A genetic risk score predicts coronary artery disease in familial hypercholesterolaemia: enhancing the precision of risk assessment.

Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD); however, risk prediction and stratification remain a challenge. Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk. The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.3-8.2; P = .009] and mutation-negative FH patients (OR = 1.8; 95% CI = 1.0-3.3; P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.

Improved Glycemic Outcomes With Diabetes Technology Use Independent of Socioeconomic Status in Youth With Type 1 Diabetes.

OBJECTIVE: Technology use in type 1 diabetes (T1D) is impacted by socioeconomic status (SES). This analysis explored relationships between SES, glycemic outcomes, and technology use. RESEARCH DESIGN AND METHODS: A cross-sectional analysis of HbA1c data from 2,822 Australian youth with T1D was undertaken. Residential postcodes were used to assign SES based on the Index of Relative Socio-Economic Disadvantage (IRSD). Linear regression models were used to evaluate associations among IRSD quintile, HbA1c, and management regimen. RESULTS: Insulin pump therapy, continuous glucose monitoring, and their concurrent use were associated with lower mean HbA1c across all IRSD quintiles (P < 0.001). There was no interaction between technology use and IRSD quintile on HbA1c (P = 0.624), reflecting a similar association of lower HbA1c with technology use across all IRSD quintiles. CONCLUSIONS: Technology use was associated with lower HbA1c across all socioeconomic backgrounds. Socioeconomic disadvantage does not preclude glycemic benefits of diabetes technologies, highlighting the need to remove barriers to technology access.

Socioeconomic status and diabetes technology use in youth with type 1 diabetes: a comparison of two funding models.

Background: Technology use, including continuous glucose monitoring (CGM) and insulin pump therapy, is associated with improved outcomes in youth with type 1 diabetes (T1D). In 2017 CGM was universally funded for youth with T1D in Australia. In contrast, pump access is primarily accessed through private health insurance, self-funding or philanthropy. The study aim was to investigate the use of diabetes technology across different socioeconomic groups in Australian youth with T1D, in the setting of two contrasting funding models. Methods: A cross-sectional evaluation of 4957 youth with T1D aged <18 years in the national registry was performed to determine technology use. The Index of Relative Socio-Economic Disadvantage (IRSD) derived from Australian census data is an area-based measure of socioeconomic status (SES). Lower quintiles represent greater disadvantage. IRSD based on most recent postcode of residence was used as a marker of SES. A multivariable generalised linear model adjusting for age, diabetes duration, sex, remoteness classification, and location within Australia was used to determine the association between SES and device use. Results: CGM use was lower in IRSD quintile 1 in comparison to quintiles 2 to 5 (p<0.001) where uptake across the quintiles was similar. A higher percentage of pump use was observed in the least disadvantaged IRSD quintiles. Compared to the most disadvantaged quintile 1, pump use progressively increased by 16% (95% CI: 4% to 31%) in quintile 2, 19% (6% to 33%) in quintile 3, 35% (21% to 50%) in quintile 4 and 51% (36% to 67%) in the least disadvantaged quintile 5. Conclusion: In this large national dataset, use of diabetes technologies was found to differ across socioeconomic groups. For nationally subsidised CGM, use was similar across socioeconomic groups with the exception of the most disadvantaged quintile, an important finding requiring further investigation into barriers to CGM use within a nationally subsidised model. User pays funding models for pump therapy result in lower use with socioeconomic disadvantage, highlighting inequities in this funding approach. For the full benefits of diabetes technology to be realised, equitable access to pump therapy needs to be a health policy priority.

Cascade testing for elevated lipoprotein(a) in relatives of probands with high lipoprotein(a).

