Juris Imants Aivars

Relation of inflammatory chemokines to insulin resistance and hypoadiponectinemia in coronary artery disease patients

BACKGROUND Although many studies have shown that the metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) both are associated with chronic inflammatory state and are risk factors for coronary artery disease (CAD), it is still unclear which condition is a more important contributor to the increased production of inflammatory chemokines. The purpose of this study was to assess monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) levels and their association with insulin resistance and adiponectin concentrations in CAD patients, who were categorized as having T2DM, MS, or neither. METHODS CAD male patients were categorized into three groups: 24 non-obese patients with T2DM (D), 24 obese patients with MS (M) and 24 patients without T2DM or MS (W). 20 healthy subjects were selected as controls (C). Insulin resistance was assessed by the HOMA-IR method, but serum MCP-1, IL-8, and adiponectin levels were measured by xMAP technology. RESULTS Serum levels of MCP-1 and IL-8 in D and M groups were increased in comparison with W and C groups (p<0.001, p<0.01), but the increase in the M group was significantly higher than that in the D group (p<0.05, p<0,001), besides MCP-1 and IL-8 concentrations were correlated with HOMA-IR indexes (r=0.52; r=0.49, p<0.0001) and adiponectin levels (r=-0.59, p<0.0001). The M group demonstrated a diminution in the adiponectin level (p<0.01) and pronounced increase of HOMA-IR in comparison with the other three groups (p<0.01). CONCLUSION Obese CAD patients with MS have a more pronounced increase of MCP-1, IL-8 and HOMA-IR and more decreased adiponectin levels than non-obese CAD patients without MS.

Effect of acute systemic hypoxia on human cutaneous microcirculation and endothelial, sympathetic and myogenic activity

The regulation of cutaneous vascular tone impacts vascular vasomotion and blood volume distribution as a challenge to hypoxia, but the regulatory mechanisms yet remain poorly understood. A skin has a very compliant circulation, an increase in skin blood flow results in large peripheral displacement of blood volume, which could be controlled by local and systemic regulatory factors. The aim of this study was to determine the acute systemic hypoxia influence on blood flow in skin, local regulatory mechanism fluctuations and changes of systemic hemodynamic parameters. Healthy subjects (n=11; 24.9±3.7years old) participated in this study and procedures were performed in siting position. After 20min of acclimatization 15min of basal resting period in normoxia (pO2=21%) was recorded, followed by 20min in acute systemic hypoxia (pO2=12%), and after 15min of recovery period in normoxia (pO2=21%). HRV was used to evaluate autonomic nervous system activity to heart from systemic hemodynamic parameters which continuously evaluated cardiac output, total peripheral resistance and mean arterial blood pressure. Regional blood flow was evaluated by venous occlusion plethysmography and skin blood flow by laser-Doppler flowmetry. To evaluate local factor influences to cutaneous circulation wavelet analysis was used; fluctuations in the frequency intervals of 0.0095-0.021, 0.021-0.052, and 0.052-0.145Hz correspondingly represent endothelial, sympathetic, and myogenic activities. Our results from HRV data suggest that acute systemic hypoxia causes statistically significant increase of sympathetic (LF/HF; N1=0.46±0.25 vs. H=0.67±0.36; P=0.027) and decrease of parasympathetic (RMSSD; 80.0±43.1 vs. H=69.9±40.4, ms; P=0.009) outflow to heart. Acute hypoxia causes statistically significant increase of heart rate (RR interval; N1=960.3±174.5 vs. H=864.7±134.6, ms; P=0.001) and cardiac output (CO; N1=5.4 (5.2; 7.9) vs. H=6.7±1.4, l/min; P=0.020). Regional blood flow and vascular conductance were not changed during acute systemic hypoxia, but forearm skin blood flow (skin blood flow; N1=39.7 (34.0; 53.2) vs. H=51.6±13.9, PU; P=0.002) increases however local regulatory factor activity was not changed by acute systemic hypoxia. Acute systemic hypoxia causes sympathetic stimulation to heart which results in increased heart rate and larger cardiac output which could be the reason of forearm skin blood flow increase in acute systemic hypoxia without impact of local regulatory factors.

