Objective: This retrospective study, based on real-life data, aimed to evaluate the clinical characteristics and 2-year cardiovascular outcomes in patients presenting with early acute coronary syndrome (ACS) in a tertiary healthcare center. Methods: Information including at least 2-year endpoint data after index ACS event was retrieved from hospital records. Age limit for early ACS was considered <55 years for males and <60 years for females. Results: Of 985 consecutive ACS patients (770 males; age range, 21-93 years) 361 (36.6%) met early ACS criteria. Frequency familial hypercholesterolemia (FH) was 7.6% and higher in the young-age group (15.5%) than in the old-age group (3%) (p<0.001). During the follow-up (30 monts), the risk predictors for cardiovascular events were the index event being ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction and the presence of hypertension, and the risk predictors for mortality were female sex, older age, in-hospital cardiovascular complications. Conclusion: A very high rate of early ACS (36.6%) was observed in this retrospective ACS cohort of a single center from Turkey. Compared to older patients, young patients were more smoking, more obese, less diabetic, and less hypertensive. High total cholesterol, high triglycerides, low HDL-cholesterol levels, high non-HDL cholesterol, family history of CAD, and FH were also more commonly observed in the young group. High FH prevalence might be a major factor of the high prevalence of premature ACS in this population. Both the in-hospital and 2-year follow-up mortality rates were significantly lower in the old-age group.
{"title":"Evaluation of Clinical Features including the frequency of Familial Hypercholesterolemia, and 2-Year Cardiovascular Outcomes in Patients with Early Acute Coronary Syndrome: Real-Life Data from a Retrospective Cohort","authors":"Meral Kayikcioglu, Bahadir Alan, Burcu Yağmur","doi":"10.56095/eaj.v2i2.27","DOIUrl":"https://doi.org/10.56095/eaj.v2i2.27","url":null,"abstract":"Objective: This retrospective study, based on real-life data, aimed to evaluate the clinical characteristics and 2-year cardiovascular outcomes in patients presenting with early acute coronary syndrome (ACS) in a tertiary healthcare center. Methods: Information including at least 2-year endpoint data after index ACS event was retrieved from hospital records. Age limit for early ACS was considered <55 years for males and <60 years for females. Results: Of 985 consecutive ACS patients (770 males; age range, 21-93 years) 361 (36.6%) met early ACS criteria. Frequency familial hypercholesterolemia (FH) was 7.6% and higher in the young-age group (15.5%) than in the old-age group (3%) (p<0.001). During the follow-up (30 monts), the risk predictors for cardiovascular events were the index event being ST-segment elevation myocardial infarction or non-ST-segment elevation myocardial infarction and the presence of hypertension, and the risk predictors for mortality were female sex, older age, in-hospital cardiovascular complications. Conclusion: A very high rate of early ACS (36.6%) was observed in this retrospective ACS cohort of a single center from Turkey. Compared to older patients, young patients were more smoking, more obese, less diabetic, and less hypertensive. High total cholesterol, high triglycerides, low HDL-cholesterol levels, high non-HDL cholesterol, family history of CAD, and FH were also more commonly observed in the young group. High FH prevalence might be a major factor of the high prevalence of premature ACS in this population. Both the in-hospital and 2-year follow-up mortality rates were significantly lower in the old-age group.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"14 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136035756","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}
Angela Pirillo, Lale Tokgözoğlu, Alberico L. Catapano
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that belongs to the serine protease family and plays a key role in regulating low-density lipoprotein cholesterol (LDL-C) levels in the blood. PCSK9 binds to the LDL receptor (LDLR), targeting it for degradation, resulting in an increase in circulating LDL-C levels. Loss-of-function mutations in the PCSK9 gene are associated with lower LDL-C levels and lower cardiovascular risk; in contrast, gain-of-function mutations are a cause of familial hypercholesterolaemia. The identification of PCSK9 as a pharmacological target led to the development of inhibitors for the treatment of hypercholesterolaemia. To date, the monoclonal antibodies evolocumab and alirocumab (which target plasma PCSK9) and the small-interfering RNA inclisiran (which targets hepatic PCSK9 mRNA) have been approved for the treatment of hypercholesterolaemia. Although hepatic PCSK9 plays a central role in regulating plasma LDL-C levels, this protein is also expressed in other tissues, including the brain, pancreas, heart, kidney, intestine and adipose tissue. In extrahepatic tissues, the functions of PCSK9 are both dependent and independent of LDLR and not necessarily harmful. For this reason, it is essential to uncover any potentially harmful effects of therapies that inhibit PCSK9, beyond their known LDL-C-lowering and CV risk-reducing effects.
