bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of achieving LDL-C <1.8 mmol/L to prevent the first atherosclerotic cardiovascular events in the primary prevention settings of severe heterozygous familial hypercholesterolemia
Authors: Funabashi S , Kataoka Y , Hori M , Ogura M , Doi T , Noguchi T , Shiba M
Published: October 2022

Introduction

The International Atherosclerosis Society (IAS) has proposed “severe familial hypercholesterolemia” (FH) as a phenotype with the highest cardiovascular risk. LDL-C <2.5 mmol/l is a recommended therapeutic goal for the primary prevention settings of severe FH. However, given that ESC guidelines recommends LDL-C <1.8 mmol/l in FH patients, this stricter goal may be better to prevent the first atherosclerotic cardiovascular disease (ASCVD) in severe FH patients.

Purpose

To determine whether achieving LDL-C<1.8 mg/dl is more beneficial to reduce the first ASCVD events.

Methods

A total of 148 severe FH subjects without any history of ASCVD were analyzed. Severe FH was defined as untreated LDL-C >10.3 mmol/l, LDL-C >8.0 mmol/l+ 1 high-risk feature, LDL-C >4.9 mmol/l + 2 high-risk features according to IAS proposed statement. The occurrence of ASCVD (all-cause death, CAD, ischemic stroke and lower extremity artery disease (LEAD)) were compared in those with on-treatment LDL-C < and ≥1.8 mmol/L.

Results

10.1% (=15/148) of study subjects achieved on-treatment LDL-C <1.8 mmol/l. They were more likely to receive PCSK9 inhibitor (15.0 vs. 66.7%, p<0.01), whereas there was no significant difference in FH-related physical characteristics (tendon xanthomas: 72.2 vs. 93.3%, p=0.12) and causative genotypes (LDLR: 68.4 vs. 66.7%, p=1.00, PCSK9: 8.3 vs. 6.7%, p=1.00, LDLR/PCSK9: 3.8 vs. 6.7%, p=0.48), untreated LDL-C (7.3±1.7 vs. 7.9±1.8 mmol/l, p=0.22) and lipoprotein(a) (23 [11–42] vs. 25 [15–70] mg/dl, p=0.41) levels between two groups. During the observational period (median=7.0 years), severe FH achieving on-treatment LDL-C <1.8 mmol/l was associated with a lower likelihood of experiencing ASCVD events (Figure 1). Of note, any cardiovascular events did not occur in severe FH who achieved on-treatment LDL-C <1.8 mmol/l. In those with on-treatment LDL ≥1.8 mmol/L, CAD (76.5%=26/34) was more dominant component of ASCVD, followed by ischemic stroke (17.6%=6/34) and LEAD (5.9%=2/34).

Conclusions

A significantly lower frequency of ASCVD was observed in severe FH who achieved LDL-C <1.8 mmol/L in the primary prevention settings. Given that only 10.1% of severe FH patients achieved LDL-C <1.8 mmol/l, more actions are required to motivate physicians for further intensified management of LDL-C in severe FH patients in the primary prevention settings.

Funding Acknowledgement

Type of funding sources: None.
Effectiveness of roux-en-Y gastric bypass vs sleeve gastrectomy on lipid levels in type 2 diabetes: a meta-analysis
Authors: Lobo L M , Nogueira J P , Clos C , Masson W , Molinero G , Lavalle Cobo A , Benincasa F , Delgado J , Losada P , Valero R
Published: October 2022

Introduction

Obesity and its co-morbidities, including type 2 diabetes (T2DM) and dyslipidemia, are accompanied by excess cardiovascular morbi-mortality. Aside from excess low density lipoprotein-cholesterol (LDL-C), atherogenic dyslipidemia (AD), mainly characterized by elevated triglycerides and decreased high density lipoprotein-cholesterol (HDL-C) levels, is often present in T2DM obese patients. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), has become a reference treatment in that population. However, the respective effects of RYGB vs SG on lipid metabolism in T2DM patients have been rarely studied.

Methods

A meta-analysis of randomized controlled trials, comparing the effects of RGYBG vs SG on lipid metabolism 12 months after surgery in T2DM patients, was performed.

Results

Four studies including a total of 298 patients (151 patients in the RYGB and 147 patients in the SG group) were examined. Despite a greater decrease in body mass index and greater improvement in glycaemic control in RYGB compared to SG. RYGB vs SG was more effective in reducing total cholesterol, LDL-C and non-HDL-C levels (mean difference [MD] −24.10 mg/dL, 95% CI −33.76 to −14.44, p<0.00001; [MD] −23.24 mg/dL, 95% CI −34.84 to −11.63, p<0.00001 and MD 31.70 mg/dL, 95% CI −46.00 to −17.40, p<0.00001, respectively).

Conclusions

The superiority of RYGB vs SG in reducing LDL-C, with an effect comparable to a moderate-intensity statin, suggests RYBG should be favoured in hypercholesterolemic T2DM patients in order to further reduce cardiovascular risk.

Funding Acknowledgement

Type of funding sources: None.
Association of propionate with coronary artery disease in a large cross-sectional study
Authors: Pagonas N , Sasko B , Seibert F , Ritter O , Babel N , Westhoff T
Published: October 2022

Background

Microbiome has been linked to the pathogenesis of coronary artery disease (CAD) but data providing direct evidence for an association of short-chain fatty acids (SCFA) like propionate with CAD are lacking.

Purpose

To study the association of propionate in blood samples with the presence of CAD

Methods

This was a cross-sectional study enrolling patients admitted to invasive coronary angiography in a university hospital in Germany. Patients were prospectively recruited between from March 2017 to January 2020. Patients with known or suspected CAD and risk factors for cardiovascular diseases were screened for eligibility to participate in the trial. Main exclusion criteria were inflammatory/rheumatic disease, active cancer disease and acute infection. Blood sampling was performed after overnight fasting and before invasive procedures. Measurement of propionate was performed though liquid chromatography.