Usability of photoplethysmography method in estimation of conduit artery stiffness

Three channel photoplethysmography (PPG) signal waveform studies of leg conduit arteries during a provocative occlusion test were performed. PPG waveform second derivative amplitude ratio and arterial pulse wave velocity values showed significant correlations with ultrasound (US) reference method of local and regional arterial stiffness (AS), showing the ability to use PPG for AS change quantitative assessment.

Nail fold capillary diameter changes in acute systemic hypoxia

The present study was undertaken to determine the effect of arterial blood hypoxemia induced by acute systemic hypoxia (pO2=12%) on capillary recruitment and diameter, and red blood cell (RBC) velocity in human nail fold capillaries during rest, arterial post-occlusive reactive hyperemia (PRH), and venous occlusion (VO) using intravital video-capillaroscopy. Capillary recruitment was unchanged in acute systemic hypoxia (H) versus normoxia (N). There was no difference in RBC velocity measurements between normoxia and hypoxia (P<0.63). However, a statistically significant increase in nail fold capillary total width (N, 39.9±9.1 vs. H, 42.7±10.3 μm; P<0.05), apical diameter (N, 15.5±4.3 vs. H, 16.8±4.3 μm; P<0.05), arterial diameter (N, 11.9±3.5 vs. H, 13.9±4.1 μm; P<0.05), and venous diameter (N, 15.5±4.3 vs. H, 17.2±4.8 μm; P<0.05) was observed and continued to be significant most often during post-occlusive reactive hyperemia (PRH) and venous congestion (VO). These data suggest that acute systemic hypoxia does not increase capillary recruitment, but instead increases capillary diameter, resulting in increased capillary blood flow.

Two-stage multi-Gaussian fitting of conduit artery photoplethysmography waveform during induced unilateral hemodynamic events

Abstract. Photoplethysmography (PPG) is an optical technique with high diagnostic potential, yet clinical applications remain underdeveloped. Standardization of signal recording and quantification of waveform are essential prerequisites for broader clinical use. The aim of this study was to utilize a two-stage multi-Gaussian fitting technique in order to examine the parameters of conduit artery PPG waveform recorded during increasing the unilateral regional vascular resistance (RVR). This study was conducted on 14 young and healthy volunteers; various external compressions (ECs) were performed by inflating a tight cuff at 0, 40, 80, and 200 mmHg, while registering femoral PPG (wavelength 880 nm), diameter, blood flow linear velocity (vascular ultrasound), and the arterial pressure (Finapres) during the states of the baseline, partial, and total arterial occlusion, and resultant reactive hyperemia. An increase of the EC elevated the arterial stiffness (AS) and the unilateral distal RVR, and caused a shift of the fitted multi-Gaussian parameters: a decreased delay between reflected and traverse wave components and an increased ratio of their amplitudes. It was concluded that two-stage multi-Gaussian waveform quantification demonstrates an approach potentially extending the use of arterial site PPG in the assessment of diagnostically useful markers e.g., the RVR and the AS.

Assessment of conduit artery vasomotion using photoplethysmography

Vasomotion is a spontaneous oscillation of vascular tone. The phenomenon has been observed in small arterioles and capillaries as well as in the large conduit arteries. The layer of smooth muscle cells that surrounds a blood vessel can spontaneously and periodically change its tension and thereby the arterial wall stiffness also changes. As the understanding of the phenomenon is still rather obscure, researchers would benefit from a low-cost and reliable investigation technique such as photoplethysmography (PPG). PPG is an optical blood pulsation measurement technique that can offer substantial information about the arterial stiffness. The aims of this pilot study were to evaluate the usefulness of the PPG technique in the research of vasomotion and to investigate vasomotion in the relatively large conduit arteries. Continuous 15 minute long measurements of posterior tibial artery wall stiffness were taken. Artery diameter, electrocardiogram, blood pressure and respiration were also simultaneously registered. Fast Fourier Transform power spectra were calculated to identify unique stiffness oscillations that did not correspond to fluctuations in the systemic parameters and thus would indicate vasomotion. We concluded that photoplethysmography is a convenient method for the research of the vasomotion in large arteries. Local stiffness parameter b/a is more accurate to use and easier to measure than the pulse wave velocity which describes stiffness of a segment of an artery. Conduit arteries might exhibit a low amplitude high frequency vasomotion ( 9 to 27 cycles per minute). Low frequency vasomotion is problematic to distinguish from the passive oscillations imposed by the arterial pressure.

