Association between adjunctive metformin therapy in young type 1 diabetes patients with excess body fat and reduction of carotid intima-media thickness.

INTRODUCTION    Lipoprotein-associated phospholipase A2 (Lp-PLA2) and cholesteryl ester lipase (CEL) may oxidize low-density lipoproteins (oxLDL). OBJECTIVES    The aim of the study was to determine the influence of metformin on the metabolism of atherogenic lipid fractions in relation to Lp-PLA2 and CEL levels, as well as assess consequent improvement in the intima-media thickness (IMT) of the common carotid artery in young type 1 diabetes patients with excess body fat. PATIENTS AND METHODS    It was an open-label randomized clinical trial that lasted 6 months. It included a total of 84 people with metabolic decompensation (glycated hemoglobin >7.5%, >58.5 mmol/mol) of diabetes. Adjunctive metformin therapy (in addition to insulin) was administered in 42 patients, and the remaining 42 patients received insulin alone. Glycated low-density lipoproteins (LDLs), oxLDL, Lp-PLA2, and CEL were assessed by commercially available enzyme-linked immunosorbent assay kits. Cartoid IMT was measured using the Carotid Analyser for Research tool. Biochemical analyses were performed using routine laboratory techniques. RESULTS    The reduction of mean carotid IMT was observed in young type 1 diabetic adults treated additionally with metformin (0.6 ±0.1 cm vs 0.53 ±0.1 cm; P = 0.002). This effect was probably due to weight reduction (90 ±16 kg vs 87 ±15 kg, P = 0.054) and the decrease in atherogenic glycated LDL levels (1.5 ±0.5 mg/dl vs 1.6 ±1.046 mg/dl, P = 0.006). No such correlations were observed in patients treated with insulin alone. Additionally, in patients receiving metformin, glycated LDL levels were inversely correlated with Lp-PLA2 levels (r = -0.31, P <0.05). CONCLUSIONS    Additional use of metformin in young type 1 diabetic patients with excess body fat leads to a significant reduction of mean IMT in the common carotid artery. Concentrations of CEL and Lp-PLA2 were significantly increased in both study arms despite improved glucose metabolism.

Arterial stiffness, body fat compartments, central hemodynamics, renal function and left atrial size.

BACKGROUND: Left atrial (LA) size is an important predictor of stroke, death, and atrial fibrillation. It was demonstrated recently that body fat, arterial stiffness and renal functions are associated with LA diameter. However, data are lacking for comprehensive assessments of all these risk factors in a single population. Therefore, the aim of the present study was to investigate the association between LA size and different fat descriptors, central hemodynamics, arterial stiffness, and renal function in healthy subjects. METHODS: To this end, body fat percentage, abdominal, subcutaneous fat, and general descriptors of body fat were estimated in 162 healthy subjects (mean age 51 years). Echocardiography was performed to assess LA diameter. Arterial stiffness and peripheral and central hemodynamics were estimated by digital volume pulse analysis and pulse wave analysis. Glomerular filtration rate was estimated by MDRD formula. RESULTS: There were significant (p < 0.05) bivariate correlations between LA diameter and all descriptors of body fat (except subcutaneous fat). Arterial stiffness and estimated glomerular filtration rate (eGFR) were also significantly correlated with LA size. Multiple regression analysis including all significant confounders, such as sex, mean arterial pressure, arterial stiffness, eGFR and body fat descriptors, explained 35% of variance in LA diameter. CONCLUSIONS: In conclusion, the present study reveals significant, independent relationships between body fat, arterial stiffness, and LA size.

Metformin added to intensive insulin therapy reduces plasma levels of glycated but not oxidized low­density lipoprotein in young patients with type 1 diabetes and obesity in comparison with insulin alone: a pilot study.