Results

The study included 691 patients (median n [IQR] age, 69 [60–78] years; 406 men [59%]). A total of 368 had invasively confirmed CAD with at least one coronary artery stenosis ≥50% and 323 had non CAD and 194 had invasively excluded CAD. 129 additional patients without suspicion for CAD and without diabetes/smoking were also recruited in the no CAD group. CAD patients had significant lower levels of propionate (median) 6.08 μM (IQR, 4.31–7.65) compared to the no CAD groups 6.92 μM (4.89–9.25, <0.05). Linear regression multivariate analysis adjusted for age, gender, body mass index, hypertension, smoking, diabetes and hyperlipidemia revealed an odds ratio of 0.92 (CI 0.89–0,96, p<0.001) for propionate as predictor of CAD.

Conclusions

The study provides large-scale data for a protective role of propionate in the development of CAD, independent of the presence of other known cardiovascular risk factors.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Internal Grant, Medical School of Brandenburg
Longitudinal associations of cumulative dyslipidaemia from mid-adolescence through young adulthood with arterial stiffness progression: the ALSPAC study
Authors: Agbaje A O , Lloyd-Jones D M , Magnussen C G , Tuomainen T P
Published: October 2022

Background

Arterial stiffness assessed with carotid-femoral pulse wave velocity (cfPWV) strongly predicts the risk of cardiovascular morbidity and mortality. Recent temporal causal evidence suggests that cfPWV progression may precede the development of cardiometabolic diseases in adolescence, young adults, and middle-aged adults. However, the longitudinal relationship between cfPWV progression and dyslipidaemia in the young population is unclear.

Purpose

To investigate the longitudinal associations of total cholesterol (TC), non–high-density lipoprotein cholesterol (non–HDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, and low-density lipoprotein cholesterol (LDL-C) with cfPWV progression in adolescents.

Methods

We studied 1779 British 15-year-olds (50% females) followed up for 9 years. TC, triglyceride, and HDL-C were measured in line with standard protocols at ages 15, 17, and 24 years, respectively. LDL-C and non-HDL-C were estimated. Lipid phenotypes were categorized based on the 2011 National Heart, Lung, and Blood Institute classification into normal (reference), and elevated/dyslipidaemia. At age 17 and 24 years, cfPWV was computed from pressure waveforms obtained using the Vicorder device. We conducted linear mixed-effect model analyses and adjusted for sex, age, high sensitivity C-reactive protein, glucose, insulin, total fat mass, lean mass, heart rate, systolic blood pressure, diastolic blood pressure, sedentary time, light physical activity, moderate to vigorous physical activity, family history of cardiometabolic disease, socioeconomic status, pubertal attainment, and smoking status, in addition to lipid covariates such as HDL-C, LDL-C, or triglyceride depending on the predictor. However, TC and non-HDL-C analyses were not adjusted for lipids.

Results

Participants' mean (SD) age in years at different time points were 15.43 (0.29), 17.69 (0.31), and 24.53 (0.72). Persistently elevated/dyslipidaemia TC: effect estimate 0.006 m/s [95% CI −0.023 to 0.035; p=0.683], non–HDL-C: 0.004 m/s [−0.025 to 0.033; p=0.771], LDL-C: 0.017 m/s [−0.019 to 0.052; p=0.351], and Triglyceride: −0.009 m/s [−0.036 to 0.018; p=0.532] from 15 through 24 years were not cumulatively associated with the 7-year cfPWV progression. Persistent borderline-low/very-low HDL-C: 0.007 m/s [−0.017 to 0.031; p=0.556] was not associated with cfPWV progression.

Conclusion

These findings suggest that elevated lipids and dyslipidaemia from mid-adolescence through young adulthood were not associated with arterial stiffness progression, a marker of preclinical arteriosclerosis. Thus, lipid-lowering interventions targeted at preventing or reversing arterial stiffness progression in the young may be ineffective, particularly in a healthy young population.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Finnish Cultural Foundation
Evaluation of the effects of immunization against PCSK9 on selected microRNAs involved in cholesterol homeostasis
Authors: Ataei S , Ganjali S , Banach M , Sahebkar A
Published: October 2022

Background

MicroRNAs (miRNAs) have been discovered as novel modulators of gene expression. These molecules are involved in regulating lipid metabolism through a complicated interactive mechanism involving gene regulatory networks and can play a role in metabolic diseases. PCSK9 (proprotein convertase subtilisin/Kexin 9) is a critical regulator in cholesterol homeostasis. PCSK9 inhibition is an effective therapeutic strategy for the treatment of dyslipidemia. Accordingly, it is essential to identify the controlling mechanisms of the PCSK9 and the effects of its inhibitors on microRNAs involved in cholesterol homeostasis.

Purpose

Considering the role that miR-27a, miR-30c, and miR-191 play in regulating genes involved in cholesterol homeostasis, we investigated the effect of immunization against PCSK9 on the mentioned miRNAs.

Methods

A PCSK9 immunogenic peptide constructed by linking a short PCSK9 mimotope peptide to a tetanus peptide was used for immunization. The PCSK9 immunogenic peptide construct was mixed homogeneously with 0.4% alum adjuvant at a ratio of 1:1 for use as vaccine formulation. Mice in the vaccinated group were inoculated subcutaneously in four terms with bi-weekly intervals. In order to assess the expression of miRNAs in vaccinated mice' livers, sampling was carried out two weeks after the last injection. The levels of miR-27a, miR-30c, and miR-191 expression in the liver of vaccinated mice were evaluated using real-time quantitative PCR, and relative expression levels were presented as fold change normalized to U6 as the internal control.