Objective: Elevated lipoprotein(a) [Lp(a)] is a common inherited condition associated with cardiovascular disease. This study investigated whether cascade testing for Lp(a) was effective in detecting new cases of elevated Lp(a) in families. Methods: Relatives from adult probands with Lp(a) concentration ≥100 mg/dL were tested for elevated Lp(a) (≥50 mg/dL) via a cascade testing program in a tertiary hospital setting. The prevalence and yield of detecting new cases of elevated Lp(a) among the relatives were assessed. Results: Of the 83 probands, 43.4% had familial combined hyperlipidemia (FCHL) and 34.9% common hypercholesterolemia (CH). Among 182 relatives tested (151 adults and 31 children), elevated Lp(a) was found in 68.1%, with 32.9% having Lp(a) between 50 and 99 mg/dL and 35.2% having Lp(a) ≥100 mg/dL. One new case of elevated Lp(a) ≥50 mg/dL was identified for every 1.5 relatives tested and 1 new case of elevated Lp(a) ≥100 mg/dL for every 2.8 relatives tested. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) >150 mg/dL compared with those with Lp(a) between 100 and 150 mg/dL (81.1% vs. 55.5%; P = 0.001). The concordance rates (kappa coefficient) for the detection of elevated Lp(a) with FCHL and CH were 34.8% (0.026) and 53.2% (0.099), respectively. Conclusion: Cascade testing for elevated Lp(a) from affected probands with phenotypic dyslipidemia is highly effective in identifying new cases of high Lp(a) in families. The yield of detecting elevated Lp(a) is greater when probands have higher levels of Lp(a) and exceeds the detection of relatives with FCHL and CH.

A variant in the fibronectin (FN1) gene, rs1250229-T, is associated with decreased risk of coronary artery disease in familial hypercholesterolaemia.

BACKGROUND: Increased risk of coronary artery disease (CAD) in familial hypercholesterolaemia (FH) is modified by factors beyond defects in the low-density lipoprotein receptor pathway. The rs1250229-T single nucleotide polymorphism (SNP) in the FN1 gene is associated with CAD in genome-wide association studies and is in linkage disequilibrium with another SNP (rs1250259-T) in FN1 that is associated with decrease fibronectin secretion. OBJECTIVE: We investigated whether rs1250229-T was also associated with prevalent CAD in patients with genetically confirmed FH. METHODS: We collected clinical data from 256 patients with genetically confirmed FH. The FN1 rs1250229 SNP was genotyped on a SEQUENOM platform. The association between rs1250229-T and prevalent CAD was assessed using simple and multiple regression analyses. RESULTS: In patients with FH, the FN1 rs1250229-T (minor) allele was a significant negative predictor of prevalent CAD (odds ratio [OR] 0.353; 95% confidence interval [CI] 0.193 - 0.647; P = 0.001). FN1 rs1250229-T remained a significant predictor of prevalent CAD after adjusting for age, sex, obesity, hypertension, smoking status and lipoprotein(a) concentration (OR 0.200; 95% CI 0.091 - 0.441; P < 0.001). CONCLUSION: The FN1 rs1250229-T allele is inversely associated with CAD in patients with genetically confirmed FH, independently of traditional risk factors. While this finding requires replication, it suggests that the biology of fibronectin may contribute to variation in the risk of CAD in FH.

Cascade testing for elevated lipoprotein(a) in relatives of probands with familial hypercholesterolaemia and elevated lipoprotein(a).

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) and elevated plasma lipoprotein(a) [Lp(a)] are inherited conditions independently associated with atherosclerotic cardiovascular disease. This study investigated the detection of new cases of elevated Lp(a) during cascade testing of relatives of probands with a definite diagnosis of FH and elevated Lp(a) (≥50 mg/dL). METHODS: Relatives from 62 adult probands were tested for FH genetically and for elevated Lp(a) using an immunoassay. The prevalence and yield of new cases of FH with or without elevated Lp(a) among relatives and the association between the detection of elevated Lp(a) and the Lp(a) concentration of the probands were assessed. RESULTS: Among 162 relatives tested (136 adults and 26 children), the prevalence of FH and elevated Lp(a) was 60.5% and 41.4%, respectively: FH alone was detected in 31.5%, elevated Lp(a) alone in 12.3%, FH with elevated Lp(a) in 29.0%, and neither disorder in 27.2% of the relatives. Cascade testing detected a new case of FH, elevated Lp(a) and FH with elevated Lp(a) for every 1.5, 2.1 and 3.0 relatives tested, respectively. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) ≥100 mg/dL compared with those from probands with Lp(a) between 50 and 99 mg/dL (53% vs 34%, p = 0.018). The concordance between the detection of FH and elevated Lp(a) was 56.2% (kappa statistic 0.154), indicating a poor agreement. CONCLUSIONS: A dual approach to cascade testing families for FH and high Lp(a) from appropriate probands can effectively identify not only new cases of FH, but also new cases of elevated Lp(a) with or without FH. The findings accord with the co-dominant and independent heritability of FH and Lp(a).