INTRODUCTION: There are scarce data about the effect of metformin on lipid profile in patients with type 1 diabetes. OBJECTIVES: The present study is the first prospective clinical trial evaluating the effect of combined therapy of metformin and insulin on the pool of oxidized and glycated low­density lipoproteins (LDL) in young patients with type 1 diabetes and concomitant obesity. PATIENTS AND METHODS: A total of 33 obese patients with type 1 diabetes treated with intensive insulin therapy were randomized into a group where metformin was added. The remaining 19 patients continued to receive intensive insulin therapy (control group). In all patients, lipid profile and glycemia were assessed using routine laboratory tests. Oxidized and glycated LDL were measured using commercially available kits. Laboratory tests were performed at baseline and at a control visit after 6 months of treatment. RESULTS: A significant decrease in the levels of glycated hemoglobin, fasting plasma glucose, postprandial glucose, average glucose, triglycerides, glycated LDL, and body mass index was observed in the group receiving combined therapy. A similar decrease was not observed in the control group. The remaining lipid parameters were not changed during follow­up in any of the groups. CONCLUSIONS: Addition of metformin to intensive insulin therapy in young obese patients with type 1 diabetes results in a significant reduction of glycated LDL levels. This can be possibly explained by better glucose control, which improved insulin sensitivity of the peripheral tissues and reduced body mass in this patient group.

Low-density lipoprotein, its susceptibility to oxidation and the role of lipoprotein-associated phospholipase A2 and carboxyl ester lipase lipases in atherosclerotic plaque formation.

An increased level of low-density lipoprotein (LDL) is a very well established risk factor of coronary artery disease (CAD). Unoxidized LDL is an inert transport vehicle of cholesterol and other lipids in the body and is thought to be atherogenic. Recently it has been appreciated that oxidized products of LDL are responsible for plaque formation properties previously attributed to the intact particle. The goal of this article is to review the recent understanding of the LDL oxidation pathway. The role of oxidized products and key enzymes (lipoprotein-associated phospholipase A2 and carboxyl ester lipase) are also extensively discussed in the context of clinical conditions.

Renal morphology assessed by ultrasound in relation to central haemodynamics and body fat.

There is a correlation between renal function and the morphological characteristics of the kidney. However, little is known about the association between renal morphology and other important predictors of the risk of cardiovascular diseases, such as central haemodynamics or body fat. Thus, in the present study we investigated correlations between renal morphology, body fat and central haemodynamics. Renal morphology and intra-abdominal and subcutaneous fat were assessed by ultrasound, whereas central haemodynamics were evaluated by pulse wave analysis, in 93 healthy, non-obese subjects (mean (±SEM) age 52 ± 1 years; 43 men, 50 women). Significant correlations were found for indices of body fat (waist : hip ratio, body mass index and intra-abdominal fat) and renal morphology (kidney length, width and volume). Significant inverse correlations were found between central augmentation pressure (cAP) and kidney length (r = -0.33; P = 0.0009), width (r = -0.24; P = 0.01) and volume (r = -0.27; P = 0.007). In addition, significant negative correlations were found between the central augmentation index (cAIx) and kidney length (r = -0.36; P = 0.0003), width (r = -0.29; P = 0.003) and volume (r = -0.33; P = 0.0008). Multiple linear regression analysis revealed independent associations between kidney length and both cAP and cAIx. In conclusion, common morphometric characteristics of the kidney, as assessed by ultrasound, are associated with measures of body fat and descriptors of central haemodynamics. The relationships demonstrated in the present study indicate that these associations may be a biologically plausible phenomenon.

Association between insulin like growth factor-1 and lipoprotein metabolism in stable angina patients on statin therapy: a pilot study.

