Early vascular damage in retinal microcirculation in arterial hypertension: the Czech post-MONICA study.

Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Wall-to-lumen ratio (WLR) may represent the earliest step in hypertension-mediated organ damage.Our objective was to compare functional and structural parameters of retinal microcirculation in a randomly selected urban population sample, in hypertensive and normotensive individuals. DESIGN AND METHOD: A total of 398 randomly selected individuals from an urban population aged 25-65 years, residing in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry, with data evaluable in 343 patients. Complete data were available for 342 individuals divided into four groups based on blood pressure and control status of hypertension: normotensive individuals ( n  = 213), treated controlled hypertensive individuals ( n  = 30), treated uncontrolled hypertensive individuals ( n  = 26), and newly detected/untreated hypertensive individuals ( n  = 73). RESULTS: There was a tendency to higher wall thickness in treated but uncontrolled hypertensive patients (compared to normotensive and treated controlled hypertensive individuals). WLR was significantly increased in treated but uncontrolled hypertensive patients as well as in individuals with newly detected thus untreated hypertension or in patients with known but untreated hypertension. There was no difference in WLR in treated, controlled hypertensive patients compared with normotensive individuals. CONCLUSION: Our results show that an increased WLR, reflecting early vascular damage, was found in newly detected individuals with hypertension and in untreated hypertensive patients, reflecting early hypertension-mediated vascular damage. Early initiation of hypertension treatment may be warranted.

Liddle syndrome.

Liddle syndrome is an inherited form of arterial hypertension with autosomal dominant pattern of inheritance. It is caused by activating mutation of genes coding of the epithelial sodium channel in distal nephron. Mutation leads to excessive reabsorbtion of sodium ions and volume expansion resulting in arterial hypertension. Antoher typical laboratory findings are hypokalaemia, low levels of serum aldosteron and metabolic alkalosis. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, often resulting in misdiagnosis and severe complications at early age. Genetic studies should be done to confirm the diagnosis. Therapy of Liddle syndrome is based on administration of epithelial sodium channel blocker amilorid.

Blood pressure response to close or loose contact between physician and patient during attended office blood pressure measurement.

PURPOSE: Compared to unattended office blood pressure (uOBP), attended office blood pressure (aOBP) is higher. It is not known, however, to what extent distance between physician and patient influences blood pressure (BP) values. MATERIALS AND METHODS: Participants were stable hypertensive patients, followed in the university hospital-based out-patient center. During a session, automated office BP was measured three times after a pre-set five-minute pause, using the Omron 907 device; both aOBP and uOBP were done, in a random order. Simultaneously, beat-to-beat BP measurement was performed using the Finapress device. During aOBP, some participants were in close contact with the physician while others were in loose contact where the doctor was sitting in the room about 2.5 m apart. One year later, the second session with the same protocol was organized, but the close and loose contact were interchanged. The data were analyzed using a paired t-test. RESULTS: Complete data were collected in 32 patients, baseline uOBP was 122.8 ± 14.8/69.5 ± 11.7 mmHg. Systolic and diastolic aOBP with close contact was higher by 4.6 ± 6.9 and 1.9 ± 3.4 mmHg (p < 0.0007 and 0.0039, respectively), while aOBP with loose contact was not different from uOBP. Beat-to-beat BP increased during aOBP by 6.5 ± 8.5/3.3 ± 4.8 mmHg. The increase persisted during all the three aOBP measurements (p < 0.0001 for all systolic and diastolic BP values); the results were similar for close and loose contact. The peak increase during uOBP was of similar magnitude as during aOBP but it lasted shorter: it reached the significance level of p < 0.0001 only during the first uOBP measurement. CONCLUSIONS: Compared to uOBP, aOBP values were higher with close, but not with loose contact between physician and patient. These differences were, however, not detected by beat-to-beat BP measurement.

A novel nonsense mutation in the ß-subunit of the epithelial sodium channel causing Liddle syndrome.

