Adaptations in mitochondrial function parallel, but fail to rescue, the transition to severe hyperglycemia and hyperinsulinemia: a study in Zucker diabetic fatty rats.

Cross-sectional human studies have associated mitochondrial dysfunction to type 2 diabetes. We chose Zucker diabetic fatty (ZDF) rats as a model of progressive insulin resistance to examine whether intrinsic mitochondrial defects are required for development of type 2 diabetes. Muscle mitochondrial function was examined in 6-, 12-, and 19-week-old ZDF (fa/fa) and fa/+ control rats (n = 8-10 per group) using respirometry with pyruvate, glutamate, and palmitoyl-CoA as substrates. Six-week-old normoglycemic-hyperinsulinemic fa/fa rats had reduced mitochondrial fat oxidative capacity. Adenosine diphosphate (ADP)-driven state 3 and carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP)-stimulated state uncoupled (state u) respiration on palmitoyl-CoA were lower compared to controls (62.3 ± 9.5 vs. 119.1 ± 13.8 and 87.8 ± 13.3 vs. 141.9 ± 14.3 nmol O2/mg/min.). Pyruvate oxidation in 6-week-old fa/fa rats was similar to controls. Remarkably, reduced fat oxidative capacity in 6-week-old fa/fa rats was compensated for by an adaptive increase in intrinsic mitochondrial function at week 12, which could not be maintained toward week 19 (140.9 ± 11.2 and 57.7 ± 9.8 nmol O2/mg/min, weeks 12 and 19, respectively), whereas hyperglycemia had developed (13.5 ± 0.6 and 16.1 ± 0.3 mmol/l, weeks 12 and 19, respectively). This mitochondrial adaptation failed to rescue the progressive development of insulin resistance in fa/fa rats. The transition of prediabetes state toward advanced hyperglycemia and hyperinsulinemia was accompanied by a blunted increase in uncoupling protein-3 (UCP3). Thus, in ZDF rats insulin resistance develops progressively in the absence of mitochondrial dysfunction. In fact, improved mitochondrial capacity in hyperinsulinemic hyperglycemic rats does not rescue the progression toward advanced stages of insulin resistance

In-vivo, cardiac-cycle related intimal displacement of coronary plaques assessed by 3-D ECG-gated intravascular ultrasound: Exploring its correlate with tissue deformability identified by palpography

Background: ECG-gated image acquisition of intravascular ultrasound (IVUS) has been shown to provide more accurate measurements at different phases of the cardiac cycle. Objective: We sought to explore the ability dynamic assessment of ECG-gated 3-D IVUS to identify deformable regions of coronary plaques, by testing the hypothesis that at a given pressure and region, a faster displacement of the intima would correspond to high strain (soft tissue) regions assessed by palpography. Methods: ECG-gated 3-D IVUS and palpograms were acquired using 30 and 20 MHz IVUS imaging catheters respectively. Frames with high and/or low strain spots identified by palpography were randomly selected and the spots were assigned to a respective quadrant within the cross section. A color-blinded side-by-side view was performed to enable the co-localization of the same region. Subsequently, the pressure driven displacement of the intima was established for each quadrant and a binary score (significant displacement or no displacement) was decided. Results: One hundred and twenty-four quadrants were studied and the prevalence of highly deformable quadrants was low (n=7, 5.6% of the total). The sensitivity, specificity, positive predictive value and negative predictive value of 3-D ECG-gated IVUS to detect deformable quadrants as assessed by palpography were 42.9, 87.2, 16.7, and 96.2% respectively. Conclusion: In this pilot in vivo study, the intimal displacement velocity in the radial direction assessed by gray-scale 3-D ECG-gated IVUS failed to correlate with highly deformable regions. However, these preliminary findings suggest that the absence of significant displacement of the intima might be accurate to predict the absence of deformable tissue

Reproducibility of computed tomography angiography data analysis using semiautomated plaque quantification software: Implications for the design of longitudinal studies

Reproducibility of the quantitative assessment of atherosclerosis by computed tomography coronary angiography (CTCA) is paramount for the design of longitudinal studies. The purpose of this study was to assess the inter- and intra-observer reproducibility using semiautomated CT plaque analysis software in symptomatic individuals. CTCA was performed in 10 symptomatic patients after percutaneous treatment of the culprit lesions and was repeated after 3 years. The plaque quantitative analysis was performed in untreated vessels with mild-tomoderate atherosclerosis and included geometrical and compositional characteristics using semiautomated CT plaque analysis software. A total of 945 matched crosssections from 21 segments were analyzed independently by a second reviewer to assess inter-observer variability; the first observer repeated all the analyses after 3 months to assess intra-observer variability. The observer variability was also compared to the absolute plaque changes detected over time. Agreement was evaluated by Bland-Altman analysis and co

