Search

Aim: No data are currently available regarding the association between Lp(a) and the cardiovascular outcomes in patients with coronary artery disease (CAD) according to their family history (FHx) of CAD. This study aimed to evaluate the significance of Lp(a) in predicting major adverse cardiovascular events (MACEs) in patients with chronic coronary syndrome (CCS) with or without FHx., Methods: A total of 6056 patients with CCS were enrolled. Information on FHx was collected, and the plasma Lp(a) levels were measured. All patients were followed up regularly. The independent and joint associations of Lp(a) and FHx with the risk of MACEs, including cardiovascular death, nonfatal myocardial infarction, and stroke, were analyzed., Results: With over an average of 50.35±18.58 months follow-up, 378 MACEs were recorded. A Cox regression analysis showed an elevated Lp(a) level to be an independent predictor for MACEs in patients with [hazard ratio (HR): 2.77, 95% confidence interval (CI): 1.38-5.54] or without FHx (HR: 1.35, 95% CI: 1.02-1.77). In comparison to subjects with non-elevated Lp(a) and negative FHx, patients with elevated Lp(a) alone were at a nominally higher risk of MACEs (HR: 1.26, 95% CI: 0.96-1.67), while those with both had the highest risk (HR: 1.93, 95% CI: 1.14-3.28). Moreover, adding Lp(a) to the original model increased the C-statistic by 0.048 in subjects with FHx (p=0.004) and by 0.004 in those without FHx (p=0.391)., Conclusions: The present study is the first to suggest that Lp(a) could be used to predict MACEs in CCS patients with or without FHx; however, its prognostic significance was more noteworthy in patients with FHx.

Background: Endothelin-1 (ET-1) is an endogenous vasoconstrictor implicated in coronary artery disease (CAD) and diabetes. This study aimed to determine the prognostic value of ET-1 in the patients with stable CAD under different glucose metabolism states., Methods: In this prospective, large-cohort study, we consecutively enrolled 7,947 participants with angiography-diagnosed stable CAD from April 2011 to April 2017. Patients were categorized by baseline glycemic status into three groups (normoglycemia, prediabetes, and diabetes) and further divided into nine groups by circulating ET-1 levels. Patients were followed for the occurrence of cardiovascular events (CVEs), including nonfatal myocardial infarction, stroke, and cardiovascular mortality., Results: Of the 7,947 subjects, 3,352, 1,653, and 2,942 had normoglycemia, prediabetes, and diabetes, respectively. Over a median follow-up of 37.5 months, 381 (5.1%) CVEs occurred. The risk for CVEs was significantly higher in patients with elevated ET-1 levels after adjustment for potential confounders. When patients were categorized by both status of glucose metabolism and plasma ET-1 levels, the high ET-1 levels were associated with higher risk of CVEs in prediabetes (adjusted hazard ratio [HR], 2.089; 95% confidence interval [CI], 1.151 to 3.793) and diabetes (adjusted HR, 2.729; 95% CI, 1.623 to 4.588; both P<0.05)., Conclusion: The present study indicated that baseline plasma ET-1 levels were associated with the prognosis in prediabetic and diabetic patients with stable CAD, suggesting that ET-1 may be a valuable predictor in CAD patients with impaired glucose metabolism.

Background: Triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) are reliable surrogate indices of insulin resistance and used for risk stratification and outcome prediction in patients with atherosclerotic cardiovascular disease (ASCVD). Here, we inserted estimated average glucose (eAG) into the TyG (TyAG) and TyG-BMI (TyAG-BMI) as derived parameters and explored their clinical significance in cardiovascular risk prediction., Methods: This was a population-based cohort study of 9,944 Chinese patients with ASCVD. The baseline admission fasting glucose and A1C-derived eAG values were recorded. Cardiovascular events (CVEs) that occurred during an average of 38.5 months of follow-up were recorded. We stratified the patients into four groups by quartiles of the parameters. Baseline data and outcomes were analyzed., Results: Distribution of the TyAG and TyAG-BMI indices shifted slightly toward higher values (the right side) compared with TyG and TyG-BMI, respectively. The baseline levels of cardiovascular risk factors and coronary severity increased with quartile of TyG, TyAG, TyG-BMI, and TyAG-BMI (all P <0.001). The multivariate-adjusted hazard ratios for CVEs when the highest and lowest quartiles were compared from low to high were 1.02 (95% confidence interval [CI], 0.77 to 1.36; TyG), 1.29 (95% CI, 0.97 to 1.73; TyAG), 1.59 (95% CI, 1.01 to 2.58; TyG-BMI), and 1.91 (95% CI, 1.16 to 3.15; TyAG-BMI). The latter two showed statistical significance., Conclusion: This study suggests that TyAG and TyAG-BMI exhibit more information than TyG and TyG-BMI in disease progression among patients with ASCVD. The TyAG-BMI index provided better predictive performance for CVEs than other parameters.

Background: Emerging data suggested that lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. Previous studies indicated fibrinogen (Fib) had synergetic effect on Lp(a)-induced events. However, combined impact of Fib and Lp(a) on ischemic stroke has not been elucidated., Methods: In this prospective study, we consecutively enrolled 8263 patients with stable coronary artery diseases (CAD) from 2011 to 2017. Patients were categorized into three groups according to tertiles of Lp(a) levels [Lp(a)-low, Lp(a)-medium, and Lp(a)-high] and further divided into nine groups by Lp(a) and Fib levels. All subjects were followed up for the occurrence of ischemic stroke., Results: During a median follow-up of 37.7 months, 157 (1.9%) ischemic strokes occurred. Stroke incidence increased by Lp(a) (1.1 vs. 2.1 vs. 2.5%, Cochran-Armitage p < .001) and Fib (1.1 vs. 2.0 vs. 2.6%, Cochran-Armitage p < .001) categories. When further classified into nine groups by Lp(a) and Fib levels, the incidence of ischemic stroke in group 9 [Lp(a)-high and Fib-high] was significantly higher than that in group 1 [Lp(a)-low and Fib-low] (3.1 vs. 6%, p < .001). The group 9 was associated with a highest risk for ischemic stroke (adjusted HR 4.907, 95% CI: 2.154-11.18, p < .001), compared with individuals in the Lp(a)-high (adjusted HR 2.290, 95% CI: 1.483-3.537, p < .001) or Fib-high (adjusted HR 1.184, 95% CI: 1.399-3.410, p = .001). Furthermore, combining Lp(a) with Fib increased C-statistics by .045 (p = .004)., Conclusions: Current study first demonstrated that elevated Lp(a) combining with Fib evaluation enhanced the risk of ischemic stroke in patients with CAD beyond Lp(a) or Fib alone., (© 2024 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)

The clinical benefits of statins have well-established and recognized worldwide. Although statins are well-tolerated generally, however, the report of statin-related adverse event and statin intolerance are common in China, which results in insufficient use of statins and poor adherence. The main reason may be attributed to confusions or misconceptions in the clinical diagnosis and management in China, including the lack of unified definitions and diagnostic standards, broad grasp of diagnosis, and unscientific management strategies. Based on that, this consensus carefully summarized the statin-related gene polymorphism and statin usage issue among Chinese population, and comprehensively reviewed global research data on statin intolerance, referenced guidelines, and consensus literature on statin intolerance in foreign and different regions, proposes an appropriate and easy to implement statin intolerance definition as well as corresponding diagnostic criteria and management strategies for Chinese clinicians, in order to improve the clinical application of statin drugs and enhance the prevention and treatment level of atherosclerotic cardiovascular disease in China., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Objectives: Stress-related glycemic indicators, including admission blood glucose (ABG), stress-hyperglycemia ratio (SHR), and glycemic gap (GG), have been associated with worse outcomes after acute myocardial infarction (AMI). However, data regarding their prognostic value in the oldest old with AMI are unavailable. Therefore, this study aimed to investigate the association of stress-related glycemic indicators with short- and long-term cardiovascular mortality (CVM) in the oldest old (≥ 80 years) with AMI., Methods: In this prospective study, a total of 933 consecutive old patients with AMI admitted to FuWai hospital (Beijing, China) were enrolled. On admission, ABG, SHR, and GG were assessed and all participants were classified according to their quartiles. Kaplan-Meier, restricted cubic splines (RCS), and multivariate Cox regression analyses were performed to evaluate the association between these glycemic indicators and CVM within 30 days and long-term follow-up., Results: During an average of 1954 patient-years of follow-up, a total of 250 cardiovascular deaths were recorded. Kaplan-Meier analyses showed the lowest CVM in quartile 1 of ABG and in quartile 2 of SHR and GG. After adjusting for potential covariates, patients in quartile 4 of ABG, SHR, and GG had a respective 1.67-fold (95% CI: 1.03-2.69; P = 0.036), 1.80-fold (95% CI: 1.16-2.79; P = 0.009), and 1.78-fold (95% CI: 1.14-2.79; P = 0.011) higher risk of long-term CVM risk compared to those in the reference groups (quartile 1 of ABG and quartile 2 of SHR and GG). Furthermore, RCS suggested a J-shaped relationship of ABG and a U-shaped association of SHR and GG with long-term CVM. Additionally, we observed similar associations of these acute glycemic parameters with 30-day CVM., Conclusions: Our data first indicated that SHR and GG consistently had a U-shaped association with both 30-day and long-term CVM among the oldest old with AMI, suggesting that they may be useful for risk stratification in this special population., Competing Interests: The authors declare that they have no competing interests., (© 2024 JGC All rights reserved; www.jgc301.com.)