PURPOSE: Liddle syndrome is a hereditary form of arterial hypertension caused by mutations in the genes coding of the epithelial sodium channel - SCNN1A, SCNN1B and SCNN1G. It is characterised by early onset of hypertension and variable biochemical features such as hypokalaemia and low plasma concentrations of renin and aldosterone. Phenotypic variability is large and, therefore, LS is probably underdiagnosed. Our objective was to examine a family suspected from Liddle syndrome including genetic testing and evaluate clinical and biochemical features of affected family members. MATERIALS AND METHODS: Thirteen probands from the Czech family, related by blood, underwent physical examination, laboratory tests, and genetic testing. Alleles of SCNN1B and SCNN1G genes were examined by PCR amplification and Sanger sequencing of amplicons. RESULTS: We identified a novel mutation in the ß-subunit of an epithelial sodium channel coded by the SCNN1B gene, causing the nonsense mutation in the protein sequence p.Tyr604*. This mutation was detected in 7 members of the family. The mutation carriers differed in the severity of hypertension and hypokalaemia which appeared only after diuretics in most of them; low aldosterone level (< 0.12 nmol/l) was, however, present in all. CONCLUSIONS: This finding expands the spectrum of known mutations causing Liddle syndrome. Hypoaldosteronemia was 100% sensitive sign in the mutation carriers. Low levels are observed especially in the Caucasian population reaching 96% sensitivity. Assessment of plasma aldosterone concentration is helpful for differential diagnosis of arterial hypertension. CONDENSED ABSTRACT: Liddle syndrome is a hereditary form of arterial hypertension caused by mutations in the genes encoding the epithelial sodium channel's α-, ß- and γ-subunit. It is usually manifested by early onset of hypertension accompanied by low potassium and aldosterone levels. We performed a physical examination, laboratory tests and genetic screening in 13 members of a Czech family. We found a new mutation of the SCNN1B gene which encodes the ß-subunit of the epithelial sodium channel. We describe the variability of each family member phenotype and point out the relevance of using aldosterone levels as a high sensitivity marker of Liddle syndrome in Caucasians.

Serum biomarkers, skin autofluorescence and other methods. Which parameter better illustrates the relationship between advanced glycation end products and arterial stiffness in the general population?

Stiffening of large arteries, clinically manifesting as increased aortic pulse wave velocity (PWV), is an inevitable outcome of aging. Among other mechanisms, impaired glucose metabolism plays an important role, leading to the deposition of advanced glycation end products (AGEs). This process is counterbalanced by the circulating soluble receptor for AGEs (sRAGE). We investigated the association between arterial stiffness on one side and multiple circulating biomarkers and the degree of skin deposition of AGEs on the other. In a cross-sectional design, 867 participants based on a general population sample (Czech post-MONICA studies) were examined. PWV was measured by SphygmoCor device (AtCor Medical Ltd.), while skin AGEs were measured using a dedicated autofluorescence method (AGE Reader mu®). To quantify the circulating status of AGEs, carboxymethyl lysine (CML) and sRAGE concentrations were assessed by ELISA, along with conventional glucose metabolism indicators. When analyzing the whole sample using multiple linear or logistic regression models and after adjustment for potential covariates, a significant association with PWV was found for fasting glycemia, HbA1c, sRAGE, skin AGEs, and the skin AGE-to-sRAGE ratio. Among these parameters, stepwise models identified the strongest association for the skin AGEs and AGE-to-sRAGE ratio, and this was also true when diabetic subjects were excluded. In contrast, neither CML nor its ratio relative to sRAGE showed any association with arterial stiffness. In conclusion, skin AGEs along with their ratio relative to sRAGE were closely associated with arterial stiffness and is a better indicator of the current status of deposited AGEs than other relevant factors.

The role of advanced glycation end products in vascular aging: which parameter is the most suitable as a biomarker?

