Ivan Pećin

Effects of statin therapy on augmentation index as a measure of arterial stiffness: A systematic review and meta-analysis

OBJECTIVE To evaluate the effects of statin therapy on augmentation index (AIx) as a measure of arterial stiffness using a meta-analysis of clinical trials. METHODS The search included PubMed-Medline, Embase, SCOPUS, Web of Science and Google Scholar databases to identify randomized controlled trials investigating the effects of statin therapy on arterial stiffness measured as AIx. A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. Random-effects meta-regression was performed using unrestricted maximum likelihood method to evaluate the impact of potential confounders. RESULTS 18 trials examining the effects of statin therapy on arterial stiffness were included. A significant reduction in aortic AIx following statin therapy was proven (WMD: -2.40%, 95% CI: -4.59, -0.21, p=0.032; I(2): 51.20%). HR-adjusted AIx 75% values also revealed a significant improvement by statin therapy (WMD: -5.04%, 95% CI: -7.81, -2.27, p<0.001; I(2): 0%), but not when analysis was restricted to unadjusted AIx values (WMD: -2.30%, 95% CI: -4.83, 0.23, p=0.075; I(2): 53.83%). There was no significant change in carotid (WMD: -2.75%, 95% CI: -8.06, 2.56, p=0.309; I(2): 26.86%) and peripheral (WMD: 0.25%, 95% CI: -3.31, 3.82, p=0.889; I(2): 72.19%) AIx due to statin treatment. There was also no difference in the effect size calculated for different statins subgroups. The impact of statins on AIx was independent of LDL-cholesterol level (slope: 0.05; 95% CI: -0.02, 0.13; p=0.181). CONCLUSION Statin therapy causes a significant reduction in aortic AIx which is independent of LDL-cholesterol changes.

Mutation detection in Croatian patients with Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is caused by mutations in the genes for LDLR, APOB or PCSK9, and identification of the causative mutation provides definitive diagnosis so that the patient can be treated, their relatives tested and, therefore, premature heart disease prevented.

Prevention of cardiovascular disease in patients with familial hypercholesterolaemia: The role of PCSK9 inhibitors

Familial hypercholesterolaemia is an autosomal dominant inherited disorder characterised by elevated low-density lipoprotein cholesterol levels and consequently an increased risk of atherosclerotic cardiovascular disease (ASCVD). Familial hypercholesterolaemia is relatively common, but is often underdiagnosed and undertreated. Cardiologists are likely to encounter many individuals with familial hypercholesterolaemia; however, patients presenting with premature ASCVD are rarely screened for familial hypercholesterolaemia and fasting lipid levels are infrequently documented. Given that individuals with familial hypercholesterolaemia and ASCVD are at a particularly high risk of subsequent cardiac events, this is a missed opportunity for preventive therapy. Furthermore, because there is a 50% chance that first-degree relatives of individuals with familial hypercholesterolaemia will also be affected by the disorder, the underdiagnosis of familial hypercholesterolaemia among patients with ASCVD is a barrier to cascade screening and the prevention of ASCVD in affected relatives. Targeted screening of patients with ASCVD is an effective strategy to identify new familial hypercholesterolaemia index cases. Statins are the standard treatment for individuals with familial hypercholesterolaemia; however, low-density lipoprotein cholesterol targets are not achieved in a large proportion of patients despite treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce low-density lipoprotein cholesterol levels considerably in individuals with familial hypercholesterolaemia who are concurrently receiving the maximal tolerated statin dose. The clinical benefit of PCSK9 inhibitors must, however, also be considered in terms of their cost-effectiveness. Increased awareness of familial hypercholesterolaemia is required among healthcare professionals, particularly cardiologists and primary care physicians, in order to start early preventive measures and to reduce the mortality and morbidity associated with familial hypercholesterolaemia and ASCVD.

Kidney volume and albuminuria as markers of birth weight-blood pressure relationship in essential hypertension.

