cinzia Del Giovane, Moa Haller, Martin Feller, Benoît Boland, Antoine Christiaens, Wilma Knol, Denis O'Mahony, Viktoria Gastens, Baris Gencer, Stéphanie Baggio, Nicolas Rodondi","doi":"10.1111/eci.70126","DOIUrl":"10.1111/eci.70126","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The benefit of statins in multimorbid older adults is controversial. Prior observational studies evaluating statin discontinuation in older adults were retrospective cohorts, did not focus on multimorbidity, or lacked adjustment for geriatric syndromes. We aimed to assess the effect of statin discontinuation on cardiovascular and mortality outcomes using the target trial emulation framework.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a prospective cohort study using data from the OPERAM trial in adults aged ≥70 years with ≥3 chronic conditions and ≥5 chronic drugs, comparing statin discontinuation to continuation. The primary composite outcome was cardiovascular events or all-cause mortality at 12 months. We calculated adjusted hazard ratios (HR) using weighted pooled logistic regressions without (model-A) and with adjustment for two geriatric syndromes (falls and weight loss; model-B).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 2668 person-trial units (mean age 78.5 years), 2533 (95%) continued and 133 (5%) discontinued statins. Discontinuation was associated with higher composite outcome risk (27% vs. 18%; HR model-A 1.53 [95% CI 1.14–2.06]; model-B 1.49 [1.12–1.99]). This was mainly attributable to increased non-cardiovascular deaths (20% vs. 11%; HR model-A 1.56 [1.08–2.27]; model-B 1.52 [1.06–2.19]); there was no clear evidence for an association with cardiovascular events (7% vs. 8%; HR model-A 1.36 [.86–2.14]; model-B 1.35 [.86–2.12]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In this first target trial emulation in a multimorbid older population, statin discontinuation was associated with increased risk of the composite of cardiovascular events or all-cause mortality, primarily driven by non-cardiovascular deaths. Geriatric syndromes did not modify these increased risks. Only clinical trials can clarify the safety of statin discontinuation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12817241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Several mental disorders has been associated with cardiovascular disease (CVD), although stress may have the strongest correlation. In this narrative review, we examine how stress is linked to CVD.
Results
Stress can be secondary to multiple factors and it can be imposed on an individual in more or less manifest ways. Psychosocial stress can result from adverse social circumstances such as poverty, racial, gender, religious disparities or discrimination, violence and environmental pollution. Large segments of the population are forced to endure poor working conditions, low food quality, physical and verbal abuse not only in the developing world but also in more flourishing societies as well. Wars that have ignited widely of late are inherently stressful events with potential enduring effects after the conflicts. Isolation and loneliness are growing issues in modern societies and impose a heavy burden of stress. Epidemiological studies have shown that stress is linked to CVD through an increased incidence of traditional risk factors (smoking, hypertension, insulin resistance and obesity). Experimental and laboratory evidence has shown a link between stress and CVD via neuro-endocrine, inflammatory and immune pathways. Patients with prior CV events affected by stress are at higher risk of recurrent events compared to similar patients without stressful conditions.
Conclusions
The close association between stress and CVD suggests that interventions to limit the effect of stress may result in a reduced incidence of de novo and recurrent CV events. Physicians should be aware of the importance of screening for stress in patients with CVD. Future efforts should be directed to the development of easily implementable screening tools and targeted interventions within healthcare frameworks.