Advanced glycation end products (AGEs) are involved in several pathophysiologic processes in vascular diseases, including progressive loss of elasticity of the vessel wall (arterial stiffness). Circulating soluble receptors for AGEs (sRAGE) act as a decoy and counterbalanced the harmful properties of AGEs as the natural protective factor. We compared the role of circulating or skin-deposed AGEs and sRAGE regarding the natural course of arterial stiffening. In a prospective cohort study, we longitudinally followed 536 general population-based subjects (subsample of Czech post-MONICA study). Aortic pulse-wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE and carboxymethyl lysine (circulating AGEs) were assessed at the follow-up visit by ELISA, while skin AGEs were measured using the autofluorescence-based device AGE Reader. Using multiple regressions, we found significant association between ∆PWV/year as a dependent variable, and both, sRAGE and skin AGEs as independent ones (each on its own model). However, the closest associations to ∆PWV/year were found for the ratio of these two factors (skin AGEs/sRAGE) [ß coeff = 0.0747 (SE 0.0189), p < 0.0001]. In a categorized manner, subjects with skin AGEs/sRAGE ratio ≥ 3.3 showed about twofold higher risk having ΔPWV/year ≥ 0.2 m/s [adjusted odds ratio was 2.09 (95% CI: 1.35-3.22), p = 0.001]. In contrast, neither circulating AGEs nor circulating AGEs/sRAGE showed any significant relation to ΔPWV/year. In conclusion, skin AGEs/sRAGE ratio seems to be a more sensitive biomarker of vascular aging than these single factors themselves or circulation status of AGEs.

Reference values of retinal microcirculation parameters derived from a population random sample.

Retinal microcirculation reflects retinal perfusion abnormalities and retinal arterial structural changes at relatively early stages of various cardiovascular diseases. Our objective has been to establish reference values for major functional and structural parameters of retinal microcirculation in a randomly selected urban population sample. A total of 398 randomly selected individuals from an urban population aged 25 to 65 years, resident in Pilsen, Czech Republic, were screened for major cardiovascular risk factors. Retinal microcirculation was assessed using scanning laser Doppler flowmetry (SLDF), with data evaluable in 343 patients. Of this number, complete data were available for 256 individuals free from manifest cardiovascular disease, diabetes and drug treatment for hypertension and/or dyslipidemia, constituting the reference value population. Juxtapapillary retinal capillary blood flow has increased significantly with age whereas vessel and luminal diameters have decreased. No sex differences in retinal microcirculation parameters have been found. Therefore, reference values for retinal microcirculation parameters have been established by age groups. Unattended automated office systolic BP, after adjusting for age, correlated significantly with wall-to-lumen ratio (WLR) and wall thickness (WT). Moreover, after adjusting for age and mean BP, a positive relationship has been found between carotid femoral pulse wave velocity and WT, WLR and wall cross-sectional area, indicating the interaction between micro- and macro-vasculature. In conclusion, our study is the first to provide reference values of retinal microcirculation parameters in a random Caucasian population sample. Our results have shown that, at the population level, the first structural changes in retinal microcirculation are those in lumen diameters. Of note, a close relationship between BP and vascular remodeling of retinal arterioles and between aortic stiffness and WLR of retinal arterioles suggests an interaction between micro- and macro-vasculature.

Adherence to cardiovascular prevention principles in subjects at high risk.

BACKGROUND: Asymptomatic high-risk individuals represent one of the highest priorities of cardiovascular prevention, in clinical practice frequently overlooked. We analyzed the real adherence to recommended principles of cardiovascular prevention in primary care subjects. METHODS: Our analysis is based on random general population sample, examined in the frame of post-MONICA survey in 2016/17. Each subject was categorized with regard to its individual cardiovascular risk (based on Sixth Joint European Guidelines) and the real adherence to recommended targets was ascertained. RESULTS: In total 898 subjects aged 25-75 years (47% males) were analyzed. Of them, 16.7% were classified into “very high risk“ and 36.8% into “high risk“ subgroup; remaining 46.5% were only at moderate or low risk. Regarding adherence to recommended principles, in “very high risk“ category only 58.7% abstain from any form of tobacco, 38% reported appropriate physical activity (150 minutes of at least moderate activity weekly), 16.7% had recommended body constitution (BMI 20-25 kg/m2 ), 39.3% appropriate blood pressure (.