Our aim was to analyze whether birth weight contributes to future hypertension through reduced kidney volume, and whether albuminuria could be a marker of this pathway. We included 103 patients with newly diagnosed essential hypertension and 92 normotensive controls. Blood pressure (BP) was measured using a mercury sphygmomanometer and a ABP monitor. Kidney volume was determined by ultrasound. Data on birth weight were obtained from mothers. Albuminuria was determined in 24-hour urine samples. Hypertensive patients had lower birth weight and higher albuminuria than normotensives. There was no difference in kidney volume between the two groups. We found a negative correlation between birth weight and systolic BP in the hypertensive group. BP was significantly correlated with BMI and albuminuria in the hypertensive group. Multiple regression analysis had shown the greatest impact of BMI on BP and had also demonstrated that 24-hour systolic BP showed the greatest risk for developing albuminuria in hypertensive patients. In conclusion, birth weight influences BP values in adult age, but it is not mediated by a reduced kidney volume. A strong correlation, independent of birth weight, was observed between albuminuria and BP values. Increased BMI is the most important independent risk factor responsible for BP increase, even in an early phase of essential hypertension.

[OP.2B.03] GLOMERULAR HYPERFILTRATION AS A RISK FACTOR FOR RENAL IMPAIRMENT AND HYPERTENSION IN APPARENTLY HEALTHY SUBJECTS.

Objective: Chronic kidney disease(CKD) is established CV risk factor, and already early renal impairment(RI) increases risk for hypertension(HT) and loss of renal function. It was reported that blood pressure (BP) and metabolic derangements are associated with glomerular hyperfiltration(GHF), and GHF increases risk of developing microalbuminuria (MA) in HT stage 1. Our aim was to analyze whether GHF predicts progression to HT and RI in apparently healthy subjects. Design and method: Out of 954 subjects enrolled in ENAH follow-up study, 371 (137 m, 234 w; mean age = 46 years) were eligible for further analysis:100 with optimal, 72 with normal BP, 70 with PHT (high normal BP), and 129 with newly diagnosed untreated HT. Follow-up period was 77 ± 12 months. Exclusion criteria were treatment with antihypertensive drugs, diabetes, pregnancy, eGFR<60 ml/min, CV or cerebrovascular incident, chronic terminal diseases, dementia, immobility and missing data. BP and heart rate were measured using Omron 6 device following the ESH guidelines. Uric acid, glucose, lipids, serum creatinine, hsCRP, leptin and adiponektin were determined; HOMA index was used to calculate insulin resistance and MDRD formula to estimate GFR. Albumin to creatinine ratio (ACR) was determined from the first morning spot urine. GHF was defined as eGFR above the cut off value of the 5th quintile of the whole group. Results: In the GHF group eGFR(ml/min/year) decreased significantly more than in others (−3.4 (IQ−5.8 to −1.76 vs. −1.5 (IQ−2.6 to −0.3); total decrease −17.7% vs. −9.8%; per year −2.8% vs. −1.5%; all p < 0.001). ACR was non-significantly higher in GHF group at enter and at the end of follow-up (5.73 (IQ3.35–8.6) vs. 4.5 (IQ3.31–7.25); p = 0.06, 5.93 (IQ4.26–8.64) vs. 5.7 (IQ4.08–9.82; NS, respectively). In the GHF group, at the end of follow-up ACR did not increase significantly. At enter and at the end of follow-up BP was significantly lower in GHF group (p < 0.001). At the end of study we failed to observe difference in increase of BP and new-onset HT between GHF and others. Conclusions: In our group of healthy subjects GHF was associated only with more rapid decrease of GFR. No impact of GHF on ACR increase and development of new-onset HT in healthy subjects was observed. GHF has less prominent effect on HT and kidney function in apparently healthy subjects than in those with HT and metabolic disorder.

Adiponectin is Not Associated With Blood Pressure in Normotensives and Untreated Hypertensives With Normal Kidney Function

AbstractThe role of adiponectin in hypertension is still a matter of debate. Obtained conflicting results could be mostly explained with diversity of subjects included in different studies. Our aim was to analyze association of adiponectin with blood pressure (BP) in a group of normotensive and untreated hypertensive subjects.Participants (N = 257) were selected from a random sample of 2487 subjects enrolled in an observational cross-sectional study. Subjects with diabetes and chronic kidney diseases were excluded. BP was measured using Omron M6 device following ESH/ESC guidelines. Adiponectin concentration was determined by ELISA.There were no differences in adiponectin values (mg/L) between hypertensives and normotensives (median 9.75; iqr: 7.44–17.88 vs 11.35; iqr: 7.43–12.63; P = 0.17). On univariate linear regression adiponectin was not associated with systolic or diastolic BP (P > 0.05). Furthermore, multivariate analysis did not show significant contribution of log-transformed adiponectin either to systolic (&bgr; = −0.040; P = 0.43) or diastolic BP (&bgr; = 0.066; P = 0.33).In our group of normotensives and untreated hypertensives with normal kidney function adiponectin was not associated with BP even after adjustment for other risk factors. Our results and conclusions should not be extrapolated to subjects with other characteristics.

