Intravascular imaging in the diagnosis and management of patients with suspected intracoronary pathologies: A CJC White Paper.

Intravascular imaging has become an integral part of the diagnostic and management strategies for intracoronary pathologies. This White Paper summarizes current evidence and its implications on the use of intravascular imaging in interventional cardiology practice. The areas addressed are planning and optimization of percutaneous coronary intervention, management of stent failure, and evaluation of ambiguous coronary lesions and myocardial infarction with non-obstructive coronary disease (MINOCA). Findings are presented following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system in an expert consensus process involving a diverse Writing group and vetted by a Review group. Expert consensus was achieved around nine statements. Use of intravascular imaging in guiding percutaneous revascularization is supported by high quality evidence, particularly for lesions with increased risk of recurrent events or stent failure. Specific considerations for intravascular imaging guidance of intervention in left main lesions, chronic occlusion lesions as well as patients at high risk of contrast nephropathy are explored. Use of intravascular imaging to identify pathologies associated with stent failure and guide repeat intervention, resolve ambiguities in lesion assessment and establish diagnoses in patients presenting with MINOCA is supported by moderate to low quality evidence. Each topic is accompanied by clinical pointers to aid the practicing interventional cardiologist in implementation of the White paper findings. The findings of this White Paper will help to guide the utilization of intravascular imaging towards those situations in which the balance of efficacy, safety and cost are most optimal.

Increased prevalence of the COVID-19 associated Neanderthal mutations in the Central European Roma population.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent COVID-19 has spread world-wide and become pandemic with about 7 million deaths reported so far. Interethnic variability of the disease has been described, but a significant part of the differences remain unexplained and may be attributable to genetic factors. AIM: To analyse genetic factors potentially influencing COVID-19 susceptibility and severity in European Roma minority. SUBJECTS AND METHODS: Two genetic determinants, within OAS-1 (2-prime,5-prime-oligoadenylate synthetase 1, a key protein in the defence against viral infection; it activates RNases that degrade viral RNAs; rs4767027 has been analysed) and LZTFL1 (leucine zipper transcription factor-like 1, expressed in the lung respiratory epithelium; rs35044562 has been analysed) genes were screened in a population-sample of Czech Roma (N = 302) and majority population (N = 2,559). RESULTS: For both polymorphisms, Roma subjects were more likely carriers of at least one risky allele for both rs4767027-C (p < 0.001) and rs35044562-G (p < 0.00001) polymorphism. There were only 5.3% Roma subjects without at least one risky allele in comparison with 10.1% in the majority population (p < 0.01). CONCLUSIONS: It is possible that different genetic background plays an important role in increased prevalence of COVID-19 in the Roma minority.

A Tagging Polymorphism in Fat Mass and Obesity-Associated (FTO) Gene Is Associated with Sepsis Status in Children.

INTRODUCTION: Sepsis is one of the most common causes of death in patients admitted to intensive care units (ICUs). The development of sepsis is significantly influenced by genetic predisposition. In this study, we highlight a potential association between a variant of the fat mass and obesity-associated (FTO) gene and risk of sepsis in children and adolescents. METHODS: We investigated a first-intron tagging FTO polymorphism (rs17817449) by comparing a severe condition (SC) group, comprising 598 paediatric patients (ages 0-19 years) admitted to an ICU with fever, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple organ dysfunction syndrome (MODS), with a control group consisting of 616 healthy young adults. RESULTS: We observed a lower prevalence (p < 0.01; OR = 0.59, 95% CI = 0.39-0.87) of the FTO TT genotype in febrile and SIRS patients compared to patients with severe illness. There was a borderline trend towards a lower prevalence of the FTO TT genotype in the control group compared to the SC group (p < 0.09, OR = 0.81, 95% CI = 0.62-1.06). CONCLUSIONS: Our findings suggest that rs17817449, a common FTO polymorphism, may be a predictor of sepsis in paediatric patients, and that higher body weight is protective against this clinical complication.

Case Report: Neurological adverse events in subject with myasthenia gravis after PCSK9 inhibitor administration.