{"title":"Mental stress as a trigger of cardiovascular events: A narrative review","authors":"Paolo Raggi","doi":"10.1111/eci.70128","DOIUrl":"10.1111/eci.70128","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Several mental disorders has been associated with cardiovascular disease (CVD), although stress may have the strongest correlation. In this narrative review, we examine how stress is linked to CVD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Stress can be secondary to multiple factors and it can be imposed on an individual in more or less manifest ways. Psychosocial stress can result from adverse social circumstances such as poverty, racial, gender, religious disparities or discrimination, violence and environmental pollution. Large segments of the population are forced to endure poor working conditions, low food quality, physical and verbal abuse not only in the developing world but also in more flourishing societies as well. Wars that have ignited widely of late are inherently stressful events with potential enduring effects after the conflicts. Isolation and loneliness are growing issues in modern societies and impose a heavy burden of stress. Epidemiological studies have shown that stress is linked to CVD through an increased incidence of traditional risk factors (smoking, hypertension, insulin resistance and obesity). Experimental and laboratory evidence has shown a link between stress and CVD via neuro-endocrine, inflammatory and immune pathways. Patients with prior CV events affected by stress are at higher risk of recurrent events compared to similar patients without stressful conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The close association between stress and CVD suggests that interventions to limit the effect of stress may result in a reduced incidence of de novo and recurrent CV events. Physicians should be aware of the importance of screening for stress in patients with CVD. Future efforts should be directed to the development of easily implementable screening tools and targeted interventions within healthcare frameworks.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12817239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juan Carlos Rivillas-García, Emilie Courtin, Eleanor Winpenny, Olaide Adebayo-Clement, Raúl Devia-Rodríguez, Ornella Moreno-Mattar, Paolo Vineis
Background
Evidence on the impacts of parental and early life socio-economic position (SEP) on health outcomes in adulthood remains mixed. This systematic review and meta-analysis investigated the association between low parental SEP and adult cardiometabolic and inflammatory markers in individuals aged 18 years and older.
Methods
A systematic search across five databases (EMBASE, Ovid MEDLINE, Cinahl, Global Health and Maternity and Infant Care until January 01, 2022) identified observational studies linking parental SEP with adult cardiometabolic and inflammatory markers. Pooled Standardized Mean Differences (SMD) were estimated using random-effects models. Risk of bias, heterogeneity and publication bias were assessed using the Cochrane tool, subgroup analysis and Egger's test, respectively.
Results
The review included 38 studies (12 in meta-analysis, n = 388,674). Findings showed that lower parental SEP was significantly associated with elevated blood pressure (SMD = .30 mmHg; 95% CI: .10, .50; I2 94%; n = 5), increased adiposity (SMD = .56; 95% CI: .05, 1.07: I2 98%; n = 6), higher C-reactive protein levels (SMD = 1.45 mg/dL; 95% CI: .06, 2.85; I2 80%; n = 9), elevated IL-6 (SMD = 2.12 pg./mL; 95% CI: −.72, 4.97; I2 100%; n = 4) and higher allostatic load (SMD = .85; 95% CI: .30, 1.40; I2 99%; n = 4). No consistent associations were found for glucose or lipid markers. Gender-specific variations were observed.
Conclusions
Low parental socio-economic position negatively impacts adult offspring health, manifesting as higher blood pressure, elevated C-reactive protein, increased interleukin-6, greater adiposity and higher allostatic load. Future research should prioritise three critical areas: mechanistic specificity, intersectional pathways and life-course timing and critical period detection.
