Pub Date : 2024-05-27eCollection Date: 2024-05-01DOI: 10.1093/ehjopen/oeae043
Eloi Gagnon, Arnaud Girard, Jérôme Bourgault, Erik Abner, Dipender Gill, Sébastien Thériault, Marie-Claude Vohl, André Tchernof, Tõnu Esko, Patrick Mathieu, Benoit J Arsenault
Aims: Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed.
Methods and results: To prioritize anticoagulant targets with the strongest efficacy [venous thromboembolism (VTE) prevention] and safety (low bleeding risk) profiles, we performed two-sample Mendelian randomization and genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery data set and Fenland and Atherosclerosis Risk in Communities as replication data sets] and one liver gene expression data set (Institut Universitaire de Cardiologie et de Pneumologie de Québec bariatric biobank) to evaluate evidence for a causal effect of 26 coagulation cascade proteins on VTE from a new genome-wide association meta-analysis of 44 232 VTE cases and 847 152 controls, stroke subtypes, bleeding outcomes, and parental lifespan as an overall measure of efficacy/safety ratio. A 1 SD genetically predicted reduction in F2 blood levels was associated with lower risk of VTE [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.38-0.51, P = 2.6e-28] and cardioembolic stroke risk (OR = 0.55, 95% CI = 0.39-0.76, P = 4.2e-04) but not with bleeding (OR = 1.13, 95% CI = 0.93-1.36, P = 2.2e-01). Genetically predicted F11 reduction was associated with lower risk of VTE (OR = 0.61, 95% CI = 0.58-0.64, P = 4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI = 0.69-0.86, P = 4.1e-06) but not with bleeding (OR = 1.01, 95% CI = 0.95-1.08, P = 7.5e-01). These Mendelian randomization associations were concordant across the three blood protein data sets and the hepatic gene expression data set as well as colocalization analyses.
Conclusion: These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
{"title":"Genetic assessment of efficacy and safety profiles of coagulation cascade proteins identifies Factors II and XI as actionable anticoagulant targets.","authors":"Eloi Gagnon, Arnaud Girard, Jérôme Bourgault, Erik Abner, Dipender Gill, Sébastien Thériault, Marie-Claude Vohl, André Tchernof, Tõnu Esko, Patrick Mathieu, Benoit J Arsenault","doi":"10.1093/ehjopen/oeae043","DOIUrl":"10.1093/ehjopen/oeae043","url":null,"abstract":"<p><strong>Aims: </strong>Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed.</p><p><strong>Methods and results: </strong>To prioritize anticoagulant targets with the strongest efficacy [venous thromboembolism (VTE) prevention] and safety (low bleeding risk) profiles, we performed two-sample Mendelian randomization and genetic colocalization. We leveraged three large-scale plasma protein data sets (deCODE as discovery data set and Fenland and Atherosclerosis Risk in Communities as replication data sets] and one liver gene expression data set (Institut Universitaire de Cardiologie et de Pneumologie de Québec bariatric biobank) to evaluate evidence for a causal effect of 26 coagulation cascade proteins on VTE from a new genome-wide association meta-analysis of 44 232 VTE cases and 847 152 controls, stroke subtypes, bleeding outcomes, and parental lifespan as an overall measure of efficacy/safety ratio. A 1 SD genetically predicted reduction in F2 blood levels was associated with lower risk of VTE [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.38-0.51, <i>P</i> = 2.6e-28] and cardioembolic stroke risk (OR = 0.55, 95% CI = 0.39-0.76, <i>P</i> = 4.2e-04) but not with bleeding (OR = 1.13, 95% CI = 0.93-1.36, <i>P</i> = 2.2e-01). Genetically predicted F11 reduction was associated with lower risk of VTE (OR = 0.61, 95% CI = 0.58-0.64, <i>P</i> = 4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI = 0.69-0.86, <i>P</i> = 4.1e-06) but not with bleeding (OR = 1.01, 95% CI = 0.95-1.08, <i>P</i> = 7.5e-01). These Mendelian randomization associations were concordant across the three blood protein data sets and the hepatic gene expression data set as well as colocalization analyses.</p><p><strong>Conclusion: </strong>These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.</p>","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11200102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tilman Steudel, Gina Barzen, D. Frumkin, Elena Romero-Dorta, Sebastian Spethmann, Gerhard Hindricks, Karl Stangl, Fabian Knebel, Bettina Heidecker, Sima Canaan-Kühl, Helena Franziska Pernice, K. Hahn, I. Mattig, Anna Brand
Layer-specific left ventricular (LV) strain alterations have been suggested as a specific finding in Fabry Disease (FD). Our study aimed to assess the diagnostic value of layer specific radial strain (RS) indices compared to the established LV regional strain pattern in Cardiac Amyloidosis (CA) and FD, i.e. apical sparing, and posterolateral strain deficiency. We retrospectively analyzed the global, subendocardial, subepicardial LV radial strain, the corresponding strain gradient, as well as the regional and global longitudinal strain. The diagnostic accuracy of the diverse LV strain analyses was comparatively assessed using receiver operating curve (ROC) and multivariable regression analyses. In 40 FD and 76 CA patients, CA featured more reduced layer strain values [Global RS -12.3 (-15.6 to -9.6) in CA vs. -16.7 (-20.0 to-13.6) in FD; p < 0.001; subendocardial RS -22.3 (-27.4 to -15.9) vs. -28.3 (-31.8 to -23.6), p < 0.001; subepicardial RS -6.6 (-8.6 to -4.7) in CA vs. -8.9 (-11.7 to- 6.5 in FD; p < 0.001]. Global radial and longitudinal strain held an AUC of 0.75 (0.66 to 0.84) and AUC 0.73 (0.63 to 0.83). While the apical sparing and PLSD strain pattern showed the highest accuracy as single parameters [AUC 0.87 (0.79 to 0.95) and 0.81 (0.72 to 0.89), p < 0.001], the combination of subendocardial RS and the apical sparing pattern featured the highest diagnostic accuracy [AUC 0.92 (0.87 to 0.97)]. Combining radial strain derived parameters to the established strain pattern apical sparing and PLSD improve the diagnostic accuracy in the echocardiographic assessment in suspected storage disease.