蛋白转化酶subtilisin/ keexin type 9 (PCSK9)是丝氨酸蛋白酶家族的一种酶，在调节血液中低密度脂蛋白胆固醇(LDL-C)水平中起关键作用。PCSK9与LDL受体(LDLR)结合，靶向其降解，导致循环LDL- c水平升高。PCSK9基因的功能缺失突变与较低的LDL-C水平和较低的心血管风险相关;相反，功能获得突变是家族性高胆固醇血症的一个原因。PCSK9作为药理学靶点的鉴定导致了治疗高胆固醇血症的抑制剂的开发。迄今为止，单克隆抗体evolocumab和alirocumab(靶向血浆PCSK9)和小干扰RNA inclisiran(靶向肝脏PCSK9 mRNA)已被批准用于治疗高胆固醇血症。尽管肝脏PCSK9在调节血浆LDL-C水平中起核心作用，但该蛋白也在其他组织中表达，包括脑、胰腺、心脏、肾脏、肠和脂肪组织。在肝外组织中，PCSK9的功能既依赖又独立于LDLR，并不一定有害。因此，除了已知的降低ldl - c和降低CV风险的作用外，有必要发现抑制PCSK9的治疗方法的任何潜在有害影响。
{"title":"PCSK9 in extrahepatic tissues: What can we expect from its inhibition?","authors":"Angela Pirillo, Lale Tokgözoğlu, Alberico L. Catapano","doi":"10.56095/eaj.v2i2.47","DOIUrl":"https://doi.org/10.56095/eaj.v2i2.47","url":null,"abstract":"Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme that belongs to the serine protease family and plays a key role in regulating low-density lipoprotein cholesterol (LDL-C) levels in the blood. PCSK9 binds to the LDL receptor (LDLR), targeting it for degradation, resulting in an increase in circulating LDL-C levels. Loss-of-function mutations in the PCSK9 gene are associated with lower LDL-C levels and lower cardiovascular risk; in contrast, gain-of-function mutations are a cause of familial hypercholesterolaemia. The identification of PCSK9 as a pharmacological target led to the development of inhibitors for the treatment of hypercholesterolaemia. To date, the monoclonal antibodies evolocumab and alirocumab (which target plasma PCSK9) and the small-interfering RNA inclisiran (which targets hepatic PCSK9 mRNA) have been approved for the treatment of hypercholesterolaemia. Although hepatic PCSK9 plays a central role in regulating plasma LDL-C levels, this protein is also expressed in other tissues, including the brain, pancreas, heart, kidney, intestine and adipose tissue. In extrahepatic tissues, the functions of PCSK9 are both dependent and independent of LDLR and not necessarily harmful. For this reason, it is essential to uncover any potentially harmful effects of therapies that inhibit PCSK9, beyond their known LDL-C-lowering and CV risk-reducing effects.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"29 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136035757","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}
M. Marozzi, Teresa Panebianco, A. Vacca, Valeria Dipaola, S. Noviello, Antonio Giovanni Solimando, S. Cicco
Aim: Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis. Inflammation of the vessel wall may induce multiple vascular damages. Atherosclerosis is accelerated during vasa inflammation. Metabolic profile and cardiovascular risk are far to be determined in these patients. Thus, Cardiovascular atherosclerotic disease (ASCVD) may represent a risk for patients' outcomes. The purpose is to evaluate ASCVD risk in GPA over time during disease follow-up. Methods: We retrospectively evaluated 37 patients (22 Females, aged 51.45±17.15) who received a diagnosis of GPA (T0). Patients were evaluated at 1 (T1) and 2 (T2) year follow-up. All patients were treated with high steroid dose followed by a one-year tapering, associated to another immunosuppressant. Lipid profile included total cholesterol, HDL, LDL and Triacylglycerol. To evaluate inflammatory activity, we evaluate erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and neutrophil to lymphocyte ratio (NLR) at the same time points. ANOVA for repeated values was used to evaluate the trend over time and Tukey's multiple comparisons test was a second step evaluation. Results: At T1 there was an increase in total cholesterol compared to baseline (T1vsT0, p<0.05) and T2 (T1vs T2, p<0.05). Similarly, LDL (T1vsT0, p<0.05) presents the same trend, while Triacylglycerol increased in T1 compared to baseline (T1vsT0, p<0.05), but no difference there was in T2 compared to T1 or T0. No difference was found in HDL between the different time points. CRP was no different, despite a reduction being noticed. On the contrary, we found a reduction at T2 but not in T1 in ESR (T1vsT0, p<0.05) and NLR (T1vsT0, p<0.05). Conclusion: Our data suggest that a change in lipid profile may not relate to better control of inflammation. On the contrary, the increase in the first year of follow-up should be a consequence of steroid treatment needed to spread disease control. These data may be helpful in the evaluation of both cardiovascular disease and lipid metabolism due to the connection between the two parameters with vessel inflammation. Further studies are needed to better evaluate the cardiovascular effect of vasculitis and consequent treatment.
{"title":"Change over time of lipid profile relates to steroid treatment but not to an inflammatory state in Granulomatosis with poliangioitis polyangiitis (GPA)","authors":"M. Marozzi, Teresa Panebianco, A. Vacca, Valeria Dipaola, S. Noviello, Antonio Giovanni Solimando, S. Cicco","doi":"10.56095/eaj.v2i1.37","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.37","url":null,"abstract":"Aim: Granulomatosis with polyangiitis (GPA) is a small vessel vasculitis. Inflammation of the vessel wall may induce multiple vascular damages. Atherosclerosis is accelerated during vasa inflammation. Metabolic profile and cardiovascular risk are far to be determined in these patients. Thus, Cardiovascular atherosclerotic disease (ASCVD) may represent a risk for patients' outcomes. The purpose is to evaluate ASCVD risk in GPA over time during disease follow-up. Methods: We retrospectively evaluated 37 patients (22 Females, aged 51.45±17.15) who received a diagnosis of GPA (T0). Patients were evaluated at 1 (T1) and 2 (T2) year follow-up. All patients were treated with high steroid dose followed by a one-year tapering, associated to another immunosuppressant. Lipid profile included total cholesterol, HDL, LDL and Triacylglycerol. To evaluate inflammatory activity, we evaluate erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and neutrophil to lymphocyte ratio (NLR) at the same time points. ANOVA for repeated values was used to evaluate the trend over time and Tukey's multiple comparisons test was a second step evaluation. Results: At T1 there was an increase in total cholesterol compared to baseline (T1vsT0, p<0.05) and T2 (T1vs T2, p<0.05). Similarly, LDL (T1vsT0, p<0.05) presents the same trend, while Triacylglycerol increased in T1 compared to baseline (T1vsT0, p<0.05), but no difference there was in T2 compared to T1 or T0. No difference was found in HDL between the different time points. CRP was no different, despite a reduction being noticed. On the contrary, we found a reduction at T2 but not in T1 in ESR (T1vsT0, p<0.05) and NLR (T1vsT0, p<0.05). Conclusion: Our data suggest that a change in lipid profile may not relate to better control of inflammation. On the contrary, the increase in the first year of follow-up should be a consequence of steroid treatment needed to spread disease control. These data may be helpful in the evaluation of both cardiovascular disease and lipid metabolism due to the connection between the two parameters with vessel inflammation. Further studies are needed to better evaluate the cardiovascular effect of vasculitis and consequent treatment.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"28 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129170064","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}