Reproducibility of intravascular ultrasound radiofrequency data analysis: Implications for the design of longitudinal studies

Objectives: The purpose of this study was to assess in vivo the reproducibility of tissue characterization using spectral analysis of intravascular ultrasound (IVUS) radiofrequency data (IVUS-VH). Background: Despite the need for reproducibility data to design longitudinal studies, such information remains unexplored. Methods and results: IVUS-VH (Volcano Corp., Rancho Cordova, USA) was performed in patients referred for elective percutaneous intervention and in whom a non-intervened vessel was judged suitable for a safe IVUS interrogation. The IVUS catheters used were commercially available catheters (20 MHz, Volcano Corp., Rancho Cordova, USA). Following IVUS-VH acquisition, and after the disengagement and re-engagement of the guiding catheter, an additional acquisition was performed using a new IVUS catheter. Fifteen patients with 16 non-significant lesions were assessed by 2 independent observers. The relative inter-catheter differences regarding geometrical measurements were negligible for both observers. The inter-catheter relative difference in plaque cross-sectional area (CSA) was 3.2% for observer 1 and 0.5% for observer 2. The limits of agreement for (observer 1 measurements) lumen, vessel, plaque and plaque burden measurements were 0.82, -1.10 mm 2;0.80, -0.66 mm2;1.08, -0.66 mm2; and 5.83, -3.89%; respectively. Limits of agreement for calcium, fibrous, fibrolipidic and necrotic core CSA measurements were 0.22, -0.25 mm2;1.02, -0.71 mm2;0.61, -0.65 mm2; and 0.43, -0.38 mm2 respectively. Regarding the inter-observer agreement, the limits of agreement for lumen, vessel, plaque and plaque burden measurements were 2.61, -2.09 mm2;2.20-3.03 mm2;1.70, -3.04 mm2; and 9.16, -16.41%; respectively, and for calcium, fibrous, fibrolipidic and necrotic core measurements of 0.08, -0.09 mm2;0.89, -1.28 mm2;0.74, -1.06 mm2; and 0.16, -0.20 mm2; respectively. Conclusions: The present study demonstrates that the geometrical and compositional output of IVUS-VH is acceptably reproducible

Early or advanced stage type 2 diabetes is not accompanied by in vivo skeletal muscle mitochondrial dysfunction

Objective: Several lines of evidence support a potential role of skeletal muscle mitochondrial dysfunction in the pathogenesis of insulin resistance and/or type 2 diabetes. However, it remains to be established whether mitochondrial dysfunction represents either cause or consequence of the disease. We examined in vivo skeletal muscle mitochondrial function in early and advanced stages of type 2 diabetes, with the aim to gain insight in the proposed role of mitochondrial dysfunction in the aetiology of insulin resistance and/or type 2 diabetes. Methods: Ten long-standing, insulin-treated type 2 diabetes patients, 11 subjects with impaired fasting glucose, impaired glucose tolerance and/ or recently diagnosed type 2 diabetes, and 12 healthy, normoglycaemic controls, matched for age and body composition and with low habitual physical activity levels were studied. In vivo mitochondrial function of the vastus lateralis muscle was evaluated from post-exercise phosphocreatine (PCr) recovery kinetics using 31P magnetic resonance spectroscopy (MRS). Intramyocellular lipid (IMCL) content was assessed in the same muscle using single-voxel 1H MRS. Results: IMCL content tended to be higher in the type 2 diabetes patients when compared with normoglycaemic controls (P=0.06). The 31P MRS parameters for mitochondrial function, i.e. PCr and ADP recovery time constants and maximum aerobic capacity, did not differ between groups. Conclusions: The finding that in vivo skeletal muscle oxidative capacity does not differ between long-standing, insulin-treated type 2 diabetes patients, subjects with early stage type 2 diabetes and sedentary, normoglycaemic controls suggests that mitochondrial dysfunction does not necessarily represent either cause or consequence of insulin resistance and/or type 2 diabetes. © 2008 Society of the European Journal of Endocrinology

Myofibrillar distribution of succinate dehydrogenase activity and lipid stores differs in skeletal muscle tissue of paraplegic subjects.