Background: Myasthenia gravis is a rare chronic autoimmune neuromuscular disorder mainly caused by autoantibodies to the nicotinic acetylcholine receptor. Cholesterol is an essential molecule that affects the distribution and proper functioning of this receptor. Several reports have described the potential worsening of myasthenia gravis in patients treated with statins. Case presentation: The patient was an obese 72 years old man, past smoker, diagnosed with ischaemic heart disease, type 2 diabetes mellitus and lipid metabolism disorder. Statin treatment was not implemented because of chronic myasthenia gravis and PCSK9i monotherapy [Repatha (evolucamab), 140 mg] was implemented to treat dyslipidaemia. Within 24 h after the first dose of PCSK9i the patient developed severe muscle weakness, joint pain, fever, and general discomfort, lasting for several days. Despite strong advice against the second dose administration, this was self-administered approximately 2 weeks later, leading to report significant worsening of the muscle problems, leading to the patient admittion to the neurology department where he was being treated for myasthenia gravis attack. Conclusion: Based on the neurologist's conclusion, it can be assumed that in this case, treatment with PCSK9i resulted in significant worsening of the patient's chronic disease.

Monitoring of plasma circulating donor DNA reflects cardiac graft injury: Report of two cases.

The current standard for graft rejection surveillance is endomyocardial biopsy (EMB), an invasive procedure with rare but potentially serious complications. Detection of circulating donor-derived cell-free DNA (ddcfDNA) is an option for noninvasive monitoring of graft injury and rejection. A 63-year-old man and a 65-year-old woman were monitored by EMB for allograft rejection. A total of 48 single-nucleotide polymorphisms with a minor allele frequency range of 0.4-0.5 were screened to distinguish donor and recipient DNA based on homozygosity, and digital droplet PCR was used to analyze ddcfDNA concentrations. Both subjects suffered rejection within the first 6 months after transplantation. The maximal ddcfDNA level of 270 copies (cp)/ml during EMB-confirmed acute cellular rejection (ACR; mild grade 1R/2, patient 1), and the maximal concentration of 1,846 cp/ml in the case of EMB-confirmed antibody-mediated rejection (AMR; grade 1+; patient 2), was detected. Individual monitoring of ddcfDNA dynamics from the 1st to the 6th month posttransplant reflected cardiac graft injury in patients suffering ACR or AMR, meaning that ddcfDNA may serve as a noninvasive biomarker.

Cholesterol associated genetic risk score and acute coronary syndrome in Czech males.

BACKGROUND: Despite a general decline in mean levels across populations, LDL-cholesterol levels remain a major risk factor for acute coronary syndrome (ACS). The APOB, LDL-R, CILP, and SORT-1 genes have been shown to contain variants that have significant effects on plasma cholesterol levels. METHODS AND RESULTS: We examined polymorphisms within these genes in 1191 controls and 929 patients with ACS. Only rs646776 within SORT-1 was significantly associated with a risk of ACS (P < 0.05, AA vs. + G comparison; OR 1.21; 95% CI 1.01-1.45). With regard to genetic risk score (GRS), the presence of at least 7 alleles associated with elevated cholesterol levels was connected with increased risk (P < 0.01) of ACS (OR 1.26; 95% CI 1.06-1.52). Neither total mortality nor CVD mortality in ACS subjects (follow up-9.84 ± 3.82 years) was associated with the SNPs analysed or cholesterol-associated GRS. CONCLUSIONS: We conclude that, based on only a few potent SNPs known to affect plasma cholesterol, GRS has the potential to predict ACS risk, but not ACS associated mortality.

Genetic risk score in patients with the APOE2/E2 genotype as a predictor of familial dysbetalipoproteinemia.