Introduction: Dyslipidemia significantly contributes to atherosclerotic cardiovascular disease (ASCVD). Patients with lipid-rich vulnerable plaques are particularly susceptible to cardiovascular complications. Despite available lipid-lowering therapies (LLTs), challenges in effective lipid management remain., Areas Covered: This article reviews monoclonal antibody (mAb) therapy in dyslipidemia, particularly focusing on vulnerable plaques and patients. We have reviewed the definitions of vulnerable plaques and patients, outlined the efficacy of traditional LLTs, and discussed in-depth the mAbs targeting PCSK9. We extensively discuss the potential mechanisms, intracoronary imaging, and clinical evidence of PCSK9mAbs in vulnerable plaques and patients. A brief overview of promising mAbs targeting other targets such as ANGPTL3 is also provided., Expert Opinion: Research consistently supports the potential of mAb therapies in treating adult dyslipidemia, particularly in vulnerable patients. PCSK9mAbs are effective in regulating lipid parameters, such as LDL-C and Lp(a), and exhibit anti-inflammatory and anti-thrombotic properties. These antibodies also maintain endothelial and smooth muscle health, contributing to the stabilization of vulnerable plaques and reduction in adverse cardiovascular events. Future research aims to further understand PCSK9 and other targets like ANGPTL3, focusing on vulnerable groups. Overall, mAbs are emerging as a promising and superior approach in dyslipidemia management and cardiovascular disease prevention.

Background: The recently introduced ultrasonic flow ratio (UFR), is a novel fast computational method to derive fractional flow reserve (FFR) from intravascular ultrasound (IVUS) images. In the present study, we evaluate the diagnostic performance of UFR in patients with intermediate left main (LM) stenosis., Methods: This is a prospective, single center study enrolling consecutive patients with presence of intermediated LM lesions (diameter stenosis of 30%-80% by visual estimation) underwent IVUS and FFR measurement. An independent core laboratory assessed offline UFR and IVUS-derived minimal lumen area (MLA) in a blinded fashion., Results: Both UFR and FFR were successfully achieved in 41 LM patients (mean age, 62.0 ± 9.9 years, 46.3% diabetes). An acceptable correlation between UFR and FFR was identified ( r = 0.688, P < 0.0001), with an absolute numerical difference of 0.03 (standard difference: 0.01). The area under the curve (AUC) in diagnosis of physiologically significant coronary stenosis for UFR was 0.94 (95% CI: 0.87-1.01), which was significantly higher than angiographic identified stenosis > 50% (AUC = 0.66, P < 0.001) and numerically higher than IVUS-derived MLA (AUC = 0.82; P = 0.09). Patient level diagnostic accuracy, sensitivity and specificity for UFR to identify FFR ≤ 0.80 was 82.9% (95% CI: 70.2-95.7), 93.1% (95% CI: 82.2-100.0), 58.3% (95% CI: 26.3-90.4), respectively., Conclusion: In patients with intermediate LM diseases, UFR was proved to be associated with acceptable correlation and high accuracy with pressure wire-based FFR as standard reference. The present study supports the use of UFR for functional evaluation of intermediate LM stenosis., Competing Interests: None., (© 2024 JGC All rights reserved; www.jgc301.com.)

Background: For the patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) for at least 1 year is recommended in the guidelines to minimize the risk of stent thrombosis. Persistently uncovered stent strut means delayed neointima formation and extend the window of time in which the stent is prone to thrombosis. Previous studies showed that statins could improve post-stenting strut endothelial coverage for patients undergoing PCI. However, there are lack of evidences on whether early initiation of proprotein convertase subtilisin/Kexin type 9 monoclonal antibody (PCSK9mAb) after PCI in ACS patients can further improve the rate of stent strut coverage on the background of oral lipid-lowering therapy (LLT)., Methods: This is a single-center, randomized trial to enroll 36 patients undergoing PCI with a clinical diagnosis of non-ST-segment elevation ACS. The baseline level of low-density lipoprotein cholesterol (LDL-C) of these patients are between 1.4 mmol/L and 3.4 mmol/L. Patients will be assigned to intensive lipid-lowering therapy (LLT) with PCSK9mAb group and conventional LLT without PCSK9mAb group for 12 weeks in a clinical follow-up setting according to 1: 1 randomization. the rate of stent strut endothelial coverage by optical coherence tomography (OCT) examination at 12 weeks after enrollment between the groups will be compared., Conclusion: This will be the first study to investigate changes in the rate of stent strut endothelial coverage under intensive LLT with PCSK9mAb by OCT examination in ACS patients undergoing PCI. The finding of this study will provide clinical evidence for future research about the hypothesis of a novel strategy of "intensive LLT (PCSK9mAb + statin ± ezetimibe) combined with shortened DAPT duration" for ACS patients undergoing PCI.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: ChiCTR2200063395., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Background: Low-density lipoprotein-triglyceride (LDL-TG), a novel lipid marker, has been reported to be associated with cardiovascular events (CVEs). However, whether inflammatory status has a combined effect with LDL-TG on CVEs in patients with chronic coronary syndrome (CCS) receiving percutaneous coronary intervention (PCI) remains uncertain., Methods: A total of 4,415 patient with coronary angiography were primarily enrolled. Among them, 2,215 patients undergoing PCI were finally classified into subgroups according to LDL-TG and high-sensitivity C-reactive protein (hs-CRP) concentrations. Patients were followed up for up to 7 y for CVEs. The associations between LDL-TG, hs-CRP and CVEs were analyzed., Results: Patients with CVEs showed higher concentrations of LDL-TG compared to those without. In Cox regression analysis, LDL-TG was independently associated with CVEs (hazard ratio [HR]: 2.003, 95 % confidence intervals [CI]: 1.365-2.940, p < 0.001). Interestingly, when patients were further categorized into six subgroups according to hs-CRP and LDL-TG concentrations, LDL-TG was correlated with increased events only in patients with high hs-CRP concentrations (HR: 1.726, 95 %CI: 1.055-2.826, p = 0.030). Moreover, the Kaplan-Meier survival curves indicated that patients in the higher plasma concentrations of hs-CRP in combination with the highest LDL-TG concentrations were associated with the highest risk of CVEs., Conclusions: LDL-TG was associated with increased CVEs among patients receiving PCI with increased hs-CRP concentrations, suggesting that measurement of LDL-TG combined with hs-CRP facilitates prognostic utility for cardiovascular risks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Purpose: Given the beneficial effects of sacubitril/valsartan on blood pressure generally, this study investigates its antihypertension effects in diabetes mellitus (DM) patients with primary hypertension specifically, and the effect of sacubitril/valsartan on glycolipid metabolism., Methods: We conducted a randomized, open-label, active-controlled study to compare the antihypertension effects of sacubitril/valsartan in DM individuals with primary hypertension. The primary end point was reduction in mean systolic blood pressure (SBP) from baseline with sacubitril/valsartan vs. olmesartan at week 8. The secondary endpoints included the changes in diastolic blood pressure (DBP), daytime SBP/DBP, nighttime SBP/DBP, BP achievement (office sitting BP < 130/80 mmHg), and lipid profile. The trial was registered with chictr.org.cn (ChiCTR2200066428) on Dec 22, 2022., Results: A total of 124 patients were included in the final analysis. SBP decreased to a greater extent in the sacubitril/valsartan group from baseline to 8 weeks [between-treatment difference: 3.51 mm Hg, 95% confidence interval (95% CI) 0.41 to 6.62 mm Hg, P = 0.03]. Furthermore, more patients achieved the blood pressure goal with sacubitril/valasartan (74.60% vs. 54.70%, P = 0.03). Multiple logistical regression analysis showed that sacubitril/valsartan was associated with BP achievement [odds ratio (OR) 0.33, 95% CI 0.14-0.73, P = 0.007], but the difference in SBP, DBP, day time SBP/DBP, and night time SBP/DBP reduction did not approach statistical significance. HbA1C1, total cholesterol, and low-density lipoprotein-cholesterol were lower than baseline in both groups (P < 0.05); however, there was no difference in the effects on glucose and lipid metabolism from sacubitril/valsartan compared to olmesartan., Conclusions: Sacubitril/valsartan not only provided superior BP reduction compared to olmesartan, it did so without adverse effects on glycemic control and lipid parameters in DM patients with primary hypertension., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among urban and rural residents in China, and elevated low-density lipoprotein cholesterol (LDL-C) is a risk factor for ASCVD. Considering the increasing burden of ASCVD, lipid management is of the utmost importance. In recent years, research on blood lipids has made breakthroughs around the world, hence a revision of China guidelines for lipid management is imperative, especially since the target lipid levels in the general population vary in respect to the risk of ASCVD. The level of LDL-C, which can be regarded as appropriate in a population without frisk factors, can be considered abnormal in people at high risk of developing ASCVD. As a result, the "Guidelines for the prevention and treatment of dyslipidemia" were adapted into the "China Guidelines for Lipid Management" (henceforth referred to as the new guidelines) by an Experts' committee after careful deliberation. The new guidelines still recommend LDL-C as the primary target for lipid control, with CVD risk stratification to determine its target value. These guidelines recommend that moderate intensity statin therapy in adjunct with a heart-healthy lifestyle, be used as an initial line of treatment, followed by cholesterol absorption inhibitors or/and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, as necessary. The new guidelines provide guidance for lipid management across various age groups, from children to the elderly. The aim of these guidelines is to comprehensively improve the management of lipids and promote the prevention and treatment of ASCVD by guiding clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 JGC All rights reserved; www.jgc301.com.)

Background: There are several reports on the prevalence and characteristics of intracranial hemorrhage (ICH) following percutaneous coronary intervention (PCI), which is a rare but severe complication with high mortality. However, the clinical landscapes of computed tomography (CT)-confirmed, symptomatic ICH in hospitalized patients are not fully characterized., Methods: Among 121,066 patients receiving PCI treatment in the Fu Wai Hospital between 2013 and 2022, there were 18 CT-defined, symptomatic patients with ICH occurring during post-PCI hospitalization. Symptomatic ICH was defined as clinical suspicion of hemorrhage and/or new focal neurological signs. We analyzed ICH timing, clinical and imaging features, and subsequent outcomes., Results: Overall, in this retrospective analysis, the incidence of CT-defined, symptomatic ICH was 0.015% (18/121,066). More than half of the cases (55.6%) occurred within the first 12 h following PCI. The most common initial manifestation of ICH patients was disturbance of consciousness. Thirteen patients (72.2%) had a hematoma volume ≥ 30 cm 3 . Additionally, the ICH was observed in the cerebral lobe (66.7%), cerebellum (22.2%), and the basal ganglia and thalamus (11.1%). The 90-day mortality of ICH patients undergoing PCI was very high (72.2%). Consciousness disturbance ( p = 0.036), intracerebral hemorrhage volume > 30 mm 3 ( p = 0.001), and intracerebral hemorrhage originating from the infratentorial origin ( p = 0.044) were significantly higher in patients who died., Conclusions: Symptomatic ICH events occur with a rate of around 0.015%, with significantly higher short-term mortality risk in our cohort receiving PCI, which has not yet been demonstrated in other cohorts.

