Paradoxical Decrease Research Articles

Extended characterisation of the serotonin 2A (5-HT2A) receptor-selective PET radiotracer 11C-MDL100907 in humans: Quantitative analysis, test–retest reproducibility, and vulnerability to endogenous 5-HT tone

Scanning properties and analytic methodology of the 5-HT2A receptor-selective positron emission tomography (PET) tracer 11C-MDL100907 have been partially characterised in previous reports. We present an extended characterisation in healthy human subjects. 64 11C-MDL100907 PET scans with metabolite-corrected arterial input function were performed in 39 healthy adults (18-55 years). 12 subjects were scanned twice (duration 150 min) to provide data on plasma analysis, model order estimation, and stability and test-retest characteristics of outcome measures. All other scans were 90 min duration. 3 subjects completed scanning at baseline and following 5-HT2A receptor antagonist medication (risperidone or ciproheptadine) to provide definitive data on the suitability of the cerebellum as reference region. 10 subjects were scanned under reduced 5-HT and control conditions using rapid tryptophan depletion to investigate vulnerability to competition with endogenous 5-HT. 13 subjects were scanned as controls in clinical protocols. Pooled data were used to analyse the relationship between tracer injected mass and receptor occupancy, and age-related decline in 5-HT2A receptors. Optimum analytic method was a 2-tissue compartment model with arterial input function. However, basis function implementation of SRTM may be suitable for measuring between-group differences non-invasively and warrants further investigation. Scan duration of 90 min achieved stable outcome measures in all cortical regions except orbitofrontal which required 120 min. Binding potential (BPP and BPND) test-retest variability was very good (7-11%) in neocortical regions other than orbitofrontal, and moderately good (14-20%) in orbitofrontal cortex and medial temporal lobe. Saturation occupancy of 5-HT2A receptors by risperidone validates the use of the cerebellum as a region devoid of specific binding for the purposes of PET. We advocate a mass limit of 4.6 μg to remain below 5% receptor occupancy. 11C-MDL100907 specific binding is not vulnerable to competition with endogenous 5-HT in humans. Paradoxical decreases in BPND were found in right prefrontal cortex following reduced 5-HT, possibly representing receptor internalisation. Mean age-related decline in brain 5-HT2A receptors was 14.0±5.0% per decade, and higher in prefrontal regions. Our data confirm and extend support for 11C-MDL100907 as a PET tracer with very favourable properties for quantifying 5-HT2A receptors in the human brain.

Altered Oxido-Reductive State in the Diabetic Heart: Loss of Cardioprotection due to Protein Disulfide Isomerase

Diabetes is associated with an increased risk of heart failure, in part explained by endoplasmic reticulum stress and apoptosis. Protein disulfide isomerase (PDI) prevents stressed cardiomyocytes apoptosis. We hypothesized that diabetes impairs PDI function by an alteration in its oxido-reductive state. Myocardial biopsies harvested from the anterolateral left ventricular wall from diabetic (n = 7) and nondiabetic (n = 8) patients were used to assess PDI expression and cardiomyocyte death. A mouse model of diabetes (streptozotocin injection, 130 mg/mL) was used to study PDI expression and its redox state after ischemia/reperfusion injury induced by 30-min occlusion of the left anterior coronary artery followed by reperfusion. Transthoracic echocardiography was performed to assess cardiac remodeling after 1 wk. Western blot analysis was used to analyze PDI expression, and methoxy-polyethyleneglycol-maleimide was used to assess its redox state. Dehydroascorbate (DHA) administration was used to restore the PDI redox state. Diabetic patients had a greater number of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells than nondiabetic patients despite a greater myocardial PDI expression suggesting altered PDI function. Diabetic mice had a worse postinfarction remodeling associated with an altered PDI redox state. DHA treatment restored functional PDI redox state and ameliorated post-myocardial infarction remodeling. An increase in PDI levels with a paradoxical decrease of its active form occurs in the diabetic heart after ischemia and may explain the lack of protective effects of PDI in diabetes. Restoration of PDI redox state prevents adverse remodeling. The potential significance of these findings deserves to be validated in a clinical setting.

Fetal uninephrectomy in male sheep alters the systemic and renal responses to angiotensin II infusion and AT1R blockade