[PP.07.18] ASSOCIATION OF ADIPONECTIN GENE POLYMORPHISMS WITH BLOOD PRESSURE AND HYPERTENSION

Objective: The role of adiponectin in hypertension (HT) is still a matter of debate. Obtained conflicting results could be mostly explained with diversity of subjects included in different studies. Our aim was to analyze association of adiponectin and its gene polymorphisms with blood pressure (BP) in a group of normotensive (NT) and untreated HT subjects with normal kidney function. Design and method: Analyses was conducted in 192 subjects (68 m; age 44 (IQR 31–53)). Those with diabetes, treated HT and chronic kidney disease (eGFR < 60 ml/min) were excluded. BP was measured using Omron M6 device following ESH/ESC guidelines. Adiponectin concentration was determined by ELISA. Genotyping was done using PCR-FRET. Genetic association analyses were done with Arlequin and haplotype analysis with Unphased. Results: There were no differences in plasma adiponectin values (mg/L) between HT and NT (9.75; iqr:7.44–17.88 vs.11.35;iqr:7.43–12.63;P = 0.17) and no associations with systolic or diastolic BP (P > 0.05). Ninety-three persons had genotype −11377C/C, 77 had −11377C/G and 18 −11377G/G; minor allele frequency (MAF) 30%,with no difference between NT and HT. Polymorphism −11377C > G was not associated with HT in the dominant, codominant, overdominant, recessive or additive model (all p > 0.05). Polymorphism −11391G > A (164 were dominant homozygots and 22 were heterozygots; MAF 12%, with no difference between NT and HT) also was not associated with HT (OR 2.12 [0.73–6.16]). Haplotype analysis established three haplotypes, C-G (freq. 64%), G-G (30%), C-A (6%) which showed no association with HT well. Conclusions: In our group of NT and untreated HT with normal kidney function adiponectin was not associated with BP even after adjustment for other risk factors. Even more, we did not find an association of two common adiponectin gene polymorphisms with HT. Adiponectin-BP relationship is complex and differs between specific populations. Our conclusions should not be extrapolated to subjects with other characteristics. Studies on larger number are needed.

[OP.5C.04] HEART RATE IS ASSOCIATED WITH GLOMERULAR HYPERFILTRATION IN APPARENTLY HEALTHY SUBJECTS.

Objective: Glomerular hyperfiltration (GHF) was associated with progression of kidney disease and hypertension (HT). It was reported that high metabolic risk is related to increase of GHF. Our aim was to analyze in apparently healthy subjects which factor(s) influence (s) GHF and determine(s) clinical course in long-term prospective study. Design and method: Out of 954 subjects enrolled in ENAH follow-up study, 371 (137 m, 234w; mean age = 46years) were eligible for further analysis:100 with optimal, 72 with normal BP, 70 with PHT (high normal BP), and 129 with newly diagnosed untreated HT. Follow-up period was 77 ± 12 months. Exclusion criteria were treatment with antihypertensive drugs, diabetes, pregnancy, eGFR < 60 ml/min, CV or cerebrovascular incident, chronic terminal diseases, dementia, immobility and missing data. BP and heart rate were measured using Omron 6 device following the ESH guidelines. Uric acid, glucose, lipids, serum creatinine, hsCRP, leptin and adiponectin were determined; HOMA index was used to calculate insulin resistance and MDRD formula to estimate GFR. Albumin to creatinine ratio (ACR) was determined from the first morning spot urine. GHF was defined as eGFR above the cut off value of the 5th quintile of the whole group. Results: Subjects with GHF were younger (38.1 vs. 48 13), had smaller waist circumfernce (87 ± 17 vs. 92 ± 16), lower BP (121/76 vs. 131/81), total cholesterol (5.3 ± 1.1 vs. 5.8 ± 1.1) LDL-cholesterol (3.1 ± 0.9 vs. 3.5 ± 1.0) and leptin (C 5,1 (IQ2.8–10.7) vs. 10.4 (5.4–16.6) compared to others; all p < 0.05. Neither metabolic factors nor BP values were assosiated with GHF. However, GHF was positively associated with HR in a way that every 1 beat/min increases odds for hyperfiltration for 7% (1.07 [1.02, 1.13]) at baseline for 6% at the end of follow up (1.06 [1.01, 1.10]). Conclusions: Contrary to some reports from literature, our group of apparently healthy subjects with GHF did not have increased metabolic risk. Interestingly, according to our results heart rate is positively associated with GFH indicating that increased sympathetic activity might have important role.