Background: Although experimental studies have demonstrated the protective role of total bilirubin (TBil) in cardiovascular diseases, several previous clinical observations are controversial. More importantly, no data are currently available regarding the relation of TBil to major adverse cardiovascular events (MACE) in patients with previous myocardial infarction (MI)., Objectives: This study sought to explore the association between TBil and long-term clinical outcomes in patients with previous MI., Methods: A total of 3,809 patients who are post-MI were consecutively enrolled in this prospective study. Cox regression models using HRs and CIs were applied to investigate associations between the TBil concentration category (group 1: bottom to median tertiles within the reference range; group 2: top tertile; group 3: above reference range) and main outcome (recurrent MACE) as well as secondary outcomes (hard endpoints and all-cause mortality)., Results: During the 4-year follow-up period, 440 patients (11.6%) suffered from recurrent MACE. Kaplan-Meier survival analysis showed the lowest MACE incidence in group 2 ( P < 0.001). When compared with the reference group (group 1) in multivariable analysis, a J-shaped association was apparent for MACE, with decreased risk in group 2 (HR: 0.76; 95% CI: 0.59-0.96) and elevated risk in group 3 (HR: 1.29; 95% CI: 1.03-1.61). Similar associations were identified regarding hard endpoints and all-cause mortality. Moreover, TBil demonstrated incremental discriminatory strength when added to the predictive model., Conclusions: In this prospective cohort study with long-term follow-up, higher TBil levels within the physiological range reduced the incidence of long-term cardiovascular events in patients who are post-MI., Competing Interests: This work was supported by the Capital Health Development Fund (grant 201614035), the Chinese Academy of Medical Sciences Major Collaborative Innovation Project (grant 2016-I2M-1-011), and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant 2021-I2M-1-008). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Poly ADP-ribose polymerase inhibitor (PARPi) treatment is effective in triple-negative breast cancer (TNBC) with BRCA mutation. However, its efficacy in BRCA-proficient TNBC remains unexplored. It is, therefore, an exciting proposition to broaden the indication of PARPi for BRCA-proficient TNBC patients. Chemokine receptor (CXCR4) is a transmembrane G protein-coupled receptor, which is involved in cell migration, proliferation, apoptosis, and damage repair, and it initiates many signalling pathways. Although administration of CXCR4 inhibitor alone is not ideal as a target drug, it can play a strong synergistic role in combination with other drugs. We explored the effect of CXCR4 and PARP1 on tumour cell proliferation, migration, metastasis, and apoptosis in vitro and in vivo and found that a CXCR4 inhibitor, AMD3100, enhanced the anti-tumour effect of PARP1 inhibitor, olaparib, on BRCA-proficient TNBC. When CXCR4 was inhibited and silenced, DNA damage repair and DNA replication fork activity were suppressed by up-regulating caspase-3-mediated increase in PARP1 cleavage; in combination with the inhibition of PARP1, AMD3100 resulted in the accumulation of fatal DNA damage and induction of apoptosis. This combination regimen can be effective against BRCA-proficient TNBC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Hypertension is a known risk factor for cardiovascular disease; however, its impact on clinical outcomes in patients with heterozygous familial hypercholesterolemia (HeFH) is unclear. Hence, we aimed to investigate the effects of hypertension on severity of coronary artery atherosclerosis and cardiovascular outcomes in patients with HeFH., Methods: A total of 480 patients with clinical or molecular diagnosis of definite or probable familial hypercholesterolemia according to Dutch Lipid Clinic Network criteria (DLCN score ≥6) were included in the study. They were divided into the two groups according to their blood pressure status: hypertension group and normotension group. The severity of coronary stenosis was assessed by a number of diseased vessels, Gensini, Syntax, and Jeopardy scores. All individuals were followed up for cardiovascular events (CVEs) and cox proportion hazard models were used to evaluate the association of hypertension with cardiovascular outcomes., Results: Patients with hypertension had more severe coronary stenosis and a higher incidence of CVEs compared with the ones with normotension (log-rank P < 0.001). After multivariable adjustment, there was a 2.1-fold increased risk of CVEs among patients with hypertension compared with patients with normotension (adjusted hazard ratio 2.06, 95% confidential interval 1.17-3.65, P < 0.01). Hypertension control status was also associated with CVEs even after adjustment of multiple variables. However, no combined effect on increased cardiovascular risks was detected in this HeFH cohort., Conclusion: In patients with HeFH, hypertension is an independent risk factor for cardiovascular events. Moreover, blood pressure control status in patients with hypertension is associated with the worse outcomes., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Postprocedural cardiac troponin I (cTnI) elevation commonly occurs in patients undergoing percutaneous coronary intervention (PCI); however, its prognostic value remains controversial. This study aimed to investigate the prognostic value of peak postprocedural cTnI in cardiac patients with or without three-vessel disease (TVD) undergoing complete PCI. A total of 1237 consecutive patients (77% males, mean age 58 ± 10 years) with normal baseline cTnI levels were enrolled, 439 patients (77% males, 59 ± 10 years) with TVD, and 798 patients (77% males, 57 ± 10 years) with single- or double-vessel disease (non-TVD). The primary outcome was the occurrence of major adverse cardiovascular events (MACE), defined as a composite of non-fatal MI, non-fatal stroke, unplanned revascularization, re-hospitalization due to heart failure or severe arrhythmias, and all-cause death. During the median follow-up of 5.3 years, a total of 169 patients (13.7%) developed MACE, including 73 (16.6%) in the TVD group and 96 (12.0%) in the non-TVD group ( p = 0.024). After adjustment, the multivariate Cox analysis showed that hypertension (HR 1.50; 95% CI: 1.01-2.20; p = 0.042), TVD (HR 1.44; 95% CI: 1.03-2.02; p = 0.033), and cTnI ≥ 70× URL (HR 2.47; 95% CI: 1.28-4.78, p = 0.007) were independently associated with increased MACE during long-term follow-up. Further subgroup analyses showed that cTnI ≥ 70× URL was an independent predictor of MACE in TVD patients (HR 3.32, 95% CI: 1.51-7.34, p = 0.003), but not in non-TVD patients (HR 1.01, 95%CI: 0.24-4.32, p = 0.991). In conclusion, elevation of post-PCI cTnI ≥ 70× URL is independently associated with a high risk of MACE during long-term follow-up in patients with TVD, but not in those with non-TVD.

Objective: We evaluated the safety and efficacy of lipoprotein apheresis (LA) in patients with familial hypercholesterolemia (FH) who can't reach low-density lipoprotein cholesterol(LDL-C) target goals with the maximal tolerated dose of lipid-lowering agents. Methods: This was a retrospective cross-sectional study. Between February 2015 and November 2019, patients with FH who were admitted in Fuwai hospital and treated with LA were consecutively enrolled. Based on intensive lipid-lowering agents, these patients received LA by double filtration plasma pheresis (DFPP) method. The changes of lipid levels such as LDL-C and lipoprotein(a)[Lp(a)] were compared before and after LA treatment, and the changes of immunoglobulin (Ig) concentration and LA-related adverse effects were also discussed. Results: A total of 115 patients with FH were enrolled in this study, of which 8 cases were homozygous FH and 107 cases were heterozygous FH. The age was (43.9±12.2) years and there were 75 (65.2%) males, and 108 (93.8%) with coronary artery disease. For pre-and immediately after LA treatment, the LDL-C was (5.20±2.94) mmol/L vs. (1.83±1.08) mmol/L, Lp(a) concentration was 428.70(177.00, 829.50)mg/L vs. 148.90(75.90, 317.00) mg/L ( P <0.001), with a decrease of 64.2% and 59.8% respectively. The levels of IgG and IgA measured 1 day after LA treatment were both in the normal range and IgM concentration was below the reference value, the reductions of which were 15.1%, 25.0% and 58.7% respectively ( P <0.001). Six patients had mild symptoms of nausea, hypotension dyspnea and palpitation, the symptoms were relieved by symptomatic treatment. Conclusion: For patients with FH who do not achieve LDL-C target goal with the maximal tolerated lipid-lowering agents, especially those with elevated Lp(a) levels, LA, which can significantly further reduce LDL-C and Lp(a) levels, is an effective and safe option.

Refractory hypercholesterolemia (RH), including homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia, is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) despite existing cholesterol-lowering methods at maximal tolerable doses. Patients with RH have early onset and higher risk of atherosclerotic cardiovascular disease (ASCVD) under insufficient treatment. Therefore, it is urgent to seek new therapies to maintain the blood lipids in refractory hyperlipidemia at normal levels. Currently, new cholesterol-lowering strategies are on the market, not only at the protein level [i.e., bempedoic acid (inhibiting ATP-citrate lyase), alirocumab and evolocumab (monoclonal antibodies against PCSK9), evinacumab (monoclonal antibody against ANGPTL3)] but also at the transcript level [i.e., mipomersen (antisense oligonucleotide inhibiting ApoB), inclisiran (siRNA targeting PCSK9)], providing more options for RH patients to achieve their lipid-lowering targets. More RNA-based therapies targeting RH-related genes have been designed for the treatment. However, for a proportion of patients, especially those with LDLR deficiency, the available treatments are still insufficient. More recently, emerging genome engineering based on CRISPR/Cas9 techniques, and advanced delivery technologies such as lentiviral vectors, adenoviral vectors, adeno-associated viral vectors, lipid nanoparticles, and exosomes are being rapidly developed and implemented as novel therapies for RH. Gene therapy targeting RH-related genes has been successfully conducted in cells, mice, and non-human primates with high efficacy in lipid lowering and good tolerability. Especially the new generation of genome editing technique, base editing, performed in vivo with ideal lipid-lowering effect and limited occurrence of unwanted results. Excitingly, a phase I/II clinical study of LDLR gene replacement has been recently completed in RH patients, likely to be employed in clinical practice in the future. Furthermore, new targets for cholesterol reduction such as REV-ERB, G protein-coupled receptor, Ubiquitin specific peptidase 20 are continually being developed. This narrative review updates recent advances in treatment for RH, summarizes related clinical trials and preclinical studies, especially on the prospect of gene therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer HT declared a past co-authorship with the author NQW to the handling editor., (Copyright © 2022 Li and Wu.)