Results

Hepatic miR-27a expression was significantly decreased in vaccinated mice compared with the control mice (fold change: 0.731±0.1, p=0.027). There was a borderline nonsignificant reduction in the hepatic expression of miR-30c in the vaccine group compared to the control group (fold change: 0.569±0.1, p=0.078). No significant difference was detected in the hepatic expression of miR-191 between the vaccine and control groups (fold change: 0.852±0.1, p=0.343).

Conclusions

Immunization against PCSK9 leads to decreased hepatic expression of miR-27a. Since miR-27a is involved in the regulation of targets like angiopoietin-like 3 and glycerol-3-phosphate acyltransferase 1, its reduction may explain part of the lipid-lowering activity of PCSK9 vaccine.

Funding Acknowledgement

Type of funding sources: None.
Realistic approach to evaluate the effect of baseline lipid profile in post cardiac surgery: Restricted Cubic Spline model
Authors: Sheikhy A , Fallahzadeh A S , Fallahzadeh A , Hosseini K , Hosseini K
Published: October 2022

Background

There are still many uncertainties in the association between lipid profile and post coronary artery bypass grafting (CABG) outcomes. Although simplifying the association to linear equations makes it understandable but cannot explain many findings.

Methods

Total 17,555 patients who underwent isolated CABG between 2014 and 2016 were evaluated. During the median follow-up of 75.24 months the Restricted Cubic Splines (RCS) estimated from the Cox regression model adjusted for all possible confounders was applied to show a nonlinear relationship of lipid profile contents with the “ln hazard ratio” of mortality and major cerebro-cardiac events.

Results

The relationship between LDL-C and HDL-C with all-cause mortality were non-linear (non-linear P were 0.004 and <0.001, respectively). The relationship between remnant cholesterol and all-cause mortality was linear (linearity P=0.023). Among men, those in the highest LDL-C level (Q4, LDL-C >114) and those in the lowest HDL-C level (Q1, HDL-C <30) showed a significantly higher risk of all-cause mortality compared to other groups (compared with Q3, LDL-C Q4, HR=1.16, 95% CI: 1.02–1.26, P=0.014; HDL-C Q1, HR=1.14, 95% CI: 1.01–1.31, P=0.041). Female patients in the lowest HDL-C level (Q1, HDL-C <30) showed a significantly higher (compared with Q3, HR=1.14, 95% CI: 1.01–1.31, P=0.028) and those in the highest HDL-C level (Q4, HDL-C >43) showed a significantly lower (compared with Q3, HR=0.74, 95% CI: 0.58–0.98, P=0.019) risk of all-cause mortality.

Conclusion

Determining a universal cut off for components of lipid profile may be misleading and should better be revised. Extreme values (very low or very high) for HDL-C and LDL-C have different effects on cardiovascular outcomes.

Funding Acknowledgement

Type of funding sources: None.
Comparison over 25 years of the burden of familial hypercholesterolemia on hospitalizations for coronary heart disease in a French-Canadian founder population
Authors: Lauziere A , Brisson D , Tremblay G , Bedard S , Khoury E , Gaudet D
Published: October 2022

Background

Over the last 25 years, effective treatments, such as potent statins, ezetimibe and PCSK9 inhibitors have gradually emerged to treat heterozygous familial hypercholesterolemia (FH) and guidelines have been progressively developed internationally to promote FH health surveillance, early diagnosis and optimal clinical management. However, the impact of these measures on the burden of FH is not well documented. Although recent genetic and epidemiological studies suggest that the prevalence of familial hypercholesterolaemia (FH) is approximately twice than initialy expected (1:250) (1), it remains significantly higher among French Canadians (FC) (2,3).

Purpose

To compare over 25 years the management and burden of FH among patients hospitalized for an acute coronary heart disease (CHD) event in a FC founder population with a high prevalence of FH.

Methods

Lipid profiles, cardiovascular risk factors, lipid management and FH status of 2,029 FC patients consecutively hospitalized for an acute CHD event between 2017 and 2022 (2022 Cohort) were compared to those of 2,506 patients with angiographically-confirmed CHD who were admitted between 1995 and 1998 (1998 Cohort) (4). FH status was based on molecular, Simon Broome or FH Canada (5) criteria. Statistical comparisons were made using Chi-square and Student's t-tests for independent samples.

Results

Over a 25-year interval, most patients hospitalized for CHD were men (74.5% in 1998 vs 73.4% in 2022). At the time of admission, 23.0% of CHD patients had LDL-Cholesterol levels >5.0 mmol/L in 1998 compared to 1.3% in 2022 (p<0.001). FH was diagnosed in 9.6% of patients in the 1998 cohort compared to 5.5% in 2022 (p<0.001). Overall, the prevalence of obesity, type 2 diabetes and uncontrolled hypertension tended to be higher in 1998, including in FH (p<0.05). The proportion of FH patients hospitalized for CHD who were treated with a statin or a combination of lipid-lowering agents at the moment of admission was 28.4% in 1998 compared to 61.2% in 2022 (p<0.001). FH patients hospitalized for CHD were significantly older in 2022 than in 1998 (59.03±11.17 vs 50.14±11.32 years; p<0.001). Accordingly, the prevalence of premature CHD requiring an hospitalization significantly decreased from 1998 to 2022 in FH (64.3% vs. 44.1%, p<0.001).

Conclusions

Over a 25-year period, FH patients hospitalized for CHD tend to be older and contribute to a lower proportion of hospitalizations. Despite significant improvement in treatment, FH diagnosis and management remain sub-optimal, even in a founder population where FH represents a significant population burden.