G. Palma, C. Caccioppoli, R. D'Oria, V. A. Genchi, Isabella Calderoni, Antonio Braun, Giuseppe Santarpino, A. D. Milano, A. Cignarelli, A. Natalicchio, L. Laviola, A. Pezzolla, F. Giorgino, Sebastio Perrini
Aim: Dapagliflozin (DAPA), an SGLT2 inhibitor, has been shown to counteract heart failure outcomes in subjects with obesity and diabetes. We investigated the protective mechanisms of DAPA in human cardiac progenitor cells (hCPC) exposed to the conditioned medium (CM) from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC) and from AV mature adipocytes from obese subjects. Methods: ASC and mature adipocytes were isolated from AV adipose tissue biopsies of 27 obese (Ob) and 19 non-Ob subjects (n-Ob), and from E adipose tissue biopsies of 9 Ob and 10 non-Ob subjects, respectively. hCPC were isolated from right auricle biopsies of 10 healthy non-Ob donors. Results: Exposure of hCPC to the CM of adipose cells from Ob, but not from non-Ob subjects, induced apoptosis, c-Jun phosphorylation, and impairment of actin filaments, while these effects were not observed when hCPC were pretreated with DAPA. The CM of adipose cells from Ob compared to n-Ob subjects displayed a different pattern of cytokines. The levels of pro-inflammatory cytokines RANTES and MIP1β were increased in the CM from AV-ASC with higher BMI (p<0.05), while the levels of the cardioprotective factor GCSF in the CM of E-ASC were inversely correlated with BMI (p<0.05). SGLT2 was found to be expressed as both mRNA and protein in hCPC, and silencing of SGLT2 with a specific siRNA abrogated the capacity of DAPA to counteract the pro-apoptotic effects of the CM. Conclusions: In human obesity, the CM of both AV- and E-ASC and mature adipocytes is characterized by pro-inflammatory cytokines that induce stress kinase activation and apoptosis in hCPC. DAPA prevents the hCPC damage induced by the CM through an SGLT2-dependent mechanism.
{"title":"Dapagliflozin counteracts the pro-apoptotic effects of the secretome of visceral adipose cells from obese subjects in human cardiac progenitor cells via the SGLT2 co-transporter","authors":"G. Palma, C. Caccioppoli, R. D'Oria, V. A. Genchi, Isabella Calderoni, Antonio Braun, Giuseppe Santarpino, A. D. Milano, A. Cignarelli, A. Natalicchio, L. Laviola, A. Pezzolla, F. Giorgino, Sebastio Perrini","doi":"10.56095/eaj.v2i1.40","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.40","url":null,"abstract":"Aim: Dapagliflozin (DAPA), an SGLT2 inhibitor, has been shown to counteract heart failure outcomes in subjects with obesity and diabetes. We investigated the protective mechanisms of DAPA in human cardiac progenitor cells (hCPC) exposed to the conditioned medium (CM) from abdominal visceral (AV) and epicardial (E) adipose stem cells (ASC) and from AV mature adipocytes from obese subjects. Methods: ASC and mature adipocytes were isolated from AV adipose tissue biopsies of 27 obese (Ob) and 19 non-Ob subjects (n-Ob), and from E adipose tissue biopsies of 9 Ob and 10 non-Ob subjects, respectively. hCPC were isolated from right auricle biopsies of 10 healthy non-Ob donors. Results: Exposure of hCPC to the CM of adipose cells from Ob, but not from non-Ob subjects, induced apoptosis, c-Jun phosphorylation, and impairment of actin filaments, while these effects were not observed when hCPC were pretreated with DAPA. The CM of adipose cells from Ob compared to n-Ob subjects displayed a different pattern of cytokines. The levels of pro-inflammatory cytokines RANTES and MIP1β were increased in the CM from AV-ASC with higher BMI (p<0.05), while the levels of the cardioprotective factor GCSF in the CM of E-ASC were inversely correlated with BMI (p<0.05). SGLT2 was found to be expressed as both mRNA and protein in hCPC, and silencing of SGLT2 with a specific siRNA abrogated the capacity of DAPA to counteract the pro-apoptotic effects of the CM. Conclusions: In human obesity, the CM of both AV- and E-ASC and mature adipocytes is characterized by pro-inflammatory cytokines that induce stress kinase activation and apoptosis in hCPC. DAPA prevents the hCPC damage induced by the CM through an SGLT2-dependent mechanism.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"76 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127240211","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}
Giulia Cassioli, Ada Kura, A. Sodero, E. Sticchi, A. Magi, Samuele Suraci, Rosina De Cario, A. Consoli, A. Rosi, S. Nappini, L. Renieri, N. Limbucci, Benedetta Piccardi, F. Arba, C. Sarti, D. Inzitari, S. Mangiafico, R. Marcucci, A. Gori, B. Giusti
Background: Acute ischemic stroke (AIS) represents one of the principal causes of neurological morbidity and mortality worldwide. For a prompt and efficient cerebral blood restoration, intravenous treatment with rt-PA is often combined with mechanical thrombectomy (MT) which provides cerebral thrombi (CT) as study material, allowing the investigation of its cellular composition, morphological and histopathological features. Indeed, the determination of stroke etiology, typically defined by the TOAST classification, is paramount for prognostic factors, outcome, and management of the event. Aim of the study is therefore to highlight and analyze gene expression profiles in thrombotic tissue and peripheral blood (PB) in the comparison between strokes of cardioembolic (CE) and atherosclerotic (LAA) origin. Methods: We performed gene expression profiles of 92 patients. CT were stored in RNA later and RNA was extracted by PAX gene blood miRNA kit. The global gene expression profile was assessed by Affymetrix technology using GeneChip Human Transcriptome Array 2.0 combined with Affymetrix Transcriptome Analysis Console (TAC) Software. Results: Currently, we focused our attention on CT data analysis. The analysis revealed a significant difference (p-value<0.05 and FoldChange=2 as threshold) in gene expression when comparing LAA and CE stroke. In particular, from CT of atherosclerotic origin emerges an overexpression of 1766 genes. Prominent among them are genes such as MMP-9, TGFB, TGFBR and CXCL1, primarily involved in neutrophil-mediated immunity, Blood-Brain Barrier (BBB) disruption processes, and associated with atherosclerotic plaque instability and related to poor neurological outcome, suggesting a deleterious role in human brain injury. As concerns CE patients, 57 genes mainly involved in transcriptional regulatory processes turn out to be significantly overexpressed. Conclusions: Transcriptome profiling is a powerful weapon for revealing expression patterns associated with complex disorders. The variation of gene expression profiles confirmed and extended several known pathophysiological mechanisms and may be one way of delineating different stroke etiology.