法布里病（Fabry Disease，FD）的特异性左心室（LV）应变改变被认为是一种特异性发现。我们的研究旨在评估各层特异性径向应变（RS）指数与心脏淀粉样变性（CA）和法布里病已确立的左心室区域应变模式（即心尖稀疏和后外侧应变缺乏）相比的诊断价值。 我们回顾性分析了整体、心内膜下、心外膜下左心室径向应变、相应的应变梯度以及区域和整体纵向应变。利用接收器操作曲线（ROC）和多变量回归分析比较评估了各种左心室应变分析的诊断准确性。在40例FD和76例CA患者中，CA患者的层应变值更低[CA患者的全层RS为-12.3（-15.6至-9.6），而FD患者为-16.7（-20.0至-13.6）；P < 0.001; 心内膜下 RS -22.3 (-27.4 to -15.9) vs. -28.3 (-31.8 to -23.6), p < 0.001; 心外膜下 RS -6.6 (-8.6 to -4.7) in CA vs. -8.9 (-11.7 to -6.5 in FD; p < 0.001]。全球径向和纵向应变的 AUC 分别为 0.75（0.66 至 0.84）和 0.73（0.63 至 0.83）。心尖疏松和 PLSD 应变模式作为单一参数显示出最高的准确性[AUC 0.87（0.79 至 0.95）和 0.81（0.72 至 0.89），p < 0.001]，而心内膜下 RS 和心尖疏松模式的组合则显示出最高的诊断准确性[AUC 0.92（0.87 至 0.97）]。 将径向应变衍生参数与已建立的应变模式心尖疏松和 PLSD 相结合，可提高疑似储层疾病超声心动图评估的诊断准确性。
{"title":"Diagnostic value of left ventricular layer strain and specific regional strain patterns in cardiac amyloidosis and Fabry disease","authors":"Tilman Steudel, Gina Barzen, D. Frumkin, Elena Romero-Dorta, Sebastian Spethmann, Gerhard Hindricks, Karl Stangl, Fabian Knebel, Bettina Heidecker, Sima Canaan-Kühl, Helena Franziska Pernice, K. Hahn, I. Mattig, Anna Brand","doi":"10.1093/ehjopen/oeae041","DOIUrl":"https://doi.org/10.1093/ehjopen/oeae041","url":null,"abstract":"\u0000 \u0000 \u0000 Layer-specific left ventricular (LV) strain alterations have been suggested as a specific finding in Fabry Disease (FD). Our study aimed to assess the diagnostic value of layer specific radial strain (RS) indices compared to the established LV regional strain pattern in Cardiac Amyloidosis (CA) and FD, i.e. apical sparing, and posterolateral strain deficiency.\u0000 \u0000 \u0000 \u0000 We retrospectively analyzed the global, subendocardial, subepicardial LV radial strain, the corresponding strain gradient, as well as the regional and global longitudinal strain. The diagnostic accuracy of the diverse LV strain analyses was comparatively assessed using receiver operating curve (ROC) and multivariable regression analyses. In 40 FD and 76 CA patients, CA featured more reduced layer strain values [Global RS -12.3 (-15.6 to -9.6) in CA vs. -16.7 (-20.0 to-13.6) in FD; p < 0.001; subendocardial RS -22.3 (-27.4 to -15.9) vs. -28.3 (-31.8 to -23.6), p < 0.001; subepicardial RS -6.6 (-8.6 to -4.7) in CA vs. -8.9 (-11.7 to- 6.5 in FD; p < 0.001]. Global radial and longitudinal strain held an AUC of 0.75 (0.66 to 0.84) and AUC 0.73 (0.63 to 0.83). While the apical sparing and PLSD strain pattern showed the highest accuracy as single parameters [AUC 0.87 (0.79 to 0.95) and 0.81 (0.72 to 0.89), p < 0.001], the combination of subendocardial RS and the apical sparing pattern featured the highest diagnostic accuracy [AUC 0.92 (0.87 to 0.97)].\u0000 \u0000 \u0000 \u0000 Combining radial strain derived parameters to the established strain pattern apical sparing and PLSD improve the diagnostic accuracy in the echocardiographic assessment in suspected storage disease.\u0000","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141112450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The aging process notably induces structural changes in the arterial system, primarily manifesting as increased aortic stiffness, a precursor to cardiovascular events. While wave separation analysis is a robust tool for decomposing the components of blood pressure waveform, its relationship with cardiovascular events, such as aortic stiffening, is incompletely understood. Furthermore, its applicability has been limited due to the need for concurrent measurements of pressure and flow. Our aim in this study addresses this gap by introducing a spectral regression learning method for pressure-only wave separation analysis. Leveraging data from the Framingham Heart Study (2,640 individuals, 55% women), we evaluate the accuracy of pressure-only estimates, their interchangeability with reference method based on ultrasound-derived flow waves, and their association with Carotid-femoral pulse wave velocity. Method-derived estimates are strongly correlated with the reference ones for forward wave amplitude (R2=0.91), backward wave amplitude (R2=0.88), reflection index (R2=0.87), and moderately correlated with time delay between forward and backward waves (R2=0.38). The proposed pressure-only method shows interchangeability with reference method through covariate analysis. Adjusting for age, sex, body size, mean blood pressure, and heart rate, results suggest that both pressure-only and pressure-flow evaluations of wave separation parameters yield similar model performance for predicting Carotid-femoral pulse wave velocity with forward wave amplitude as the only significant factor (p < 0.001; 95% confidence interval, 0.056-0.097). We propose an interchangeable pressure-only wave separation analysis method and demonstrate its clinical applicability in capturing aortic stiffening. The proposed method provides valuable non-invasive tool for assessing cardiovascular health.