Association of genetic variation in the natriuretic peptide system with cardiovascular outcomes.

Polymorphisms within individual natriuretic peptide genes have been associated with risk factors for cardiovascular disease, but their association with clinical outcomes was previously unknown. This study aimed to investigate the association between genetic variants in key genes of the natriuretic peptide system with cardiovascular outcomes in patients with coronary artery disease. Coronary disease patients (n=1810) were genotyped for polymorphisms within NPPA, NPPB, NPPC, NPR1 and NPR2. Clinical history, natriuretic peptide concentrations, echocardiography, all-cause mortality and cardiovascular hospital readmissions were recorded over a median 2.8 years. Minor alleles of NPPA rs5068, rs5065 and rs198358 were associated with less history of hypertension; minor alleles of NPPA rs5068 and rs198358 was also associated with higher circulating natriuretic peptide levels (p=0.003 to p=0.04). Minor alleles of NPPB rs198388, rs198389, and rs632793 were associated with higher circulating BNP and NT-proBNP (p=0.001 to p=0.03), and reduced E/E(1) (p=0.011), or LVESVI (p=0.001) and LVEDVI (p=0.004). Within NPPC, both rs11079028 and rs479651 were associated with higher NT-proBNP and CNP (p=0.01 to p=0.03), and rs479651 was associated with lower LVESVI (p=0.008) and LVEDVI (p=0.018). NPR2 rs10758325 was associated with smaller LVMI (p<0.02). A reduced rate of cardiovascular readmission was observed for minor alleles of NPPA rs5065 (p<0.0001), NPPB rs632793 (p<0.0001), rs198388 (p<0.0001), rs198389 (p<0.0001), and NPR2 rs10758325 (p<0.0001). There were no associations with all-cause mortality. In established cardiovascular disease, natriuretic peptide system polymorphisms were associated with natriuretic peptide levels, hypertension, echocardiographic indices and the incidence of hospital readmission for cardiovascular events.

CYP1A1 MSPI (T6235C) gene polymorphism is associated with mortality in acute coronary syndrome patients.

1. The CYP1A1 T6235C polymorphism (rs4646903) gene polymorphism has been linked to the development of coronary heart disease and cigarette smoking-related lung cancer. The present study investigated associations between survival in acute coronary syndromes (ACS), smoking and the CYP1A1 T6235C polymorphism. 2. Patients with ACS (n = 1251) were genotyped for the CYP1A1 T6235C polymorphism. Patients had a mean age of 67.0 years, 69.8% were male and follow up occurred over a median of 1.9 years. 3. Overall genotype frequencies were CC 2.2%, TC 21.7% and TT 76.1%. The CC genotype was associated with baseline characteristics of a higher incidence of Type 2 diabetes (P = 0.017), elevated body mass index (P = 0.001) and younger age (P = 0.045). Patients with the CC genotype had significantly worse survival than TT/TC patients (P = 0.014), independent of ethnicity and established clinical risk factors. When survival was stratified by smoking history, the T6235C genotype was particularly associated with mortality in past or current smokers (mortality 23.5 vs 9.4% in CC and TT/TC patients, respectively; P = 0.019) compared with those who had never smoked (mortality 11.1 vs 11.5% in CC and TT/TC patients, respectively; P = 0.853). 4. The results indicate that the homozygous CYP1A1 6235C genotype is associated with greater mortality following the onset of ACS, independent of ethnicity and clinical risk factors, but related to smoking history.

Coronary artery disease and the risk-associated LPA variants, rs3798220 and rs10455872, in patients with suspected familial hypercholesterolaemia.