Funding Acknowledgement

Type of funding sources: None.
Correlation of lipoprotein(a) with parameters of lipid profile and other cardiovascular risk factors in patients with familial combined hyperlipidemia
Authors: Andrikou I , Dima I , Lazarou E , Grigoriou K , Skoumas I , Tsioufis K , Vlachopoulos C
Published: October 2022

Background

According to previous studies, Familial Combined Hyperlipidemia (FCH) is related to metabolic syndrome. However, it is unclear whether the presence of increased Lipoprotein (a) [Lp (a)] modifies the characteristics of metabolic syndrome in patients with FCH. Thus, the aim of our study was to identify and compare the components of metabolic syndrome in patients with FCH according to their Lp (a) levels.

Methods

We enrolled 906 patients (592 males, mean age 49±11 years) who fulfilled the FCH criteria, from the outpatient lipid clinic of our hospital.Venous blood samples were obtained for the determination of plasma glucose and lipid profile [i.e., total cholesterol, triglycerides (TG), low and high-lipoprotein cholesterol, (LDL, HDL)], as well as levels of Lp (a). Moreover, information was obtained regarding demographic characteristics and blood pressure (BP) levels. Diagnosis of hypertension was based on BP levels≥140/90 mmHg and metabolic syndrome was defined according to ATP III criteria.

Results

In the total population of 906 patients with FCH, 58% (n=524) had metabolic syndrome. We identified a negative correlation between levels of Lp (a) and TG (r=−0.07, p=0.03) and a positive correlation between levels of Lp (a) and HDL (r=0.08, p=0.02). Also, there was a trend towards a negative correlation between levels of Lp (a) and waist circumference (r=−0.6, p=0.06). Moreover, the group of patients with increased Lp (a) levels (≥30mg/dl, n=289, 32%) compared to those with low Lp (a) levels (<30mg/dl, n=616, 68%)had hypertension in a greater percentage (44% vs 36%, p=0.02), lower levels of TG (278±146 vs 302±172 mg/dl, p=0.04), higher levels of HDL (42±11 vs 39±9 mg/dl, p=0.01) and increased levels of LDL (193±55 vs 185±53 mg/dl, p=0.05), while there was no difference in glucose levels (104±24 vs 102±20 mg/dl, p=0.18). In multiple logistic regression analysis increased Lp (a) levels were independent determinants of lower triglycerides levels (<150mg/dl) (OR 0.59, 95% CI 0.36–0.95), after adjustment for confounding factors.

Conclusions

In patients with FCH, increased Lp (a) is related to lower levels of triglycerides, higher levels of HDL, lower waist circumference levels and increased prevalence of hypertension. Thus, it seems that Lp (a) differentiates the expression of metabolic syndrome characteristics in patients with Familial Combined Hyperlipidemia.

Funding Acknowledgement

Type of funding sources: None.
Lipoprotein (a) and new-onset type-2 diabetes in patients with familial combined hyperlipidemia: a 9 years follow-up study
Authors: Andrikou I , Dima I , Grigoriou K , Lazarou E , Skoumas I , Tsioufis K , Vlachopoulos C
Published: October 2022

Background

Elevated lipoprotein(a) [Lp(a)] levels have been related with increased cardiovascular (CV) risk in the general population. However, its relationship with type-2 diabetes and CV risk in patients with Familial Combined Hyperlipidemia (FCH) is rather unclear. Thus, the aim of our study was to investigate the prognostic role of Lp(a) regarding new-onset type-2 diabetes and major adverse cardiovascular outcomes in patients with FCH.

Methods

485 patients from the outpatient lipid clinic of our hospital (301 males,mean age 49.8±10.8 years, 35%smokers, 16% with diabetes mellitus), without history of CV disease, who fulfilled the FCH criteria participated in the study. Participants were evaluated for a mean follow-up period of 8.9±7.5 years with at least one annual visit. Venous blood samples were obtained at baseline in all patients for the determination of plasma glucose, lipid profile, and levels of Lp(a). All subjects were on lipid-lowering medication (statin and ezetimibe or fibrate) during the follow-up period. The endpoints of our study was new-onset diabetes and the composite of major CV events (coronary artery disease events and stroke).

Results

The incidence of new-onset diabetes during the follow-up period was 10% (n=42). The group of patients with new-onset diabetes (n=42) had lower levels of Lp(a) at baseline compared to those without new-onset diabetes (n=376) (23.8±19.2 vs 32.9±39.5 mg/dl, p=0.01). Also, those with new-onset diabetes had a lower percentage of increased Lp(a) levels (≥30 mg/dl) at baseline compared to those without new-onset diabetes (21% vs 34%). Multiple Cox regression analysis revealed that increased Lp(a) (≥30 mg/dl) is an independent predictor of lower diabetes incidence during the follow-up period (HR 0.39, 95% CI 0.17–0.90), after adjustment for confounding factors. Moreover, the incidence of new-onset CV events in the total population was 6.4% (n=31).In the group of patients with increased Lp(a) levels at baseline (≥30 mg/dl, n=159, 33%) there was a trend towards a greater incidence of CV events during the follow-up period, compared to the group of patients with lower Lp(a) levels (<30 mg/dl, n=326, 67%), although the difference between the two groups was not statistically significant (8.8% vs 5.1%, p=0.1).

Conclusions

In patients with FCH, increased baseline Lp(a) is an independent predictor of lower incidence of new-onset type-2 diabetes after an almost 9 years follow-up period. Moreover, increased Lp(a) seems to convey an increased CV risk also in patients with FCH.

Funding Acknowledgement

Type of funding sources: None.
Comparison of severe hypercholesterolemia patients with and without pathogenic variants
Authors: Nanchen D , Von Kanel T , Ehret G , Brun N , Sudano I , Rodondi N , Rickli H , Girod G , Ballhausen D , Falciano R , Beer J H , Gallino A
Published: October 2022

Introduction

A pathogenic variant causally related to familial hypercholesterolemia (FH) is found in less than half of adults with severe hypercholesterolemia. The characteristics of adults with severe hypercholesterolemia without pathogenic variant have been poorly described, and it remains unclear whether intensive preventive strategies should be recommended. In this study we compared the characteristics of adults with severe hypercholesterolemia with and without pathogenic variant for FH.