{"title":"Assessing Pressure Wave Components for Aortic Stiffness Monitoring through Spectral Regression Learning","authors":"Arian Aghilinejad, Morteza Gharib","doi":"10.1093/ehjopen/oeae040","DOIUrl":"https://doi.org/10.1093/ehjopen/oeae040","url":null,"abstract":"\u0000 \u0000 \u0000 The aging process notably induces structural changes in the arterial system, primarily manifesting as increased aortic stiffness, a precursor to cardiovascular events. While wave separation analysis is a robust tool for decomposing the components of blood pressure waveform, its relationship with cardiovascular events, such as aortic stiffening, is incompletely understood. Furthermore, its applicability has been limited due to the need for concurrent measurements of pressure and flow. Our aim in this study addresses this gap by introducing a spectral regression learning method for pressure-only wave separation analysis.\u0000 \u0000 \u0000 \u0000 Leveraging data from the Framingham Heart Study (2,640 individuals, 55% women), we evaluate the accuracy of pressure-only estimates, their interchangeability with reference method based on ultrasound-derived flow waves, and their association with Carotid-femoral pulse wave velocity. Method-derived estimates are strongly correlated with the reference ones for forward wave amplitude (R2=0.91), backward wave amplitude (R2=0.88), reflection index (R2=0.87), and moderately correlated with time delay between forward and backward waves (R2=0.38). The proposed pressure-only method shows interchangeability with reference method through covariate analysis. Adjusting for age, sex, body size, mean blood pressure, and heart rate, results suggest that both pressure-only and pressure-flow evaluations of wave separation parameters yield similar model performance for predicting Carotid-femoral pulse wave velocity with forward wave amplitude as the only significant factor (p < 0.001; 95% confidence interval, 0.056-0.097).\u0000 \u0000 \u0000 \u0000 We propose an interchangeable pressure-only wave separation analysis method and demonstrate its clinical applicability in capturing aortic stiffening. The proposed method provides valuable non-invasive tool for assessing cardiovascular health.\u0000","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141118163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-15eCollection Date: 2024-05-01DOI: 10.1093/ehjopen/oeae038
Pankaj Garg, Ciaran Grafton-Clarke, Gareth Matthews, Peter Swoboda, Liang Zhong, Nay Aung, Ross Thomson, Samer Alabed, Ahmet Demirkiran, Vassilios S Vassiliou, Andrew J Swift
Aims: Heart failure (HF) with preserved ejection fraction disproportionately affects women. There are no validated sex-specific tools for HF diagnosis despite widely reported differences in cardiac structure. This study investigates whether sex, as assigned at birth, influences cardiac magnetic resonance (CMR) assessment of left ventricular filling pressure (LVFP), a hallmark of HF agnostic to ejection fraction.
Methods and results: A derivation cohort of patients with suspected pulmonary hypertension and HF from the Sheffield centre underwent invasive right heart catheterization and CMR within 24 h of each other. A sex-specific CMR model to estimate LVFP, measured as pulmonary capillary wedge pressure (PCWP), was developed using multivariable regression. A validation cohort of patients with confirmed HF from the Leeds centre was used to evaluate for the primary endpoints of HF hospitalization and major adverse cardiovascular events (MACEs). Comparison between generic and sex-specific CMR-derived PCWP was undertaken. A total of 835 (60% female) and 454 (36% female) patients were recruited into the derivation and validation cohorts respectively. A sex-specific model incorporating left atrial volume and left ventricular mass was created. The generic CMR PCWP showed significant differences between males and females (14.7 ± 4 vs. 13 ± 3.0 mmHg, P > 0.001), not present with the sex-specific CMR PCWP (14.1 ± 3 vs. 13.8 mmHg, P = 0.3). The sex-specific, but not the generic, CMR PCWP was associated with HF hospitalization (hazard ratio 3.9, P = 0.0002) and MACE (hazard ratio 2.5, P = 0.001) over a mean follow-up period of 2.4 ± 1.2 years.