Background: Currently, remnant cholesterol (RC), lipoprotein(a) [Lp(a)], and inflammation are considered the principal residual cardiovascular risk (RCVR) factors. This study sought to evaluate the combined impact of RC, Lp(a), and inflammation on prognosis of statin-treated patients with chronic coronary syndrome (CCS), which has not been investigated., Methods: A total of 6839 patients with CCS were consecutively enrolled. Baseline RC, Lp(a), and high-sensitivity C-reactive protein (hsCRP) concentrations were measured and their medians were used for categorizations. All patients were followed for the major adverse cardiovascular events (MACEs), including cardiovascular death, non-fatal myocardial infarction, and stroke. The individual and combined effects of RC, Lp(a), and hsCRP on MACEs were examined and stratification analysis according to low-density lipoprotein cholesterol (LDL-C) was performed., Results: Over an average of 54.93 ± 18.59 months follow-up, 462 MACEs were recorded. Multivariate Cox analysis showed that elevated RC and Lp(a) levels were significantly associated with an increased risk of MACEs, while high hsCRP levels were related to a slightly but non-significantly increased MACEs risk. Moreover, when participants were subgrouped according to RC, Lp(a), and hsCRP levels together, only High RC-High Lp(a)-High hsCRP group had significantly higher risk of MACEs [hazard ratio (HR) 1.99, 95% confidence interval (CI) 1.15-3.47] compared with the reference group (Low RC-Low Lp(a)-Low hsCRP), especially in patients with LDL-C < 2.6 mmol/L., Conclusions: The combination of elevated levels of RC, Lp(a), and hsCRP potentiated the adverse effect on MACEs among statin-treated patients with CCS, suggesting that multiple RCVR factors assessment may be a better strategy to improve stratification in very-high risk population., (© 2022. The Author(s).)

Background: The positive relationship between metabolic healthy obesity (MHO) and cardiovascular risk has been under debate in recent years. Previously, strong evidence supported the causal role of increased plasma lipoprotein(a) [Lp(a)] levels in cardiovascular disease (CVD). The current study aimed to investigate the different associations of Lp(a) and cardiovascular events (CVEs) in patients with coronary artery disease (CAD) and different metabolic phenotypes., Methods: A total of 5,089 patients who were angiography-proven CAD were consecutively included and followed up for CVEs. Obesity was defined as a body mass index (BMI) ≥25 kg/m 2 according to Asia-specific BMI criteria. Patients were divided into four groups according to metabolic phenotypes, namely metabolically healthy/unhealthy non-obese and metabolically healthy/unhealthy obese [metabolically healthy non-obese (MHN), MHO, metabolically unhealthy non-obese (MUN), and metabolically unhealthy obesity (MUO)]. Comparisons of CAD severity and outcomes were performed among four groups. Cox regression analyses and cubic spline models were used to examine the relationship between Lp(a) and CVEs in patients with different metabolic phenotypes., Results: During a median of 7.5 years' follow-up, 540 (10.6%) CVEs occurred. MUN and MUO populations had more severe coronary stenosis than MHN ones, while no significant difference in the Gensini score (GS) was observed between MHN and MHO. Patients with MUN and MUO presented a higher risk of CVEs than patients with MHN (hazard ratio [ HR ]: 1.414, 95% CI : 1.024-1.953-1.556 and HR : 1.747, 95% CI : 1.295-1.363, p < 0.05). In subgroup analysis, restricted cubic spline models showed that there was no association between Lp(a) and CVEs in patients in MHN and MHO, while the MUN and MUO groups presented increasing associations between Lp(a) and CVEs and such association was stronger in the MUO group. In Cox regression analysis, Lp(a) >50 mg/dl was associated with a 2.032- and 2.206-fold higher risk of subsequent CVEs in the MUO and MUN subgroups, respectively., Conclusion: Among patients with angiography-proven stable CAD, Lp(a) had a more significant prognostic value in both MUO and MUN individuals regardless of obesity, suggesting the importance of screening for cardiovascular risk with Lp(a) in metabolically unhealthy patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jin, Zhang, Liu, Zhu, Guo, Wu, Xu, Dong and Li.)

Background: Familial hypercholesterolemia (FH) is a metabolic disease in which patients are prone to develop premature atherosclerosis (AS). Sorbin and SH3 Domain Containing 2 (SORBS2) is known to play a role in coronary heart disease (CHD). However, the mechanism underlying SORBS2 involvement in the development of hypercholesterolemia remains unknown. Here, we investigated the effects of SORBS2 on inflammation and foam cell formation and its underlying mechanisms., Methods: Using Bioinformatics analysis, we established that SORBS2 is upregulated in patients with FH. Circulating concentrations of SORBS2 were measured using ELISA kit (n = 30). The association between circulating SORBS2 levels and inflammatory factors or lipid indexes were conducted using Spearman correlation analysis. We further conducted in vitro experiments that the expression of SORBS2 were analyzed, and SORBS2 siRNA were transfected into oxidized LDL (OxLDL)-induced macrophages, followed by western blot and immunofluorescence., Results: Circulating SORBS2 levels were positively associated with inflammatory factors and lipid indexes. We also observed that high in vitro expression of SORBS2 in OxLDL-induced macrophages. After SORBS2 silencing, Nod like receptor family pyrin domain-containing 3 protein(NLRP3)-Caspase1 activation and NF-κB activation were attenuated, and secretion of pro-inflammatory cytokines (IL-1β and IL-18) was decreased. Moreover, SORBS2 silencing blocked reactive oxygen species (ROS) production and lipid accumulation, and promoted cholesterol efflux through ABCG1-PPARγ pathway., Conclusions: SORBS2 regulates lipid-induced inflammation and foam cell formation, and is a potential therapeutic target for hypercholesterolemia., (© 2022. The Author(s).)

Aim: The aim of this study was to evaluate the relationship between renal function and low-density lipoprotein cholesterol (LDL-C) goal achievement and compare the strategy of lipid-lowering therapy (LLT) among the patients with coronary artery disease (CAD) with different renal functions., Methods: In this study, we enrolled 933 Chinese patients with CAD from September 2020 to June 2021 admitted to the Cardiometabolic Center of Fuwai Hospital in Beijing consecutively. All individuals were divided into two groups based on their estimated glomerular filtration rate (eGFR). The multiple logistical regression analysis was performed to identify and compare the independent factors which impacted LDL-C goal achievement in the two groups after at least 3 months of treatment., Results: There were 808 subjects with eGFR ≥ 60 ml/min/1.73 m 2 who were divided into Group 1 (G1). A total of 125 patients with eGFR <60 ml/min/1.73 m 2 were divided into Group 2 (G2). The rate of LDL-C goal attainment (LDL-C <1.4 mmol/L) was significantly lower in G2 when compared with that in G1 (24.00% vs. 35.52%, P = 0.02), even though there was no significant difference in the aspect of LLT between the two groups (high-intensity LLT: 82.50% vs. 85.60% P = 0.40). Notably, in G1, the proportion of LDL-C goal achievement increased with the intensity of LLT (23.36% vs. 39.60% vs. 64.52% in the subgroup under low-/moderate-intensity LLT, or high-intensity LLT without proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (PCSK9i), or high-intensity LLT with PCSK9i, respectively, P < 0.005). In addition, in G2, there was a trend that the rate of LDL-C goal achievement was higher in the subgroup under high-intensity LLT (26.60% in the subgroup under high-intensity LLT without PCSK9i and 25.00% in the subgroup under high-intensity LLT with PCSK9i) than that under low-/moderate-intensity LLT (15.38%, P = 0.49). Importantly, after multiple regression analysis, we found that eGFR <60 ml/min/1.73 m 2 [odds ratio (OR) 1.81; 95%CI, 1.15-2.87; P = 0.01] was an independent risk factor to impact LDL-C goal achievement. However, the combination strategy of LLT was a protective factor for LDL-C goal achievement independently (statin combined with ezetimibe: OR 0.42; 95%CI 0.30-0.60; P < 0.001; statin combined with PCSK9i: OR 0.15; 95%CI 0.07-0.32; P < 0.001, respectively)., Conclusion: Impaired renal function (eGFR <60 ml/min/1.73 m 2 ) was an independent risk factor for LDL-C goal achievement in the patients with CAD. High-intensity LLT with PCSK9i could improve the rate of LDL-C goal achievement significantly. It should be suggested to increase the proportion of high-intensity LLT with PCSK9i for patients with CAD, especially those with impaired renal function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Li, Shi, Zhang, Sui, Li, Dou, Qian and Wu.)