Methods

Between November 2020 and February 2022, we recruited individuals older than 16 years with a Dutch Lipid Clinic Network (DLCN) score ≥6 and genotyped LDLR, APOB and PCSK9. Participants were part of the multicenter CATCH study, testing the implementation of genetic cascade screening for FH in Switzerland. All genetic analyses were performed in a single central laboratory. Variants classified as likely pathogenic or pathogenic were interpreted as FH-causing. We also assessed socio-economic status, cardiovascular risk factors, lifestyle behavior, and use of lipid-lowering drugs.

Results

In total, 150 non-related adults with a DLCN score of ≥6 were included, out of whom 62 (41.3%) had genetically confirmed FH. Most variants were found in the LDLR gene (77%). Overall, 70% were using a lipid-lowering drug and 20% were current smokers. Compared to adults with genetically confirmed FH, those without pathogenic variants were older (57.6 vs 50.4 years old), had lower untreated LDL-cholesterol levels (p<0.001), higher triglyceride levels (p=0.032), higher BMI (p=0.014), and had more frequently hypertension (62.5% vs 36.1%). No socio-economic differences were observed. Although adherence to Mediterranean diet was higher among adults without pathogenic variant, they reached less frequently the recommended level of physical activity than adults with genetically confirmed FH (66.2% vs 82.1%). Xanthomas or xanthelasmas, but not corneal arcus, were more frequent among genetically confirmed FH (5.7% vs 20.3%).

Conclusions

Adults with severe hypercholesterolemia and without a pathogenic FH variant had less optimal control of cardiovascular risk factors than genetically confirmed FH. One fifth were smokers and one third of all patients included in this study were not taking any lipid-lowering drugs, regardless of the presence of a pathogenic variant.

Funding Acknowledgement

Type of funding sources: Foundation. Main funding source(s): Swiss Heart Foundation
The association between cholesterol remnants and cardiac structure and function
Authors: Galatius E S , Lassen M C H , Gruntvig Skaarup K , Dyrby Johansen N , Galatius S , Biering T , Boje Jensen G , Schnohr P , Moegelvang R
Published: October 2022

Background

Cardiac disease is the most common cause of death in Europe and is a rising problem globally. Recently, a causal relationship between ischemic heart disease and cholesterol remnants has been suggested by genetic studies. Additionally, new studies have shown that cholesterol remnants were independently related to later development of ischemic disease in individuals free of known heart disease. Finally, in patients suffering from type 1 diabetes, one study demonstrated an association between cholesterol remnants and cardiac function indicating early signs of cardiac pathology.

Purpose

To investigate whether cholesterol remnants are associated with alterations in cardiac structure and function, as evaluated by sensitive echocardiographic measures, in individuals from the general population without known heart disease.

Methods

The study sample consisted of 3,792 participants from a general population cohort without known heart disease. All participants had blood samples withdrawn for analysis and were examined with comprehensive echocardiography including both conventional measurements and two-dimensional speckle tracking analysis. Cholesterol remnant levels were calculated from lipid analyses in non-fasting venous blood samples using the following formula: cholesterol remnants = total-cholesterol − HDL-cholesterol − LDL-cholesterol.

Results

In multivariable analyses increasing levels of cholesterol remnants were associated with significant alterations in cardiac function, demonstrated as a decrease in left ventricular ejection fraction (β=−0.686, P=0.001), a decrease in E/A ratio (β=−0.109, P<0.001) and a decrease in global longitudinal strain (β=−1.195 P=0.014) (Figure 1). The multivariable model was adjusted for age, sex, body mass index, hypertension, diabetes and smoking status. This association was significantly stronger than the association with cardiac alterations and LDL levels with the most significant difference regarding LVEF (cholesterol remnants: β=−0.158, P<0.001) and (LDL: β=−0.016, P=0.353). Additionally, increasing levels of cholesterol remnants were associated with alterations in cardiac structure (IVSd, LVIDd, LVPWd, LVMi and RWT) in the univariable analysis, but these associations were attenuated after multivariable adjustment.

Conclusion

In a general population sample without known heart disease, alterations in cardiac function expressed as both impaired systolic and impaired diastolic function were present with increasing levels of cholesterol remnants. This association was stronger than the association between the cardiac alterations and LDL-cholesterol levels. The findings support the need for testing treatment options aimed specifically at cholesterol remnants, also in the general population.

Funding Acknowledgement

Type of funding sources: None.
The effect of bariatric surgery on circulating levels of lipoprotein(a): a systematic review and meta-analysis
Authors: Jamialahmadi T , Reiner Z , Alidadi M , Kroh M , Almahmeed W , Ruscica M , Sirtori C , Santos R D , Banach M , Sahebkar A
Published: October 2022

Background

Obesity, and especially severe obesity, are strongly related to higher risk of atherosclerotic cardiovascular disease (ASCVD) morbidity and mortality. Bariatric surgery is an effective weight loss therapy for people with severe obesity and weight-related co-morbid conditions. Elevated plasma level of lipoprotein(a) [Lp(a)] is causally associated with ASCVD.

Purpose

The aim of the present meta-analysis was to analyze whether bariatric surgery could influence Lp(a) concentrations.

Methods

A systematic literature search in PubMed, Scopus, Embase, and Web of Science was performed from inception to May 1st, 2021. A random-effects model and the generic inverse variance weighting method were used to compensate for the heterogeneity of studies in terms of study design, treatment duration, and the characteristics of the studied populations. A random-effect meta-regression model was used to explore the association with an estimated effect size. Evaluation of funnel plot, Begg's rank correlation and Egger's weighted regression tests were used to assess the presence of publication bias in the meta-analysis.

