Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the genes coding for the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, a molecular analysis of LDLR and APOB was performed in a group of 378 unrelated ADH patients, to explore the mutation spectrum that causes hypercholesterolemia in Poland. All patients were clinically diagnosed with ADH according to a uniform protocol and internationally accepted WHO criteria. Mutational analysis included all exons, exon-intron boundaries and the promoter sequence of the LDLR, and a fragment of exon 26 of APOB. Additionally, the MLPA technique was applied to detect rearrangements within LDLR. In total, 100 sequence variations were identified in 234 (62%) patients. Within LDLR, 40 novel and 59 previously described sequence variations were detected. Of the 99 LDLR sequence variations, 71 may be pathogenic mutations. The most frequent LDLR alteration was a point mutation p.G592E detected in 38 (10%) patients, followed by duplication of exons 4-8 found in 16 individuals (4.2%). Twenty-five cases (6.6%) demonstrated the p.R3527Q mutation of APOB. Our findings imply that major rearrangements of the LDLR gene as well as 2 point mutations (p.G592E in LDLR and p.R3527Q in APOB) are frequent causes of ADH in Poland. However, the heterogeneity of LDLR mutations detected in the studied group confirms the requirement for complex molecular studies of Polish ADH patients.

Clinical significance of apoptotic index in non-small cell lung cancer: correlation with p53, mdm2, pRb and p21WAF1/CIP1 protein expression.

PURPOSE: The aim of this study was to assess the prognostic relevance of apoptotic index (AI), considered alone or together with expression of several proteins controlling G1 check point (p53, mdm2, pRb and p21WAF1/CIP1) in non-small cell lung cancer (NSCLC) patients. METHODS: Study group included 50 NSCLC patients who underwent curative pulmonary resection. Apoptosis was detected with the use of TUNEL technique and AI was defined as the number of apoptotic cells per 1,000 tumor cells. The expression of p53, mdm2, pRb and p21WAF1/CIP1 was assessed immunohistochemically. RESULTS: The mean and median AI calculated for all 50 patients was 14 and 9, respectively. Patients with lower (<14) and higher (> or =14) AI constituted 35 (70%) and 15 (30%) of cases, respectively. AI was not correlated with patient clinical characteristics, and expression of p53, pRb and p21WAF1/CIP1 . However, lower AI was correlated with over-expression of mdm2 protein (P=0.04). Median survival for patients with lower and higher AI was 43 months and 22 months, respectively, and 5-year survival probability-60 and 25%, respectively (P=0.03). In multivariate analysis, the only variable associated with shortened survival was AI (P=0.03, HR=2.9, 95% CI 1.95-3.86). CONCLUSIONS: These results suggest that AI correlates with mdm2 protein expression and influences survival in NSCLC.

Genetic influences on insulinemia in normotensive twins.

The aim of this study was to establish the contribution of genetic factors to the variance of plasma insulin concentration in healthy, normotensive twins. Seventeen pairs of monozygotic (MZ) and 17 pairs of dizygotic (DZ) twins were investigated. The test of genetic variance revealed a significantly larger within-pair variance of fasting plasma insulin (FPI) and a relative insulin resistance (RIR) in the DZ twins, in comparison with the MZ twins. Both FPI and RIR had a higher intraclass correlation coefficient in the MZ twins than in the DZ twins; the corresponding heritability estimates were 0.54 for FPI and 0.66 for RIR. Adjusting for age, gender, and body mass index did not affect heritability estimates for either FPI or RIR. Our data indicate that genetic factors are important determinants of insulinemia in normal subjects, independent of body mass index.

Awareness and treatment of arterial hypertension in Poland.

In order to find out the general public's opinion on blood pressure (BP) control in Poland a poll was conducted on a representative sample of 2080 randomly selected subjects. Overall 71% of the subjects were aware of their BP level. The awareness of BP level increased progressively with age and education level. Among those who were aware of their BP level, 21% had hypertension. Only 43% of hypertensives were treated on a regular basis. Cigarettes were smoked by 33% of the patients. Only 16% of the hypertensives used a low-salt diet, and only 31% tried to reduce animal fat in their diet. More than a half of the hypertensives did not adjust their lifestyle and daily habits to the disease. In conclusion, these results indicate that the prevention and treatment of hypertension in Poland should be urgently improved.