BACKGROUND AND AIM: The aim of this study was to test whether there was an association between systemic levels of insulin like growth factor-1 (IGF-1), IGF-1 binding protein-3 (IGFBP3) and selected parameters of lipid metabolism depending on the lipid-lowering therapy. This work was conducted in patients described by us previously who had either highly probable, or documented, coronary artery disease, and controlled serum lipids with prolonged statin therapy. METHODS: The study was conducted among 140 patients undergoing coronary angiography. The following parameters were measured: LDL- and HDL-cholesterol levels, TG, TC, apoB-100, apoA1, Lp(a) and IGF-1 and IGFBP3, as well as the level of oxidation products of proteins and lipids. RESULTS AND CONCLUSIONS: In the group of patients with LDL target up to 100 mg/dl and statins use, as well as in the entire population, IGF-1 and IGFBP3 were associated with protein oxidation products and Lp(a). Additionally, in the whole studied group, IGF-1 was associated with TG and LDL. More differences were observed when we used multivariate analysis. Even then, IGF-1 and IGFBP3 in the group with LDL up to 100 mg/dL, as well as in the entire group, were associated with protein oxidation products, Lp(a) and with quantitative arteriosclerosis scale (Gensini score). These results seem to confirm our previous findings, wherein significantly higher levels of systemic IGF-1 were found in patients with advanced coronary atherosclerosis.

Fibrinogen and d-dimer in contrasting relation with measures of wave reflection and arterial stiffness.

INTRODUCTION: The relationship between the results of coagulation tests and measures of arterial stiffness or wave reflection has been investigated in different diseases. This exploratory study aimed at the evaluation of similar associations in healthy individuals. MATERIAL AND METHODS: Pulse wave analysis of reconstructed aortic pressure waveform for the central augmentation index, augmentation pressure and pulse pressure, and digital volume pulse for the stiffness index were measured at supine rest in 91 healthy volunteers (54.1 ± 8.5 years; 56 female). Standard coagulation tests for the d-dimer and fibrinogen concentrations were performed in fasting venous blood. RESULTS: In univariate linear regression d-dimer and fibrinogen concentrations were significantly and positively, although weakly, associated with measures related to pulse wave analysis. Multivariate linear regression adjusted to subjects' age, resting pulse rate and mean blood pressure showed that the d-dimer concentration was significantly related to central augmentation index (p = 0.014), augmentation pressure (p = 0.003) and pulse pressure (p = 0.029) whereas fibrinogen was linked to the stiffness index (p = 0.04). Higher concentrations of d-dimers and fibrinogen are associated with increased arterial stiffness and faster pulse wave propagation in healthy people and the observed associations are independent of typical determinants of the shapes of pulse pressure waveforms like age, pulse rate and mean blood pressure. CONCLUSIONS: The independent relationships between the results of the coagulation tests and pulse wave analysis suggest that the existence of such associations may indicate a biologically plausible phenomenon.

[Co-existence of severe aortic valve stenosis and recoarctation of the aorta treated surgically in childhood]. / Wspolistnienie ciezkiej stenozy aortalnej i restenozy skorygowanej w dziecinstwie koarktacji aorty.

Coarctation of the aorta is treated surgically in most of patients during childhood. However, some of them experience recoarctation in future. A 57 year-old woman suffering from chest pain and decreased activity tolerance was admitted to the cardiac department. Physical examinations, lab tests and cardiovascular imaging revealed severe aortic valve stenosis and insignificant narrowing of the aorta. The patient underwent a surgical replacement of the aortic valve without recoarctation repair.