BACKGROUND: The rs3798220 and rs10455872 single nucleotide polymorphisms (SNPs) in LPA are associated with increased plasma concentrations of lipoprotein(a) [Lp(a)] and coronary artery disease (CAD). METHODS: We investigated the association between rs3798220 and rs10455872 and prevalent CAD in 763 patients with suspected familial hypercholesterolaemia (FH). The rs3798220 and rs10455872 SNPs in LPA were detected using a SEQUENOM platform. RESULTS: Both LPA SNPs were significantly associated with CAD, but only rs3798220 after adjustment for other risk factors (odds ratio [OR] 2.05; 95% confidence interval [CI] 1.02-4.12; p = 0.045), and neither after adjustment for Lp(a) concentrations. Both SNPs were positively and independently associated with increased Lp(a) (rs3798220: OR 1.27; 95% CI 0.96-1.57; p < 0.001. rs10455872: OR 1.41; 95% CI 1.24-1.58; p < 0.001). Plasma concentrations of Lp(a) were independently associated with prevalent CAD (OR 1.28; 95% CI 1.08-1.52, p = 0.005) after adjustment for LPA SNPs and other cardiovascular risk factors. While both the rs3798220 and rs10455872 SNPs were associated with Lp(a) concentrations and prevalent CAD in patients with suspected FH, this was not independent of Lp(a) concentration. CONCLUSIONS: Quantification of Lp(a) is more likely to be useful than assessment of these Lp(a)-associated SNPs to augment CAD risk prediction.

To test, or not to test: that is the question for the future of lipoprotein(a).

INTRODUCTION: Lipoprotein(a) [Lp(a)] is a potent, highly heritable and common risk factor for atherosclerotic cardiovascular disease (ASCVD). Evidence for a causal association between elevated Lp(a) and ASCVD has been provided by large epidemiological investigations that have demonstrated a curvilinear association with increased risk, as well as from genetic examinations and cellular and transgenic animal studies. Although there are several therapies available for lowering Lp(a), none are selective for Lp(a) and there is no clinical trial data that has specifically shown that lowering Lp(a) reduces the risk of ASCVD. Hence, screening for elevated Lp(a) is not routinely incorporated into clinical practice. Areas covered: This paper reviews the current evidence supporting the causal role of Lp(a) in the primary and secondary prevention of ASCVD, screening approaches for high Lp(a), current guidelines on testing Lp(a), and barriers to the routine screening of elevated Lp(a) in clinical practice. Expert opinion: At present, there is a moderate level of evidence supporting the routine screening of elevated Lp(a). Current guidelines recommend testing for elevated Lp(a) in individuals at intermediate or high risk of ASCVD.

Value of Measuring Lipoprotein(a) During Cascade Testing for Familial Hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] are inherited disorders associated with premature atherosclerotic cardiovascular disease (ASCVD). Cascade testing is recommended for FH, but there are no similar recommendations for elevated Lp(a). OBJECTIVES: This study investigated whether testing for Lp(a) was effective in detecting and risk stratifying individuals participating in an FH cascade screening program. METHODS: Family members (N = 2,927) from 755 index cases enrolled in SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) were tested for genetic FH and elevated Lp(a) via an established screening program. Elevated Lp(a) was defined as levels ≥50 mg/dl. The authors compared the prevalence and yield of new cases of high Lp(a) in relatives of FH probands both with and without high Lp(a), and prospectively investigated the association between elevated Lp(a) and ASCVD events among family members. RESULTS: Systematic screening from index cases with both FH and elevated Lp(a) identified 1 new case of elevated Lp(a) for every 2.4 screened. Opportunistic screening from index cases with FH, but without elevated Lp(a), identified 1 individual for 5.8 screened. Over 5 years' follow-up, FH (hazard ratio [HR]: 2.47; p = 0.036) and elevated Lp(a) (HR: 3.17; p = 0.024) alone were associated with a significantly increased risk of experiencing an ASCVD event or death compared with individuals with neither disorder; the greatest risk was observed in relatives with both FH and elevated Lp(a) (HR: 4.40; p < 0.001), independent of conventional risk factors. CONCLUSIONS: Testing for elevated Lp(a) during cascade screening for FH is effective in identifying relatives with high Lp(a) and heightened risk of ASCVD, particularly when the proband has both FH and elevated Lp(a).