[Significant negative correlation between fasting plasma insulin and ambulatory blood pressure in patients on chronic hemodialysis]. / Znamienna ujemna korelacja miedzy stezeniem insuliny na czczo i ambulatoryjnym cisnieniem tetniczym u chorych przewlekle dializowanych.

Positive correlation between blood pressure and insulin is well established in patients with essential hypertension. The aim of the present study was to examine the relationship between fasting plasma insulin level and ambulatory blood pressure (ABPM) in patients with chronic renal failure. The study group consisted of 20 patients (11 females, 9 males, mean age 39 +/- 12 years) on chronic haemodialysis (mean 2.5 years). Fasting plasma insulin (FPI) was measured by radioimmunoassay. The patients were investigated before and after haemodialysis. FPI significantly increased after haemodialysis from 18.4 +/- 12.0 to 40.1 +/- 31.9 mIU/l (p < 0.01), while creatinine concentration decreased from 1158 +/- 130 to 910 +/- 159 mumol/l (p < 0.001). Night-time systolic blood pressure (SBP) was significantly lower during the day of haemodialysis (141.9 +/- 19.6 mmHg vs. 136 +/- 27.7 mmHg, p < 0.05). 24-hour and daytime SBP was nonsignificantly lower after haemodialysis. 24-hour diastolic blood pressure (DBP) was significantly lower during the day of haemodialysis (92.9 +/- 12.5 mmHg vs. 87.3 +/- 14.3 mmHg, p < 0.05), as well as daytime (94.9 +/- 12.1 mmHg vs. 88.8 +/- 14.6 p < 0.05) and night-time DBP (88.9 +/- 16.0 mmHg vs. 83.8 +/- 17.4 mmHg p < 0.05). FPI was found to be significantly negatively correlated with 24-hour, daytime and night-time SBP on the day of haemodialysis (r = -0.63, p < 0.005; r = 0.64, (p < 0.005 and r = -0.54, p < 0.05, respectively). The significant negative correlation between FPI and 24-hour SBP suggests that insulin could reveal its hypotensive effect after the haemodialysis.

Heart rate power spectral analysis in patients before and 6 weeks after coronary artery bypass grafting.

Decreased cardiac vagal activity is a known risk factor in coronary artery disease. The aim of our study was to determine the effect of coronary artery bypass grafting (CABG) on heart rate variability (HRV) before and 6 weeks after CABG. The study group consisted of 34 patients (4 women, 30 men, mean age 56 +/- 9 years). ECGs were recorded in 10 minutes periods in both supine and standing position with controlled breathing rate (0.25Hz). The analysis of HRV power spectrum was done by means of fast Fourier transformation. The total spectral power (TPS), power in very low frequency band (VLF: < 0.05 Hz), low frequency band (LF:0.05-0.15Hz), high frequency band (HF:0.15-0.5Hz), LF/HF ratio and percentage fraction of total power in these frequency bands (%VLF, %LF, %HF) were analysed. Significant attenuation of all spectral components of HRV were found during orthostatic load before CABG (p < 0.05). TPS, VLF, LF, %HF decreased in standing position to about half of their level in supine position, HF decreased to as little as one fourth, while LF/HF ratio and %LF increased significantly (p < 0.05). After the CABG these changes were not significant. We have found significant increase of HF (p < 0.05) and %HF (p < 0.01) in standing position after the CABG. The results suggest that CABG causes an improvement in cardiac vagal activity especially in standing position.

Ambulatory blood pressure and insulinaemia in different clinical conditions.

The aim of our study was to examine the relation between insulin and ambulatory blood pressure (ABPM) in several clinical conditions. ABPM monitoring was performed with Spacelabs device. Fasting plasma insulin (FPI) was measured by radioimmunoassay. In young, non-obese normotensive subjects (n = 32) there were correlations between FPI and both asleep (r = 0.61, p < 0.001), and awake systolic ABPM (r = 0.44, p < 0.01). We have not observed any significant correlation between FPI and ABP in borderline hypertensives or in patients with established hypertension. In a group of 21 hypertensive type 2 diabetics (age 52 +/- 8 years) there was no significant correlation between FPI and ABPM. Among 14 normotensive type 1 diabetics (age 31 +/- 7 years, diabetes duration > 10 years) there was a significant negative correlation between the daily dose of insulin and 24-h systolic ABPM (r =-0.63, p < 0.02). In 20 patients with renal failure on chronic haemodialysis we have found a significant negative correlation between FPI and 24-h systolic APBM (r = 0.80, p < 0.001) and 24-h diastolic ABPM (r = -0.55, p < 0.05). Similar negative correlations were found in 20 nondialysed subjects with moderate chronic renal failure. Taken together, our results suggest that insulin could reveal its hypertensive or vasodilatory effect which depends on a clinical condition of the studied subjects.