Background and Aims: Heterogeneity exists among patients with atherosclerotic cardiovascular disease (ASCVD) with regard to the risk of recurrent events. Current guidelines have definitely refined the disease and we aimed to examine the practicability in Chinese population., Methods: A cohort of 9944 patients with ASCVD was recruited. Recurrent events occurred during an average of 38.5 months' follow-up were collected. The respective and combinative roles of major ASCVD (mASCVD) events and high-risk conditions, being defined by 2018 AHA/ACC guideline, in coronary severity and outcome were studied., Results: The number of high-risk conditions was increased with increasing number of mASCVD events (1.95 ± 1.08 vs. 2.16 ± 1.10 vs. 2.42 ± 1.22). Trends toward the higher to the highest frequency of multi-vessel coronary lesions were found in patients with 1- (71.1%) or ≥2 mASCVD events (82.8%) when compared to those without (67.9%) and in patients with 2- (70.5%) or ≥3 high-risk conditions (77.4%) when compared to those with 0-1 high-risk condition (61.9%). The survival rate was decreased by 6.2% between none- and ≥2 mASCVD events or by 3.5% between 0-1 and ≥3 high-risk conditions. Interestingly, diabetes was independently associated with outcome in patients with 1- [1.54(1.06-2.24)] and ≥2 mASCVD events [1.71(1.03-2.84)]. The positive predictive values were increased among groups with number of mASCVD event increasing (1.10 vs. 1.54 vs. 1.71)., Conclusion: Propitious refinement of ASCVD might be reasonable to improve the survival. Concomitant diabetes was differently associated with the incremental risk among different ASCVD categories, suggesting the need of an appropriate estimate rather than a 'blanket' approach in risk stratification., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Liu, Guo, Zhu, Wu, Xu, Dong, Qian, Dou and Li.)

Background: Patients with previous myocardial infarction (MI) have a poor prognosis and stratification for recurrent major adverse cardiovascular events (MACE) among these patients is of considerable interest. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) are considered to be potential cardiovascular risk factors, but less is known about their prognostic importance in post-MI patients. This study aimed to evaluate the prognostic value of NT-proBNP and hs-CRP alone or together in patients who reported a prior MI., Methods: In this prospective study, we consecutively enrolled 3,306 post-MI patients to assess the recurrent MACE. The predictive values of NT-proBNP and hs-CRP alone and together were assessed by multivariable Cox regression using hazard ratios (HR) and 95% confidence intervals (CI)., Results: During the 4-year follow-up period, 335 patients developed recurrent MACE. Multivariate Cox regression analysis showed a significant correlation between NT-proBNP levels and MACE (HR: 2.99, 95%CI: 2.06-4.36, p < 0.001), hard endpoints (HR: 5.44, 95%CI: 2.99-9.90, p < 0.001), cardiac mortality (HR: 5.92, 95%CI: 2.34-14.96, p < 0.001) and all-cause mortality (HR: 5.03, 95%CI: 2.51-10.09, p < 0.001). However, hs-CRP was not an independent predictor after adjusting for NT-proBNP. When patients were divided into six groups by using tertiles values of NT-proBNP and median values of hsCRP, patients with high NT-proBNP/hs-CRP values were 3.27 times more likely to experience MACE than patients with low NT-proBNP/hs-CRP values. The addition of NT-proBNP and hs-CRP to a prognostic model revealed a significant improvement in C-statistic, net reclassification, and integrated discrimination., Conclusions: Increased NT-proBNP levels were associated with long-term worse outcomes and the combination of NT-proBNP and hs-CRP has an incremental value in the further risk stratification of post-MI patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cao, Li, Liu, Zhang, Guo, Wu, Zhu, Dong, Sun, Dou and Li.)

The function of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), a novel plasma protein, has mainly been involved in cholesterol metabolism in the liver, while, more interestingly, recent data have shown that PCSK9 also took part in the modulation of inflammation, which appeared to be another explanation for the reduction of cardiovascular risk by PCSK9 inhibition besides its significant effect on lowering lower-density lipoprotein cholesterol (LDL-C) concentration. Overall, a series of previous studies suggested an association of PCSK9 with inflammation. Firstly, PCSK9 is able to induce the secretion of proinflammatory cytokines in macrophages and in other various tissues and elevated serum PCSK9 levels could be observed in pro-inflammatory conditions, such as sepsis, acute coronary syndrome (ACS). Secondly, detailed signaling pathway studies indicated that PCSK9 positively regulated toll-like receptor 4 expression and inflammatory cytokines expression followed by nuclear factor-kappa B (NF-kB) activation, together with apoptosis and autophagy progression. Besides, PCSK9 enhanced and interacted with scavenger receptors (SRs) of inflammatory mediators like lectin-like oxidized-LDL receptor-1 (LOX-1) to promote inflammatory response. Additionally, several studies also suggested that the role of PCSK9 in atherogenesis was intertwined with inflammation and the interacting effect shown between PCSK9 and LOX-1 was involved in the inflammatory response of atherosclerosis. Finally, emerging clinical trials indicated that PCSK9 inhibitors could reduce more events in patients with ACS accompanied by increased inflammatory status, which might be involved in its attenuating impact on arterial plaque. Hence, further understanding of the relationship between PCSK9 and inflammation would be necessary to help prevent and manage the atherosclerotic cardiovascular disease (ASCVD) clinically. This review article will update the recent advances in the link of PCSK9 with inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wu, Shi and Li.)

Background: Lipoprotein (a) [Lp(a)] is a causal risk factor for cardiovascular diseases, while its role in vascular calcification has not been well-established. Here, we investigated an association of Lp(a) with vascular calcification using population-based and in vitro study designs., Methods: A total of 2806 patients who received coronary computed tomography were enrolled to assess the correlation of Lp(a) with the severity of coronary artery calcification (CAC). Human aortic smooth muscle cells (HASMCs) were used to explore mechanisms of Lp(a)-induced vascular calcification., Results: In the population study, Lp(a) was independently correlated with the presence and severity of CAC (all p < 0.05). In vitro study showed that cell calcific depositions and alkaline phosphatase (ALP) activity were increased and the expression of pro-calcific proteins, including bone morphogenetic protein-2 (BMP2) and osteopontin (OPN), were up-regulated by Lp(a) stimulation. Interestingly, Lp(a) activated Notch1 signaling, resulting in cell calcification, which was inhibited by the Notch1 signaling inhibitor, DAPT. Lp(a)-induced Notch1 activation up-regulated BMP2-Smad1/5/9 pathway. In contrast, Noggin, an inhibitor of BMP2-Smad1/5/9 pathway, significantly blocked Lp(a)-induced HASMC calcification. Notch1 activation also induced translocation of nuclear factor-κB (NF-κB) accompanied by OPN overexpression and elevated inflammatory cytokines production, while NF-κB silencing alleviated Lp(a)-induced vascular calcification., Conclusions: Elevated Lp(a) concentrations are independently associated with the presence and severity of CAC and the impact of Lp(a) on vascular calcification is involved in the activation of Notch1-NF-κB and Notch1-BMP2-Smad1/5/9 pathways, thus implicating Lp(a) as a potential novel therapeutic target for vascular calcification., Competing Interests: Declaration of competing interest No conflict of interest with this manuscript was reported., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Type 2 diabetes mellitus (T2DM) is an independent risk factor for cardiovascular disease. However, the association between T2DM and coronary artery disease (CAD) in patients with heterozygous familial hypercholesterolaemia (HeFH) has not been thoroughly evaluated. Our study aimed to assess the effect of T2DM on CAD severity and hard cardiovascular endpoints in a HeFH cohort., Methods and Results: A total of 432 patients with HeFH with a molecular and/or clinical Dutch Lipid Clinic Network score ≥6 (definite and probable) were enrolled. Patients were divided into a T2DM group (n = 99) and a non-T2DM group (n = 333). The severity of coronary stenosis was assessed by the number of diseased vessels and Gensini, SYNTAX, and Jeopardy scores. Hard endpoints included a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiac death. Cox regression and Kaplan-Meier analyses were used to evaluate the effect of T2DM on hard cardiovascular endpoints. The prevalence of CAD was higher in patients with T2DM compared with those without (96.0% vs. 77.5%, respectively; P < 0.001). Patients with T2DM demonstrated a greater number of diseased vessels (P = 0.029) and more severe coronary lesions with high Gensini, SYNTAX, and Jeopardy score tertiles (P = 0.031, P = 0.001, and P = 0.024, respectively). During a median of 3.75 years up to a maximum of 9 years of follow-up, hard endpoints occurred in 13 of 99 patients with T2DM and 16 of 333 without T2DM at baseline. Compared with patients without T2DM, patients with T2DM were at a significantly greater risk of hard endpoints [multivariate adjusted hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.02-4.84; P = 0.025]. Additionally, patients with T2DM and good glucose control (HbA1c < 7.0%) were at a lower risk of hard endpoints compared with those with poor glucose control (HbA1c ≥ 7.0%, HR 0.08, 95% CI 0.01-0.56; P = 0.011)., Conclusion: We conclude that T2DM is an independent predictor of CAD severity when assessed by number of diseased vessels, Gensini, SYNTAX, Jeopardy scores, and hard cardiovascular endpoints, suggesting that T2DM could be further used for risk stratification of patients with HeFH., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Background: The risk of liver fibrosis in non-alcoholic fatty liver disease (NAFLD) can be easily evaluated by noninvasive scoring systems, of which the NAFLD fibrosis score (NFS) is the most commonly used. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a new predictor of cardiovascular events, has been reported to be associated with cardiovascular outcomes and NAFLD. However, the relationship of NFS with PCSK9 and their prognostic abilities in cardiovascular risks are unknown., Methods: A total of 2008 hospitalized subjects who had chest pain without lipid-lowering therapy were consecutively included. Baseline clinical data were collected, and the NFS was calculated. The circulating PCSK9 concentration was determined by enzyme immunoassay. The major adverse cardiovascular event (MACE) occurrences were recorded in the follow-up period. Associations of PCSK9 concentration with NFS were examined. All of the participants were categorized into three groups according to NFS levels and were further stratified by PCSK9 tertiles to evaluate the MACEs., Results: 158 (7.87%) MACEs were observed during a mean of 3.2 years of follow-up. NFS levels were independently related to higher PCSK9 levels according to multivariable linear regression analysis. Furthermore, elevated PCSK9 and NFS concentrations were respectively associated with increased MACE incidence in multivariable Cox regression models. When combining NFS status with PCSK9 tertiles as a stratifying factor, patients with intermediate-high NFS and high PCSK9 levels had higher risks of events than those with low NFS and low PCSK9 levels., Conclusions: This study revealed for the first time that NFS is positively related to PCSK9 and that the combination of NFS and PCSK9 greatly increased the risk of MACEs in patients with chest pain, providing a potential link between NFS and PCSK9 for predicting cardiovascular events., (© 2021. The Author(s).)