BACKGROUND: Familial dysbetalipoproteinemia (FD) is an autosomal recessive (rarely dominant) inherited disorder that is almost exclusively associated with the apolipoprotein E gene (APOE) variability. Nonetheless, only a small proportion of APOE2/E2 subjects develop the phenotype for mixed dyslipidemia; the context of other trigger metabolic or genetic factors remains unknown. METHODS: One hundred and one patients with FD and eighty controls (all APOE2/E2 homozygotes; rs429358) were screened for 18 single-nucleotide polymorphisms (SNPs) within the genes involved in triglyceride metabolism. RESULTS: Two SNPs were significantly associated with the FD phenotype (rs439401 within APOE; P < 0.0005 and rs964184 within ZPR1/APOA5/A4/C3/A1 gene cluster; P < 0.0001). Unweighted genetic risk scores - from these two SNPs (GRS2), and, also, additional 13 SNPs with P-value below 0.9 (GRS15) - were created as an additional tool to improve the risk estimation of FD development in subjects with the APOE2/E2 genotype. Both GRS2 and GRS15 were significantly (P < 0.0001) increased in patients and both GRSs discriminated almost identically between the groups (P = 0.86). Subjects with an unweighted GRS2 of three or more had an almost four-fold higher risk of FD development than other individuals (OR 3.58, CI: 1.78-7.18, P < 0.0005). CONCLUSIONS: We identified several SNPs that are individual additive factors influencing FD development. The use of unweighted GRS2 is a simple and clinically relevant tool that further improves the prediction of FD in APOE2/E2 homozygotes with corresponding biochemical characteristics.

Long-Term LDL-Apheresis Treatment and Dynamics of Circulating miRNAs in Patients with Severe Familial Hypercholesterolemia.

Lipoprotein apheresis (LA) is a therapeutic option for patients with severe hypercholesterolemia who have persistently elevated LDL-C levels despite attempts at drug therapy. MicroRNAs (miRNAs), important posttranscriptional gene regulators, are involved in the pathogenesis of atherosclerosis. Our study aimed to monitor the dynamics of twenty preselected circulating miRNAs in patients under long-term apheresis treatment. Plasma samples from 12 FH patients (men = 50%, age = 55.3 ± 12.2 years; mean LA overall treatment time = 13.1 ± 7.8 years) were collected before each apheresis therapy every sixth month over the course of four years of treatment. Eight complete follow-up (FU) samples were measured in each patient. Dynamic changes in the relative quantity of 6 miRNAs (miR-92a, miR-21, miR-126, miR-122, miR-26a, and miR-185; all p < 0.04) during FU were identified. Overall apheresis treatment time influenced circulating miR-146a levels (p < 0.04). In LDLR mutation homozygotes (N = 5), compared to heterozygotes (N = 7), we found higher plasma levels of miR-181, miR-126, miR-155, and miR-92a (all p < 0.03). Treatment with PCSK9 inhibitors (N = 6) affected the plasma levels of 7 miRNAs (miR-126, miR-122, miR-26a, miR-155, miR-125a, miR-92a, and miR-27a; all p < 0.04). Long-term monitoring has shown that LA in patients with severe familial hypercholesterolemia influences plasma circulating miRNAs involved in endothelial dysfunction, cholesterol homeostasis, inflammation, and plaque development. The longer the treatment using LA, the better the miRNA milieu depicting the potential cardiovascular risk.

Role of genetics in the development of cardiac allograft vasculopathy.

