Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases.

N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.

Association of β-blocker use at discharge and prognosis of oldest old with acute myocardial infarction: a prospective cohort study.

PURPOSE:It is uncertain whether β-blockers are beneficial for long-term prognosis in older patients following acute myocardial infarction (AMI). Thus, this study sought to examine the effect of β-blockers on long-term cardiovascular mortality (CVM) in the oldest old (≥ 80 years) with AMI.METHODS:In this prospective, consecutive, non-randomized study, a total of 1156 patients with AMI admitted within 24 h after onset of symptoms were enrolled from January 2012 to February 2020. Univariate and multivariate Cox regression analyses were performed to examine the impact of β-blocker use on prognosis. Furthermore, one-to-one propensity score matching (PSM) and inverse probability treatment weighting (IPTW) analyses were used to control for systemic differences between groups. The primary outcome was long-term CVM.RESULTS:Among the enrolled subjects, 972 (85.9%) were prescribed with β-blockers at discharge. Over a mean follow-up of 26.3 months, 224 cardiovascular deaths were recorded. Both univariate [hazard ratio (HR), 1.41, 95% confidence interval (CI) 0.93-2.13] and multivariate (HR, 1.29, 95% CI 0.79-2.10) Cox regression analyses showed that β-blocker use had no significant association with the long-term CVM, which was further demonstrated by PSM (HR, 1.31, 95% CI 0.75-2.28) and IPTW (HR, 1.41, 95% CI 0.73-2.69) analyses. Subgroup analyses according to sex, heart rate, hypertension, diabetes, revascularization, left ventricular ejection fraction, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers use showed consistent results as well.CONCLUSION:Our findings first suggested that the use of β-blockers at discharge in oldest old with AMI was not useful for reducing post-discharge CVM, which need to be further verified by randomized controlled trials.

Circulating Total Bilirubin and Long-Term Prognosis in Patients With Previous Myocardial Infarction.

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.

Letter by Li et al Regarding Article, "Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study".

Current Guideline Risk Stratification and Cardiovascular Outcomes in Chinese Patients Suffered From Atherosclerotic Cardiovascular Disease.

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.

Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity C-Reactive Protein in Patients With Previous Myocardial Infarction.

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.

Landscape of cardiometabolic risk factors in Chinese population: a narrative review.

With rapid economic growth and changes at all levels (including environmental, social, individual), China is facing a cardiovascular disease (CVD) crisis. In China, more than 40% of deaths are attributable to CVDs, and the number of CVD deaths has almost doubled in the past decades, in contrast to a decline in high-income countries. The increasing prevalence of cardiometabolic risk factors underlies the rise of CVDs, and thus curbing the rising cardiometabolic pandemic is imperative. Few articles have addressed this topic and provided an updated review of the epidemiology of cardiometabolic risk factors in China.In this narrative review, we describe the temporal changes in the prevalence of cardiometabolic risk factors in the past decades and their management in China, including both the well-recognized risk factors (general obesity, central obesity, diabetes, prediabetes, dyslipidemia, hypertension) and the less recognized ones (hyperhomocysteinemia, hyperuricemia, and high C-reactive protein). We also summarize findings from landmark clinical trials regarding effective interventions and treatments for cardiometabolic risk factors. Finally, we propose strategies and approaches to tackle the rising pandemic of cardiometabolic risk factors in China. We hope that this review will raise awareness of cardiometabolic risk factors not only in Chinese population but also global visibility, which may help to prevent cardiovascular risk.

Improvement of Definite Diagnosis of Familial Hypercholesterolemia Using an Expanding Genetic Analysis.

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.

Improvement of evaluation in Chinese patients with atherosclerotic cardiovascular disease using the very-high-risk refinement: a population-based study.

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.

Association of triglyceride-rich lipoprotein-cholesterol with recurrent cardiovascular events in statin-treated patients according to different inflammatory status.

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.

Application of improved GalNAc conjugation in development of cost-effective siRNA therapies targeting cardiovascular diseases.