背景:急性缺血性脑卒中(AIS)是世界范围内神经系统发病和死亡的主要原因之一。为了迅速有效地恢复脑血，静脉注射rt-PA治疗通常与机械取栓术(MT)相结合，后者提供脑血栓(CT)作为研究材料，可以研究其细胞组成、形态和组织病理学特征。事实上，卒中病因的确定，通常由TOAST分类定义，对于预后因素、结果和事件管理至关重要。因此，该研究的目的是强调和分析血栓组织和外周血(PB)中的基因表达谱，比较心脏栓塞(CE)和动脉粥样硬化(LAA)起源的中风。方法:对92例患者进行基因表达谱分析。CT后保存于RNA中，用PAX基因血miRNA试剂盒提取RNA。使用GeneChip Human Transcriptome Array 2.0结合Affymetrix转录组分析控制台(TAC)软件，采用Affymetrix技术评估全局基因表达谱。结果:目前，我们主要关注CT数据分析。分析结果显示，LAA与CE卒中患者基因表达差异有统计学意义(p值<0.05,FoldChange=2为阈值)。特别是，动脉粥样硬化起源的CT显示1766个基因过表达。其中突出的是MMP-9、TGFB、TGFBR和CXCL1等基因，它们主要参与中性粒细胞介导的免疫、血脑屏障(BBB)破坏过程，与动脉粥样硬化斑块不稳定相关，并与不良的神经预后相关，表明它们在人脑损伤中具有有害作用。在CE患者中，有57个主要参与转录调控过程的基因显著过表达。结论:转录组分析是揭示与复杂疾病相关的表达模式的有力武器。基因表达谱的变化证实并扩展了几种已知的病理生理机制，可能是描述不同中风病因的一种方法。
{"title":"Acute ischemic stroke: how to investigate the association between disease etiology and gene expression profiles","authors":"Giulia Cassioli, Ada Kura, A. Sodero, E. Sticchi, A. Magi, Samuele Suraci, Rosina De Cario, A. Consoli, A. Rosi, S. Nappini, L. Renieri, N. Limbucci, Benedetta Piccardi, F. Arba, C. Sarti, D. Inzitari, S. Mangiafico, R. Marcucci, A. Gori, B. Giusti","doi":"10.56095/eaj.v2i1.32","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.32","url":null,"abstract":"Background: Acute ischemic stroke (AIS) represents one of the principal causes of neurological morbidity and mortality worldwide. For a prompt and efficient cerebral blood restoration, intravenous treatment with rt-PA is often combined with mechanical thrombectomy (MT) which provides cerebral thrombi (CT) as study material, allowing the investigation of its cellular composition, morphological and histopathological features. Indeed, the determination of stroke etiology, typically defined by the TOAST classification, is paramount for prognostic factors, outcome, and management of the event. Aim of the study is therefore to highlight and analyze gene expression profiles in thrombotic tissue and peripheral blood (PB) in the comparison between strokes of cardioembolic (CE) and atherosclerotic (LAA) origin. Methods: We performed gene expression profiles of 92 patients. CT were stored in RNA later and RNA was extracted by PAX gene blood miRNA kit. The global gene expression profile was assessed by Affymetrix technology using GeneChip Human Transcriptome Array 2.0 combined with Affymetrix Transcriptome Analysis Console (TAC) Software. Results: Currently, we focused our attention on CT data analysis. The analysis revealed a significant difference (p-value<0.05 and FoldChange=2 as threshold) in gene expression when comparing LAA and CE stroke. In particular, from CT of atherosclerotic origin emerges an overexpression of 1766 genes. Prominent among them are genes such as MMP-9, TGFB, TGFBR and CXCL1, primarily involved in neutrophil-mediated immunity, Blood-Brain Barrier (BBB) disruption processes, and associated with atherosclerotic plaque instability and related to poor neurological outcome, suggesting a deleterious role in human brain injury. As concerns CE patients, 57 genes mainly involved in transcriptional regulatory processes turn out to be significantly overexpressed. Conclusions: Transcriptome profiling is a powerful weapon for revealing expression patterns associated with complex disorders. The variation of gene expression profiles confirmed and extended several known pathophysiological mechanisms and may be one way of delineating different stroke etiology.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"52 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127687802","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}
Sining Xie, F. Galimberti, E. Olmastroni, A. Catapano, M. Casula
Aim: Epidemiological studies, Mendelian randomized studies, and genome-wide association studies confirmed that elevated lipoprotein(a) [Lp(a)] concentration is an independent risk factor for cardiovascular diseases. However, no approved therapy for patients with elevated Lp(a) levels is available. Our aim is to investigate to what extent PCSK9 inhibitors (PCSK9i), statins, and ezetimibe affect Lp(a) level. Methods: This meta-analysis was conducted according to the PRISMA guidelines. Databases were searched from inception to February 2023. Inclusion criteria were: (1) randomized controlled trials (RCTs) in adults (≥18 years), phase II, III or IV; (2) English language; (3) reporting the effects on Lp(a) levels; (4) with intervention duration more than 3 weeks. Pooled estimates were assessed by a random-effects model. Between-study heterogeneity was tested and measured by Cochrane’s Q test and I2 statistics. Results: Overall, 51 RCTs were included for PCSK9i (39,271 participants), 35 RCTs for statins (15,425 participants), and 14 RCTs for ezetimibe (5,607 participants). Starting from a baseline Lp(a) level of 33.12 mg/dL, participants treated with PCSK9i compared to placebo experienced an additional reduction in Lp(a) levels of -26.34% (95%CI -28.83 to -23.85). Lp(a) levels were marginally reduced by statins by -3.43% (95%CI -9.09 to 2.23) from a baseline Lp(a) level of 15.87 mg/dL, although this reduction was not statistically significant. Finally, ezetimibe had a negligible and still not statistically significant effect on Lp(a) levels (0.51% [95%CI -1.67 to 2.70]), from a baseline Lp(a) level of 20.80 mg/dL. Conclusions: Among the lipid-lowering approaches evaluated, only PCSK9i seemed to lower Lp(a) levels. Further research is requested to understand whether it translates into a clinically relevant cardiovascular benefit.