Conclusion: Accounting for sex improves precision and prognostic performance of CMR biomarkers for HF.
{"title":"Sex-specific cardiac magnetic resonance pulmonary capillary wedge pressure.","authors":"Pankaj Garg, Ciaran Grafton-Clarke, Gareth Matthews, Peter Swoboda, Liang Zhong, Nay Aung, Ross Thomson, Samer Alabed, Ahmet Demirkiran, Vassilios S Vassiliou, Andrew J Swift","doi":"10.1093/ehjopen/oeae038","DOIUrl":"10.1093/ehjopen/oeae038","url":null,"abstract":"<p><strong>Aims: </strong>Heart failure (HF) with preserved ejection fraction disproportionately affects women. There are no validated sex-specific tools for HF diagnosis despite widely reported differences in cardiac structure. This study investigates whether sex, as assigned at birth, influences cardiac magnetic resonance (CMR) assessment of left ventricular filling pressure (LVFP), a hallmark of HF agnostic to ejection fraction.</p><p><strong>Methods and results: </strong>A derivation cohort of patients with suspected pulmonary hypertension and HF from the Sheffield centre underwent invasive right heart catheterization and CMR within 24 h of each other. A sex-specific CMR model to estimate LVFP, measured as pulmonary capillary wedge pressure (PCWP), was developed using multivariable regression. A validation cohort of patients with confirmed HF from the Leeds centre was used to evaluate for the primary endpoints of HF hospitalization and major adverse cardiovascular events (MACEs). Comparison between generic and sex-specific CMR-derived PCWP was undertaken. A total of 835 (60% female) and 454 (36% female) patients were recruited into the derivation and validation cohorts respectively. A sex-specific model incorporating left atrial volume and left ventricular mass was created. The generic CMR PCWP showed significant differences between males and females (14.7 ± 4 vs. 13 ± 3.0 mmHg, <i>P</i> > 0.001), not present with the sex-specific CMR PCWP (14.1 ± 3 vs. 13.8 mmHg, <i>P</i> = 0.3). The sex-specific, but not the generic, CMR PCWP was associated with HF hospitalization (hazard ratio 3.9, <i>P</i> = 0.0002) and MACE (hazard ratio 2.5, <i>P</i> = 0.001) over a mean follow-up period of 2.4 ± 1.2 years.</p><p><strong>Conclusion: </strong>Accounting for sex improves precision and prognostic performance of CMR biomarkers for HF.</p>","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Johan Hopfgarten, Stefan James, L. Lindhagen, T. Baron, Elisabeth Ståhle, C. Christersson
There is a lack of robust data on optimal medical treatment of heart failure in patients with severe aortic stenosis, with no randomized controlled trials guiding treatment. To study the association between exposure to renin-angiotensin-aldosterone system (RAS) inhibitors or beta-blockers and outcome after aortic valve replacement in patients with aortic stenosis and heart failure. The study included all patients with heart failure undergoing aortic valve replacement for aortic stenosis in Sweden between 2008-2016 (n = 4668 patients). Exposure to treatment was assessed by continuous tracking of drug dispensations and outcome events were all-cause mortality and hospitalization for heart failure collected from national patient registries. After adjustment for age, sex, atrial fibrillation, hypertension, diabetes mellitus and prior myocardial infarction Cox regression analysis showed that RAS inhibition was associated with a lower risk of all-cause mortality in patients with reduced LV-EF (HR 0.58, 95% CI 0.51 - 0.65) and preserved LV-EF (HR 0.69, 95% CI 0.56 - 0.85). Beta-blockade was associated with a lower risk of all-cause mortality in patients with reduced LV-EF (HR 0.81, 95% CI 0.71–0.92), but not in preserved LV-EF (HR 0.87, 95% CI 0.69 - 1.10). There was no association between RAS inhibition or beta-blockade and the risk of hospitalization for heart failure. RAS inhibition was associated with lower all-cause mortality after valve replacement in patients with both reduced and preserved LV-EF. Beta-blockade was associated with lower all-cause mortality only in patients with reduced LV-EF.