The aim of our study is to evaluate the association of rotational atherectomy (RA) operation procedural indices and baseline lipid parameters with the prognosis of the patients with severe coronary calcification who underwent RA. Our study population consists of 287 patients treated with RA in Fuwai Hospital from January 2013 to December 2019. We analyzed the patients' rotation procedural indices including the number of burrs, the size of burrs, approach site, the size of guiding catheter, along with the baseline level of lipoprotein(a) (Lp(a)), low-density lipoprotein-cholesterol (LDL-C) and high-sensitivity C-reactive protein (hs-CRP) to examine the association of these measurements with the prognosis of these patients using Cox regression analysis and Kaplan-Meier survival analysis. We find that during the follow-up period of 56.7 months with the median, the use of single burr in the patients who underwent RA was significantly associated with the occurrence of cumulative major adverse cardiac events (MACE) when compared with using non-single burrs [Hazard Ratio (HR) 0.43, 95% confidence interval (95% CI) 0.24-0.77, p = 0.004] from univariate Cox regression analysis; (HR 0.36, 95% CI 0.20-0.66, p = 0.001) from multivariate Cox regression analysis In addition, we find a higher event-free survival rate in the single-burr group after Kaplan-Meier survival analysis (Log rank p = 0.0033). However, there was no significant association of the size of burrs with the occurrence of MACE (HR 0.90, 95% CI 0.47-1.73, p = 0.76). Similarly, we find no significant associations between the approach site and the occurrence of MACE (HR 0.79, 95% CI 0.24-2.53, p = 0.69), the baseline Lp(a) (HR 1.07, 95% CI 0.76-1.49, p = 0.71), the level of LDL-C (HR 0.83, 95% CI 0.55-1.26, p = 0.38) or hs-CRP (HR 0.85, 95% CI 0.45-1.58, p = 0.60). We find that the patients who receive RA with a single burr have better outcomes than those who receive RA with non-single burrs. Moreover,we find that the number of burrs used in RA instead of the size of burrs, approach site, the size of guiding catheter, or baseline levels of Lp(a), LDL-C or hs-CRP had significant association with the prognosis of RA patients., Competing Interests: The authors declare no conflict of interest., (© 2021 The Author(s). Published by IMR Press.)

Background: Although the presence of physical signs [tendon xanthomas and/or corneal arcus (TX/CA)], are associated with the risk of coronary artery disease in patients with heterozygous familial hypercholesterolemia (HeFH), their relationship with genotypes and clinical characteristics has not been fully determined. This study aimed to examine the association of TX/CA with genetic mutation, lipid- and inflammation-related markers, the severity of coronary stenosis or calcification, and cardiovascular events (CVEs) in patients with HeFH., Methods: LDLR, APOB, and PCSK9 genes were screened in 523 HeFH patients, and patients with TX/CA (n = 50) were 1:4 propensity score-matched to patients without TX/CA (n = 200) to adjust for age and sex. Laboratory markers (proprotein convertase subtilisin/kexin type 9 [PCSK9], lipoprotein(a) and high-sensitivity C-reactive protein [hsCRP]), computed tomography angiography, coronary angiography, and follow-up for CVEs were performed., Results: Patients with physical signs had significantly higher low-density lipoprotein cholesterol levels; higher PCSK9 or hsCRP concentrations; more LDLR positive mutations; and higher prevalence of high tertiles of Gensini, SYNTAX and Jeopardy scores as well as coronary artery calcium scores than did those without. Over an average follow-up of 3.7 years, the incidence of CVEs was significantly higher in patients with TX/CA (log-rank p < 0.001). Patients with physical signs and mutation positivity had threefold higher risks of CVEs (adjusted hazard ratio 3.34, 95% confidence interval 1.04-10.72, p = 0.024)., Conclusions: Physical signs were associated with genotypes and phenotypes, and worse outcomes in patients with HeFH, suggesting that these signs may help in risk stratification in these patients., (© 2021. The Author(s).)

Background and Aims: A consensus of experts suggests that nonalcoholic fatty liver disease (NAFLD) does not appropriately reflect current knowledge and metabolic-associated fatty liver disease (MAFLD) is supposed to be a more suitable overarching concept. However, the association of MAFLD with cardiovascular outcomes in patients with coronary artery disease has not been examined yet. Thus, this study aimed to assess the impact of MAFLD on major adverse cardiac events (MACEs) in patients with chronic coronary syndrome (CCS)., Methods: This study included 3306 patients with CCS who were diagnosed with MAFLD. Controls without MAFLD were matched (1:1) to cases by age and gender. All participants were followed up for the occurrence of MACEs. Finally, the association between MAFLD and the risk of MACEs was assessed., Results: During an average of 55.09 ± 19.92 months follow-up, 376 and 248 MACEs were observed in MAFLD and control groups, respectively. When compared with controls, Kaplan-Meier analysis showed that patients with MAFLD had significantly lower event-free survival rate and multivariate Cox regression analysis further revealed that MAFLD group had significantly increased MACEs risk (both p < 0.05). Stratification analysis suggested that patients with MAFLD overlapped with NAFLD or MAFLD-only had 1.33-fold and 2.32-fold higher risk of MACEs respectively compared with controls (both p < 0.05)., Conclusion: This study firstly showed that MAFLD was significantly associated with the risk of MACEs in patients with CCS. Moreover, this relationship remained unchanged irrespective of whether satisfying the NAFLD criteria, providing novel evidence for the good utility of MAFLD criteria in clinical practice., (© 2021. Asian Pacific Association for the Study of the Liver.)

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is considered to have multiple roles in the development of atherosclerosis, which is recently reported to participate in the thrombotic process. We aimed to examine the relationship between PCSK9 concentration, coagulation indexes and cardiovascular events., Methods: A total of 2293 consecutive patients with angina-like chest pain and without lipid-lowering drugs treatment were enrolled and followed up for major adverse cardiovascular events (MACEs). Circulating PCSK9 concentration was determined by ELISA. The routine coagulation tests including activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time were performed. The associations between PCSK9 concentration, routine coagulation indicators and MACEs were analyzed., Results: Patients with high PCSK9 levels had lower PT and APTT levels (all p <  0.05). However, PCSK9 concentration was only independently and negatively correlated with PT (β = - 0.115, p <  0.001). During a mean of 38.3 months, 186 (8.1%) MACEs were occurred. Multiple Cox regression analysis indicated high PCSK9 or low PT levels as risk factors related to MACEs. When the prognosis was analyzed by the combination of PCSK9 and PT levels, patients with high PCSK9 and low PT had higher incidence of MACEs compared to those with low PCSK9 and high PT., Conclusions: Our study firstly suggested that PCSK9 concentration was negatively correlated with plasma levels of PT. Furthermore, high PCSK9 and low PT were associated with MACEs and the combination of PCSK9 with PT had an addictive effect on predicting cardiovascular outcomes in patients with chest pain, which was useful for further subdivision of cardiovascular risks., (© 2021. The Author(s).)

Background: It has been demonstrated that patients with type 2 diabetes mellitus (DM) is associated with increased cardiovascular risk. However, little is known regarding the long-term prognosis in diabetic patients who experience mild-to-intermediate coronary artery stenosis (CAS). This study was to assess the clinical outcomes of diabetic patients with different severity of CAS., Methods: We consecutively enrolled 10,940 patients hospitalized due to angina-like chest pain and followed up for major adverse cardiovascular events (MACEs) covering cardiac death, myocardial infarction, ischemic stroke, unplanned coronary revascularization and angina-related hospitalization. According to coronary angiography, patients were divided into non-obstructive CAS (NOCAS, < 50% stenosis), intermediate CAS (ICAS, 50-69% stenosis), and severe CAS (SCAS, 70-100% stenosis) subgroups, and were further categorized into six groups as NOCAS with DM and non-DM, ICAS with DM and non-DM, and SCAS with DM and non-DM., Results: During a median follow-up of 40 months, 1,017 (11.1%) MACEs occurred. In patients with ICAS or SCAS, the incidence of events was higher when patients coexisted with DM (p < 0.05, respectively). In subgroup analyses, patients with ICAS and DM, SCAS and non-DM, SCAS and DM had increased risk of events [adjusted hazard ratio (HR): 1.709, 95% confidence interval (CI) 1.106-2.641, p = 0.016; HR: 1.911, 95% CI 1.460-2.501, p < 0.001; HR: 2.053, 95% CI 1.514-2.782, p < 0.001] compared to ones with NOCAS and non-DM. Besides, the Kaplan-Meier curves indicated the highest risk of MACEs in patients with SCAS and DM than others (p < 0.001)., Conclusions: Diabetic patients with ICAS had the worse outcome, which was comparable to patients with SCAS alone., (© 2021. The Author(s).)

Background: Continuous refinement of atherosclerotic cardiovascular disease (ASCVD) stratification has raised the definition of very-high-risk (VHR) recently, which has been underutilized in China. We aimed to identify patients at VHR and evaluate their performances in a Chinese population., Methods: A total of 9944 patients with ASCVD was continuously enrolled. Patients at VHR was identified according to 2018 AHA/ACC guideline. Median follow-up was 36.4 months. Clinical characteristics, low-density lipoprotein cholesterol (LDL-C) achievements, and the prognostic value of VHR mapping for cardiovascular events (CVEs) were evaluated., Findings: Overall, 26% (2542/9944) of patients were deemed as VHR, which were subsequently divided into two subgroups of VHR-1 [31% (779/2542)] and VHR-2 [69% (1763/2542)]. The rates of VHR were higher among patients of male (30%,2157/7268), young with age <45 years (46%,518/1130), and low-income regions (27%, 498/1838). Patients at VHR carried higher rates of risk factors than those at non-VHR (all p<0.001). However, only 3% (80/2542) of patients at VHR were prescribed with high-intensity of statins, and just 13% (321/2542) of them reached the LDL-C goal (<1.4mmol/L). Furthermore, of patients with coronary stenosis (n=9806), multiple-diseased vessels (47%, 1192/2523 vs. 36%,2587/7283) and occlusive lesions (36%, 902/2523 vs. 13%, 949/7283) were detected more commonly in those at VHR than non-VHR. The adjusted hazard ratios of VHR-1 and VHR-2 for primary CVEs were 2.58(1.61-4.14) and 2.23(1.55-3.20), respectively., Interpretation: Our study firstly reported that patients at VHR carried more severe ASCVD burden, lower LDL-C achievement, and higher CVEs risk, suggesting that the refinement of ASCVD might be considered in China to further understand patients at VHR., Funding: Capital Health Development Fund and CAMS Major Collaborative Innovation Project., Competing Interests: We declare no competing interests., (© 2021 The Author(s). Published by Elsevier Ltd.)

