Maya S. Safarova

Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography.

AIM To evaluate the effect of specific lipoprotein(a) [Lp(a)] apheresis on coronary atherosclerosis progression in coronary heart disease (CHD) patients with elevated Lp(a) levels. METHODS A total of 30 subjects (mean age 53.5 ± 8.3 years, 70% male) with CHD verified by angiography, Lp(a) > 50 mg/dL, and low density lipoprotein cholesterol (LDL-C) ≤ 2.5 mmol/L on chronic statin treatment were prospectively evaluated for 18 months. Patients were allocated to receive specific Lp(a) apheresis, which was carried out weekly with Lp(a) Lipopak(®) columns (POCARD Ltd., Russia) (n = 15), or atorvastatin only (n = 15). Blinded quantitative coronary angiography analyses of percent diameter stenosis and minimal lumen diameter (MLD) were performed at baseline and after the 18-month treatment period. RESULTS By the single specific Lp(a) apheresis procedure, Lp(a) level decreased by an average of 73 ± 12% to a mean of 29 ± 16 mg/dL, and mean Lp(a)-corrected LDL-C decreased by 7% to a mean of 1.4 mmol/L. Median percent diameter stenosis was reduced by -2.0 (95% confidence interval [CI], -5.0-0.0) with apheresis (p < 0.01 in comparison with baseline), and increased by 3.5 (0.0-6.9) with atorvastatin (p < 0.001 between the groups). The effect on MLD was more favorable with apheresis than with atorvastatin: 0.20 ± 0.39 mm, as compared with 0.01 ± 0.34 mm, p = 0.04. Lp(a) apheresis had greater efficacy regarding the amount of regressed/stabilized coronary segments than atorvastatin alone in the majority of patients (chi-square test 13.61, p < 0.005). CONCLUSION Specific Lp(a) apheresis for 18 months produced coronary atherosclerosis regression in stable CHD patients with high Lp(a) levels and reached LDL-C goals.

My Approach to the Patient With Familial Hypercholesterolemia

Familial hypercholesterolemia (FH), a relatively common Mendelian genetic disorder, is associated with a dramatically increased lifetime risk of premature atherosclerotic cardiovascular disease due to elevated plasma low-density lipoprotein cholesterol (LDL-C) levels. The diagnosis of FH is based on clinical presentation or genetic testing. Early identification of patients with FH is of great public health importance because preventive strategies can lower the absolute lifetime cardiovascular risk and screening can detect affected relatives. However, low awareness, detection, and control of FH pose hurdles in the prevention of FH-related cardiovascular events. Of the estimated 0.65 million to 1 million patients with FH in the United States, less than 10% carry a diagnosis of FH. Based on registry data, a substantial proportion of patients with FH are receiving no or inadequate lipid-lowering therapy. Statins remain the mainstay of treatment for patients with FH. Lipoprotein apheresis and newly approved lipid-lowering drugs are valuable adjuncts to statin therapy, particularly when the LDL-C-lowering response is suboptimal. Monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 provide an additional approximately 60% lowering of LDL-C levels and are approved for use in patients with FH. For homozygous FH, 2 new drugs that work independent of the LDL receptor pathway are available: an apolipoprotein B antisense oligonucleotide (mipomersen) and a microsomal triglyceride transfer protein inhibitor (lomitapide). This review attempts to critically examine the available data to provide a summary of the current evidence for managing patients with FH, including screening, diagnosis, treatment, and surveillance.