Angiotensin-converting enzyme 2 A1075G polymorphism is associated with survival in an acute coronary syndromes cohort.

BACKGROUND: Polymorphisms of the angiotensin-converting enzyme 2 (ACE2) gene, which is located on the X chromosome, have been associated with hypertension and left ventricular hypertrophy in previous studies. We tested the hypothesis that the rare allele of an ACE2 gene polymorphism was associated with risk factors for and adverse outcome after acute coronary syndrome (ACS) events. METHODS: Patients (n = 1,042) were recruited after admission for an ACS event and were genotyped for the A1075G polymorphism of the angiotensin-converting enzyme 2 gene. This genetic marker was tested for association with baseline measurements, echocardiographic measurements, and clinical outcome, over a median 2.19 years follow-up. As the ACE2 gene is X-linked, analyses were performed separately for males and females. Patients were predominantly of European ethnicity (90.1%). RESULTS: The A1075 allele was significantly associated with covariate-adjusted mortality in male patients (hazard ratio 1.95, 95% CI 1.10-3.46, P = .047) but not unadjusted (hazard ratio 1.14, 95% CI 0.736-1.76, P = .56). The G1075 (P < .035) allele was more frequent in patients of Maori compared to European ancestry. E/E', an echocardiographic index of left ventricular diastolic function and filling pressure, was higher in males in the A1075 group (G allele group 10.5 [95% CI 10.0-11.0], A allele group 11.4 [95% CI 10.8-12.1], P = .024). A1075 genotype was significantly associated with male survival in the absence of (mortality: A 12.8%, n = 39; G 29.2%, n = 48; P = .037) but not in the presence of beta-blocker treatment (mortality: A 13.5% n = 273; G 8.2% n = 304, P = nonsignificant). CONCLUSIONS: The A1075 allele was associated with covariate-adjusted mortality in male patients.

Is Lipoprotein(a) Ready for Prime-Time Use in the Clinic?

Lipoprotein (a) is a low-density lipoprotein-like particle covalently bound to a glycoprotein called apolipoprotein(a) that is under potent genetic control. Plasma levels of lipoprotein (a) vary by up to 1000-fold among individuals, with 1 in 4 having levels that increase the risk of atherosclerotic cardiovascular disease. New evidence supports a causal role for lipoprotein (a) in atherosclerotic cardiovascular disease and aortic valve stenosis. Individuals with elevated lipoprotein (a) have a high life-time burden of atherosclerotic cardiovascular disease. This notion is important for coronary prevention. But is lipoprotein (a) ready for prime-time use in coronary prevention clinics?

Elevated lipoprotein(a) and low-density lipoprotein cholesterol as predictors of the severity and complexity of angiographic lesions in patients with premature coronary artery disease.

BACKGROUND: Elevated lipoprotein(a) (Lp[a]) and low-density lipoprotein (LDL) cholesterol are important inheritable risk factors for premature coronary artery disease (CAD). Lp(a) mediates cardiovascular risk through prothrombotic, proinflammatory, and proatherogenic properties. The association of Lp(a) and LDL cholesterol with angiographic disease severity and complexity in patients with premature CAD has yet to be established. OBJECTIVE: To investigate the relationship of Lp(a) and LDL cholesterol with the severity and complexity of coronary artery lesions using the SYNergy between percutaneous coronary intervention with TAXUS and Cardiac Surgery (SYNTAX) and Gensini scores, in patients with premature CAD. METHODS: Plasma Lp(a) levels were consecutively measured by an automated latex-enhanced immunoassay in 147 patients with premature coronary events (aged <60 years). Elevated Lp(a) was defined as >0.5 g/L, and elevated LDL cholesterol as an untreated LDL cholesterol of >5.0 mmol/L (>193 mg/dL). Demographical, biochemical, and clinical data were retrospectively collected from medical records. SYNTAX and Gensini scores were independently assessed by 2 investigators. RESULTS: Patients were subdivided into tertiles using SYNTAX scores. The proportion of patients with elevated Lp(a) and elevated LDL cholesterol were significantly higher in patients with higher SYNTAX and Gensini scores (P < .05). In multivariate analysis (adjusting for age, diabetes, hypertension, and previous coronary event), elevated Lp(a) and elevated LDL cholesterol remained significant, independent predictors of higher SYNTAX and Gensini scores (P < .05). Patients with both elevated Lp(a) and elevated LDL cholesterol constituted most of the patients in the highest SYNTAX tertile, while patients with nonelevated Lp(a) and nonelevated LDL cholesterol were predominantly in the lowest SYNTAX tertile (P < .05). CONCLUSION: In patients with premature CAD, elevated Lp(a) and LDL cholesterol (in a range consistent with familial hypercholesterolemia) were significant, independent predictors of the severity of CAD. Both lipid disorders should be routinely screened for in younger patients presenting to the coronary care unit.