PS 14-88 BLOOD PRESSURE PREDICTS NEW-ONSET CHRONIC KIDNEY DISEASE INDEPENDENTLY OF METABOLIC SYNDROME – LONGITUDINAL DATA FROM THE CROATIAN RURAL STUDY (ENAH)

Objective: Chronic kidney disease (CKD) and metabolic syndrome (MetSy) are important predictors of mortality. Our objective was to assess the predictors of new onset CKD in rural population with and without MetSy. Design and Method: Out of 954 subjects enrolled in ENAH follow-up study, 521 (147 m, 374 w) were eligible for further analysis and followed up for total of 3333 person-years (median 7 (5–7) years). Exclusion criteria were pregnancy, CV or cerebrovascular incident and chronic terminal diseases. Blood pressure (BP) was measured using Omron M6. Fasting blood was analysed for glucose, lipids, serum creatinine and other parameters. MetSy was diagnosed according to NCEP-ATP III criteria. Results: Prevalence of MetSy at baseline was 24.0% being similar in men and women (24.6% vs. 22.4%, p = 0.35). The prevalence of individual MetSy components in subjects with MetSy were: high BP (88.9%), pathological WC (81.6%), high FBG (60.0%), high TG (48.8%) and low HDL-C (30.4%); women having pathological WC more frequently (98.9% vs. 87.9%, p = 0.017). The incidence rate of new onset MetSy was 3.7% per year. Prevalence of CKD at baseline in our group was 5.6%, being similar in subjects with MetSy and controls (8.1% vs 5.1%, p = 0.13). Contrary to this, 31 subjects developed new onset CKD for an incidence rate of 1.0% per year and an incidence almost 2.5-fold higher in subjects with MetSy (11.5% vs. 4.8%, p = 0.02). There was no difference in number of MetSy components or their individual prevalence between CKD and non-CKD subjects (p > 0.05). In whole group, BP (OR 3.0,95% CI 0.9,10.0) and older age (OR 1.2,95% CI 1.1,1.3) were predictors of new onset CKD. Conclusions: MetSy is highly prevalent in Croatian rural population and frequently associated with CKD. Beside age, BP is predictor of new-onset CKD. Dietary and BP lowering population-level strategies might show efficient in preventing not just MetSy, but to a certain extent CKD.

Angiotensin-converting enzyme gene polymorphism and N-Acetyl-β-D-glucosaminidase excretion in endemic nephropathy.

Background: Tubular proteinuria and enzymuria are hallmarks of endemic nephropathy (EN). The role of I/D angiotensin convertase (ACE) gene polymorphism has not yet been elucidated in this peculiar chronic tubulointerstitial nephritis, and our aim was to investigate the role of this polymorphism in EN focusing on the urinary N-acetyl-β-D-glucosaminidase (NAG) excretion, a biomarker of proximal tubular damage. Methods:ACE genotype and allele frequencies were determined in 229 farmers (147 women and 82 men) from an endemic Croatian village. The farmers were stratified according to the WHO criteria into the following subgroups: those ‘at risk’ for EN (n = 37), ‘suspected of having EN’ (n = 57), and ‘others’ (n = 135). Results: There were 74 (32.3%) subjects homozygous for the D allele, 99 (43.2%) heterozygous (ID genotype) and 56 (24.4%) homozygous for the I allele. No differences in allele frequency were found between the established WHO subgroups (p > 0.05). In the whole group, DD subjects had significantly higher values of diastolic blood pressure (p = 0.003) and urinary NAG than subjects with ID and II genotype (5.5 ± 1.2 vs. 4.0 ± 3.0 vs. 3.8 ± 4.2, respectively; p = 0.023). The highest values of serum creatinine (p = 0.02), proteinuria (p = 0.03) and urinary NAG (6.0 ± 3.7 vs. 3.7 ± 2.1 vs. 3.0 ± 1.6, respectively; p = 0.008) were observed in those suspected of having EN group with the DD genotype. Conclusion:ACE gene polymorphism is not a risk factor for EN. However, it might influence the clinical course of EN, and increased excretion of NAG might be a prognostic marker of this chronic tubulointerstitial nephritis.