Gustavs Latkovskis

Familial hypercholesterolaemia: A global call to arms.

Familial Hypercholesterolaemia (FH) is the commonest autosomal co-dominantly inherited condition affecting man. It is caused by mutation in one of three genes, encoding the low-density lipoprotein (LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene coding for PCSK9 (which is involved in the degradation of the LDL-receptor during its cellular recycling). These mutations result in impaired LDL metabolism, leading to life-long elevations in LDL-cholesterol (LDL-C) and development of premature atherosclerotic cardiovascular disease (ASCVD) [1], [2] and [3]. If left untreated, the relative risk of premature coronary artery disease is significantly higher in heterozygous patients than unaffected individuals, with most untreated homozygotes developing ASCVD before the age of 20 and generally not surviving past 30 years [2], [3], [4] and [5]. Although early detection and treatment with statins and other LDL-C lowering therapies can improve survival, FH remains widely underdiagnosed and undertreated [1], thereby representing a major global public health challenge.

Lipid lowering nutraceuticals in clinical practice: position paper from an International Lipid Expert Panel

Arrigo F.G. Cicero, University of Bologna Alessandro Colletti, University of Bologna Gani Bajraktari, University Clinical Centre of Kosovo Olivier Descamps, Centres Hospitaliers Jolimont Dragan M. Djuric, University of Belgrade Marat Ezhov, Russian Cardiology Research and Production Centre Zlatko Fras, University Medical Centre Ljubljana Niki Katsiki, Aristotle University of Thessaloniki Michel Langlois, AZ Sint-Jan Hospital Gustavs Latkovskis, University of Latvia

Diabetes is Associated with Higher Trimethylamine N-oxide Plasma Levels.

Recent studies have revealed strong associations between systemic trimethylamine N-oxide (TMAO) levels, atherosclerosis and cardiovascular risk. In addition, plasma L-carnitine levels in patients with high TMAO concentrations predicted an increased risk for cardiovascular disease and incident major adverse cardiac events. The aim of the present study was to investigate the relation between TMAO and L-carnitine plasma levels and diabetes. Blood plasma samples were collected from 12 and 20 weeks old db/db mice and patients undergoing percutaneous coronary intervention. Diabetic compared to non-diabetic db/L mice presented 10-fold higher TMAO, but lower L-carnitine plasma concentrations at 12 weeks of age. After 8 weeks of observation, diabetic db/db mice had significantly increased body weight, insulin resistance and TMAO concentration in comparison to non-diabetic control. In 191 patients undergoing percutaneous coronary intervention the median (interquartile range) plasma concentration of TMAO was 1.8 (1.2-2.6) µmol/L. Analysis of the samples showed a bivariate association of TMAO level with age, total cholesterol and L-carnitine. The multivariate linear regression analysis revealed that, in addition to L-carnitine as the strongest predictor of log transformed TMAO (p<0.001), the parameters of age, diabetes status and body mass index (BMI) were independently associated with increased log transformed TMAO levels (p<0.01).Our data provide evidence that age, diabetes and BMI are associated with higher TMAO levels independently of L-carnitine. These data support the hypothesis of TMAO as a cardiovascular risk marker and warrant further investigation of TMAO for diabetes research applications.

Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: Rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration

BACKGROUND The potential for global collaborations to better inform public health policy regarding major non-communicable diseases has been successfully demonstrated by several large-scale international consortia. However, the true public health impact of familial hypercholesterolaemia (FH), a common genetic disorder associated with premature cardiovascular disease, is yet to be reliably ascertained using similar approaches. The European Atherosclerosis Society FH Studies Collaboration (EAS FHSC) is a new initiative of international stakeholders which will help establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide. METHODS The EAS FHSC will maximise the potential exploitation of currently available and future FH data (retrospective and prospective) by bringing together regional/national/international data sources with access to individuals with a clinical and/or genetic diagnosis of heterozygous or homozygous FH. A novel bespoke electronic platform and FH Data Warehouse will be developed to allow secure data sharing, validation, cleaning, pooling, harmonisation and analysis irrespective of the source or format. Standard statistical procedures will allow us to investigate cross-sectional associations, patterns of real-world practice, trends over time, and analyse risk and outcomes (e.g. cardiovascular outcomes, all-cause death), accounting for potential confounders and subgroup effects. CONCLUSIONS The EAS FHSC represents an excellent opportunity to integrate individual efforts across the world to tackle the global burden of FH. The information garnered from the registry will help reduce gaps in knowledge, inform best practices, assist in clinical trials design, support clinical guidelines and policies development, and ultimately improve the care of FH patients.