Pulse pressure amplification in relation to body fatness.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Aortic-brachial pulse pressure amplification (PPA) is a measure of arterial elasticity and it is also an independent cardiovascular risk factor. The PPA is mainly determined by age, height, central and peripheral pressure waveforms characteristics, including measures of arterial stiffness and wave reflection. WHAT THIS STUDY ADDS: In this study, however, we demonstrate that PPA is also significantly associated with indirect indices of body fatness. As the body fatness is treatable, our findings might be used as a reference for future studies on the effects of body fat reduction on PPA and the PPA-related cardiovascular risk. AIMS Arterial pressure transfer to the periphery is accompanied by pulse pressure amplification (PPA). Pulse pressure is influence by body fat. The purpose of the present study was to evaluate any possible inter-relation between body fatness and PPA in healthy subjects. METHODS: Haemodynamic and wave reflection indices were estimated by pulse wave analysis. Body fat was measured by bio-impedance. RESULTS: A total of 367 healthy volunteers (136 men and 231 women) was studied. Pulse pressure amplification correlated significantly with percentage of body fat (r=-0.53, P < 0.0001), age (r=-0.62, P < 0.0001), height (r= 0.43, P < 0.0001), heart rate (r= 0.28, P < 0.0001) and mean blood pressure (r=-0.29, P < 0.0001). The association of PPA with body fat was also significant in a multiple linear regression model. Age was an independent predictor of PPA and analysis of study subjects subdivided into two groups, those <50 years and those >50 years showed that body fatness correlated inversely and significantly with PPA in individuals both younger and older than 50 years (r=-0.44, P < 0.0001, r=-0.37, P < 0.0001 respectively). Augmentation pressure was also associated significantly with percentage of body fat in both subgroups (r= 0.48, P < 0.0001 and r= 0.49, P < 0.0001 respectively). CONCLUSIONS: This study performed on healthy subjects showed that pulse pressure amplification is related to body fatness over a wide age range. Percentage body fat is significantly associated with augmentation pressure, a component of central pulse pressure.

[Is the regression of atherosclerosis only possible by lowering LDL levels and is this sufficient to reduce the tendency of these lipoproteins to oxidative modification?]. / Czy regresja zmian miazdzycowych jest mozliwa tylko przez obnizanie stezenia LDL i czy jest to dzialanie wystarczajace, by zredukowac sklonnosc tych lipoprotein do oksydacyjnej modyfikacji?

The process of atherogenesis can be conditioned by the imbalance between the tendency to oxidative modification of the lipoproteins containing apoprotein B100 and antioxidant plasma properties. The paper discusses the situations leading to disruption of oxidative homeostasis on the basis of available data.

Arterial stiffness, central hemodynamics and wave reflection in normal pregnancy and control nonpregnant women.

OBJECTIVES: Pregnancy is accompanied by different physiological adaptations in the cardiovascular system. However, information on central blood pressures, wave reflection, arterial stiffness in uncomplicated pregnancy compared with nonpregnant women is limited. STUDY DESIGN: Forty-six women (mean age 28 years) in the third trimester of pregnancy and 45 healthy age- and height-matched controls were evaluated. Arterial stiffness, central hemodynamics and wave reflection was assessed with the use of digital volume pulse analysis and pulse wave analysis. RESULTS: In comparison with nonpregnant participants, pregnant women had significantly lower mean (p=0.04) and central systolic (p=0.02) blood pressure, central pulse pressure (p=0.02), augmentation index (p=0.02) and augmentation pressure (p=0.002), whereas their pulse pressure amplification was significantly higher (p=0.001). Similarly, arterial stiffness index was higher in pregnant women than in healthy nonpregnant controls (p=0.006). This index was correlated significantly with central augmentation index and augmentation pressure (r=0.5, p=0.0005 and r=0.52, p=0.0002, respectively) but only in nonpregnant women. CONCLUSIONS: Healthy pregnancy is associated with increased pulse pressure amplification as well as diminished wave reflection, which results in lower central augmentation index and augmentation pressure. Women in the third trimester of pregnancy have slightly higher arterial stiffness in comparison with healthy nonpregnant, age- and height-matched controls. The increased value of measures of arterial stiffness might be secondary to a known physiological increase of cardiac output and the amount of circulating blood.

Asymmetric features of short-term blood pressure variability.

Prolongations of cardiac cycles have a significantly larger contribution to short-term heart rate variability than shortenings--this is called heart rate asymmetry. Our aim is to establish the existence of blood pressure asymmetry phenomenon, which has not been done so far. We used 30-min resting continuous recordings of finger pressure waveforms from 227 healthy young volunteers (19-31 years old; 97 female), and performed Poincaré plot analysis of systolic blood pressure (SBP) to quantify the effect. Median contribution of SBP increases (C(i)) to short-term blood pressure variability was 52.8% (inter-quartile range: 50.9-55.1%) and median number of SBP increases (N(i)) was 48.8% (inter-quartile range: 47.2-50.1%). The C(i)>50% was found in 82% (P<0.0001; binomial test) and N(i)<50% in 75% (P<0.0001) of the subjects. Although SBP increases are significantly less abundant than reductions, their contribution to short-term blood pressure variability is significantly larger, which means that short-term blood pressure variability is asymmetric. SBP increases and reductions have unequal contribution to short-term blood pressure variability at supine rest in young healthy people. As this asymmetric behavior of blood pressure variability is present in most of the healthy studied people at rest, it can be concluded that blood pressure asymmetry is a physiological phenomenon.