BACKGROUND: The association between genetic polymorphisms and early cardiac allograft vasculopathy (CAV) development is relatively unexplored. Identification of genes involved in the CAV process may offer new insights into pathophysiology and lead to a wider range of therapeutic options. METHODS: This prospective study of 109 patients investigated 44 single nucleotide polymorphisms (SNPs) within the susceptibility loci potentially related to coronary artery disease, carotid artery intima-media thickness (cIMT), and in nitric oxide synthase gene. Genotyping was done by the Fluidigm SNP Type assays and Fluidigm 48.48 Dynamic Array IFC. The intima thickness progression (IT) was evaluated by coronary optical coherence tomography performed 1 month and 12 months after heart transplantation (HTx). RESULTS: During the first post-HTx year, the mean intima thickness (IT) increased by 24.0 ± 34.2 µm (p < 0.001) and lumen area decreased by ‒0.9 ± 1.8 mm2 (p < 0.001). The rs1570360 (A/G) SNP of the vascular endothelial growth factor A (VEGFA) gene showed the strongest association with intima thickness progression, even in the presence of the traditional CAV risk factors. SNPs previously related to carotid artery intima-media thickness rs11785239 (PRAG1), rs6584389 (PAX2), rs13225723 (LINC02577) and rs17477177 (CCDC71L), were among the five most significantly associated with IT progression but lost their significance once traditional CAV risk factors had been added. CONCLUSION: Results of this study suggest that genetic variability may play an important role in CAV development. The vascular endothelial growth factor A gene SNP rs1570360 showed the strongest association with intima thickness (IT) progression measured by OCT, even in the presence of the traditional CAV risk factors (Tab. 3, Fig. 3, Ref. 36). Text in PDF www.elis.sk Keywords: cardiac allograft vasculopathy, optical coherence tomography, vascular endothelial growth factor A, intimal thickening, genetic polymorphism.

Genetic risk score is associated with T2DM and diabetes complications risks.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a prototypical complex disease with polygenic architecture playing an important role in determining susceptibility to develop the disease (and its complications) in subjects exposed to modifiable lifestyle factors. A current challenge is to quantify the degree of the individual's genetic risk using genetic risk scores (GRS) capturing the results of genome-wide association studies while incorporating possible ethnicity- or population-specific differences. METHODS: This study included three groups of T2DM (T2DM-I, N = 1,032; T2DM-II, N = 353; and T2DM-III, N = 399) patients and 2,481 diabetes-free subjects. The status of the microvascular and macrovascular diabetes complications were known for the T2DM-I patients. Overall, 21 single nucleotide polymorphisms (SNPs) were analyzed, and selected subsets were used to determine the GRS (both weighted - wGRS and unweighted - uGRS) for T2DM risk predictions (6 SNPs) and for predicting the risks of complications (7 SNPs). RESULTS: The strongest T2DM markers (P < 0.0001) were within the genes for TCF7L2 (transcription factor 7-like 2), FTO (fat mass and obesity associated protein) and ARAP1 (ankyrin repeat and PH domain 1). The T2DM-I subjects with uGRS values greater (Odds Ratio, 95 % Confidence Interval) than six had at least twice (2.00, 1.72-2.32) the risk of T2DM development (P < 0.0001), and these results were confirmed in the independent groups (T2DM-II 1.82, 1.45-2.27; T2DM-III 2.63, 2.11-3.27). The wGRS (>0.6) further improved (P < 0.000001) the risk estimations for all three T2DM groups. The uGRS was also a significant predictor of neuropathy (P < 0.0001), nephropathy (P < 0.005) and leg ischemia (P < 0.0005). CONCLUSIONS: If carefully selected and specified, GRS, both weighted and unweighted, could be significant predictors of T2DM development, as well as the diabetes complications development.

Possible effect of OAS1 and TMPRSS6 but not DPP4 and ZNF335 polymorphisms on COVID-19 severity in the Czech population.

OBJECTIVES: The acute respiratory syndrome, known as COVID-19, is characterised by high morbidity and increased mortality. Genetic factors may partially explain the differences in susceptibility to and severity of COVID-19. METHODS: We have analysed common functional polymorphisms within the OAS1 (rs4767027), TMPRSS6 (rs855791), DPP4 (rs3788979), and ZNF335 (rs3848719) genes in SARS-CoV-2 positive subjects (n = 521, different disease severity) and in population controls (n = 2,559 subjects, COVID-19 status unknown). RESULTS: Neither DPP4 nor ZNF335 were associated with disease susceptibility or severity in the Czech population in any of the models used for calculation. T allele carriers of the OAS1 polymorphism seem to be protective against symptomatic COVID-19 (p = 0.002 calculated for trend; asymptomatic, symptomatic, hospitalised). Similarly, within the TMPRSS6, minor TT homozygotes associated with lower plasma Fe concentrations were underrepresented in the overall patient group (p = 0.044; OR = 0.77, 95% CI: 0.59-0.99), and the difference was mainly driven by the severe COVID-19 subjects. In general, risky homozygotes of these two polymorphisms were less frequent than expected in the group of hospitalised COVID-19 survivors. CONCLUSIONS: Common variants within OAS1 (rs4767027) and TMPRSS6 (rs855791) play some role in COVID-19 pathology in the Czech Caucasian population. Whether the depletion of minor allele carriers of these two variants is associated with increased COVID-19 mortality, needs to be analysed in an external confirmatory study.