Lack of physical activity has been related to an increased risk of developing insulin resistance. This study aimed to assess the impact of chronic muscle deconditioning on whole body insulin sensitivity, muscle oxidative capacity, and intramyocellular lipid (IMCL) content in subjects with paraplegia. Nine subjects with paraplegia and nine able-bodied, lean controls were recruited. An oral glucose tolerance test was performed to assess whole body insulin sensitivity. IMCL content was determined both in vivo and in vitro using 1H-magnetic resonance spectroscopy and fluorescence microscopy, respectively. Muscle biopsy samples were stained for succinate dehydrogenase (SDH) activity to measure muscle fiber oxidative capacity. Subcellular distributions of IMCL and SDH activity were determined by defining subsarcolemmal and intermyofibrillar areas on histological samples. SDH activity was 57 ± 14% lower in muscle fibers derived from subjects with paraplegia when compared with controls (P < 0.05)

(31)P MR spectroscopy and in vitro markers of oxidative capacity in type 2 diabetes patients

Background: Skeletal muscle mitochondrial function in type 2 diabetes (T2D) is currently being studied intensively. In vivo (31)P magnetic resonance spectroscopy ((31)P MRS) is a noninvasive tool used to measure mitochondrial respiratory function (MIFU) in skeletal muscle tissue. However, microvascular co-morbidity in long-standing T2D can interfere with the (31)P MRS methodology. Aim: To compare (31)P MRS-derived parameters describing in vivo MIFU with an in vitro assessment of muscle respiratory capacity and muscle fiber-type composition in T2D patients. Methods: (31)P MRS was applied in long-standing, insulin-treated T2D patients. (31)P MRS markers of MIFU were measured in the M. vastus lateralis. Muscle biopsy samples were collected from the same muscle and analyzed for succinate dehydrogenase activity (SDH) and fiber-type distribution. Results: Several (31)P MRS parameters of MIFU showed moderate to good correlations with the percentage of type I fibers and type I fiber-specific SDH activity (Pearson's R between 0.70 and 0.75). In vivo and in vitro parameters of local mitochondrial respiration also correlated well with whole-body fitness levels (VO (2peak)) in these patients (Pearson's R between 0.62 and 0.90). Conclusion: Good correlations exist between in vivo and in vitro measurements of MIFU in long-standing insulin-treated T2D subjects, which are qualitatively and quantitatively consistent with previous results measured in healthy subjects. This justifies the use of (31)P MRS to measure MIFU in relation to T2D

EFFECT OF PERINDOPRIL ON CORONARY REMODELLING: INSIGHTS FROM A MULTICENTRE, RANDOMIZED STUDY.

Aims This study sought to evaluate the effect of perindopril in coronary remodelling. Methods and results In this sub-study of a double-blind, multicentre trial, patients without clinical evidence of heart failure were randomized to perindopril 8 mg/day or placebo for at least 3 years and IVUS investigation was performed at both time-points. Positive and negative remodelling were defined as a relative increase (positive remodelling) or decrease (negative remodelling) of the mean vessel crosssectional area (CSA) .2 SD of the mean intra-observer difference. A total of 118 matched evaluable IVUS (711 matched 5 mm segments) were available at follow-up. After a median follow-up of 3.0 (inter-quartile range 1.9, 4.1) years, there was no significant difference in the change of plaque CSA between perindopril (360 segments) and placebo (351 segments) groups, P ¼ 0.27. Conversely, the change in vessel CSA was significantly different between groups (perindopril 20.18+2.4 mm2 vs. placebo 0.19+2.4, P ¼ 0.04). Negative remodelling occurred more frequently in the perindopril than in the placebo group (34 vs. 25%, P ¼ 0.01). In addition, the placebo group showed a larger, although not significant, mean remodelling index (RI) than the perindopril group (1.03+0.2 vs. 1.00+0.2, P ¼ 0.06). The temporal change in vessel dimensions assessed by the RI was significantly correlated with the change in plaque dimensions (r ¼ 0.48, P , 0.0001). Conclusion In this sub-analysis of a multicentre, controlled study, long-term administration of perindopril was associated with a constrictive remodelling pattern without affecting the lumen

The effect of coronary bifurcation and haemodynamics in prediction of atherosclerotic plaque development: a serial computed tomographic coronary angiographic study

Cardiovascular Aspects of Radiolog