Lipoprotein(a) and apolipoprotein(a) isoform size: Associations with angiographic extent and severity of coronary artery disease, and carotid artery plaque.

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is an emerging genetic risk factor for cardiovascular disease (CVD). We examined whether plasma Lp(a) concentration and apolipoprotein(a) [apo(a)] isoform size are associated with extent and severity of coronary artery disease (CAD), and the presence of carotid artery plaque. METHODS: We included in our study male participants (n = 263) from a cohort with angiographically defined premature CAD (Carotid Ultrasound in Patients with Ischemic Heart Disease). The angiographic extent and severity of CAD were determined by the modified Gensini and Coronary Artery Stenosis≥20% (CAGE) scores. Carotid artery plaque was assessed by bilateral carotid B-mode ultrasound. Apo(a) isoform size was determined by LPA Kringle IV-2 copy number (KIV-2 CN). RESULTS: Lp(a) concentration, but not KIV-2 CN, was positively associated with the Gensini score. The association remained significant following adjustment for conventional CVD risk factors (all p < 0.05). Lp(a) concentration and elevated Lp(a) [≥50 mg/dL] were positively associated with the CAGE≥20 score, independent of conventional CVD risk factors. KIV-2 C N Q1 (lowest KIV-2 CN quartile) was associated with CAGE≥20 score and KIV-2 CN, with the CAGE≥20 score in those without diabetes. In multivariate models that included phenotypic familial hypercholesterolemia or low-density lipoprotein cholesterol, Lp(a) concentration, but not KIV-2 CN, was independently associated with the Gensini and CAGE≥20 scores. No significant associations between Lp(a) concentration and KIV-2 CN with carotid artery plaque were observed. CONCLUSIONS: Lp(a) concentration, but not apo(a) isoform size, is independently associated with angiographic extent and severity of CAD. Neither Lp(a) nor apo(a) isoform size is associated with carotid artery plaque.

Elevated lipoprotein(a) and familial hypercholesterolemia in the coronary care unit: Between Scylla and Charybdis.

BACKGROUND: Elevated lipoprotein(a) (Lp[a]) and familial hypercholesterolemia (FH) are inherited lipid disorders. Their frequencies, coexistence, and associations with premature coronary artery disease (CAD) in patients admitted to the coronary care unit (CCU) remain to be defined. HYPOTHESIS: Elevated Lp(a) and FH are commonly encountered among CCU patients and independently associated with increased premature CAD risk. METHODS: Plasma Lp(a) concentrations were measured in consecutive patients admitted to the CCU with an acute coronary syndrome (ACS) or prior history of CAD for 6.5 months. Elevated Lp(a) was defined as concentrations ≥0.5 g/L. Patients with LDL-C ≥ 5 mmol/L exhibited phenotypic FH. Premature CAD was diagnosed in those age < 60 years, and the relationship between this and elevated Lp(a) and FH was determined by logistic regression. RESULTS: 316 patients were screened; 163 (51.6%) had premature CAD. Overall, elevated Lp(a) and FH were identified in 27.0% and 11.6% of patients, respectively. Both disorders were detected in 4.4% of individuals. Elevated Lp(a) (32.0% vs 22.2%; P = 0.019) and FH phenotype (15.5% vs 8.0%; P = 0.052) were more common with premature vs nonpremature CAD. Elevated Lp(a) alone conferred a 1.9-fold, FH alone a 3.2-fold, and the combination a 5.3-fold increased risk of premature CAD (P = 0.005). CONCLUSIONS: Elevated Lp(a) and phenotypic FH were commonly encountered and more frequent with premature CAD. The combination of both disorders is especially associated with increased CAD risk. Patients admitted to the CCU with ACS or previously documented CAD should be routinely screened for elevated Lp(a) and FH.