CD14 Polymorphism Is Not Associated with SARS-CoV-2 Infection in Central European Population.

A 2021 in silico study highlighted an association between the CD14 polymorphism rs2569190 and increased susceptibility to SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19). The aim of our study was to confirm this finding. We analysed the CD14 polymorphism (C→T; rs2569190) in 516 individuals who tested positive for SARS-CoV-2, with differing disease severity (164 asymptomatic, 245 symptomatic, and 107 hospitalized). We then compared these patients with a sample from the general population consisting of 3,037 individuals using a case-control study design. In comparison with carriers of the C allele, TT homozygotes accounted for 21.7 % of controls and 20.5 % in SARS-CoV-2-positive individuals (P = 0.48; OR; 95 % CI - 0.92; 0.73-1.16). No significant differences in the distribution of genotypes were found when considering co-dominant and recessive genetic models or various between-group comparisons. The CD14 polymorphism is unlikely to be an important predictor of COVID-19 in the Caucasian population in Central Europe.

Posttransplant Complications and Genetic Loci Involved in Telomere Maintenance in Heart Transplant Patients.

Reaching critically short telomeres induces cellular senescence and ultimately cell death. Cellular senescence contributes to the loss of tissue function. We aimed to determine the association between variants within genes involved in telomere length maintenance, posttransplant events, and aortic telomere length in heart transplant patients. DNA was isolated from paired aortic samples of 383 heart recipients (age 50.7 ± 11.9 years) and corresponding donors (age 38.7 ± 12.0 years). Variants within the TERC (rs12696304), TERF2IP (rs3784929 and rs8053257), and OBCF1 (rs4387287) genes were genotyped, and telomere length was measured using qPCR. We identified similar frequencies of genotypes in heart donors and recipients. Antibody-mediated rejection (AMR) was more common (p < 0.05) in carriers of at least one G allele within the TERF2IP locus (rs3784929). Chronic graft dysfunction (CGD) was associated with the TERC (rs12696304) GG donor genotype (p = 0.05). The genetic risk score did not determine posttransplant complication risk prediction. No associations between the analyzed polymorphisms and telomere length were detected in either donor or recipient DNA. In conclusion, possible associations between donor TERF2IP (rs3784929) and AMR and between TERC (rs12696304) and CGD were found. SNPs within the examined genes were not associated with telomere length in transplanted patients.

Educational gradients in all-cause mortality in two cohorts in the Czech Republic during the early stage of the postcommunist transition.

OBJECTIVES: We investigated whether social gradient in all-cause mortality in the Czech Republic changed during the postcommunist transition by comparing two cohorts, recruited before and after the political changes in 1989. METHODS: Participants (aged 25-64 years) in two population surveys (n=2530 in 1985, n=2294 in 1992) were followed up for mortality for 15 years (291 and 281 deaths, respectively). Education was classified into attainment categories and years of schooling (both continuous and in tertiles). Cox regression was used to estimate HR of death by educational indices in each cohort over a 15-year follow-up. RESULTS: All three educational variables were significantly associated with reduced risk of death in both cohorts when men and women were combined; for example, the adjusted HRs of death in the highest versus lowest tertile of years of schooling were 0.65 (95% CI 0.47 to 0.89) in 1985 and 0.67 (95% CI 0.48 to 0.93) in 1992. Adjustment for covariates attenuated the gradients. In sex-specific analysis, the gradient was more pronounced and statistically significant in men. There were no significant interactions between cohort and educational indices. CONCLUSIONS: The educational gradient in mortality did not differ between the two cohorts (1985 vs 1992), suggesting no major increase in educational inequality during the early stage of postcommunist transition. Further research is needed to understand trends in health inequalities during socioeconomic transitions.