N-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve in vivo efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior in vivo efficacy compared to triantennary GalNAc-conjugated siRNAs.

Association of β-blocker use at discharge and prognosis of oldest old with acute myocardial infarction: a prospective cohort study.

PURPOSE:It is uncertain whether β-blockers are beneficial for long-term prognosis in older patients following acute myocardial infarction (AMI). Thus, this study sought to examine the effect of β-blockers on long-term cardiovascular mortality (CVM) in the oldest old (≥ 80 years) with AMI.METHODS:In this prospective, consecutive, non-randomized study, a total of 1156 patients with AMI admitted within 24 h after onset of symptoms were enrolled from January 2012 to February 2020. Univariate and multivariate Cox regression analyses were performed to examine the impact of β-blocker use on prognosis. Furthermore, one-to-one propensity score matching (PSM) and inverse probability treatment weighting (IPTW) analyses were used to control for systemic differences between groups. The primary outcome was long-term CVM.RESULTS:Among the enrolled subjects, 972 (85.9%) were prescribed with β-blockers at discharge. Over a mean follow-up of 26.3 months, 224 cardiovascular deaths were recorded. Both univariate [hazard ratio (HR), 1.41, 95% confidence interval (CI) 0.93-2.13] and multivariate (HR, 1.29, 95% CI 0.79-2.10) Cox regression analyses showed that β-blocker use had no significant association with the long-term CVM, which was further demonstrated by PSM (HR, 1.31, 95% CI 0.75-2.28) and IPTW (HR, 1.41, 95% CI 0.73-2.69) analyses. Subgroup analyses according to sex, heart rate, hypertension, diabetes, revascularization, left ventricular ejection fraction, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers use showed consistent results as well.CONCLUSION:Our findings first suggested that the use of β-blockers at discharge in oldest old with AMI was not useful for reducing post-discharge CVM, which need to be further verified by randomized controlled trials.

Circulating Total Bilirubin and Long-Term Prognosis in Patients With Previous Myocardial Infarction.

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.

Letter by Li et al Regarding Article, "Severe Infection and Risk of Cardiovascular Disease: A Multicohort Study".

Current Guideline Risk Stratification and Cardiovascular Outcomes in Chinese Patients Suffered From Atherosclerotic Cardiovascular Disease.

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.

Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide and High-Sensitivity C-Reactive Protein in Patients With Previous Myocardial Infarction.

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.

Landscape of cardiometabolic risk factors in Chinese population: a narrative review.

With rapid economic growth and changes at all levels (including environmental, social, individual), China is facing a cardiovascular disease (CVD) crisis. In China, more than 40% of deaths are attributable to CVDs, and the number of CVD deaths has almost doubled in the past decades, in contrast to a decline in high-income countries. The increasing prevalence of cardiometabolic risk factors underlies the rise of CVDs, and thus curbing the rising cardiometabolic pandemic is imperative. Few articles have addressed this topic and provided an updated review of the epidemiology of cardiometabolic risk factors in China.In this narrative review, we describe the temporal changes in the prevalence of cardiometabolic risk factors in the past decades and their management in China, including both the well-recognized risk factors (general obesity, central obesity, diabetes, prediabetes, dyslipidemia, hypertension) and the less recognized ones (hyperhomocysteinemia, hyperuricemia, and high C-reactive protein). We also summarize findings from landmark clinical trials regarding effective interventions and treatments for cardiometabolic risk factors. Finally, we propose strategies and approaches to tackle the rising pandemic of cardiometabolic risk factors in China. We hope that this review will raise awareness of cardiometabolic risk factors not only in Chinese population but also global visibility, which may help to prevent cardiovascular risk.

Improvement of Definite Diagnosis of Familial Hypercholesterolemia Using an Expanding Genetic Analysis.

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.

Improvement of evaluation in Chinese patients with atherosclerotic cardiovascular disease using the very-high-risk refinement: a population-based study.

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.

Association of triglyceride-rich lipoprotein-cholesterol with recurrent cardiovascular events in statin-treated patients according to different inflammatory status.

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.