New data on familial hypercholesterolaemia and acute coronary syndromes: The promise of PCSK9 monoclonal antibodies in the light of recent clinical trials.

Background Familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by substantially elevated low-density lipoprotein (LDL) cholesterol. Although affecting approximately one in 250 individuals worldwide, FH is currently underreported and a greater awareness of this condition is required. Opportunistic screening for FH in acute coronary syndrome patients offers utility for identifying previously undiagnosed individuals and for initiating treatment. Methods The purpose of this commentary is to provide a brief update on recent data investigating several key aspects of FH in patients with acute coronary syndromes, including prevalence, risk of coronary artery disease, molecular diagnosis, cardiac imaging, as well as the efficacy of PCSK9 inhibition. Results FH is relatively common among patients with coronary artery disease and is associated with a considerably increased risk of premature and recurrent cardiovascular events. Computed tomographic coronary angiography may be useful for identifying high-risk FH individuals. FH patients with a pathogenic mutation have a greater risk of the same LDL cholesterol than individuals without a mutation. PCSK9 monoclonal antibodies significantly lower LDL cholesterol in heterozygous and homozygous FH patients, with a greater attainment of LDL cholesterol targets, and can reduce the need for lipoprotein apheresis. Conclusions These data support the opportunistic screening for FH at the time of angiography or an acute coronary syndrome, followed by cascade testing of relatives of index cases. PCSK9 monoclonal antibodies are an important therapeutic advance for safely inhibiting the progression of atherosclerotic burden in FH, as supported by the most recent clinical endpoint trials.

The renaissance of lipoprotein(a): Brave new world for preventive cardiology?

Lipoprotein(a) [Lp(a)] is a highly heritable cardiovascular risk factor. Although discovered more than 50 years ago, Lp(a) has recently re-emerged as a major focus in the fields of lipidology and preventive cardiology owing to findings from genetic studies and the possibility of lowering elevated plasma concentrations with new antisense therapy. Data from genetic, epidemiological and clinical studies have provided compelling evidence establishing Lp(a) as a causal risk factor for atherosclerotic cardiovascular disease. Nevertheless, major gaps in knowledge remain and the identification of the mechanistic processes governing both Lp(a) pathobiology and metabolism are an ongoing challenge. Furthermore, the complex structure of Lp(a) presents a major obstacle to the accurate quantification of plasma concentrations, and a universally accepted and standardized approach for measuring Lp(a) is required. Significant progress has been made in the development of novel therapeutics for selectively lowering Lp(a). However, before these therapies can be widely implemented further investigations are required to assess their efficacy, safety, and cost-efficiency in the prevention of cardiovascular events. We review recent advances in molecular and biochemical aspects, epidemiology, and pathobiology of Lp(a), and provide a contemporary update on the significance of Lp(a) in clinical medicine. "Progress lies not in enhancing what is, but in advancing toward what will be." (Khalil Gibran).

Progress in the care of common inherited atherogenic disorders of apolipoprotein B metabolism.

Familial hypercholesterolaemia, familial combined hyperlipidaemia (FCH) and elevated lipoprotein(a) are common, inherited disorders of apolipoprotein B metabolism that markedly accelerate the onset of atherosclerotic cardiovascular disease (ASCVD). These disorders are frequently encountered in clinical lipidology and need to be accurately identified and treated in both index patients and their family members, to prevent the development of premature ASCVD. The optimal screening strategies depend on the patterns of heritability for each condition. Established therapies are widely used along with lifestyle interventions to regulate levels of circulating lipoproteins. New therapeutic strategies are becoming available, and could supplement traditional approaches in the most severe cases, but their long-term cost-effectiveness and safety have yet to be confirmed. We review contemporary developments in the understanding, detection and care of these highly atherogenic disorders of apolipoprotein B metabolism.