{"title":"The intergenerational effects of low parental socio-economic position on cardiometabolic and inflammatory outcomes: A systematic review and meta-analysis","authors":"Juan Carlos Rivillas-García, Emilie Courtin, Eleanor Winpenny, Olaide Adebayo-Clement, Raúl Devia-Rodríguez, Ornella Moreno-Mattar, Paolo Vineis","doi":"10.1111/eci.70125","DOIUrl":"10.1111/eci.70125","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Evidence on the impacts of parental and early life socio-economic position (SEP) on health outcomes in adulthood remains mixed. This systematic review and meta-analysis investigated the association between low parental SEP and adult cardiometabolic and inflammatory markers in individuals aged 18 years and older.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A systematic search across five databases (EMBASE, Ovid MEDLINE, Cinahl, Global Health and Maternity and Infant Care until January 01, 2022) identified observational studies linking parental SEP with adult cardiometabolic and inflammatory markers. Pooled Standardized Mean Differences (SMD) were estimated using random-effects models. Risk of bias, heterogeneity and publication bias were assessed using the Cochrane tool, subgroup analysis and Egger's test, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The review included 38 studies (12 in meta-analysis, <i>n</i> = 388,674). Findings showed that lower parental SEP was significantly associated with elevated blood pressure (SMD = .30 mmHg; 95% CI: .10, .50; <i>I</i><sup>2</sup> 94%; <i>n</i> = 5), increased adiposity (SMD = .56; 95% CI: .05, 1.07: <i>I</i><sup>2</sup> 98%; <i>n</i> = 6), higher C-reactive protein levels (SMD = 1.45 mg/dL; 95% CI: .06, 2.85; <i>I</i><sup>2</sup> 80%; <i>n</i> = 9), elevated IL-6 (SMD = 2.12 pg./mL; 95% CI: −.72, 4.97; <i>I</i><sup>2</sup> 100%; <i>n</i> = 4) and higher allostatic load (SMD = .85; 95% CI: .30, 1.40; <i>I</i><sup>2</sup> 99%; <i>n</i> = 4). No consistent associations were found for glucose or lipid markers. Gender-specific variations were observed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Low parental socio-economic position negatively impacts adult offspring health, manifesting as higher blood pressure, elevated C-reactive protein, increased interleukin-6, greater adiposity and higher allostatic load. Future research should prioritise three critical areas: mechanistic specificity, intersectional pathways and life-course timing and critical period detection.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12817245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145185138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gabriele Gaggero, Alessandro Pesaresi, Debora Giunti, Andrea Bianconi, Monica Truffelli, Massimiliano Grassi, Luca Valle, Sharon Duzioni, Paolo Nozza, Mariella Dono, Giorgia Anselmi, Gianluigi Zona, Valerio Vellone, Pietro Fiaschi
Background
Molecular expression of meningiomas has become increasingly important for predicting their biological behaviour. However, the factors influencing tumour recurrence and progression after surgery remain unclear. Recent studies suggest that programmed death-ligand 1 (PD-L1) could be a key predictive and therapeutic factor in these tumours.
Methods
This single-center retrospective study included 96 patients who underwent Simpson Grade I resection of intracranial meningiomas between 2001 and 2022. PD-L1 expression was assessed immunohistochemically (clone SP142) and categorized as overall (OE), membranous (mb), granular cytoplasmic (gr) and perinuclear dot-like. Associations with WHO grade, recurrence, mitotic count and Ki-67 index were analysed using univariate and multivariate statistics.
Results
118 samples were analysed. Grade 2 meningiomas showed significantly higher mitotic count (4.0 ± 5.5 vs. 1.0 ± 1.0 n/mm2, p < .001) and Ki-67 index (7.6 ± 2.1% vs. 3.5 ± .2%, p < .001) than Grade 1. PD-L1 OE (2.0 ± 5.0% vs. .0 ± 1.0%, p < .001), gr (1.0 ± 2.5% vs. .0 ± 1.0%, p < .001) and mb (1.0 ± 1.0% vs. .0 ± .0%, p = .003) expressions were also higher in Grade 2. At recurrence, Grade 1 tumours progressing to Grade 2 showed increased PD-L1 OE (p = .025), gr (p = .024) and mb (p = .037). Multivariate analysis confirmed PD-L1 gr and mb as independent markers of high-grade tumours.
Conclusions
Granular cytoplasmic and membranous PD-L1 expression patterns are significantly associated with tumour grade, recurrence and progression, suggesting their potential role as prognostic biomarkers in meningiomas.
背景：脑膜瘤的分子表达在预测其生物学行为方面变得越来越重要。然而，影响术后肿瘤复发和进展的因素仍不清楚。最近的研究表明，程序性死亡配体1 （PD-L1）可能是这些肿瘤的关键预测和治疗因素。方法：这项单中心回顾性研究纳入了2001年至2022年间96例接受Simpson I级颅内脑膜瘤切除术的患者。免疫组织化学检测PD-L1的表达（克隆SP142），并将其分为整体（OE）、膜状（mb）、颗粒状细胞质（gr）和核周点状。采用单因素和多因素统计分析与WHO分级、复发率、有丝分裂计数和Ki-67指数的关系。结果：对118份样品进行了分析。2级脑膜瘤有丝分裂计数（4.0±5.5 vs. 1.0±1.0 n/mm2）显著高于2级脑膜瘤（4.0±5.5 vs. 1.0±1.0 n/mm2）。结论：颗粒状细胞质和膜质PD-L1表达模式与肿瘤分级、复发和进展显著相关，提示其作为脑膜瘤预后生物标志物的潜在作用。