Relation of Endothelial Dysfunction and Adipokines Levels to Insulin Resistance in Metabolic Syndrome Patients

Relation of Endothelial Dysfunction and Adipokines Levels to Insulin Resistance in Metabolic Syndrome Patients Obese metabolic syndrome (MS) patients were categorised into three groups: 44 with type 2 diabetes mellitus (T2DM)(D); 20 with T2DM and coronary artery disease (CAD) (DC), and 26 with MS alone (M). Eighteen healthy subjects were selected as controls (C). Insulin resistance (IR) was assessed by HOMA-IR. Adiponectin, tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) concentrations were measured by xMAP technology. Endothelin-1 (ET-1) was determined by ELISA. We used laser Doppler imaging for evaluating cutaneous endothelium-dependent vasodilatation in the hand. D and DC groups had significantly elevated IR compared with M or C group (P < 0.01). TNF-α, IL-6, IL-8, MCP-1 and ET-1 levels in DC were significantly elevated compared with other groups (P < 0.001). IL-6, IL-8, MCP-1 and ET-1 in D group were higher than those in C group (P < 0.05). TNF-α, IL-6, IL-8, MCP-1 and ET-1 concentrations were correlated with HOMA-IR indexes and adiponectin levels. All patients had lower adiponectin concentrations than controls (P < 0.001), but there were no differences between the patient groups. Only D and DC groups demonstrated a significant and similar decrease in LDI-Ach marker compared to C group (P < 0.001). LDI-Ach values were significantly correlated with HOMA-IR indexes and adiponectin levels (P < 0.001). Our findings show that obese MS patients have significantly increased HOMA-IR, TNF-α, IL-6, MCP-1 and IL-8 levels, decreased adiponectin concentration, and endothelial dysfunction, but the presence of T2DM and CAD in these patients is associated with more pronounced endothelial dysfunction and increased production of inflammatory cytokines and chemokines. Endoteliālās Disfunkcijas Un Adipokīnu Pārmaiņu Saistība Ar Insulīna Rezistenci Metabolā Sindroma Pacientiem Pētījumā iesaistītie metabolā sindroma (MS) pacienti, tika iedalīti sekojošās grupās: 26 pacienti ar MS (M), 44 ar 2-tipa cukura diabētu (T2DM) (D) un 20 ar T2DM un koronāro sirds slimību (CAD). Astoņpadsmit veseli cilvēki izveidoja kontroles grupu (C). Insulīna rezistence (IR) tika novērtēta ar HOMA-IR. Adiponektīna, tumoru nekrozes faktora-alfa (TNF-α), interleikīna-6 (IL-6), monocītu hemoatraktantā proteīna-1 (MCP-1) un interleikīna-8 (IL-8) koncentrāciju noteikšanai izmantojām xMAP tehnologiju, bet endotelīna-1 (ET-1) koncentrāciju noteicām ar ELISA. Lai novērtētu endotēlija-atkarīgo vazodilatāciju plaukstas ādā, izmantojām lāzerdoplerogrāfijas attēldiagnostiku kopā ar 1% acetilholīna transdermālu jontoforēzi (LDI-Ach). D un DC grupā IR bija būtiski lielāka, salīdzinot ar M un C grupu (P < 0.01). TNF-α, IL-6, IL-8, MCP-1 un ET-1 koncentrācijas DC grupā bija būtiski lielākas, salīdzinot ar visām pārējām pētījuma grupām (P < 0.001), bet IL-6, IL-8, MCP-1 un ET-1 koncentrācija D grupā būtiski atšķīrās no koncentrācijas C grupā (P < 0.05). Turklāt TNF-α, IL-6, IL-8, MCP-1 un ET-1 koncentrācijas statistiski ticami korelēja ar HOMA-IR rādītāju un adiponektīna koncentrāciju. Adiponektīna koncentrācijas neatšķīrās starp pacientu grupām, bet bija būtiski zemākas, salīdzinot ar kontroles grupu (P < 0.001). Vienīgi D un DC grupā bija būtisks un līdzīgs LDI-Ach rādītāja samazinājums (P < 0.001). Rādītāju LDI-Ach un HOMA-IR vērtības savstarpēji būtiski korelēja (P < 0.001). Mūsu pētījuma rezultāti liecina, ka adipoziem MS pacientiem būtiski pieaug IR un TNF-α, IL-6, IL-8 un MCP-1 koncentrācijas, bet samazinās adiponektīna koncentrācijas, un ir endoteliālā disfunkcija (palielinātas ET-1 koncentrācijas un samazināta LDI-Ach), savukārt, T2DM un CAD klātbūtne šiem pacientiem saistīta ar vairāk izteiktu endoteliālo disfunkciju un iekaisuma citokīnu un hemokīnu pieaugumu.