Increased urinary C-peptide and albumin excretion in juvenile borderline hypertensives.

The study was designed to evaluate the urinary excretion of C-peptide and albumin, and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity in juvenile borderline hypertensives. The second aim was to examine the relationship between these variables and ambulatory blood pressure level and variability. The study group consisted of 21 non-obese males consecutively chosen from patients with borderline hypertension, defined by sphygmanometer readings, examined in our outpatient clinic. All subjects collected separately their day-time and night-time urines during the period of ambulatory blood pressure monitoring. In 16 patients, who were considered to have "sustained" borderline hypertension, both 24-h urinary C-peptide excretion and 24-h UAE were significantly increased in comparison to those of the controls, while NAG activity did not differ significantly between the two groups. UAE was significantly lower at night than during the day in both borderline hypertensives and controls. Twenty-four-hour UAE in borderline hypertensives correlated significantly with the ambulatory blood pressure variability, but not with the average blood pressure level. These results suggest that the 24-h insulin secretion rate estimated by means of urinary C-peptide excretion is significantly increased in "sustained" borderline hypertensives. Elevated UAE in juvenile borderline hypertensives can be explained by a possible direct effect of systemic blood pressure variability on albuminuria.

[Circadian rhythm of blood pressure and heart rate in hypertension with type 2 diabetes mellitus]. / Rytm dobowy cisnienia tetniczego i tetna w nadcisnieniu tetniczym i curkzycy typu 2.

Hypertension is an important risk factor for cardiovascular complications of diabetes. Most of the studies performed in diabetics so far, however, have dealt with the assessment of blood pressure by traditional sphygmomanometry. In order to investigate the circadian pattern of blood pressure and heart rate in patients with different categories of glucose tolerance, we performed ambulatory blood pressure monitoring in 28 obese hypertensives without clinical nephropathy divided in two groups. Group A consisted of 14 hypertensive males with type 2 diabetes mellitus (mean age 49.7 +/- 7.1 years, mean duration of diabetes 4.0 +/- 2.9 years); group B consisted of 14 hypertensive males with normal glucose tolerance according to National Diabetes Data Group (mean age 47.2 +/- 7.1 years). There was no significant difference in casual blood pressure (151.4/104.8 in group A versus 148.5/104.2 mmHg in group B). Ambulatory blood pressure monitoring revealed significantly higher systolic blood pressure in group A during the day (162.2 +/- 12.1 vs 152.1 +/- 9.0 mmHg in group B, P < 0.05) and at night (141.0 +/- 13.2 vs 125.5 +/- 12.5 mmHg in group B, P < 0.005). That suggests that casual readings underestimate systolic blood pressure as a predictor for macrovascular events in type 2 diabetics. The decline in nocturnal heart rate was significantly lower in group A (11.2 +/- 5.2 min-1) in comparison to group B (16.9 +/- 7.0 min-1; P < 0.05) suggesting reduced parasympathetic tone at night in diabetic patients. We conclude that type 2 diabetes has significant influence on systolic blood pressure and heart rate 24-h profiles even in patients without diabetic nephropathy.

Plasma insulin and blood pressure response to oral glucose tolerance test in young borderline hypertensives.

In order to evaluate whether borderline hypertension might be associated with hyperinsulinaemia, twenty non-obese borderline hypertensives and twenty matched normotensives underwent a standard oral glucose tolerance test and 24-h ambulatory blood pressure monitoring. Blood pressure, plasma glucose and insulin were measured at fasting and 15, 30, 60, 120 and 180 minutes after glucose load. Fasting plasma insulin was significantly higher in borderline hypertensives in comparison to normotensives (16.6 +/- 6.9 vs 12.4 +/- 4.2 mU/l; P < 0.05). Plasma insulin response estimated by the positive incremental area under the curve did not differ significantly between two groups but borderline hypertensives showed a larger interindividual difference. Decrease of systolic blood pressure after glucose load was significantly greater in borderline hypertensive subjects. Furthermore, blood pressure and plasma insulin relationship was different in borderline hypertensives compared to normotensives.