目前缺乏关于重度主动脉瓣狭窄患者心力衰竭最佳治疗方法的可靠数据，也没有指导治疗的随机对照试验。 研究主动脉瓣狭窄和心力衰竭患者主动脉瓣置换术后肾素-血管紧张素-醛固酮系统（RAS）抑制剂或β-受体阻滞剂的暴露与预后之间的关系。 该研究纳入了2008-2016年间在瑞典因主动脉瓣狭窄而接受主动脉瓣置换术的所有心衰患者（n = 4668名患者）。通过对配药情况的连续跟踪评估治疗暴露情况，结果事件为全因死亡率和因心力衰竭住院，这些数据均来自全国患者登记处。在对年龄、性别、心房颤动、高血压、糖尿病和既往心肌梗死进行调整后，考克斯回归分析表明，RAS 抑制与 LV-EF 降低（HR 0.58，95% CI 0.51 - 0.65）和 LV-EF 保持（HR 0.69，95% CI 0.56 - 0.85）患者的全因死亡风险降低相关。在 LV-EF 降低的患者中，β-受体阻滞与较低的全因死亡风险相关（HR 0.81，95% CI 0.71-0.92），但在 LV-EF 保持的患者中，β-受体阻滞与较低的全因死亡风险无关（HR 0.87，95% CI 0.69 - 1.10）。RAS抑制或β-受体阻滞与心衰住院风险之间没有关联。 RAS抑制与LV-EF降低或保留的患者瓣膜置换术后全因死亡率降低有关。只有 LV-EF 降低的患者服用β-受体阻滞剂才会降低全因死亡率。
{"title":"Medical treatment of heart failure with RAS inhibitors and beta blockers in aortic stenosis – association to long-term outcome after aortic valve replacement","authors":"Johan Hopfgarten, Stefan James, L. Lindhagen, T. Baron, Elisabeth Ståhle, C. Christersson","doi":"10.1093/ehjopen/oeae039","DOIUrl":"https://doi.org/10.1093/ehjopen/oeae039","url":null,"abstract":"\u0000 \u0000 \u0000 There is a lack of robust data on optimal medical treatment of heart failure in patients with severe aortic stenosis, with no randomized controlled trials guiding treatment.\u0000 \u0000 \u0000 \u0000 To study the association between exposure to renin-angiotensin-aldosterone system (RAS) inhibitors or beta-blockers and outcome after aortic valve replacement in patients with aortic stenosis and heart failure.\u0000 \u0000 \u0000 \u0000 The study included all patients with heart failure undergoing aortic valve replacement for aortic stenosis in Sweden between 2008-2016 (n = 4668 patients). Exposure to treatment was assessed by continuous tracking of drug dispensations and outcome events were all-cause mortality and hospitalization for heart failure collected from national patient registries. After adjustment for age, sex, atrial fibrillation, hypertension, diabetes mellitus and prior myocardial infarction Cox regression analysis showed that RAS inhibition was associated with a lower risk of all-cause mortality in patients with reduced LV-EF (HR 0.58, 95% CI 0.51 - 0.65) and preserved LV-EF (HR 0.69, 95% CI 0.56 - 0.85). Beta-blockade was associated with a lower risk of all-cause mortality in patients with reduced LV-EF (HR 0.81, 95% CI 0.71–0.92), but not in preserved LV-EF (HR 0.87, 95% CI 0.69 - 1.10). There was no association between RAS inhibition or beta-blockade and the risk of hospitalization for heart failure.\u0000 \u0000 \u0000 \u0000 RAS inhibition was associated with lower all-cause mortality after valve replacement in patients with both reduced and preserved LV-EF. Beta-blockade was associated with lower all-cause mortality only in patients with reduced LV-EF.\u0000","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140994580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mariame Selma Kane, J. X. M. Juncos, S. Manzoor, Maximiliano Grenett, Joo-Yeun Oh, Betty Pat, Mustafa I Ahmed, Clifton Lewis, James E Davies, Thomas S. Denney, Jonathan McConathy, Louis J. Dell'Italia
Chronic neurohormonal activation and hemodynamic load cause derangement in myocardial substrate utilization. We test the hypothesis that the primary mitral regurgitation heart (PMR) heart shows altered metabolic gene profile and cardiac ultrastructure consistent with decreased fatty acid and glucose metabolism despite LVEF > 60%. Metabolic gene expression in right atrial (RA), left atrial (LA), and left ventricular (LV) biopsies from donor hearts (n = 10) and from patients with moderate to severe PMR (n = 11) at surgery showed decreased mRNA glucose transporter type 4 (GLUT-4), GLUT-1 and insulin receptor substrate 2 and increased mRNA hexokinase 2, O-linked N-acetylglucosamine transferase and O-GlcNAcase, rate-limiting steps in the hexosamine biosynthetic pathway. Pericardial fluid levels of Neuropeptide Y were 4-fold higher than simultaneous plasma indicative of increased sympathetic drive. Quantitative TEM shows glycogen accumulation, glycophagy, increased lipid droplets, and mitochondrial cristae lysis. These findings are associated with increased mRNA for glycogen synthase kinase 3β, decreased carnitine palmitoyl transferase 2, and fatty acid synthase in PMR vs. normals. Cardiac magnetic resonance/positron emission tomography for 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake showed decreased LV [18F]FDG uptake and increased plasma HbA1c, free fatty acids, mtDAMPs in a separate cohort of stable moderate PMR patients with LVEF > 60% (n = 8) vs. normal controls (n = 8). The PMR heart has a global ultrastructural and metabolic gene expression pattern of decreased glucose uptake along with increased glycogen and lipid droplets. Further studies must determine whether this presentation is an adaptation or maladaptation in the PMR heart in the clinical evaluation of PMR.