Synergistic effect of sclerostin and angiotensin II receptor 1 polymorphism on arterial stiffening.

Aim: We aimed to establish the association between sclerostin (a glycoprotein involved in bone metabolism) and development of pulse wave velocity (PWV) in the general population. Methods: A prospective cohort study with a total of 522 subjects. Aortic PWV was measured twice (at baseline and after approximately 8 years of follow-up) and intraindividual change in PWV per year (ΔPWV/year) was calculated. Results: ΔPWV/year increased across the sclerostin quintiles, but generally in a strong age-dependent manner. However, a significant independent positive association between sclerostin and ΔPWV/year was observed exclusively in C allele carriers of rs5186 polymorphism for the angiotensin II receptor 1 (n = 246). Conclusion: Sclerostin concentrations were associated with an accelerated natural course of arterial stiffening, but only in interaction with renin-angiotension system.

Soluble receptor for advanced glycation end-products independently influences individual age-dependent increase of arterial stiffness.

Circulating levels of soluble receptor for advanced glycation end-products (sRAGE) have been suggested to have a protective role in neutralizing advanced glycation end-products (AGEs) and their pathological effects on vessel walls. We aimed to investigate the association between the circulating concentration of sRAGE and the dynamics of arterial wall stiffening as a manifestation of vascular aging in the general population. In a prospective cohort study, we longitudinally followed 530 general-population-based subjects (subsample of Czech post-MONICA study). Aortic pulse wave velocity (PWV) was measured twice (at baseline and after ~8 years of follow-up) using a SphygmoCor device (AtCor Medical Ltd), and the intraindividual change in PWV per year (∆PWV/year) was calculated. Concentrations of sRAGE were assessed at baseline by ELISA (R&D Systems). The average ∆PWV/year significantly decreased across the sRAGE quintiles (p = 0.048), and a drop by one sRAGE quintile was associated with an ~21% increase in the relative risk of accelerated age-dependent stiffening (∆PWV/year ≥ 0.2 m/s). Subjects in the bottom quintile of sRAGE (<889.74 pg/mL) had a fully adjusted odds ratio of accelerated stiffening of 1.72 (95% CI: 1.06-2.79), p = 0.028, while those with high sRAGE concentrations (≥1695.2 pg/mL) showed the opposite effect [odds ratio 0.55 (95% CI: 0.33-0.90), p = 0.017]. In conclusion, the circulating status of sRAGE independently influenced the individual progression of arterial stiffness over time. This finding strongly supports the hypothesis that high sRAGE has a protective role against vascular aging.

To what extent can the chosen blood pressure measurement technique affect the outcomes of an observational survey?

Aim: We analyzed to what extent measurement protocol influenced individual blood pressure (BP) and achievement of treatment target in patients with coronary heart disease. Methods: In a subsample of Czech EUROASPIRE III-V survey participants (n = 913), we compared the per-protocol BP measurement (by automated oscillometric device OMRON at the beginning of survey procedure) with control auscultatory measurement (by physician during interview). Results: Per-protocol approach produced significantly (p < 0.0001) higher BP values (by 9/6 mmHg in median) than auscultatory measurements and led to markedly higher proportion of patients over target BP (less than 140/90 mmHg; 59.3 vs 34.9% [p < 0.0001], per-protocol vs auscultatory technique, respectively). Conclusion: Per-protocol oscillometric technique was not equivalent to conventional auscultatory measurement and seriously over-rated the real nonachievement of BP target in observational surveys.