Single nucleotide polymorphisms of the purinergic 1 receptor are not associated with myocardial infarction in a Latvian population.

The purinergic 1 receptor (P2RY1) has been implicated in development of heart disease and in individual pharmacodynamic response to anticoagulant therapies. However, the association of polymorphisms in the P2RY1 gene with myocardial infarction (MI), and its associated conditions, has yet to be reported in the literature. We evaluated seven known SNPs in P2RY1 for association with MI in a Latvian population. Seven independent parameters that are related to MI [body mass index (BMI), type 2 diabetes (T2D), angina pectoris, hypertension, hyperlipidemia, atrial fibrillation and heart failure] were investigated. No significant association with MI was observed for any of the polymorphisms. Those SNPs for which the P value was close to significance were located in coding or promoter regions. Intriguingly, carriers of the minor allele in the P2RY1 gene locus showed a tendency towards higher onset age for MI, suggesting a possible protective effect of these SNPs against MI or their contribution in progression as opposed to onset. Finally, a linkage disequilibrium (LD) plot was generated for these polymorphisms in the Latvian population. The results of this study suggest that the role of P2RY1 in individuals from Latvian population is likely to be principally involved in platelet aggregation and thromboembolic diseases, and not as a significant contributing factor to the global metabolic syndrome.

A Nonsynonymous Variant I248L of the Adenosine A3 Receptor Is Associated with Coronary Heart Disease in a Latvian Population

Adenosine plays an important part in the cardiac response to ischemia and reperfusion. The human adenosine receptor A3 (A3R), along with other adenosine receptors, is involved in mediation of those effects. The aim of the study was to ascertain whether the nonsynonymous single-nucleotide polymorphism (SNP) I248L (reference SNP ID: rs35511654) located in the A3R gene is associated with coronary heart disease (CHD). DNA samples from 683 individuals with CHD and from 826 control subjects selected from the Latvian Genome Database were successfully screened for rs35511654 using the TaqMan SNP Genotyping Assay. We observed a significantly decreased frequency of the rs35511654 C allele in a group of CHD patients compared with that in controls (p = 0.009). The association remained significant after adjustment for age, sex, and other nongenetic factors (p = 0.02). These results suggest that A allele of rs35511654 may predispose to CHD.

Determination of trimethylamine‐N‐oxide in combination with l‐carnitine and γ‐butyrobetaine in human plasma by UPLC/MS/MS

An ultra-high-performance liquid chromatography-mass spectrometry (UPLC/MS/MS) method was developed and validated for the quantification of trimethylamine-N-oxide (TMAO) simultaneously with TMAO-related molecules L-carnitine and γ-butyrobetaine (GBB) in human blood plasma. The separation of analytes was achieved using a Hydrophilic interaction liquid chromatography (HILIC)-type column with ammonium acetate-acetonitrile as the mobile phase. TMAO determination was validated according to valid US Food and Drug Administration guidelines. The developed method was successfully applied to plasma samples from healthy volunteers.

Nitric Oxide Production and Arachidonic Acid Metabolism in Platelet Membranes of Coronary Heart Disease Patients with and without Diabetes

Aim: To evaluate the levels of nitrite (NO–2) and nitrate (NO–3) ions and the incorporation of [3H]arachidonic acid (AA) into phospholipids of platelet membranes from coronary artery disease (CAD) patients with and without diabetes (NIDDM). Subjects and Methods: Eighteen CAD patients (group A), 18 CAD patients with NIDDM (group B), and 20 healthy controls (group C) without dyslipidemia, peripheral vascular disease and hypertension were included in the study. The groups were matched for age, sex and body mass index. The diagnosis of CAD was confirmed by coronary angiography. The nitric oxide end products (NOx), NO–2 plus NO–3 ions in platelet membranes, were determined using a spectrophotometric method based on the Griess reaction. The turnover of phospholipids was evaluated by incorporation of [3H]AA into platelet membrane phospholipids. Results: A significantly smaller amount of NOx ions was in the platelet membrane of groups A (40 ± 8 µmol/l) and B (29 ± 10 µmol/l) than C (57 ± 6 µmol/l), p < 0.001. Conversely a significantly greater amount of [3H]AA was incorporated into platelet phospholipids of group B patients (5,123 ± 1,637 dpm/mg) than groups A (3,159 ± 1,253 dpm/mg; p < 0.002) and C (1,621 ± 417 dpm/mg). An inverse correlation between [3H]AA incorporation and NOx levels was established: r = –0.76 (p < 0.05, n = 36) in CAD patients. Conclusions: Diabetes in CAD patients decreased the ability to produce platelet-derived NO and affects AA metabolism. This may result in higher platelet sensitivity to aggregating stimuli.