{"title":"Gene Expression and Ultrastructural Evidence for Metabolic Derangement in the Primary Mitral Regurgitation Heart","authors":"Mariame Selma Kane, J. X. M. Juncos, S. Manzoor, Maximiliano Grenett, Joo-Yeun Oh, Betty Pat, Mustafa I Ahmed, Clifton Lewis, James E Davies, Thomas S. Denney, Jonathan McConathy, Louis J. Dell'Italia","doi":"10.1093/ehjopen/oeae034","DOIUrl":"https://doi.org/10.1093/ehjopen/oeae034","url":null,"abstract":"\u0000 \u0000 \u0000 Chronic neurohormonal activation and hemodynamic load cause derangement in myocardial substrate utilization. We test the hypothesis that the primary mitral regurgitation heart (PMR) heart shows altered metabolic gene profile and cardiac ultrastructure consistent with decreased fatty acid and glucose metabolism despite LVEF > 60%.\u0000 \u0000 \u0000 \u0000 Metabolic gene expression in right atrial (RA), left atrial (LA), and left ventricular (LV) biopsies from donor hearts (n = 10) and from patients with moderate to severe PMR (n = 11) at surgery showed decreased mRNA glucose transporter type 4 (GLUT-4), GLUT-1 and insulin receptor substrate 2 and increased mRNA hexokinase 2, O-linked N-acetylglucosamine transferase and O-GlcNAcase, rate-limiting steps in the hexosamine biosynthetic pathway. Pericardial fluid levels of Neuropeptide Y were 4-fold higher than simultaneous plasma indicative of increased sympathetic drive. Quantitative TEM shows glycogen accumulation, glycophagy, increased lipid droplets, and mitochondrial cristae lysis. These findings are associated with increased mRNA for glycogen synthase kinase 3β, decreased carnitine palmitoyl transferase 2, and fatty acid synthase in PMR vs. normals. Cardiac magnetic resonance/positron emission tomography for 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) uptake showed decreased LV [18F]FDG uptake and increased plasma HbA1c, free fatty acids, mtDAMPs in a separate cohort of stable moderate PMR patients with LVEF > 60% (n = 8) vs. normal controls (n = 8).\u0000 \u0000 \u0000 \u0000 The PMR heart has a global ultrastructural and metabolic gene expression pattern of decreased glucose uptake along with increased glycogen and lipid droplets. Further studies must determine whether this presentation is an adaptation or maladaptation in the PMR heart in the clinical evaluation of PMR.\u0000","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141050159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-30eCollection Date: 2024-05-01DOI: 10.1093/ehjopen/oeae035
Fredrik Landfors, Peter Henneman, Elin Chorell, Stefan K Nilsson, Sander Kersten
Aims: APOC3, ANGPTL3, and ANGPTL4 are circulating proteins that are actively pursued as pharmacological targets to treat dyslipidaemia and reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data to compare the predicted therapeutic and adverse effects of APOC3, ANGPTL3, and ANGPTL4 inactivation.
Methods and results: We conducted drug-target Mendelian randomization analyses using variants in proximity to the genes associated with circulating protein levels to compare APOC3, ANGPTL3, and ANGPTL4 as drug targets. We obtained exposure and outcome data from large-scale genome-wide association studies and used generalized least squares to correct for linkage disequilibrium-related correlation. We evaluated five primary cardiometabolic endpoints and screened for potential side effects across 694 disease-related endpoints, 43 clinical laboratory tests, and 11 internal organ MRI measurements. Genetically lowering circulating ANGPTL4 levels reduced the odds of coronary artery disease (CAD) [odds ratio, 0.57 per s.d. protein (95% CI 0.47-0.70)] and Type 2 diabetes (T2D) [odds ratio, 0.73 per s.d. protein (95% CI 0.57-0.94)]. Genetically lowering circulating APOC3 levels also reduced the odds of CAD [odds ratio, 0.90 per s.d. protein (95% CI 0.82-0.99)]. Genetically lowered ANGPTL3 levels via common variants were not associated with CAD. However, meta-analysis of protein-truncating variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.71 per allele [95%CI, 0.58-0.85]). Analysis of lowered ANGPTL3, ANGPTL4, and APOC3 levels did not identify important safety concerns.
Conclusion: Human genetic evidence suggests that therapies aimed at reducing circulating levels of ANGPTL3, ANGPTL4, and APOC3 reduce the risk of CAD. ANGPTL4 lowering may also reduce the risk of T2D.