Lipoprotein(a) [Lp(a)] has been documented to be associated with atherothrombotic diseases. However, the prognostic impact of Lp(a) on long-term clinical outcomes among patients with previous myocardial infarction (MI) remains unclear. In this prospective cohort study, we consecutively enrolled 3,864 post-MI patients to assess the cardiovascular events (CVEs), including MI, ischemic stroke, and cardiac mortality. Lp(a) levels were determined using an immunoturbidimetry assay and the participants were categorized according to Lp(a) quartiles. The Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). During a median follow-up of 4.1 years, 331 (8.6%) CVEs were identified. Lp(a) was significantly higher in patients with CVEs (25.17 [11.13-47.83] vs. 18.18 [7.90-40.30] mg/dL, p  = 0.001). The cumulative rates of CVEs and cardiac mortality were significantly higher in patients with high Lp(a) levels (both log-rank p  < 0.001). Multivariate Cox regression analysis showed a significant correlation between Lp (a) levels treated as a natural logarithm-transformed continuous variable and increased CVEs (adjusted HR:1.22, 95% CI:1.09-1.35, p  = 0.001) or cardiac mortality (HR:1.30, 95% CI:1.14-1.48, p  < 0.001). The addition of Lp(a) to a prognostic model revealed a significant improvement in C-statistic, net reclassification, and integrated discrimination. In conclusion, elevated levels of Lp(a) were indeed associated with long-term worse outcomes in patients with prior MI, suggesting a novel hint that the measurement of Lp(a) might help in risk stratification and future management in those high-risk individuals., Competing Interests: None declared., (Thieme. All rights reserved.)

Although emerging data suggest that circulating lipoprotein (a) [Lp (a)] could predict cardiovascular events (CVEs) in patients with cardiovascular disease, no study is currently available regarding the prognostic linkage of Lp (a) and hypertension in patients with coronary artery disease (CAD). This study sought to evaluate the association of Lp (a), hypertension and cardiovascular outcomes in patients with stable CAD. A total of 8668 patients with stable CAD were consecutively enrolled. Baseline Lp (a) concentrations were measured. All subjects were categorized according to Lp (a) levels of <10 (low), 10-30 (medium) and ≥30 mg/dL (high) and were further stratified by hypertension status. They were regularly followed-up for the occurrence of cardiovascular death, nonfatal myocardial infarction, and stroke. Over an average of 54.81 ± 18.60 months of follow-up, 584 (6.7%) CVEs occurred. Kaplan-Meier and multivariate Cox regression analyses showed that elevated Lp (a) levels had a significant association with CVEs in hypertensive patients, regardless of the control status of blood pressure, but not in normotensive subjects. Moreover, when analyzed by subgroups according to both Lp (a) category and hypertension status, the risk of CVEs was only significantly elevated in the high Lp (a) plus hypertension group compared with the reference group with low Lp (a) levels and normotension (hazard ratio: 1.80, 95% confidence interval: 1.11-2.91). Elevated Lp (a) was associated with an increased risk of CVEs in stable CAD patients with hypertension. Moreover, the coexistence of high Lp (a) concentrations and hypertension greatly worsened the clinical prognosis in patients with CAD, which may suggest a prognostic correlation between Lp (a) and hypertension., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Background and Aims: The association of triglyceride-rich lipoprotein-cholesterol (TRL-C) with recurrent cardiovascular events (RCVEs) has not been studied. Moreover, whether inflammation can affect TRL-C-associated cardiovascular risk is unknown. This study sought to examine the association between TRL-C and RCVEs, and whether this relationship is modulated by systemic inflammation in statin-treated patients with coronary artery disease (CAD) and nearly normal triglyceride., Methods: In this study, 6723 CAD patients were consecutively enrolled, following a first CVE with triglyceride <2.3 mmol/L. Baseline lipid profile and high-sensitivity C-reactive protein (hsCRP) levels were determined. All patients were searched for RCVEs. The risk of RCVEs was assessed across quartiles (Q) of baseline TRL-C and further stratified by the median of hsCRP., Results: Over a mean follow-up of 58.91 ± 17.79 months, 538 RCVEs were recorded. After adjustment for potential confounders, Q4 of TRL-C was significantly associated with the risk of RCVEs, which remained unchanged after hsCRP stratification. When subjects were grouped according to both TRL-C and hsCRP levels, patients with Q4 of TRL-C and hsCRP had the highest increase of the risk of RCVEs compared with the reference group (TRL-C Q1-3 and hsCRP Q1-3; HR, 1.90; 95%CI: 1.27-2.87). Furthermore, adding TRL-C to the original predicting model led to a slight but significant improvement., Conclusions: The present analysis firstly showed that elevated TRL-C was associated with an increased RCVEs risk in statin-treated patients with CAD independent of systemic inflammation, suggesting that it might be a useful marker for risk stratification and a treatment target in this patient population., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background & Aims: Liver fibrosis score (LFS) has been used for predicting the cardiovascular outcomes (CVOs) in diverse populations. However, the association of LFS with CVOs in patients with previous myocardial infarction (MI) remains undetermined. We aimed to examine the prognostic value of LFS in patients with prior MI in a prospective cohort., Methods: A total of 3718 patients with previous MI were consecutively enrolled from March 2009 to January 2019. Five LFSs including the fibrosis-4 (FIB-4) score, non-alcohol fatty liver disease fibrosis score (NFS), Forns score, HUI score and BARD score were used. The CVOs covered major adverse cardiac event (MACEs), cardiovascular mortality and all-cause mortality. Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs)., Results: During a mean follow-up of 47.4 ± 24.8 months, 431 (11.6%) MACEs occurred. Kaplan-Meier analysis demonstrated that higher LFSs resulted in a significantly higher probability of CVOs. Compared to the lowest score group, multivariable-adjusted HRs (95% CIs) of the highest group of FIB-4, NFS, Forns score, HUI score and BARD score were 1.75 (1.32-2.33), 2.37 (1.70-3.33), 2.44 (1.61-3.73), 1.58 (1.16-2.14) and 1.27 (1.03-1.57) respectively. These LFSs were also independent predictors of cardiovascular mortality and all-cause mortality. Similar results were observed across subgroups analysis. The addition of LFSs to a prediction model significantly increased the C-statistic for CVOs., Conclusions: The present study firstly demonstrated that LFS could be used as a risk stratification tool for predicting CVOs in patients with previous MI, which should be evaluated further., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: Familial hypercholesterolemia patients are characterized by early onset of coronary artery calcification and atherosclerosis, and high incidence of cardiovascular events. Plasma proprotein convertase subtilisin/kexin type 9 was reported to be a predictor for cardiovascular risk in the general population. However, its prognostic value for predicting recurrent cardiovascular events in familial hypercholesterolemia patients remains undetermined., Methods: A total of 249 patients with molecularly and/or clinically (Dutch Lipid Clinic Network score > 6) defined familial hypercholesterolemia who had experienced a first cardiovascular event were consecutively included and plasma proprotein convertase subtilisin/kexin type 9 concentrations were measured by enzyme-linked immunosorbent assay. Coronary artery calcification was measured using Agatston method and coronary severity was assessed by Gensini score, respectively. All patients received standard lipid-lowering therapy and were followed-up for recurrent cardiovascular events. Univariate and multivariate regression and Cox analyses was used to calculate hazard ratios with 95% confidence interval., Results: Circulating proprotein convertase subtilisin/kexin type 9 concentrations were positively associated with coronary artery calcification scores and Gensini score by both univariate and multivariate analyses. During a mean follow-up of 43 ± 19 months, 29 (11.51%) recurrent cardiovascular events occurred. Kaplan-Meier analysis showed that patients with the highest proprotein convertase subtilisin/kexin type 9 levels had the lowest event-free survival time. Multivariable Cox regression analysis revealed that proprotein convertase subtilisin/kexin type 9 was independently associated with recurrent cardiovascular events (hazard ratio: 1.45, 95% confidence interval: 1.11-1.88). The combination of proprotein convertase subtilisin/kexin type 9 to Cox prediction model led to an enhanced predictive value for recurrent cardiovascular events., Conclusions: Increased level of proprotein convertase subtilisin/kexin type 9 was a significant risk factor of atherosclerosis and independently predicted future recurrent cardiovascular events in familial hypercholesterolemia patients receiving standard lipid-lowering treatment., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Background: The prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with coronary artery disease (CAD) with different glucose status has not been established. This study sought to evaluate the significance of NT-proBNP in predicting major adverse cardiovascular events (MACEs) in patients with chronic coronary syndrome (CCS) and normal left-ventricular systolic function (LVSF) according to different glucose status, especially in those with abnormal glucose metabolism., Methods: A total of 8062 patients with CCS and normal LVSF were consecutively enrolled in this prospective study. Baseline plasma NT-proBNP levels were measured. The follow-up data of all patients were collected. Kaplan-Meier and Cox regression analyses were used to assess the risk of MACEs according to NT-proBNP tertiles stratified by glucose status., Results: Over an average follow-up of 59.13 ± 18.23 months, 569 patients (7.1 %) suffered from MACEs, including cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Kaplan-Meier analysis showed that high NT-proBNP levels had a significant association with MACEs in subjects with prediabetes mellitus (pre-DM) or DM, but not in patients with normoglycemia. Multivariate Cox regression analysis revealed that NT-proBNP remained an independent predictor of MACEs in patients with pre-DM [hazard ratio (HR): 2.56, 95% confidence interval (CI): 1.34-4.91] or DM (HR: 2.34, 95% CI: 1.32-4.16). Moreover, adding NT-proBNP to the original Cox model including traditional risk factors significantly increased the C-statistic by 0.035 in pre-DM and DM, respectively., Conclusions: The present study indicated that NT-proBNP could well predict worse outcomes in dysglycemic patients with CCS and normal LVSF, suggesting that NT-proBNP may help with risk stratification in this population.