The Relationship between Epigenetic Age and Myocardial Infarction/Acute Coronary Syndrome in a Population-Based Nested Case-Control Study.

We investigated the relationship between 'epigenetic age' (EA) derived from DNA methylation (DNAm) and myocardial infarction (MI)/acute coronary syndrome (ACS). A random population sample was examined in 2003/2005 (n = 9360, 45-69, the HAPIEE project) and followed up for 15 years. From this cohort, incident MI/ACS (cases, n = 129) and age- and sex-stratified controls (n = 177) were selected for a nested case-control study. Baseline EA (Horvath's, Hannum's, PhenoAge, Skin and Blood) and the differences between EA and chronological age (CA) were calculated (ΔAHr, ΔAHn, ΔAPh, ΔASB). EAs by Horvath's, Hannum's and Skin and Blood were close to CA (median absolute difference, MAD, of 1.08, -1.91 and -2.03 years); PhenoAge had MAD of -9.29 years vs. CA. The adjusted odds ratios (ORs) of MI/ACS per 1-year increments of ΔAHr, ΔAHn, ΔASB and ΔAPh were 1.01 (95% CI 0.95-1.07), 1.01 (95% CI 0.95-1.08), 1.02 (95% CI 0.97-1.06) and 1.01 (0.93-1.09), respectively. When classified into tertiles, only the highest tertile of ΔAPh showed a suggestion of increased risk of MI/ACS with OR 2.09 (1.11-3.94) independent of age and 1.84 (0.99-3.52) in the age- and sex-adjusted model. Metabolic modulation may be the likely mechanism of this association. In conclusion, this case-control study nested in a prospective population-based cohort did not find strong associations between accelerated epigenetic age markers and risk of MI/ACS. Larger cohort studies are needed to re-examine this important research question.

Apolipoprotein L1 variability is associated with increased risk of renal failure in the Czech population.

BACKGROUND: With stage 5 chronic kidney disease (CKD5) more prevalent in the Czech Republic than in most European countries, genetic susceptibility is potentially implicated. METHODS: In a group of 1489 CKD5 kidney transplantation patients (93% with complete clinical characteristics; mean age 52.0 years, 37% females) and 2559 healthy controls (mean age 49.0 years, 51% females), we examined the prevalence of six APOL1 SNPs (rs73885319, rs71785313, rs13056427, rs136147, rs10854688 and rs9610473) and one newly detected 55-nucleotide insertion/deletion polymorphism. RESULTS: The rs73885319 and rs71785313 variants were monomorphic in the Czech Caucasian population. Genotype frequencies of the three SNPs examined (rs13056427, rs136147 and rs9610473) were almost identical in patients and controls (all P values were between 0.39 and 0.91). Minor homozygotes of rs10854688 were more common between the patients (13.2%) than in controls (10.7%) (OR [95% CI]; 1.32 [1.08-1.64]; P < 0.01). Prevalence of the newly detected 55-bp APOL1 deletion was significantly higher in CKD5 patients (3.0% vs. 1.7%; OR [95% CI]; 1.80 [1.16-2.80]; P < 0.01) compared to controls. Frequencies of some individual APOL1 haplotypes were borderline different between patients and controls. CONCLUSION: We found an association between rs10854688 SNP within the APOL1 gene and end-stage renal disease in the Czech Caucasian population. Further independent studies are required before a conclusive association between the newly detected APOL1 insertion/deletion polymorphism and CKD5 can be confirmed.

Statins and Inflammation.