587 VASOMOTOR DYSFUNCTION AND ALTERATIONS OF CIRCULATING CYTOKINES IN DIABETIC POLYNEUROPATHY PATIENTS WITH AND WITHOUT MECHANICAL ALLODYNIA

(1.7±1.8; n = 43; per protocol) and the group treated vice versa (2.5±1.6; n =57; per protocol). These trends were supported by the results of the NPSI, SF-McGill, and allodynia severity rating. Combination therapy with 5% lidocaine medicated plaster and pregabalin did not have clinically relevant effects on laboratory parameters or vital signs. The overall incidence of discontinuations due to drug-related AEs was low. No drug-related SAE was reported during combination therapy. Conclusions: Results of this study demonstrate that 5% lidocaine medicated plaster is an efficacious combination partner. Patients with PHN or painful DPN experiencing insufficient efficacy during monotherapy with either pregabalin or lidocaine plaster can benefit from combination therapy. Funded by Grünenthal

Interleukin-6 gene promoter -174G/C polymorphism and insulin resistance: a pilot study.

Abstract Background: The aim of this pilot study was to evaluate the relationship between interleukin-6 promoter –174G/C (IL-6 –174G/C) polymorphism and insulin resistance (IR) in obese patients with coronary heart disease (CHD). Methods: Twenty obese male patients with CHD were selected from a larger database of patients (n=606). IL-6 –174G/C genotype was previously analysed and only homozygotes with the CC genotype (n=10) or GG genotype (n=10) were selected. IR was measured using the homeostasis model assessment for IR (HOMA-IR) method. Results: Differences in age, body mass index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), hypertension, IL-6, C-reactive protein and HOMA-IR were not significant between the genotypes (p>0.05), but analysis of a homogeneity-of-slopes model showed that genotype had a significant influence on HOMA-IR (p=0.037), and the interaction between genotype and HDL-C had a pronounced tendency to affect HOMA-IR (p=0.058). Using multiple regression analysis, we found that HDL-C had a significant effect on HOMA-IR (p=0.023), and TG had a tendency to affect HOMA-IR (p=0.066) only in the CC genotype. Conclusions: Our data show that IL-6 –174G/C polymorphism may have a significant effect on IR. A comparison between the effects of various cardiovascular risk factors showed that HDL-C may have a significant effect on HOMA-IR in the CC genotype but not in the GG genotype. Further research is needed to test the preliminary results. Clin Chem Lab Med 2007;45:1145–8.