Results

Meta-analysis of 13 studies including 1,551 patients showed a significant decrease of circulating Lp(a) after bariatric surgery (SMD: −0.438, 95% CI: −0.702, −0.174, p<0.001, I2: 94.05%). The results of meta-regression did not indicate any significant association between the changes in Lp(a) and duration of follow up from surgery, reduction in body mass index, or baseline Lp(a) concentration. The reduction in circulating Lp(a) was robust in the leave-one-out sensitivity analysis.

Conclusions

Based on the results of the Mata-analysis we showed that bariatric surgery significantly decreases circulating Lp(a) concentrations.

Funding Acknowledgement

Type of funding sources: None.
Effect on cholesterol remnants and residual lipid risk with PCSK9 inhibitors: the LIPID-REAL Registry
Authors: Fernandez Del Olmo R , Cordero A , Cortez Quiroga G , Romero-Menor C , Facila L , Rondan J , Bello Mora M C , Sandin M , Valle A , Freixa R , Blanch P , Baneras J , Rodriguez-Manero M , Gonzalez-Juanatey J R
Published: October 2022

Background

Monoclonal antibodies that inhibit the proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDLc) by 55%, regardless of baseline treatments. Nonetheless, the effect of other lipid parameters, as cholesterol remnants or, the so-called residual lipid risk, are unknown.

Methods

Multicenter and retrospective registry of patients treated with PCSK9 inhibitors from 14 different hospitals from Spain. Before and on-treatment lipid parameters were recorded. Cholesterol remnants were calculated by the equation: total cholesterol minus LDLc minus HDLc and values ≥30 were considered high. Residual lipid risk was estimated by 1) the estimation of LDL particle size, by the triglycerides/HDLc ratio (TG/HDL) and values <2 were assumed as low and dense LDL particles; 2) total cholesterol/HDLc (TC/HDL) and values >3 were considered high; and; 3) the triglycerides-to-glucose (TG/Gluc) index, obtained as the natural logarithm of (triglycerides * glucose/2)

Results

A total of 652 patients were analyzed, mean age 60.0 (10.5) years and 161 (24.69%) women. Baseline LDLc was 149.2 (49.9) mg/dl, cholesterol remnants 29.9 (20.3) mg/dl, TG/HDL 3.9 (4.1), TC/HDL 4.9 (1.9) and TG/Gluc index 8.9 (0.7). Most patients (92.3%) were on statins; 54.8% with ezetimibe, 8.5% with fibrates.

Evolocumab was initiated in 318 (56.6%) patients; 229 (40.7%) alirocumab 75 mg and 15 (2.7%) alirocumab 150 mg. Median time to second blood determination were 187.5 (IQR 101–242) days. Mean on-treatment LDLc was 67.46 (45.78) mg/dl what represented a 55% reduction. As shown in the figure, significant reduction in cholesterol remnants (p=0.017), TG/HDL ratio (p=0.020), TC/HDL ratio (p<0.001) and TG/Gluc index (p<0.001). The percentage of patients with remnants >30 mg/dl decreased: 34.62% to 30.07 (p<0.01). Significant reductions were also observed in the percentage of patients with TG/HDL >2 (71.25% to 61.98%; p<0.01) or TC/HDL >3 (94.28% to 38.97%; p<0.01)

Conclusions

This multicenter and retrospective registry of real-world patients treated with PCSK9 inhibitors demonstrates a positive effect on cholesterol remnants and lipid-residual risk beyond LDLc reductions.

Funding Acknowledgement

Type of funding sources: None.
Left ventricular remodeling in aortic stenosis patients referred for surgical aortic valve replacement
Authors: R Santos R , Abecasis J , Maltes S , Mendes G S , Oliveira L , Horta E , Guerreiro S , Freitas P , Ferreira A , Ribeiras R , Andrade M J , Cardim N , Gil V , Mendes M , Neves J P
Published: October 2022

Background

Left ventricular (LV) hypertrophy is a common expected finding in aortic stenosis (AS) patients. Cardiac magnetic resonance (CMR) plays an important role as a non-invasive method for determining LV mass and volume, and to characterize the LV remodeling response in AS.

Aim

To assess the prevalence, to describe the patterns and evolution of LV remodeling (by CMR) in AS patients referred for surgical aortic valve replacement (AVR).

Methods

Single-center prospective cohort of 132 consecutive patients (73 years [68–77 years], 49% men] with severe AS: mean transaortic pressure gradient (AVmean): 61±1.5 mmHg; aortic valve area (AVA): 0.7±0.1 cm2, referred for surgical AVR, with no previous history of ischemic cardiomyopathy. Before surgery, all patients underwent electrocardiogram, complete transthoracic echocardiogram (TTE) and CMR for LV assessment and tissue characterization (mean LV indexed mass [LVMi]: 80.3±26.5 g/m2; mean end-diastolic LV indexed volume [LVEDVi]: 84.4±24.5 mL/m2 and median geometric remodeling ratio [M/V]: 0.95 g/mL [IQR 0. 81–1.08 g/mL]). Patterns of LV remodeling were investigated before and after AVR by CMR measurements of LVMi, LVEDVi and M/V. Besides normal LV ventricular structure, four other patterns were considered: concentric remodeling, concentric hypertrophy, eccentric hypertrophy, and adverse remodeling (Figure 1).

Results

Overall, 43% (n=58) of the patients had concentric hypertrophy, 30% (n=40) concentric remodeling, 22% (n=29) normal ventricular geometry, 4% (n=5) eccentric hypertrophy and in two patients we observed an adverse remodeling pattern. AVR was performed in 80 patients. At the 3rd to 6th month post-AVR assessment, LV remodeling changed to: normal ventricular geometry in 46%, concentric remodeling in 31%, concentric hypertrophy in 19%, eccentric hypertrophy in 3% and adverse remodeling in only one patient (Figure 1).