PURPOSE OF REVIEW: Chronic inflammation has been recognized as one of the most important pathophysiological mechanisms' initiation and progression of atherosclerosis. Statins belong to most successful therapeutic agents in the prevention and treatment of atherothrombotic vascular disease. Their non-lipid related effects including suppression of inflammation have been repeatedly proven in both experimental and clinical settings. RECENT FINDINGS: Recently, the importance of inflammation in the process of atherosclerosis has been confirmed by interventions targeting inflammation selectively. Clinical trial with selective inhibitor of a principal inflammatory mediator interleukin 1-beta - canakinumab - confirmed the notion of direct vasculoprotective effects of primarily targeting inflammation. This has increased interest in the non-lipid, pleiotropic and, particularly, anti-inflammatory effects of statins. Anti-inflammatory effects of statins have been proven both experimentally and in clinical settings beyond any doubt. They comprise a direct positive effect on not only many cell types and pathways that are lipid independent but, also, some that are mediated by lipid modification. Undoubtedly, suppression of inflammatory response by statins contributes to their generally positive action in atherosclerosis and represents an important part of the vasculo- and atheroprotective effect of this drug class.

Longitudinal trajectories of blood lipid levels in an ageing population sample of Russian Western-Siberian urban population.

This study investigated 12-year blood lipid trajectories and whether these trajectories are modified by smoking and lipid lowering treatment in older Russians. To do so, we analysed data on 9,218 Russian West-Siberian Caucasians aged 45-69 years at baseline participating in the international HAPIEE cohort study. Mixed-effect multilevel models were used to estimate individual level lipid trajectories across the baseline and two follow-up examinations (16,445 separate measurements over 12 years). In all age groups, we observed a reduction in serum total cholesterol (TC), LDL-C and non-HDL-C over time even after adjusting for sex, statin treatment, hypertension, diabetes, social factors and mortality (P<0.01). In contrast, serum triglyceride (TG) values increased over time in younger age groups, reached a plateau and decreased in older age groups (> 60 years at baseline). In smokers, TC, LDL-C, non-HDL-C and TG decreased less markedly than in non-smokers, while HDL-C decreased more rapidly while the LDL-C/HDL-C ratio increased. In subjects treated with lipid-lowering drugs, TC, LDL-C and non-HDL-C decreased more markedly and HDL-C less markedly than in untreated subjects while TG and LDL-C/HDL-C remained stable or increased in treatment naïve subjects. We conclude, that in this ageing population we observed marked changes in blood lipids over a 12 year follow up, with decreasing trajectories of TC, LDL-C and non-HDL-C and mixed trajectories of TG. The findings suggest that monitoring of age-related trajectories in blood lipids may improve prediction of CVD risk beyond single measurements.

Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk.

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361-0.7719 and OR 0.1522; 95% CI 0.02941-0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.

Multiplex Protein Biomarker Profiling in Patients with Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH), is an autosomal dominant disorder caused by mutations in the LDLR, APOB, PCSK9, and APOE genes and is characterized by high plasma levels of total and low-density lipoprotein (LDL) cholesterol. Our study aimed to analyze the influences of two different therapies on a wide spectrum of plasma protein biomarkers of cardiovascular diseases. Plasma from FH patients under hypolipidemic therapy (N = 18; men = 8, age 55.4 ± 13.1 years) and patients under combined long-term LDL apheresis/hypolipidemic therapy (N = 14; men = 7; age 58.0 ± 13.6 years) were analyzed in our study. We measured a profile of 184 cardiovascular disease (CVD) associated proteins using a proximity extension assay (PEA). Hypolipidemic therapy significantly (all p < 0.01) influenced 10 plasma proteins (TM, DKK1, CCL3, CD4, PDGF subunit B, AGRP, IL18, THPO, and LOX1 decreased; ST2 increased). Under combined apheresis/hypolipidemic treatment, 18 plasma proteins (LDLR, PCSK9, MMP-3, GDF2, CTRC, SORT1, VEGFD, IL27, CCL24, and KIM1 decreased; OPN, COL1A1, KLK6, IL4RA, PLC, TNFR1, GLO1, and PTX3 increased) were significantly affected (all p < 0.006). Hypolipidemic treatment mainly affected biomarkers involved in vascular endothelial maintenance. Combined therapy influenced proteins that participate in cholesterol metabolism and inflammation.