Lowering of lipoprotein(a) level under niacin treatment is dependent on apolipoprotein(a) phenotype

BACKGROUND Lipoprotein(a) [Lp(a)] is a cardiovascular risk factor; in addition to being a low-density lipoprotein (LDL)-like particle, it contains highly heterogeneous apolipoprotein(a) [apo(a)]. No prior studies have evaluated extended-release (ER) niacin effect on Lp(a) level depending on apo(a) phenotype. METHODS For this 24-week, prospective, open-label clinical trial we recruited 30 men (mean age 46.2 ± 7.5 years) with Lp(a) levels >20 mg/dL. No participant had previously received lipid lowering therapy, and started ER niacin 500 mg with stepwise dose increasing up to 1.5-2.0 g. Subjects were evaluated for Lp(a), lipids, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2 (Lp-PLA2), and fibrinolytic markers (plasminogen activator inhibitor-1, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasmin-antiplasmin complex). Patients were divided into two groups with major low- (LMW) or high-molecular weight (HMW) apo(a) isoforms determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of plasma under reducing conditions followed by immunoblotting. RESULTS At baseline, groups were comparable in age, lipid, inflammatory and fibrinolytic biomarkers levels. There was a significant difference in baseline Lp(a) concentrations: 92 ± 29 mg/dL versus 54 ± 46 mg/dL in LMW and HMW apo(a) groups, respectively, p < 0.01. During the course of niacin treatment Lp(a) decreased by 28% (p < 0.003), Lp-PLA2 by 22% (p < 0.001), C-reactive protein by 24% (p = 0.07) in LMW apo(a) group, whereas no changes in Lp(a) and biomarkers levels were obtained in HMW apo(a) group. CONCLUSION High-dose ER niacin declines elevated Lp(a) level in male subjects with low- but not high-molecular weight apo(a) phenotype.

Variability in assigning pathogenicity to incidental findings: insights from LDLR sequence linked to the electronic health record in 1013 individuals

Knowledge of variant pathogenicity is key to implementing genomic medicine. We describe variability between expert reviewers in assigning pathogenicity to sequence variants in LDLR, the causal gene in the majority of cases of familial hypercholesterolemia. LDLR was sequenced on the Illumina HiSeq platform (average read depth >200 × ) in 1013 Mayo Biobank participants recruited from 2012 to 2013. Variants with a minor allele frequency (MAF) <5% predicted to be functional or referenced in HGMD (Human Gene Mutation Database) or NCBI-ClinVar databases were reviewed. To assign pathogenicity, variant frequency in population data sets, computational predictions, reported observations and patient-level data including electronic health record-based post hoc phenotyping were leveraged. Of 178 LDLR variants passing quality control, 25 were selected for independent review using either an in-house protocol or a disease/gene-specific semi-quantitative framework based on the American College of Medical Genetics and Genomics-recommended lines of evidence. NCBI-ClinVar included interpretations for all queried variants with 74% (14/19) of variants with >1 submitter showing inconsistency in classification and 26% (5/19) appearing with conflicting clinical actionability. The discordance rate (one-step level of disagreement out of five classes in variant interpretation) between the reviewers was 40% (10/25). Two LDLR variants were independently deemed clinically actionable and returnable. Interpretation of LDLR variants was often discordant among ClinVar submitters and between expert reviewers. A quantitative approach based on strength of each predefined criterion in the context of specific genes and phenotypes may yield greater consistency between different reviewers.

Lessening the Burden of Familial Hypercholesterolemia Using Health Information Technology

Despite advances in our understanding of heritable lipid disorders and the availability of highly effective lipid-lowering drugs, the awareness, detection, and control of familial hypercholesterolemia (FH) remain suboptimal. 1 A major reason for the low detection rate in the United States is the lack of a widely accepted screening strategy, despite the recommendations for universal or targeted lipid screening by several expert panels. Although the use of universal lipid screening remains a matter of debate, cascade screening (a form of targeted screening of family members of affected individuals) is acknowledged as the most cost-effective screening strategy for FH. In the Netherlands >26  000 new cases were identified over 2 decades by genotyping family members of FH probands, and it is estimated that genetic cascade screening, coupled with statin therapy for diagnosed patients, could save

Cascade plasma filtration during the first year after CABG in patients with hyperlipidemia refractory to statins