{"title":"Drug-target Mendelian randomization analysis supports lowering plasma ANGPTL3, ANGPTL4, and APOC3 levels as strategies for reducing cardiovascular disease risk.","authors":"Fredrik Landfors, Peter Henneman, Elin Chorell, Stefan K Nilsson, Sander Kersten","doi":"10.1093/ehjopen/oeae035","DOIUrl":"10.1093/ehjopen/oeae035","url":null,"abstract":"<p><strong>Aims: </strong>APOC3, ANGPTL3, and ANGPTL4 are circulating proteins that are actively pursued as pharmacological targets to treat dyslipidaemia and reduce the risk of atherosclerotic cardiovascular disease. Here, we used human genetic data to compare the predicted therapeutic and adverse effects of APOC3, ANGPTL3, and ANGPTL4 inactivation.</p><p><strong>Methods and results: </strong>We conducted drug-target Mendelian randomization analyses using variants in proximity to the genes associated with circulating protein levels to compare APOC3, ANGPTL3, and ANGPTL4 as drug targets. We obtained exposure and outcome data from large-scale genome-wide association studies and used generalized least squares to correct for linkage disequilibrium-related correlation. We evaluated five primary cardiometabolic endpoints and screened for potential side effects across 694 disease-related endpoints, 43 clinical laboratory tests, and 11 internal organ MRI measurements. Genetically lowering circulating ANGPTL4 levels reduced the odds of coronary artery disease (CAD) [odds ratio, 0.57 per s.d. protein (95% CI 0.47-0.70)] and Type 2 diabetes (T2D) [odds ratio, 0.73 per s.d. protein (95% CI 0.57-0.94)]. Genetically lowering circulating APOC3 levels also reduced the odds of CAD [odds ratio, 0.90 per s.d. protein (95% CI 0.82-0.99)]. Genetically lowered ANGPTL3 levels via common variants were not associated with CAD. However, meta-analysis of protein-truncating variants revealed that ANGPTL3 inactivation protected against CAD (odds ratio, 0.71 per allele [95%CI, 0.58-0.85]). Analysis of lowered ANGPTL3, ANGPTL4, and APOC3 levels did not identify important safety concerns.</p><p><strong>Conclusion: </strong>Human genetic evidence suggests that therapies aimed at reducing circulating levels of ANGPTL3, ANGPTL4, and APOC3 reduce the risk of CAD. ANGPTL4 lowering may also reduce the risk of T2D.</p>","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11182694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141422241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aims: This study aims to evaluate the distribution of extracellular volume fraction detected via computed tomography, clinical characteristics of high extracellular volume fraction detected via computed tomography, and the rate of incidental detection of cardiac amyloidosis in patients undergoing cardiac computed tomography for coronary artery evaluation.
Methods and results: This study included 874 consecutive patients (mean age, 74.4 ± 7.1 years; men, 65%), comprising men aged ≥60 years and women aged ≥70 years, who had undergone cardiac computed tomography between January 2020 and September 2022. The mean extracellular volume fraction detected via computed tomography was 29.7 ± 5.2%, and 108 patients (12.4%) had an extracellular volume fraction detected via computed tomography of ≥35%. Older age (75.9 ± 8.2 years vs. 74.2 ± 6.9 years; P = 0.042), male sex (75.9% vs. 63.0%; P = 0.007), impaired left ventricular ejection fraction, increased high-sensitivity cardiac troponin T and B-type natriuretic peptide levels, and increased left ventricular thickness showed significant associations with an extracellular volume fraction detected via computed tomography of ≥35%. Cardiac amyloidosis was diagnosed incidentally in 15 patients based on an increase in extracellular volume fraction detected via computed tomography. The prevalence of cardiac amyloidosis was 1.7% (15/874) and 14.3% (15/105) in the entire study population and in patients with an extracellular volume fraction detected via computed tomography of ≥35%, respectively. An increase in the extracellular volume fraction detected via computed tomography was suggestive of cardiac amyloidosis.
Conclusion: Elevated extracellular volume fraction detected via computed tomography, associated with elevated cardiac biomarker levels and myocardial structural changes, may lead to the incidental diagnosis of cardiac amyloidosis.
{"title":"Clinical characteristics of patients with high extracellular volume fraction evaluated by cardiac computed tomography for coronary artery evaluation.","authors":"Tetsuya Oguni, Seiji Takashio, Naoto Kuyama, Kyoko Hirakawa, Shinsuke Hanatani, Fumi Oike, Hiroki Usuku, Yasushi Matsuzawa, Masafumi Kidoh, Seitaro Oda, Eiichiro Yamamoto, Mitsuharu Ueda, Toshinori Hirai, Kenichi Tsujita","doi":"10.1093/ehjopen/oeae036","DOIUrl":"10.1093/ehjopen/oeae036","url":null,"abstract":"<p><strong>Aims: </strong>This study aims to evaluate the distribution of extracellular volume fraction detected via computed tomography, clinical characteristics of high extracellular volume fraction detected via computed tomography, and the rate of incidental detection of cardiac amyloidosis in patients undergoing cardiac computed tomography for coronary artery evaluation.</p><p><strong>Methods and results: </strong>This study included 874 consecutive patients (mean age, 74.4 ± 7.1 years; men, 65%), comprising men aged ≥60 years and women aged ≥70 years, who had undergone cardiac computed tomography between January 2020 and September 2022. The mean extracellular volume fraction detected via computed tomography was 29.7 ± 5.2%, and 108 patients (12.4%) had an extracellular volume fraction detected via computed tomography of ≥35%. Older age (75.9 ± 8.2 years vs. 74.2 ± 6.9 years; <i>P</i> = 0.042), male sex (75.9% vs. 63.0%; <i>P</i> = 0.007), impaired left ventricular ejection fraction, increased high-sensitivity cardiac troponin T and B-type natriuretic peptide levels, and increased left ventricular thickness showed significant associations with an extracellular volume fraction detected via computed tomography of ≥35%. Cardiac amyloidosis was diagnosed incidentally in 15 patients based on an increase in extracellular volume fraction detected via computed tomography. The prevalence of cardiac amyloidosis was 1.7% (15/874) and 14.3% (15/105) in the entire study population and in patients with an extracellular volume fraction detected via computed tomography of ≥35%, respectively. An increase in the extracellular volume fraction detected via computed tomography was suggestive of cardiac amyloidosis.</p><p><strong>Conclusion: </strong>Elevated extracellular volume fraction detected via computed tomography, associated with elevated cardiac biomarker levels and myocardial structural changes, may lead to the incidental diagnosis of cardiac amyloidosis.</p>","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-26eCollection Date: 2024-05-01DOI: 10.1093/ehjopen/oeae031
Xu Tian, Nan Zhang, Gary Tse, Guangping Li, Yihong Sun, Tong Liu
Aims: High lipoprotein(a) [Lp(a)] level has been demonstrated as an important risk factor for atherosclerotic cardiovascular diseases (ASCVD) amongst the older populations, whereas its effects in the younger population remain unclear. This study evaluated the associations between Lp(a) and the risk of premature ASCVD.