{"title":"PD-L1 expression pattern as predictive factor of biological behaviour in intracranial meningiomas: A single-center retrospective study","authors":"Gabriele Gaggero, Alessandro Pesaresi, Debora Giunti, Andrea Bianconi, Monica Truffelli, Massimiliano Grassi, Luca Valle, Sharon Duzioni, Paolo Nozza, Mariella Dono, Giorgia Anselmi, Gianluigi Zona, Valerio Vellone, Pietro Fiaschi","doi":"10.1111/eci.70124","DOIUrl":"10.1111/eci.70124","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Molecular expression of meningiomas has become increasingly important for predicting their biological behaviour. However, the factors influencing tumour recurrence and progression after surgery remain unclear. Recent studies suggest that programmed death-ligand 1 (PD-L1) could be a key predictive and therapeutic factor in these tumours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This single-center retrospective study included 96 patients who underwent Simpson Grade I resection of intracranial meningiomas between 2001 and 2022. PD-L1 expression was assessed immunohistochemically (clone SP142) and categorized as overall (OE), membranous (mb), granular cytoplasmic (gr) and perinuclear dot-like. Associations with WHO grade, recurrence, mitotic count and Ki-67 index were analysed using univariate and multivariate statistics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>118 samples were analysed. Grade 2 meningiomas showed significantly higher mitotic count (4.0 ± 5.5 vs. 1.0 ± 1.0 n/mm<sup>2</sup>, <i>p</i> < .001) and Ki-67 index (7.6 ± 2.1% vs. 3.5 ± .2%, <i>p</i> < .001) than Grade 1. PD-L1 OE (2.0 ± 5.0% vs. .0 ± 1.0%, <i>p</i> < .001), gr (1.0 ± 2.5% vs. .0 ± 1.0%, <i>p</i> < .001) and mb (1.0 ± 1.0% vs. .0 ± .0%, <i>p</i> = .003) expressions were also higher in Grade 2. At recurrence, Grade 1 tumours progressing to Grade 2 showed increased PD-L1 OE (<i>p</i> = .025), gr (<i>p</i> = .024) and mb (<i>p</i> = .037). Multivariate analysis confirmed PD-L1 gr and mb as independent markers of high-grade tumours.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Granular cytoplasmic and membranous PD-L1 expression patterns are significantly associated with tumour grade, recurrence and progression, suggesting their potential role as prognostic biomarkers in meningiomas.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Domenico Mario Giamundo, Giuliano Cassataro, Stefano Ministrini, Simon F. Stämpfli
Background
Amyloidosis is characterised by the extracellular accumulation of misfolded proteins forming amorphous aggregates called amyloid. Cardiac amyloidosis results from myocardial involvement in systemic amyloidosis, leading to impaired heart function. Besides myocardial involvement, cardiac amyloidosis may also directly and indirectly affect the central nervous system.
Methods
This narrative review summarises current evidence about on central nervous system involvement in cardiac amyloidosis and the pathophysiological mechanisms linking heart and brain in the context of this systemic disease.
Results
Although the pathophysiological relationship between cardiac amyloidosis and cognitive decline remains poorly understood, central nervous system involvement likely results from the complex interplay of direct amyloid deposition, cerebrovascular changes, and cardiac dysfunction.
Conclusion
The growing awareness of cognitive impairment in patients with cardiac amyloidosis highlights the need for further research and supports a multidisciplinary approach in the assessment and management of affected individuals.
{"title":"Central nervous system involvement in cardiac amyloidosis: Redefining the heart-brain axis","authors":"Domenico Mario Giamundo, Giuliano Cassataro, Stefano Ministrini, Simon F. Stämpfli","doi":"10.1111/eci.70122","DOIUrl":"10.1111/eci.70122","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Amyloidosis is characterised by the extracellular accumulation of misfolded proteins forming amorphous aggregates called amyloid. Cardiac amyloidosis results from myocardial involvement in systemic amyloidosis, leading to impaired heart function. Besides myocardial involvement, cardiac amyloidosis may also directly and indirectly affect the central nervous system.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This narrative review summarises current evidence about on central nervous system involvement in cardiac amyloidosis and the pathophysiological mechanisms linking heart and brain in the context of this systemic disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Although the pathophysiological relationship between cardiac amyloidosis and cognitive decline remains poorly understood, central nervous system involvement likely results from the complex interplay of direct amyloid deposition, cerebrovascular changes, and cardiac dysfunction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The growing awareness of cognitive impairment in patients with cardiac amyloidosis highlights the need for further research and supports a multidisciplinary approach in the assessment and management of affected individuals.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12811839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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