Conclusions

In this group of patients with severe aortic stenosis, concentric hypertrophy was not the sole pattern of LV remodeling and two out of every five still presented a normal ventricular geometry and mass as assessed by CMR. LV response was dynamic after AVR which stands for complex and multifactorial interaction in these group of patients despite similar valvular pathophysiology and therapeutic intervention.

Funding Acknowledgement

Type of funding sources: None.
Effect of SLCO1B1 genotypes on statin intolerance and response to statins
Authors: Ghelani R , Davis L , Neves E , Khaled M , Khan T Z
Published: October 2022

Background

Statins are a cornerstone therapy for management of hypercholesterolaemia in primary and secondary prevention of cardiovascular disease, however there is individual variation regarding efficacy of therapy and adverse side-effects experienced.

Purpose

Polymorphisms of the SLCO1B1 gene have shown correlation with the risk of statin side-effects and efficacy of treatment, however in real-world clinical practice, their utility remains to be established.

Methods

We carried out retrospective multiple linear regression analysis using robust standard errors of 129 individuals undergoing genetic testing for the SLCO1B1 polymorphisms rs4149056 and rs2306283 to investigate for an association to statin side effects and efficacy respectively. In addition, logistic regressions which account for the binary nature of the outcomes were performed. The rs4149056 gene has 3 outcomes: T/T (considered least associated with statin intolerance), C/C (considered most associated with statin intolerance) and T/C (considered intermediately associated with statin intolerance). The rs2306283 gene has 3 outcomes: A/A (considered least associated with statin response), G/G (considered most associated with statin response) and A/G (considered intermediately associated with statin response).

Results

According to multiple regression and logistic regression analyses SLCO1B1 rs4149056 genotypes (C/C and T/C relative to the base type T/T) do not predict the incidence of myalgia, myopathy, creatine kinase rise, liver function derangement or gastrointestinal side effects at 5% significance. SLCO1B1 rs2306283 (G/G and A/G relative to the base type A/A) do not predict LDL response to statins (p-values 0.33 and 0.52 respectively).

Conclusions

The presence of rs4149056 C/C and T/C genotypes was not associated with an increased risk of statin side-effects. Similarly rs2306283 genotypes did not correlate with the efficacy of statin treatment. These genotype predictors were primarily based on Simvastatin – an earlier generation statin, whereas the majority of the patients in this cohort were treated with more contemporary and widely used statins such as Atorvastatin and Rosuvastatin. We therefore conclude that these genotypic markers may have limited application in modern day clinical practice and that substantial investment of limited resources towards them may not be justified.

Funding Acknowledgement

Type of funding sources: None.
Persistence to long-term PCSK9 inhibitors treatment and its effectiveness in familial hypercholesterolemia: data from the SAFEHEART study
Authors: Alonso R , Arroyo-Olivares R , Muniz-Grijalvo O , Diaz-Diaz J L , Sanchez Munoz-Torrero J , Zambon D , Fuentes-Jimenez F , Romero M J , Aguado R , Alvarez-Banos P , Manas M D , Arrieta F , Gonzalez-Bustos P , Argueso R , Mata P
Published: October 2022

Background

Most patients with heterozygous familial hypercholesterolemia (FH) do not achieve current LDL-C goals proposed by European guidelines with conventional lipid-lowering therapy (LLT). Chronic use of PCSK9 inhibitors (PCSK9i) have shown to reduce LDL-C levels up to 61% on top of statins. Persistence to chronic LLT is important to reduce the burden of atherosclerotic cardiovascular disease (ASCVD).

Purpose

To analyze persistence and effectiveness of PCSK9i in clinical practice setting in FH patients from the SAFEHEART register with long-term follow-up.

Methods

SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of FH. Follow-up is carried out every year through a standardized phone-call to collect clinical conditions, persistence to medications, lipid profile, and cardiovascular events. This study analyses subjects ≥18 years of age on stable LLT who have received PCSK9i.

Results

696 individuals (46% females), median age 56.4 years (IQR 49–66) started with PCSK9i (49% alirocumab and 51% evolocumab). Out of them 38% had history of ASCVD, and 89% were on maximum LLT. Median LDL-C at the moment of starting PCSK9i was 145 mg/dL (IQR, 123–177), representing a poor 2016 & 2019 ESC/EAS guidelines achievement (3% and 0.1% respectively). After a median follow-up of 3.7 years (IQR, 2.3–4.8), 669 patients (96%) remained on PCSK9i treatment during entire follow-up. Only 27 patients (4%) discontinued, 5 temporarily (0.7%) and 22 permanently (3.2%). Most common reasons for PCSK9i treatment interruption were medical decision (n=6), adverse event (AE) (n=5), patient decision not related with AE (n=5) and comorbidity (n=5). Median time to permanent discontinuation was 15 months (IQR, 4–33).

Median LDL-C levels observed and % of LDL-C reduction obtained after 1 year of treatment and in the last follow-up visit were: 63 mg/dL (IQR, 43–88), 61 mg/dL (IQR, 44–82), 57.6% (IQR, 39.5–69) and 58% (IQR, 44–68), respectively. 2016 ESC/EAS guidelines LDL-C goals was achieved by 70% of patients at year 1 and 77% in the last follow-up visit after the introduction of PCSK9i (p<0.001). 2019 ESC/EAS goals were achieved by 44.5% and 48% (p=0.1).

Conclusion

Long-term persistence to PCSK9i treatment in FH patients is very high (96%) and reasons for discontinuation are diverse. This study shows that COVID-19 pandemic did not affected persistence to treatment. Effectiveness in LDL-C reduction and LDL-C goal achievement improved significantly with introduction of PCSK9i in clinical practice setting.

