Lipoprotein(a) Genotype Influences the Clinical Diagnosis of Familial Hypercholesterolemia

: Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH

Refinement of the diagnostic approach for the identification of children and adolescents affected by familial hypercholesterolemia: Evidence from the LIPIGEN study

Background and aims: We aimed to describe the limitations of familiar hypercholesterolemia (FH) diagnosis in childhood based on the presence of the typical features of FH, such as physical sings of cholesterol accumulation and personal or family history of premature cardiovascular disease or hypercholesterolemia, comparing their prevalence in the adult and paediatric FH population, and to illustrate how additional information can lead to a more effective diagnosis of FH at a younger age.Methods: From the Italian LIPIGEN cohort, we selected 1188 (>= 18 years) and 708 (<18 years) genetically-confirmed heterozygous FH, with no missing personal FH features. The prevalence of personal and familial FH features was compared between the two groups. For a sub-group of the paediatric cohort (N = 374), data about premature coronary heart disease (CHD) in second-degree family members were also included in the evaluation.Results: The lower prevalence of typical FH features in children/adolescents vs adults was confirmed: the prevalence of tendon xanthoma was 2.1% vs 13.1%, and arcus cornealis was present in 1.6% vs 11.2% of the cohorts, respectively. No children presented clinical history of premature CHD or cerebral/peripheral vascular disease compared to 8.8% and 5.6% of adults, respectively. The prevalence of premature CHD in first-degree relatives was significantly higher in adults compared to children/adolescents (38.9% vs 19.7%). In the sub-cohort analysis, a premature CHD event in parents was reported in 63 out of 374 subjects (16.8%), but the percentage increased to 54.0% extending the evaluation also to second-degree relatives.Conclusions: In children, the typical FH features are clearly less informative than in adults. A more thorough data collection, adding information about second-degree relatives, could improve the diagnosis of FH at younger age

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

“Tailored” antiplatelet bridging therapy with cangrelor: moving toward personalized medicine

In the setting of patients with indication to receive dual antiplatelet therapy undergoing surgery or invasive procedures, the risk of perioperative cardiac ischemic events, particularly stent thrombosis, is high, because surgery has a prothrombotic effect and antiplatelet therapy is withdrawn in order to avoid bleeding complications. Cangrelor, an intravenous P2Y12 receptor antagonist, has been tested in a randomized trial as a “bridge” to cardiac surgery from discontinuation of oral P2Y12 receptor antagonists. Thus, a consensus document extended its off-label use in this setting and before non-cardiac surgery. Currently, despite the implementation of a standardized bridging protocol with cangrelor, a residual risk of adverse outcome mainly due to bleeding events, still persist during the perioperative phase. Accordingly, a personalized management driven by platelet reactivity serial measurements and careful assessment of ischemic and bleeding risks has potential to optimize outcomes and costs as compared to a standardized bridging protocol, based on average pharmacodynamic data of oral P2Y12 inhibitors. While specific indications for bridging have been extensively addressed in the aforementioned consensus statement, the aim of the present document is the proposal of a “tailored” clinical decision-making algorithm inspired to the principle of personalized medicine dealing with complex clinical scenarios

Applicability of the 2013 ACC/AHA Risk Assessment and Cholesterol Treatment Guidelines in the real world: Results from a multiethnic case-control study

© 2016 Informa UK Limited, trading as Taylor & Francis Group. Background: The 2013 ACC/AHA cholesterol treatment guidelines have introduced a new cardiovascular risk assessment approach (PCE) and have revisited the threshold for prescribing statins. This study aims to compare the ex ante application of the ACC/AHA and the ATP-III guideline models by using a multiethnic case-control study. Methods: ATP-III-FRS and PCE were assessed in 739 patients with first STEMI and 739 age- and gender-matched controls; the proportion of cases and controls that would have been eligible for statin as primary prevention therapy and the discriminatory ability of both models were evaluated. Results: The application of the ACC/AHA compared to the ATP-III model, resulted in an increase in sensitivity [94% (95%CI: 91%-95%) vs. 65% (61%-68%), p < 0.0001], a reduction in specificity [19% (15%-22%) vs. 55% (51%-59%), p < 0.0001] with similar global accuracy [0.56 (0.53-0.59) vs.0.59 (0.57-0.63), p ns] . When stratifying for ethnicity, the accuracy of the ACC/AHA model was higher in Europeans than in Chinese (p = 0.003) and to identified premature STEMI patients within Europeans much better compared to the ATP-III model (p = 0.0289). Conclusion: The application of the ACC/AHA model resulted in a significant reduction of first STEMI patients who would have escaped from preventive treatment. Age and ethnicity affected the accuracy of the ACC/AHA model improving the identification of premature STEMI among Europeans only. Key messagesAccording to the ATP-III guideline model, about one-third of patients with STEMI would not be eligible for primary preventive treatment before STEMI.The application of the new ACC/AHA cholesterol treatment guideline model leads to a significant reduction of the percentage of patients with STEMI who would have been considered at lower risk before the STEMI.The global accuracy of the new ACC/AHA model is higher in the Europeans than in the Chinese and, moreover, among the Europeans, the application of the new ACC/AHA guideline model also improved identification of premature STEMI patients

Monitoring antiplatelet therapy: where are we now?