{"title":"Effect of lipid-lowering therapies on lipoprotein(a) levels: a meta-analysis of randomized controlled trials","authors":"Sining Xie, F. Galimberti, E. Olmastroni, A. Catapano, M. Casula","doi":"10.56095/eaj.v2i1.44","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.44","url":null,"abstract":"Aim: Epidemiological studies, Mendelian randomized studies, and genome-wide association studies confirmed that elevated lipoprotein(a) [Lp(a)] concentration is an independent risk factor for cardiovascular diseases. However, no approved therapy for patients with elevated Lp(a) levels is available. Our aim is to investigate to what extent PCSK9 inhibitors (PCSK9i), statins, and ezetimibe affect Lp(a) level. Methods: This meta-analysis was conducted according to the PRISMA guidelines. Databases were searched from inception to February 2023. Inclusion criteria were: (1) randomized controlled trials (RCTs) in adults (≥18 years), phase II, III or IV; (2) English language; (3) reporting the effects on Lp(a) levels; (4) with intervention duration more than 3 weeks. Pooled estimates were assessed by a random-effects model. Between-study heterogeneity was tested and measured by Cochrane’s Q test and I2 statistics. Results: Overall, 51 RCTs were included for PCSK9i (39,271 participants), 35 RCTs for statins (15,425 participants), and 14 RCTs for ezetimibe (5,607 participants). Starting from a baseline Lp(a) level of 33.12 mg/dL, participants treated with PCSK9i compared to placebo experienced an additional reduction in Lp(a) levels of -26.34% (95%CI -28.83 to -23.85). Lp(a) levels were marginally reduced by statins by -3.43% (95%CI -9.09 to 2.23) from a baseline Lp(a) level of 15.87 mg/dL, although this reduction was not statistically significant. Finally, ezetimibe had a negligible and still not statistically significant effect on Lp(a) levels (0.51% [95%CI -1.67 to 2.70]), from a baseline Lp(a) level of 20.80 mg/dL. Conclusions: Among the lipid-lowering approaches evaluated, only PCSK9i seemed to lower Lp(a) levels. Further research is requested to understand whether it translates into a clinically relevant cardiovascular benefit.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"129138205","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}
S. Colosimo, G. Tan, M. Petroni, Simona Bertoli, G. Marchesini, J. Tomlinson
Aim. The mainstays for the treatment of non-alcoholic fatty liver disease (NAFLD) are lifestyle intervention with the aim of significant weight loss alongside aggressive cardiovascular risk reduction. NAFLD is tightly associated with both obesity and type 2 diabetes (T2D). In people with T2D, glucose lowering agents that promote weight loss have shown a beneficial impact on NAFLD based on histological features. However, it remains unclear as to whether glucose lowering can improve NALFD in patients with T2D, independent of weight loss. Methods. In a consecutively recruited population of 637 patients with T2D with HbA1c levels above treatment targets, DPP-IV inhibition, GLP-1RA therapy or SGLT2 inhibition was initiated, alongside lifestyle education with maintenance of exiting background glucose lowering treatment. We examined the longitudinal impact of the optimization of glycaemic control on fatty liver index (FLI) and Fibrosis score 4 (Fib-4) adjusting for changes in BMI and choice of glucose lowering regimen over a 12-month period. Results. Change in HbA1c and change in FLI correlated significantly in a linear regression analysis after adjustment for change in BMI, age, sex, and drug class (R=0.467, p=0.031). The greatest reduction in FLI was observed in patients with the largest reduction in HbA1c (p<0.0001). The probability of improvements in FLI with optimization of glycaemic control was similar with all 3 glucose lowering agents, despite differences in weight reduction. Similar relationships were observed examining the changes in glycaemic control and Fib-4. Conclusions. Significant reductions of HbA1c are associated with improvement in NAFLD independently from weight loss. These results suggest a prominent role for the optimization of glucose control in the management of coexistent NAFLD and T2D, especially in the ‘lean’ NAFLD and where significant weight loss may not be achieved.