Prevalence of dyslipidemia in statin-treated patients in the Baltic states (Estonia, Latvia, and Lithuania): Results of the Dyslipidemia International Study (DYSIS)

BACKGROUND AND OBJECTIVE The Baltic nations (Estonia, Latvia, and Lithuania) are profoundly affected by cardiovascular disease (CVD). Studies have indicated that patients may experience persistent dyslipidemia despite chronic statin treatment. Therefore, the aim of this study was to analyze the risk factors for dyslipidemia despite statin-treatment in a large dataset from the Baltic nations. MATERIAL AND METHODS Patients in primary care centers across the Baltic nations were enrolled into the cross-sectional, observational Dyslipidemia International Study (DYSIS). Patients were ≥ 45 years old and had been treated with statins for at least three months. Patient characteristics and lipid measurements were used to determine variables contributing to dyslipidemia (abnormal low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], or total triglyceride [TG] values). RESULTS We enrolled 1797 patients with a mean age of 66.1 years and 59.1% being female. Overall 63.4% had cardiovascular disease, 30.1% were diabetic and 77.8% at high risk for cardiovascular complications. LDL-C was not at target level for 80.7%; low HDL-C levels were observed for 26.0%, and elevated TG levels were found in 35.0% of all patients. Multivariate analyses indicated that a BMI ≥ 30 kg/m(2) (OR, 2.12; 95% CI, 1.45-3.08) and hypertension (OR, 2.43; 95% CI, 1.1 6-5.10) were strongly associated with dyslipidemia (involving all three lipids) during statin therapy while age ≥ 70 years (OR, 0.63; 95% CI, 0.42-0.94) and female gender (OR, 0.48; 95% CI, 0.33-0.68) conferred reduced risk. CONCLUSIONS Our findings indicate many statin-treated patients in Estonia, Latvia, and Lithuania did not meet target lipid levels and had a very high risk of CVD. Combating other well-known CVD risk factors such as obesity and hypertension is vital to reduce the exceptionally high risk for CVD mortality seen in the Baltic nations.

Management of coronary artery disease patients in Latvia compared with practice in Central-Eastern Europe and globally: Analysis of the CLARIFY registry

BACKGROUND AND OBJECTIVE Management of outpatients with stable coronary artery disease (CAD) is important in secondary prevention. The objective was to describe differences in the characteristics of CAD patients in Latvia compared with other countries. MATERIALS AND METHODS CLARIFY is an ongoing international, prospective, observational, longitudinal registry of outpatients with CAD. Data regarding treated outpatients with established CAD from the CLARIFY registry in Latvia (n=120) were compared with those from the rest of Central-Eastern Europe (CEE) (n=2888) and worldwide (n=33,163). RESULTS Patients in Latvia had a larger waist circumference (101 [95-109] vs. 99 [91-106] in CEE, 96.5 [88-105]cm worldwide; P=0.023 and P<0.001, respectively) and higher blood pressure (systolic: 138.28±17.13 vs. 133.77±16.47 in CEE and 130.97±16.65mm Hg worldwide, P=0.003 and P<0.001; diastolic: 82.98±8.58 vs. 80.01±9.61 in CEE and 77.22±9.97mm Hg worldwide, P<0.001 and P<0.001, respectively). Body mass index in Latvia did not differ significantly from that in CEE (P=0.422), but was higher than worldwide (28.8 [26.2-32.0] vs. worldwide 27.3 [24.8-30.3]kg/m(2), P<0.001). The history of percutaneous coronary intervention was more frequent in Latvia (74.17% vs. 59.34% in CEE and 58.61% worldwide, P=0.001 and P<0.001, respectively). Latvian patients more frequently used aspirin (97.50% in Latvia vs. 89.75% in CEE and 87.64% worldwide, P=0.005 and P=0.001, respectively). CONCLUSIONS Latvian CAD patients are well managed in terms of aspirin use and frequency of percutaneous coronary intervention. Control of obesity and high BP is poorer and needs further improvement.