[Disturbances of mitochondrial energetic processes and mt-DNA and their role in the etiology of coronary artery disease]. / Zaburzenia genetycznych struktur mitochondrialnych i procesów energetycznych oraz ich rola w etiologii choroby niedokrwiennej serca.

Apart from the theory of local inflammation in etiopathogenesis of the arteriosclerosis, hypotheses concerning the role of mitochondria in this process arise growing interest. Some proteins of the respiratory chain (OXPHOS) are coded on mitochondrial DNA. Their damage leads to interruption of oxidative phosphorylation, what in turns raises the free oxygen radicals (ROS) generation. The relationship of insufficient mechanism of mitochondrial ROS elimination with the initiation of the atherosclerosis was confirmed in experimental data. The mutagenesis of mitochondrial DNA is tied with the etiology of coronary artery disease (CAD). Some disturbances of the structure of mt-DNA are primal. The second group is probably determined by the effect of CAD influence on the structure of mt-DNA in cardiomyocytes. The mitochondrial energetic transformations are described in the article, with special regard on their potential influence on the process of mt-DNA mutagenesis and secondarily on the formation of CAD.

Albuminuria and VEGF as early markers of cardiovascular disturbances in young type 1 diabetic patients.

AIMS: The aim of the study was to assess myocardial perfusion by means of non-invasive diagnostic methods and measurement of the plasma concentration of vascular endothelial growth factor (VEGF) in patients with long-lasting type 1 diabetes. METHODS AND RESULTS: The study was performed on 41 Type 1 diabetic patients (23 females, 18 males), aged 30±7.6 with a duration of disease 15.2±5.5years. 17 patients exhibited microalbuminuria (10 females, 7 males) and 24 subjects were without microalbuminuria (13 females, 11 males). The methods used included a 24-h ECG tape, an exercise treadmill test, echocardiological evaluation with dobutamine and atropine challenge and single photon emission computer tomography (SPECT) at rest, and after dipyridamol induction of ischemia. All the exercise and stress echocardiography tests were negative. There were significant differences between microalbuminuric and normoalbuminuric subjects in the duration of their exercise tests (586.9±110.5 vs. 664.9±133.2s, p=0.027), performed work (11.4±1.6.vs. 12.6±1.8 METs, p=0.045), achieved pulse limit (89.1±3.6 vs. 92.6±5.2%, p=0.037), rest ejection fraction (55.8±8.7 vs. 62.0±4.4%, p=0.040), abnormal changes in SPECT (53 vs. 21%, p=0.047) and VEGF concentration (101.5±7.8 vs. 75.15±16.5pg/ml, p<0.05). The presence of retinopathy increased 12-fold the probability of significant changes in the SPECT (OR 12.1, 95% CI 1.38-105.64, p=0.02) and nephropathy (OR 4.27; 95%CI 1.09-16.83, p=0.03). CONCLUSION: Asymptomatic patients with long lasting type 1 diabetes may have disturbances in myocardial perfusion, especially these with microalbuminuria.

J-wave formation in patients with acute intracranial hypertension.

Various electrocardiographic changes are found in patients with increased intracranial pressure. The most common findings are sinus bradycardia, QT prolongation, ST-segment changes, and T- or U-wave abnormalities. The presence of J wave is reported rarely. We describe 3 patients with increased intracranial pressure caused by different cerebral pathologies accompanied by the dynamic formation of J waves in time.