: Single antiplatelet therapy represents the cornerstone of thrombosis prevention in atherosclerotic cardiovascular disease. Dual antiplatelet therapy (DAPT), consisting of aspirin plus a P2Y 12 inhibitor, is the standard of care for patients with acute coronary syndrome or undergoing both coronary and peripheral percutaneous interventions. Recent data suggest the efficacy of DAPT also after minor stroke. In this setting, a large body of evidence has documented that genetic and acquired patients' characteristics may affect the magnitude of platelet inhibition induced by antiplatelet agents. The implementation of tools allowing the identification and prediction of platelet inhibition has recently been shown to improve outcomes, leading to an optimal balance between antithrombotic efficacy and bleeding risk. We are therefore clearly moving towards tailored antiplatelet therapy. The aim of this paper is to summarize the available evidence on the evaluation of platelet inhibition in patients with coronary, peripheral, or cerebrovascular atherosclerosis. We will here focus on antiplatelet therapy based on both aspirin and P2Y 12 inhibitors. In addition, we provide practical insights into the clinical settings in which it appears reasonable to implement antiplatelet therapy monitoring

Strength of clinical indication and therapeutic impact of the implantable cardioverter defibrillator in patients with hypertrophic cardiomyopathy

Background: The implantable cardioverter defibrillator(ICD) has revolutionized the management of patients with hypertrophic cardiomyopathy (HCM) at risk of sudden cardiac death (SCD). However, the identification of ideal candidates remains challenging. We aimed to describe the long-term impact of the ICD for primary prevention in patients with HCM based on stringent (high SCD risk) vs lenient indications (need for pacing/personal choice). Methods: Data from two Italian HCM Cardiomyopathy Units were retrospectively analyzed. Only patients >1 follow-up visits were divided into two groups according to ICD candidacy:stringent (high SCD risk) and lenient (need for pacing, patients' choice, physician advice despite lack of high SCD risk). Major cardiac events (composite of appropriate shock/intervention and SCD) was the primary endpoint. A safety endpoint was defined as a composite of inappropriate shocks and device-related complications. Results: Of 2009 patients, 252(12.5%) received an ICD, including 27(1.3%) in secondary prevention and 225(11.2%) in primary prevention (age at implantation 49 ± 16 years; men 65.3%). Among those in primary prevention, 167(74.2%) had stringent, while 58(25.8%) had lenient indications. At 5 ± 4 years, only stringent ICD patients experienced major cardiac events (2.84%/year, 5-year cumulative incidence: 8.1%, 95%CI [3.5-14.1%]). ICD-related complications were similar across stringent and lenient subgroups. However, patients implanted >60 years had a significantly higher risk of adverse events. Conclusion: One third of ICD recipients with HCM in primary prevention received a lenient implantation and had no appropriate intervention. ICD implantation due to systematic upgrade in patients requiring pacing and increased risk perception may offer little advantage and increase complication rates

Association of different oral anticoagulants use with renal function worsening in patients with atrial fibrillation. a multicentre cohort study

AIMS: To investigate the decline of estimated glomerular filtration rate (eGFR) in patients with atrial fibrillation (AF) treated with Vitamin K antagonists (VKAs) or non-VKAs oral anticoagulants (NOACs). METHODS:Multicentre prospective cohort study including 1,667 patients with non-valvular AF. The eGFR was assessed by the CKD-EPI formula at baseline and during follow-up. The primary endpoint of the study was the median annual decline of eGFR according to VKAs (n=743) or NOACs (n=924) use. As secondary endpoints, we analysed the transition to eGFR <50 ml/min/1.73 m2 , and the eGFR class worsening. RESULTS:Median age was 73.7±9.1 years and 43.3% were women. VKAs-treated patients showed an eGFR decline of -2.11 (Interquartile Range [IQR] -5.68/-0.62], which was -0.27 [IQR -9.00/4.54] (p<0.001 vs. VKAs), -1.21 [IQR -9.98/4.02] (p=0.004 vs. VKAs) and -1.32 [IQR -8.70/3.99] (p=0.003 vs. VKAs) in patients on Dabigatran Rivaroxaban and Apixaban, respectively. Transition to eGFR <50 mL/min/1.73 m2 , was lower in Dabigatran and Apixaban treated patients: Odds Ratio (OR) 0.492, 95% Confidence Interval (CI) 0.298-0.813, p=0.006 and OR 0.449, 95%CI 0.276-0.728, p=0.001, respectively. A lower rate of eGFR class worsening was found in all groups of NOACs compared to VKAs. No difference between full and reduced dose of NOAC was found. Subgroup analysis showed that the association between NOAC and eGFR changes was markedly reduced in diabetic patients. CONCLUSION: Patients prescribed on NOACs showed a lower decline of renal function compared to those on VKAs. This effect was partially lost in patients with diabetes