Funding Acknowledgement

Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): AMGEN
Simulation of bempedoic acid in the lipid-lowering treatment pathway using the European contemporary SANTORINI cohort of high- and very high-risk patients
Authors: Ray K K , Catapano A L , Diamand F , Wolowacz S , Haq I , Bilitou A
Published: October 2022

Background

Lowering LDL-C treatment goals in the 2019 ESC/EAS guidelines necessitates greater use of combination therapies (1). Cost of PCSK9 inhibitors (PCSK9i) and efficacy of ezetimibe alone as add on therapies limit population level achievement of LDL-C goals.

Purpose

This simulation study assessed the addition of oral bempedoic acid (BA) to ezetimibe in the treatment pathway in a real-world cohort of patients in order to assess the proportion of patients who might reach goal.

Methods

SANTORINI is a cohort study of European patients at high or very-high CV risk. Patients who were receiving any known LLT regimen with available data on LDL-C at baseline were eligible for this analysis. For patients not at risk-based LDL-C goals, the following treatment algorithm was applied (Figure 1), first the addition of ezetimibe and subsequently BA for those on statins, or addition of BA for those on ezetimibe and not at goal. Patients on PCSK9i remained in the cohort but no simulation was done. LDL-C reductions associated with ezetimibe and BA treatment were based on probabilistic distributions sourced from clinical trial efficacies based on prior studies (2–3). The effect of treatment on LDL-C levels was simulated through a Monte Carlo simulation run 10,000 times. No statin intensification was simulated as we assumed statin therapy was at maximum tolerated dose.

Results

At baseline (N=6252), mean age was 66 years and mean baseline LDL-C was 80.6 mg/dL with 1444 patients (23%) at goal; 93% (n=5797) were very high risk and 7% (n=455) high risk, of whom 84% (n=5227) were on statins, 23% (n=1447) on ezetimibe and 9% (n=546) on PCSK9i. Out of 4486 patients entering the simulation, 3419 received ezetimibe add-on with a third of those predicted to be achieving their risk-based goal (32%, n=1078/3419). Of those on ezetimibe and not at goal, the addition of BA would be predicted to result in another 36% goal achievement (n=1218/3408). Overall, the number of patients at goal would be expected to increase from 1444 (23%) at baseline to 2522 (40%) and 3740 (60%) after addition of ezetimibe and BA, sequentially. The mean LDL-C for the whole cohort would be expected to fall through this pathway from 80.6 mg/dL at baseline to 69.2 mg/dL and 61.1 mg/dL, respectively.

Conclusion

Few patients in the SANTORINI cohort were at goal at baseline and few would have LDL-C eligible for PCSK9i use. Optimising use of ezetimibe and BA after statins in the ESC/EAS 2019 LLT pathway could result in significantly more patients attaining lipid goals with likely additional health benefits.

Funding Acknowledgement

Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe GmbH
Worldwide comparative efficacy of nutraceuticals on lipid profile. an updated systematic review and network meta-analysis
Authors: Osadnik T , Golawski M , Lewandowski P , Morze J , Osadnik K , Pawlas N , Lejawa M , Jakubiak G , Mazur A , Schwingshackl L , Gasior M , Banach M
Published: October 2022

Introduction

In case of patients without indications to statin therapy, those being close to the target and especially with statin intolerance, nutraceuticals might be an additional option of hypercholesterolemia therapy. Despite a large number of nutraceuticals, little is known on their comparative efficacy due to the paucity of head-to-head comparisons. We aimed to assess the lipid-lowering effect of various nutraceuticals by means of network meta-analysis.

Methods

PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were carefully searched to identify eligible studies to the meta-analysis. We included parallel or crossover randomized clinical trials (RCT), comparing head-to-head or to placebo/no intervention, the following nutraceuticals: a) artichoke, b) berberine, c) bergamot, d) garlic, e) green tea extract, f) plant sterols and stanols, g) policosanols, h) red yeast rice (RYR), i) silymarin, j) spirulina. We did not include soy protein, fiber, and lupin trials, as unlike other nutraceuticals they are in fact dietary interventions. Due to strikingly inconsistent results of policosanols RCTs carried out in Cuba and other countries, we excluded Cuban trials from main analysis.

Results

From the initially identified 4151 articles we finally included 131 studies. As some studies reported clinically different groups separately, they were split and finally we included 136 records, 134 with data on total cholesterol (TC), 125 with data on low-density cholesterol (LDL-C), 127 that provided information on high-density cholesterol (HDL-c) and 129 that included data regarding triglycerides (TG). Pooled studies covered data for 6755 patients randomized to nutraceutical arms and 6370 randomized to receive placebo/no intervention. For reducing TC bergamot, was identified as the most effective approach (P-score = 1.0) followed by RYR (0.90) and berberine (0.76). For increasing HDL-C, bergamot (0.98), berberine (0.85), and RYR (0.77) were the most effective. While evaluating LDL-C reduction, bergamot (1.00) and RYR (0.90) showed the highest reduction efficacy. Reducing effect of investigated nutraceuticals on TG levels was the highest for bergamot (1.00) and RYR (0.78). Majority of reports regarding Cuban policosanol trials implicated very high effectiveness of those nutraceuticals, which was in contrast to trials conducted in other countries

Conclusions

Bergamot, berberine, and RYR seemed to be most effective nutraceuticals in terms of lipid-lowering efficacy. Alleged high effectiveness of policosanols was not confirmed in our analysis. This analysis might support the physicians and patients' decisions to use only those nutraceuticals of confirmed efficacy.

Funding Acknowledgement

Type of funding sources: Public Institution(s). Main funding source(s): Medical University of Silesia, Katowice