{"title":"Optimization of glucose control drives improvement of NAFLD independent of weight loss in people with T2D","authors":"S. Colosimo, G. Tan, M. Petroni, Simona Bertoli, G. Marchesini, J. Tomlinson","doi":"10.56095/eaj.v2i1.34","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.34","url":null,"abstract":"Aim. The mainstays for the treatment of non-alcoholic fatty liver disease (NAFLD) are lifestyle intervention with the aim of significant weight loss alongside aggressive cardiovascular risk reduction. NAFLD is tightly associated with both obesity and type 2 diabetes (T2D). In people with T2D, glucose lowering agents that promote weight loss have shown a beneficial impact on NAFLD based on histological features. However, it remains unclear as to whether glucose lowering can improve NALFD in patients with T2D, independent of weight loss. Methods. In a consecutively recruited population of 637 patients with T2D with HbA1c levels above treatment targets, DPP-IV inhibition, GLP-1RA therapy or SGLT2 inhibition was initiated, alongside lifestyle education with maintenance of exiting background glucose lowering treatment. We examined the longitudinal impact of the optimization of glycaemic control on fatty liver index (FLI) and Fibrosis score 4 (Fib-4) adjusting for changes in BMI and choice of glucose lowering regimen over a 12-month period. Results. Change in HbA1c and change in FLI correlated significantly in a linear regression analysis after adjustment for change in BMI, age, sex, and drug class (R=0.467, p=0.031). The greatest reduction in FLI was observed in patients with the largest reduction in HbA1c (p<0.0001). The probability of improvements in FLI with optimization of glycaemic control was similar with all 3 glucose lowering agents, despite differences in weight reduction. Similar relationships were observed examining the changes in glycaemic control and Fib-4. Conclusions. Significant reductions of HbA1c are associated with improvement in NAFLD independently from weight loss. These results suggest a prominent role for the optimization of glucose control in the management of coexistent NAFLD and T2D, especially in the ‘lean’ NAFLD and where significant weight loss may not be achieved.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"41 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115022696","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}
Leonardo Bencivenga, Mathilde Strumia, Yves Rolland, Sandrine Andrieu, Bruno Vellas, Philipe De Souto Barreto, Laure Rouch, for the MAPT/D. S. A. group
Aim: Increased Blood Pressure (BP) Variability (BPV) may represent an alteration in BP physiological homeostatic patterns. Most physiopathological mechanisms underlying BPV are implicated in aging. Vascular aging is associated with chronic low-grade inflammation occurring in late life, known as "inflammaging", and the hallmark “mitochondrial dysfunction” associated to stress due to age-related disorders, which in turn might contribute to higher BPV and risk of cardiovascular disease. We aimed to determine whether plasma levels of the pleiotropic stress-related mitokine Growth/Differentiation Factor 15 (GDF-15) and two inflammatory biomarkers, Interleukin 6 (IL-6) and Tumor necrosis factor receptor 1 (TNFR-1), are associated with visit-to-visit BPV in a population of community-dwelling older adults. Methods: The study population consisted of 1,096 participants [median age 75 (72-78) years; 699 females, 63.7%] selected among community-dwelling participants aged ≥70 years from the MAPT study. Plasma blood sample was collected 12 months after enrolment and BP was assessed up to seven times over a subsequent 4-year period. Systolic BPV (SBPV) and diastolic BPV (DBPV) were determined through several indicators including the coefficient of variation (CV%) and taking into account BP change over time, the order of measurements and formulas independent of mean BP levels. Results: Higher values of GDF-15 were significantly associated with increased SBPV (all indicators) after adjustment for demographics, body mass index, MAPT randomization group, baseline systolic BP, antihypertensive drugs, diabetes mellitus, cardiovascular and non-cardiovascular comorbidities [adjusted 1-SD increase in GDF-15: β (SE)= 0.07 (0.04), p< 0.044, for CV%]. GDF-15 levels were not associated with DBPV. No significant associations were found between IL-6 and BPV, whereas TNFR1 was only partially related to DBPV. Conclusions: Unlike inflammation biomarkers, higher GDF-15 levels were associated with greater SBPV. Our findings support the age-related process of mitochondrial dysfunction underlying BP instability, suggesting that BPV might be a potential marker of aging.
{"title":"Biomarkers of mitochondrial dysfunction and inflammaging in older adults and blood pressure variability","authors":"Leonardo Bencivenga, Mathilde Strumia, Yves Rolland, Sandrine Andrieu, Bruno Vellas, Philipe De Souto Barreto, Laure Rouch, for the MAPT/D. S. A. group","doi":"10.56095/eaj.v2i1.31","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.31","url":null,"abstract":"Aim: Increased Blood Pressure (BP) Variability (BPV) may represent an alteration in BP physiological homeostatic patterns. Most physiopathological mechanisms underlying BPV are implicated in aging. Vascular aging is associated with chronic low-grade inflammation occurring in late life, known as \"inflammaging\", and the hallmark “mitochondrial dysfunction” associated to stress due to age-related disorders, which in turn might contribute to higher BPV and risk of cardiovascular disease. We aimed to determine whether plasma levels of the pleiotropic stress-related mitokine Growth/Differentiation Factor 15 (GDF-15) and two inflammatory biomarkers, Interleukin 6 (IL-6) and Tumor necrosis factor receptor 1 (TNFR-1), are associated with visit-to-visit BPV in a population of community-dwelling older adults. Methods: The study population consisted of 1,096 participants [median age 75 (72-78) years; 699 females, 63.7%] selected among community-dwelling participants aged ≥70 years from the MAPT study. Plasma blood sample was collected 12 months after enrolment and BP was assessed up to seven times over a subsequent 4-year period. Systolic BPV (SBPV) and diastolic BPV (DBPV) were determined through several indicators including the coefficient of variation (CV%) and taking into account BP change over time, the order of measurements and formulas independent of mean BP levels. Results: Higher values of GDF-15 were significantly associated with increased SBPV (all indicators) after adjustment for demographics, body mass index, MAPT randomization group, baseline systolic BP, antihypertensive drugs, diabetes mellitus, cardiovascular and non-cardiovascular comorbidities [adjusted 1-SD increase in GDF-15: β (SE)= 0.07 (0.04), p< 0.044, for CV%]. GDF-15 levels were not associated with DBPV. No significant associations were found between IL-6 and BPV, whereas TNFR1 was only partially related to DBPV. Conclusions: Unlike inflammation biomarkers, higher GDF-15 levels were associated with greater SBPV. Our findings support the age-related process of mitochondrial dysfunction underlying BP instability, suggesting that BPV might be a potential marker of aging.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"56 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135757262","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}
Background and Aims: Among patients at very high cardiovascular risk, some are more likely to experience recurrent cardiovascular events. In May 2022, an article was published in the European Heart Journal proposing different definitions of patients at extreme cardiovascular risk. However, the process of defining such patient is still ongoing and more data on its prevalence are needed. Our aims consisted in assessing the prevalence of patients at extreme cardiovascular risk in cardiological rehabilitation and in evaluating the clinical features of such patients. Furthermore, we wanted to establish how the extreme cardiovascular risk condition correlates with the functional improvement obtained during cardiac rehabilitation. Methods: The study included 938 patients suffering from atherosclerosis who attended the cardiological rehabilitation of Niguarda Hospital in Milan. Patients classified as at extreme cardiovascular risk were compared with the remaining patients and a multivariate linear regression was performed with absolute functional improvement as the dependent variable. Results: Among 938 patients, 26.9% belong to the category of extreme cardiovascular risk. Patients at extreme cardiovascular risk showed a higher average age (67.8 ± 10.4 vs 64.1 ± 11.1 years; p ≤ 0.001), a higher prevalence of significant comorbidities (peripheral arterial disease, cerebrovascular disease, dyslipidemia, diabetes, chronic kidney disease, hypertension) and a lower functional improvement during cardiac rehabilitation (102.9 ± 68.6 vs 138.1 ± 86.5 m; p ≤ 0.001). At multivariate analysis extreme cardiovascular risk remains a significant determinant of the absolute functional improvement at Six-Minute Walking Test obtained during cardiac rehabilitation with b = -0.137 and p = 0.035, together with female sex (b = -0.136; p = 0.035). Conclusions: Extreme cardiovascular risk is a widespread condition among patients with chronic coronary syndrome and adversely affects the patient’s functional improvement during cardiac rehabilitation. The identification of patients at extreme cardiovascular risk is a goal to be pursued in order to intensify secondary prevention strategies.
背景和目的:在心血管风险极高的患者中，一些患者更容易出现复发性心血管事件。2022年5月，《欧洲心脏杂志》(European Heart Journal)发表了一篇文章，提出了对心血管极端风险患者的不同定义。然而，对这类患者的定义仍在进行中，需要更多关于其流行程度的数据。我们的目的是评估心脏病康复中心血管极端危险患者的患病率，并评估这类患者的临床特征。此外，我们想要确定极端心血管危险状况与心脏康复期间获得的功能改善之间的关系。方法:研究纳入938例在米兰尼瓜达医院心脏康复治疗的动脉粥样硬化患者。将归类为心血管极端危险的患者与其余患者进行比较，并以绝对功能改善为因变量进行多元线性回归。结果:938例患者中，26.9%属于心血管极端危险类别。极端心血管危险患者的平均年龄更高(67.8±10.4 vs 64.1±11.1);P≤0.001)，显著合并症(外周动脉疾病、脑血管疾病、血脂异常、糖尿病、慢性肾病、高血压)患病率较高，心脏康复期间功能改善较低(102.9±68.6 vs 138.1±86.5;P≤0.001)。在多变量分析中，极端心血管风险仍然是心脏康复期间获得的6分钟步行试验绝对功能改善的重要决定因素，b = -0.137和p = 0.035，以及女性(b = -0.136;P = 0.035)。结论:极端心血管危险在慢性冠状动脉综合征患者中普遍存在，并对患者心脏康复过程中的功能改善产生不利影响。为了加强二级预防策略，确定具有极端心血管风险的患者是一个需要追求的目标。
{"title":"Extreme cardiovascular risk in cardiological rehabilitation: prevalence and impact on patient’s functional improvement","authors":"Alfonso Riccio, Eleonora Senini, Saverio Fabbri, Claudio Ciampi, Matteo Regazzetti, Massimiliano Monticelli, Roberto Pirola, Cristina Giannattasio","doi":"10.56095/eaj.v2i1.41","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.41","url":null,"abstract":"Background and Aims: Among patients at very high cardiovascular risk, some are more likely to experience recurrent cardiovascular events. In May 2022, an article was published in the European Heart Journal proposing different definitions of patients at extreme cardiovascular risk. However, the process of defining such patient is still ongoing and more data on its prevalence are needed. Our aims consisted in assessing the prevalence of patients at extreme cardiovascular risk in cardiological rehabilitation and in evaluating the clinical features of such patients. Furthermore, we wanted to establish how the extreme cardiovascular risk condition correlates with the functional improvement obtained during cardiac rehabilitation. Methods: The study included 938 patients suffering from atherosclerosis who attended the cardiological rehabilitation of Niguarda Hospital in Milan. Patients classified as at extreme cardiovascular risk were compared with the remaining patients and a multivariate linear regression was performed with absolute functional improvement as the dependent variable. Results: Among 938 patients, 26.9% belong to the category of extreme cardiovascular risk. Patients at extreme cardiovascular risk showed a higher average age (67.8 ± 10.4 vs 64.1 ± 11.1 years; p ≤ 0.001), a higher prevalence of significant comorbidities (peripheral arterial disease, cerebrovascular disease, dyslipidemia, diabetes, chronic kidney disease, hypertension) and a lower functional improvement during cardiac rehabilitation (102.9 ± 68.6 vs 138.1 ± 86.5 m; p ≤ 0.001). At multivariate analysis extreme cardiovascular risk remains a significant determinant of the absolute functional improvement at Six-Minute Walking Test obtained during cardiac rehabilitation with b = -0.137 and p = 0.035, together with female sex (b = -0.136; p = 0.035). Conclusions: Extreme cardiovascular risk is a widespread condition among patients with chronic coronary syndrome and adversely affects the patient’s functional improvement during cardiac rehabilitation. The identification of patients at extreme cardiovascular risk is a goal to be pursued in order to intensify secondary prevention strategies.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"2 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135757261","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}
Martina Ugolotti, B. Papotti, F. Zimetti, I. Zanotti, Martina Bodria, A. Vilella, D. Giuliani, Lisa Giannessi, L. Elviri, M. Lupo, N. Ferri, M. Radi, F. Bernini
Aim: Impairment of cholesterol homeostasis is one of the multiple etiopathological mechanisms at the origin of both cardiovascular and neurodegenerative diseases. The PCSK9 protein, known for its role in the degradation of hepatic LDLR and plasma cholesterol regulation, is expressed also in the CNS, where it exacerbates -amyloid neurotoxicity and reduces neuronal cholesterol uptake, suggesting an involvement in AD. This study proposes an in vitro screening of molecules (MR) with inhibitory activity on PCSK9, selecting the best compounds to test their activity on cerebral cell models and their in vivo tolerability. Methods: 30 newly synthesized compounds were tested at increasing concentrations on human hepatoma cells (HepG2) to evaluate their cytotoxicity and efficacy in inhibiting PCSK9. MR-3 was tested on human neuroblastoma cells (SH-SY5Y) overexpressing PCSK9 to assess neurotoxicity and cholesterol uptake. Cytotoxicity was determined through MTT assay; PCSK9 secretion was quantified with an ELISA kit; and radioisotopic techniques measured cholesterol uptake . Three compounds were selected to be tested in vivo on C57BL/6 mice at a dose of 40 mg/Kg for 7 days to evaluate: tolerability with SHIRPA test; plasma lipid profile by ELISA assay; biodistribution in plasma and brain through LC-MS/MS. Results: Among the tested compounds, MR-3, MR-532, MR-533 demonstrated no sign of cytotoxicity and the greatest efficacy on HepG2 cells (IC50=1.7μM; 5.7μM; 6.1μM). Neuronal cholesterol uptake was restored after treatment with MR-3 at 10μM (p<0,05). MR-3, MR-532, and MR-533 exhibited good in vivo tolerability; MR-3 and MR-532 were detected in plasma and brain tissue. Conclusions: Preliminary in vitro screening allowed the identification of MR-3, MR-532, MR-533 as promising PCSK9 inhibitors. The outcome of MR-3 on neuronal cholesterol uptake may suggest a neuroprotective effect to be further investigated. In vivo treatment with selected inhibitors shown absence of toxicity, however, it is necessary to bring proof of efficacy.
{"title":"In vitro and in vivo studies on novel pcsk9 inhibitors as pharmacological approach for the treatment of alzheimer’s disease","authors":"Martina Ugolotti, B. Papotti, F. Zimetti, I. Zanotti, Martina Bodria, A. Vilella, D. Giuliani, Lisa Giannessi, L. Elviri, M. Lupo, N. Ferri, M. Radi, F. Bernini","doi":"10.56095/eaj.v2i1.43","DOIUrl":"https://doi.org/10.56095/eaj.v2i1.43","url":null,"abstract":"Aim: Impairment of cholesterol homeostasis is one of the multiple etiopathological mechanisms at the origin of both cardiovascular and neurodegenerative diseases. The PCSK9 protein, known for its role in the degradation of hepatic LDLR and plasma cholesterol regulation, is expressed also in the CNS, where it exacerbates -amyloid neurotoxicity and reduces neuronal cholesterol uptake, suggesting an involvement in AD. This study proposes an in vitro screening of molecules (MR) with inhibitory activity on PCSK9, selecting the best compounds to test their activity on cerebral cell models and their in vivo tolerability. Methods: 30 newly synthesized compounds were tested at increasing concentrations on human hepatoma cells (HepG2) to evaluate their cytotoxicity and efficacy in inhibiting PCSK9. MR-3 was tested on human neuroblastoma cells (SH-SY5Y) overexpressing PCSK9 to assess neurotoxicity and cholesterol uptake. Cytotoxicity was determined through MTT assay; PCSK9 secretion was quantified with an ELISA kit; and radioisotopic techniques measured cholesterol uptake . Three compounds were selected to be tested in vivo on C57BL/6 mice at a dose of 40 mg/Kg for 7 days to evaluate: tolerability with SHIRPA test; plasma lipid profile by ELISA assay; biodistribution in plasma and brain through LC-MS/MS. Results: Among the tested compounds, MR-3, MR-532, MR-533 demonstrated no sign of cytotoxicity and the greatest efficacy on HepG2 cells (IC50=1.7μM; 5.7μM; 6.1μM). Neuronal cholesterol uptake was restored after treatment with MR-3 at 10μM (p<0,05). MR-3, MR-532, and MR-533 exhibited good in vivo tolerability; MR-3 and MR-532 were detected in plasma and brain tissue. Conclusions: Preliminary in vitro screening allowed the identification of MR-3, MR-532, MR-533 as promising PCSK9 inhibitors. The outcome of MR-3 on neuronal cholesterol uptake may suggest a neuroprotective effect to be further investigated. In vivo treatment with selected inhibitors shown absence of toxicity, however, it is necessary to bring proof of efficacy.","PeriodicalId":227903,"journal":{"name":"European Atherosclerosis Journal","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"124614770","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}
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