Background: The deeper understanding of the complex hereditary basis of familial hypercholesterolemia (FH) has raised the rationale of genetic testing, which has been underutilized in clinical practice., Objectives: The present study aimed to explore the variant spectrum of FH in an expanding manner and compare its diagnostic performance., Methods: A total of 169 Chinese individuals (124 index cases and 45 relatives) with clinical definite/probable FH were consecutively enrolled. Next-generation sequencing was performed for genetic analysis of 9 genes associated with hypercholesterolemia (major genes: LDLR, APOB, and PCSK9; minor genes: LDLRAP1, LIPA, STAP1, APOE, ABCG5, and ABCG8 ) including the evaluations of small-scale variants and large-scale copy number variants (CNVs)., Results: Among the 169 clinical FH patients included, 98 (58.0%) were men. A total of 85 (68.5%) index cases carried FH-associated variants. The proportion of FH caused by small-scale variants in LDLR , APOB, and PCSK9 genes was 62.1% and then increased by 6.5% when other genes and CNVs were further included. Furthermore, the variants in LDLR , APOB , and PCSK9 genes occupied 75% of all FH-associated variants. Of note, there were 8 non- LDLR CNVs detected in the present study., Conclusions: LDLR , APOB , and PCSK9 genes should be tested in the initial genetic screening, although variants in minor genes also could explain phenotypic FH, suggesting that an expanding genetic testing may be considered to further explain phenotypic FH., Competing Interests: This work was supported by the Capital Health Development Fund (201614035), CAMS Major Collaborative Innovation Project (2016-I2M-1-011). The authors have reported that theyhave no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

Competing Interests: None.

Background: Visit-to-visit variability in lipid has been suggested as a predictor of major adverse cardiovascular events (MACEs). However, no evidence exists on the prognostic value of lipid variability in patients with familial hypercholesterolemia (FH). This prospective cohort study aimed to investigate whether lipid variability affects future MACEs in patients with FH receiving standard lipid-lowering therapy., Methods: A total of 254 patients with FH were consecutively enrolled and followed for MACEs. Variability in the triglyceride, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] were evaluated from 3 months after discharge using the standard deviation (SD), coefficient of variation (CV) and variability independent of the mean (VIM)., Results: During a mean follow-up of 49 months, 22 (8.7%) events occurred. Visit-to-visit variability in Lp(a) was significantly higher in the MACE group compared to the non-MACE group. In the multivariate Cox analysis, only Lp(a)-related parameters were independent predictors for MACEs. The hazard ratios and 95% confidence intervals of each 1-SD increase of SD, CV, and VIM of Lp(a) were 1.42 (1.12-1.80), 1.50 (1.11-2.02) and 1.60 (1.16-2.22), respectively. Kaplan-Meier analysis revealed that patients with higher Lp(a) variability presented lower event-free survival. The results were consistent in various subgroups., Conclusions: Our study firstly suggested that Lp(a) variability was associated with MACEs in real-world patients with FH, which emphasized the importance of regular lipid monitoring in the patients with high risk., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5324). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: Although non-invasive liver fibrosis scores (LFSs) have already been considered as effective tools for estimating cardiovascular risk, their roles in predicting disease severity and cardiovascular event (CVEs) in patients with stable coronary artery disease (CAD) are not comprehensively evaluated. The aim of the present study was to investigate whether non-alcoholic fatty liver disease fibrosis score (NAFLD-FS) and fibrosis-4 (FIB-4) are associated with CVEs in a large cohort with long-term follow-up., Methods: A cohort of 5143 patients with angiography-proven stable CAD were consecutively enrolled and followed up for CVEs. The degree of coronary severity was assessed using the number of diseased vessels, Gensini, Syntax, and Jeopardy scores. The predictive values of NAFLD-FS and FIB-4 scores to coronary severity, coronary calcification (CAC), and CVEs were assessed, respectively., Results: During a median follow-up of 7 years, 435 CVEs were recorded. Both NAFLD-FS and FIB-4 were predictors for the presence of CAC. The degree of coronary stenosis was significantly higher in high NAFLD-FS categories while FIB-4 was only positively associated with the number of diseased vessels and Gensini score. In Kaplan-Meier analysis, the patients with intermediate and high NAFLD-FS and FIB-4 had higher risk of CVEs and cardiovascular mortality. In multivariate Cox regression analysis, NAFLD-FS and FIB-4 were independently associated with CVEs [hazard ratio (95% confidence interval): 1.150 (1.063-1.244), p < 0.001 and 1.128 (1.026-1.240), p = 0.012]., Conclusion: The current data first indicated that both NAFLD-FS and FIB-4 scores were not only significantly related to coronary severity but also associated with CAC and CVEs., Clinical Trials Registration: None.

Objective: Previous studies have demonstrated that small dense LDL-cholesterol (sdLDL-C) is related to the pathogenesis of coronary artery disease (CAD). However, its prognostic role in hypertensive patients with CAD has been undetermined. The aim of the study was to investigate the association between sdLDL-C with disease severity, hypertensive status and clinical outcome in patients with CAD., Methods: A total of 4594 patients with angiography-proven CAD were consecutively enrolled and categorized into subgroups according to blood pressure status. Serum sdLDL-C levels were measured by direct quantitative measurement using automated chemistry analyzers. The severity of coronary artery lesions were determined by Gensini score, Syntax score and the number of lesion vessels. The associations of sdLDL-C with disease severity, hypertensive status and cardiovascular events (CVEs) were evaluated., Results: Patients with hypertension had higher sdLDL-C levels than ones without (P = 0.010). In hypertensive patients, sdLDL-C was positively associated with the severity of CAD (P < 0.05). In addition, hypertensive patients with poorly controlled hypertension had higher sdLDL-C levels than those with well controlled (P < 0.05). Moreover, 149 CVEs occurred in patients with poorly controlled hypertension and Cox regression analysis indicated that elevated sdLDL-C levels were independently associated with CVEs in hypertensive patients with poorly controlled hypertension (adjusted hazard ratio: 1.673, 95% confidence interval: 1.105-2.535, P = 0.015)., Conclusion: The current data, for the first time, showed that serum sdLDL-C levels were correlated with hypertension control, disease severity and worse outcomes in hypertensive patients with CAD, suggesting that paying more attention on sdLDL-C in these patients were warranted., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Non-fasting blood samples are routinely used to assess plasma lipid profiles except in patients with severe hypertriglyceridemia according to the previous consensus. However, the impact of statin use on non-fasting plasma lipid measurements has not been thoroughly evaluated., Methods: In this cross-sectional study, 686 patients with normal triglyceride (TG) levels, who were hospitalized due to chest pain, were enrolled. Fasting (8-12 h) and non-fasting (2-4 h after breakfast) lipid profiles were measured on the second day of admission. Patients were divided into the non-statin (n=499) group and statin treatment (n=187) group. Differences in fasting and non-fasting lipid profiles between the statin and non-statin groups were compared., Results: The mean age of participants was 57±13 years, and 54.4% were male. A linear correlation was observed between fasting and non-fasting lipid profiles. Although a postprandial impact on lipid parameters was observed, the general pattern of differences between fasting and non-fasting lipids was similar in both groups. Additionally, the diff(%) [(non-fasting-fasting)/fasting ×100%] of lipid panels did not vary by statin treatment. Moreover, no effects of statin types or duration of use on non-fasting lipid profiles were identified., Conclusions: The current study found fasting and non-fasting lipid panels were similar in individuals with or without statin treatment. Non-fasting lipid panels were not significantly affected by statin types or duration of use, suggesting that non-fasting lipid measurement is an acceptable test for patients receiving statin treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at: http://dx.doi.org/10.21037/atm-20-3962). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background Previous studies have suggested a strong association of liver fibrosis scores (LFSs) with cardiovascular outcomes in patients with different cardiovascular diseases. Nonetheless, it is basically blank regarding the prognostic significance of LFSs in patients following percutaneous coronary intervention (PCI). This study sought to examine the potential role of LFSs in predicting long-term outcomes in a large cohort of patients with stable coronary artery disease after elective PCI. Methods and Results In this multicenter, prospective study, we consecutively enrolled 4003 patients with stable coronary artery disease undergoing PCI. Eight currently available noninvasive LFSs were assessed for each subject. All patients were followed up for the occurrence of cardiovascular events including cardiovascular death, nonfatal myocardial infarction, and stroke. During an average follow-up of 5.0±1.6 years, 315 (7.87%) major cardiovascular events were recorded. Subjects who developed cardiovascular events were more likely to have intermediate or high LFSs, including nonalcoholic fatty liver disease fibrosis score; fibrosis-4 score; body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes mellitus score (BARD); and aspartate aminotransferase/alanine aminotransferase ratio. Furthermore, compared with subjects with low scores, those with intermediate plus high score levels had significantly increased risk of cardiovascular events (adjusted hazard ratios ranging 1.57-1.92). Moreover, the addition of non-alcoholic fatty liver disease fibrosis score; fibrosis-4 score; or body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes mellitus score into a model with established cardiovascular risk factors significantly improved the prediction ability. Conclusions High LFSs levels might be useful for predicting adverse prognosis in patients with stable coronary artery disease following PCI, suggesting the possibility of the application of LFSs in the risk stratification before elective PCI.