[Circadian rhythm of blood pressure and pulse rate in young men with diabetes mellitus type I depending on duration of disease]. / Przebieg rytmu dobowego cisnienia tetniczego i tetna u mlodych mezczyzn z cukrzyca typu I w zaleznosci od czasu trwania choroby.

In order to investigate the blood pressure-heart rate interrelation and their circadian pattern in type I diabetes mellitus, we performed ambulatory blood pressure monitoring in 28 normotensive patients without clinical nephropathy divided in two groups. Group A consisted of 14 males with short-term DM (mean 2 years, mean age 28 +/- 6 years), group B consisted of 14 males with long-term DM (mean 12 years, mean age 31 +/- 7 years). Ambulatory blood pressure monitoring revealed significantly higher night heart rate in B group (74 +/- 13 l/min vs. 62 +/- 11 l/min in A, p < 0.01) and day diastolic blood pressure (83 +/- 9 mm Hg vs. 74 +/- 8 mm Hg in A, p < 0.01) and night diastolic blood pressure (73 +/- 10 mm Hg vs. 62 +/- 8 mm Hg in A, p < 0.01). The linear regression SBP/HR equation were significantly different (p < 0.02) (HR = 0.48 x SBP + 21, r = 0.40 in A vs. HR = 0.29 x SBP + 69, r = 0.28 in B). We concluded that type I diabetes duration has significant influence on diastolic blood pressure and heart rate even in patients without diabetic nephropathy and could be related to changed sensitivity of the baroreceptors.

[Levels of insulin in serum during fasting and circadian blood pressure profile in young health men]. / Stezenie insuliny w osoczu na czczo a profil dobowy cisnienia tetniczego u mlodych zdrowych mezczyzn.

In order to investigate the relation of ambulatory blood pressure values to fasting plasma insulin, non-invasive 24-hour blood pressure monitoring was performed in 32 young normotensive males. Systolic and diastolic blood pressures were averaged for awake and asleep periods. Fasting plasma insulin levels correlated significantly with both asleep (r = 0.61; p < 0.001) and awake systolic blood pressures (r = 0.44; p < 0.02) but not with casual systolic blood pressure (r = 0.27). There were no significant associations of awake, asleep and causal diastolic blood pressures values with fasting plasma insulin levels (r = 0.15, 0.05 and 0.21, respectively). These results support the hypothesis that insulin may be a physiological determinant of blood pressure.

[Indices of left heart ventricle relaxation after 5-months of hypotensive therapy with guanfacine]. / Wskazniki rozkurczu lewej komory serca po 5 miesiacach terapii hipotensyjnej guanfacyna.

The subject of the work is to assess the clinical parameters and diastolic function in patients with mild or moderate essential hypertension after 5-month treatment with guanfacine 0.5-3 mg/day, mean 1.7 mg. In the group there were 8 women and 8 men, mean age 53.7 +/- 7.6. The diastolic function of the left ventricle was assessed from the echocardiographic M-mode paper sweep of the left ventricle by the method of Gibson and Brown. In clinical parameters systolic, diastolic and mean blood pressure was found to decrease significantly, the heart rate was unchanged. Essential improvement of the markers of relaxation was received while amelioration of filling was not significant. The before treatment data were compared with the similar ones of the 60 persons of the control group. The significant differences were found in values of blood pressure, markers of relaxation and indices Iv and Ip.

Relationship between fasting plasma insulin and ambulatory blood pressure in young, non-obese normotensive subjects.

In order to investigate the relationship between ambulatory blood pressure values and fasting plasma insulin, non-invasive, 24-h blood pressure monitoring was performed in 32 young normotensive males. Systolic and diastolic blood pressures were averaged for awake and asleep periods. Fasting plasma insulin levels correlated significantly with both asleep (r = 0.61; P less than 0.001) and awake (r = 0.44; P less than 0.02) systolic blood pressure, but not with casual systolic blood pressure (r = 0.27). There were no significant associations between awake, asleep and casual diastolic blood pressure, and fasting plasma insulin levels (r = 0.15, 0.05 and 0.21, respectively). These results support the hypothesis that insulin may be a physiological determinant of blood pressure.