92 million per year in the European Union. 1 Several factors lead to the low rates of cascade screening for FH in the United States. First, no nationwide strategy for the early detection of FH exists. Second, the low acceptance of genetic testing for FH in the United States is an impediment to unambiguous diagnosis and cascade screening. Third, patients and family members are often concerned about the stigma associated with genetic diagnoses. Fourth, because of the Health Insurance Portability and Accountability Act, disclosing the risk of genetic disease to family members can incur liability, even if this knowledge leads to early detection and treatment. Fifth, …

Dramatic fate of a young coronary heart disease patient rescued with specific lipoprotein(a) apheresis

OBJECTIVE To evaluate the effect of a 12-month course of weekly lipid apheresis on vein graft patency after coronary artery bypass grafting (CABG) in patients with hyperlipidemia refractory to statins. METHODS In a 12-month prospective controlled clinical trial we enrolled 34 male patients (mean age 57 ± 8 years) who passed through successful CABG and low-density lipoprotein cholesterol (LDL-C) level >2.6 mmol/L prior to the operation despite statin treatment. Patients were allocated into 2 groups: active (n = 17, weekly apheresis by cascade plasma filtration (CPF) plus atorvastatin), and control (n = 17, atorvastatin alone). Graft patency was evaluated by multislice computed tomography at 3 months and by angiography at 12 months after an operation. RESULTS Both groups were comparable in clinical and biochemical characteristics. During each CPF procedure, LDL-C level decreased by 64 ± 9%, apoB - by 65 ± 8%, Lp(a) - by 52 ± 15%,; these changes were significant compared to baseline and the control group. Mean net difference in LDL-C level between apheresis and control groups was 1.1 ± 0.3 mmol/L. Vein graft patency at study end was 88.2% (45 of 51) in the apheresis group versus 72.7% (40 of 55) in the control group (p = 0.05). Use of apheresis was associated with decreased vein graft occlusions by 46%: relative risk 0.54; 95% confidence interval 0.27 to 1.02; p = 0.05. CONCLUSION Our data suggest that the use of lipoprotein apheresis with CPF results in a better vein graft patency during the first year after CABG in patients with hyperlipidemia refractory to statins.

FAMILIAL HYPERCHOLESTEROLEMIA: AWARENESS, DETECTION AND CONTROL IN THE COMMUNITY

Lipoprotein(a) [Lp(a)] is acknowledged to be an independent atherothrombotic risk factor. Although genetic studies have highlighted the causal relationship between coronary disease and Lp(a), it is uncertain which strategies maximize the therapeutic benefit of patients with high Lp(a) levels. We report the challenging case of a young coronary heart disease (CHD) patient who underwent 10 percutaneous coronary interventions due to repeated acute coronary syndromes (2006–2009) despite an optimally controlled, traditional risk‐factor profile. For the first time, we performed specific Lp(a) immunoadsorption in the presence of very low levels of low‐density lipoprotein cholesterol (LDL‐C) while the patient was on a high‐dose statin regimen. There have been no previous reports of patients with high Lp(a) levels who achieved LDL‐C goals when treated with an isolated Lp(a)‐lowering method. Despite the very high risk of cardiovascular death, targeting Lp(a) resulted in dramatic improvement of the patients clinical condition. Thus, we suggest that specific Lp(a) apheresis should be considered an effective new treatment strategy for patients with progressive CHD who have reached LDL‐C goals but harbor elevated Lp(a) levels. J. Clin. Apheresis 30:193–195, 2015.

PHYSICIAN PERSPECTIVES ON CLINICAL DECISION SUPPORT FOR FAMILIAL HYPERCHOLESTEROLEMIA

Background: The association of Familial Hypercholesterolemia (FH) with coronary heart disease (CHD) has not been studied in a community based setting in the United States. We sought to profile the association of FH with CHD, lag in diagnosis and treatment gap in Olmsted County, MN. Methods: 6000

Variance in niacin response in individuals with elevated lipoprotein(a)

Background: Familial hypercholesterolemia (FH) is highly prevalent but <10% of patients have been diagnosed in the US, highlighting the need to increase awareness and control of FH. We conducted a survey of physicians at an academic medical center to assess familiarity with FH and gather input for a