Method and results: PubMed and Embase were searched for related studies until 12 November 2023. Fifty-one studies including 100 540 participants were included. Mean age of patients ranged from 35.3 to 62.3 years. The proportion of male participants ranged from 0% to 100%. The mean follow-up was provided in five studies ranging from 1 year to 40 years. The definition of elevated Lp(a) varied among studies, such as >30 mg/dL, >50 mg/dL, the top tertiles, the top quartiles, the top quintiles, and so on. Higher Lp(a) was significantly associated with the composite ASCVD [odds ratio (OR): 2.15, 95% confidence interval (95% CI): 1.53-3.02, P < 0.001], especially for coronary artery disease (OR: 2.44, 95% CI: 2.06-2.90, P < 0.001) and peripheral arterial disease (OR: 2.56, 95% CI: 1.56-4.21, P < 0.001). This association remained significant in familial hypercholesterolaemia (FH) (OR: 3.11, 95% CI: 1.63-5.96, P < 0.001) and type 2 diabetes mellitus (T2DM) patients (OR: 2.23; 95% CI: 1.54-3.23, P < 0.001).Significant results were observed in South Asians (OR: 3.71, 95% CI: 2.31-5.96, P < 0.001), Caucasians (OR: 3.17, 95% CI: 2.22-4.52, P < 0.001), and patients with baseline low-density lipoprotein cholesterol (LDL-c) level ≥ 2.6 mmol/L.
Conclusion: Elevated Lp(a) predicts the risk of the composite or individual ASCVD in young, regardless of study design, gender, population characteristics (community or hospitalized), different premature definitions, and various Lp(a) measurement approaches. This association was important in South Asians, Caucasians, FH patients, T2DM patients, and patients with baseline LDL-c level ≥ 2.6 mmol/L.
{"title":"Association between lipoprotein(a) and premature atherosclerotic cardiovascular disease: a systematic review and meta-analysis.","authors":"Xu Tian, Nan Zhang, Gary Tse, Guangping Li, Yihong Sun, Tong Liu","doi":"10.1093/ehjopen/oeae031","DOIUrl":"10.1093/ehjopen/oeae031","url":null,"abstract":"<p><strong>Aims: </strong>High lipoprotein(a) [Lp(a)] level has been demonstrated as an important risk factor for atherosclerotic cardiovascular diseases (ASCVD) amongst the older populations, whereas its effects in the younger population remain unclear. This study evaluated the associations between Lp(a) and the risk of premature ASCVD.</p><p><strong>Method and results: </strong>PubMed and Embase were searched for related studies until 12 November 2023. Fifty-one studies including 100 540 participants were included. Mean age of patients ranged from 35.3 to 62.3 years. The proportion of male participants ranged from 0% to 100%. The mean follow-up was provided in five studies ranging from 1 year to 40 years. The definition of elevated Lp(a) varied among studies, such as >30 mg/dL, >50 mg/dL, the top tertiles, the top quartiles, the top quintiles, and so on. Higher Lp(a) was significantly associated with the composite ASCVD [odds ratio (OR): 2.15, 95% confidence interval (95% CI): 1.53-3.02, <i>P</i> < 0.001], especially for coronary artery disease (OR: 2.44, 95% CI: 2.06-2.90, <i>P</i> < 0.001) and peripheral arterial disease (OR: 2.56, 95% CI: 1.56-4.21, <i>P</i> < 0.001). This association remained significant in familial hypercholesterolaemia (FH) (OR: 3.11, 95% CI: 1.63-5.96, <i>P</i> < 0.001) and type 2 diabetes mellitus (T2DM) patients (OR: 2.23; 95% CI: 1.54-3.23, <i>P</i> < 0.001).Significant results were observed in South Asians (OR: 3.71, 95% CI: 2.31-5.96, <i>P</i> < 0.001), Caucasians (OR: 3.17, 95% CI: 2.22-4.52, <i>P</i> < 0.001), and patients with baseline low-density lipoprotein cholesterol (LDL-c) level ≥ 2.6 mmol/L.</p><p><strong>Conclusion: </strong>Elevated Lp(a) predicts the risk of the composite or individual ASCVD in young, regardless of study design, gender, population characteristics (community or hospitalized), different premature definitions, and various Lp(a) measurement approaches. This association was important in South Asians, Caucasians, FH patients, T2DM patients, and patients with baseline LDL-c level ≥ 2.6 mmol/L.</p>","PeriodicalId":93995,"journal":{"name":"European heart journal open","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140913598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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