[Spectrum analysis of heart rate. A method of studying the role of the autonomic nervous system in the regulation of blood circulation]. / Analiza widma czestosci akcji serca. Metoda badania udzialu ukladu autonomicznego w regulacji krazenia.

Spectral analysis of heart rate variability has recently been shown to be a reliable noninvasive test for quantitative assessment of cardiovascular automatic regulatory responses. In 12 ambulant normotensive healthy young males (mean age 23 +/- 1 years) after a period of 10 min. for stabilisation, a continuous ecg recording (lead CM-5) for 8 min. was obtained in the supine and standing position, with a controlled respiration rate 15/min. Power spectrum of 512 point time series (R-R intervals) in both positions was calculated using a fast Fourier transform-based window periodogram method. Based upon results from the literature the power spectrum analysis was performed on two components: low frequency LF (0.05-0.15 Hz) and high frequency HF (0.15-0.50 Hz). Mean R-R interval decreased on standing position from 0.79 +/- 0.10 s to 0.59 +/- 0.11 s (p less than 0.001). The ratio HF/LF in supine was 0.63 +/- 0.70 and on standing position 2.54 +/- 0.73 (p less than 0.001). The relative LF component of the total HR power spectrum increased from 22.8% +/- 12.1% to 42.9 +/- 14.4% (p less than 0.001) after changing the position from supine to standing, and the relative HF component decreased from 56.3 +/- 22.4% to 25.5 +/- 16.2 (p less than 0.001). The total power was significantly lower when standing in comparison to supine position (681 +/- 519 s2, 1188 +/- 963 s2 respectively, p less than 0.05). Our results suggest that heart rate fluctuations in supine position in normal men are mainly vagally determined (HF power spectrum component).(ABSTRACT TRUNCATED AT 250 WORDS)

[Evaluation of blood pressure changes and heart rate in young health men based on results of a 24-hour monitoring of pressure]. / Ocena zmiennosci cisnienia tetniczego i tetna u mlodych zdrowych mzczyzn na podstawie calodobowego monitorowania cisnienia.

Systolic and diastolic blood pressures and heart rate were monitored in a group of 20 young healthy men for 24 hours. Period of time between 8 o'clock a.m. and 10 o'clock p.m. was treated as waking state whereas period of time from 12 p.m. to 6 a.m. as sleep phase. Mean value of systolic blood pressure for waking state was 124.6 +/- 7.6 mm Hg, and for sleep phase 110.4 +/- 11.5 mm Hg. (p < .001). Mean diastolic blood pressures were also significantly different (76.5 +/- 5.9 mm Hg and 63.8 +/- 7.7 mm Hg, respectively), the same concerns heart rate (79.6 +/- 6.4 and 63.0-7.2 min-1, respectively). In both cases p < .001. To evaluate dependence of heart rate on systolic blood pressure in waking state the following calculation was made: HR = 0.230 x systolic blood pressure +51.4 (r = 0.24; p < .001) whereas for sleep phase r did not reach a level of statistical significance (HR = 0.074 x systolic blood pressure + 53.9; r = 0.094). Single or even multiple measurements of the arterial blood pressure are not sufficient to evaluate circadian changes.

[Effects of isometric exercise on left ventricular function assessed with polycardiography in patients with early type I diabetes]. / Wplyw wysilku izometrycznego na czynnosc lewej komory serca oceniana metoda polikardiograficzna u chorych z krótkotrwajaca cukrzyca typu I.

15 patients with controlled type 1 diabetes lasting up to 24 months underwent the study. The control group consisted of 22 healthy men. Noninvasive examinations were carried out at rest and during a 3-minute isometric exercise of a load equal to 30% maximal effort. Rest systolic and diastolic blood pressures (SBP and DBP) were almost the same in both groups. Also exercise peak SBP and DBP did not significantly differ in examined groups. Rest PEP/LVET ratio were significantly lower in diabetics (means = 0.313 vs means = 0.348 in the control group; p less than 0.002). Peak isometric exercise PEP/LVET ratio significantly increased to 0.333 in diabetics, comparing with its rest value, whereas significantly decreased to 0.333 in the control group. Results indicate increased resting left ventricular contractility in patients with early, type 1 diabetes and impairment of a left ventricular adaptation for the isometric exercise in comparison with the control group.