Fetal uninephrectomy (uni-x) at 100 days of gestation results in compensatory nephrogenesis in the remaining kidney, resulting in a 30% reduction in total nephron number in male sheep. Recently, we showed that uni-x males at 6 mo of age have elevated arterial pressure, reduced renal blood flow (RBF), glomerular filtration rate (GFR), and low plasma renin levels (Singh R, Denton K, Bertram J, Jefferies A, Head G, Lombardo P, Schneider-Kolsky M, Moritz K. J Hypertens 27: 386-396, 2009; Singh R, Denton K, Jefferies A, Bertram J, Moritz K. Clin Sci (Lond) 118: 669-680, 2010). We hypothesized this was due to upregulation of the intrarenal renin-angiotensin system (RAS). In this study, renal responses to ANG II infusion and ANG II type 1 receptor (AT1R) blockade were examined in the same 6-mo-old male sheep. Uni-x animals had reduced levels of renal tissue and plasma renin and ANG II. Renal gene expression of renin, and gene and protein levels of AT1R and AT2R, were significantly lower in uni-x animals. In response to graded ANG II infusion, sham animals had the expected decrease in conscious RBF and GFR. Interestingly, the response was biphasic in uni-x sheep, with GFR initially decreasing, but then increasing at higher ANG II doses (34 ± 7%; P(group × treatment) < 0.001), due to a paradoxical decrease in renal vascular resistance (P(group × treatment) < 0.001). In response to AT1R blockade, while GFR and RBF responded similarly between groups, there was a marked increase in sodium excretion in uni-x compared with sham sheep (209 ± 35 vs. 25 ± 12%; P < 0.001). In conclusion, in 6-mo-old male sheep born with a single kidney, these studies demonstrate that this is a low-renin form of hypertension, in which responses to ANG II are perturbed and the intrarenal RAS is downregulated.

Low Incidence of Paradoxical Reductions in HDL-C Levels in Dyslipidemic Patients Treated with Fenofibrate Alone or with Ezetimibe or EZE/Simvastatin

Synopsis: Reports suggest that fibrates may cause paradoxical decreases in high-density lipoprotein cholesterol (HDL-C) in certain patients (eg, diabetic patients, high baseline HDL-C.

Role of Hypothalamic Melanocortin System in Adaptation of Food Intake to Food Protein Increase in Mice

The hypothalamic melanocortin system—the melanocortin receptor of type 4 (MC4R) and its ligands: α-melanin-stimulating hormone (α-MSH, agonist, inducing hypophagia), and agouti-related protein (AgRP, antagonist, inducing hyperphagia)—is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED) in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of α-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP-expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment.

Role of Decreased Circulating Hepcidin Concentrations in the Iron Excess of Women with the Polycystic Ovary Syndrome

Hepcidin inhibits the intestinal absorption of iron and its deficiency causes juvenile hemochromatosis. The objective of the investigation was to study the involvement of hepcidin in the iron overload of patients with polycystic ovary syndrome (PCOS). This was a case-control study followed by a randomized clinical trial. The study was conducted at an academic hospital. Thirty-four patients with PCOS and 30 women without hyperandrogenism, matched for age and body mass index, participated in the study. Patients with PCOS were randomly allocated to treatment with either an antiandrogenic oral contraceptive or metformin for 24 wk. Serum hepcidin levels and ferritin to hepcidin molar ratios were measured. Patients with PCOS showed decreased circulating hepcidin levels and increased ferritin to hepcidin molar ratios compared with controls. Patients with PCOS presenting with chronic oligoamenorrhea (an iron sparing mechanism) showed a paradoxical decrease in serum hepcidin levels and an increase in ferritin to hepcidin molar ratios compared with the patients who had regular anovulatory menstrual cycles and with the controls. The major predictor of circulating hepcidin concentrations was the presence of PCOS, whereas the main determinants of the ferritin to hepcidin molar ratio were the insulin sensitivity index and menstrual dysfunction. Serum hepcidin levels did not change during treatment with either metformin or the antiandrogenic oral contraceptive pill, yet patients treated with the oral contraceptive pill normalized the ferritin to hepcidin molar ratio. Patients with PCOS had reduced serum hepcidin concentrations that might contribute to their iron overload by favoring the intestinal absorption of iron. The imbalance between increased iron stores and reduced hepcidin levels was related to the insulin resistance and androgen excess characteristic of this syndrome.

Low incidence of paradoxical reductions in HDL-C levels in dyslipidemic patients treated with fenofibrate alone or in combination with ezetimibe or ezetimibe/simvastatin.

BackgroundFibrates have been reported to cause paradoxical decreases in HDL-C in certain patients.Design and methodsThis post-hoc analysis explored the frequency/magnitude of HDL-C reductions in a pooled database of mixed dyslipidemic patients (LDL-C:3.4-5.7 mmol/L;TG:1.7-5.7 mmol/L) receiving placebo (PBO), fenofibrate (FENO), ezetimibe plus FENO (EZE+FENO), or EZE/simvastatin plus FENO (EZE/SIMVA+FENO) for 12 weeks.ResultsPBO-treated patients had the highest incidence of HDL-C reductions from baseline (45%) compared with patients taking FENO (14%), EZE+FENO (9%), or EZE/SIMVA+FENO (9%). Reductions <30% reflected natural variability since the largest reduction in HDL-C approached 30% in the PBO group. Only 3 patients exhibited HDL-C reductions ≥30% (i.e., 2 patients in the FENO group and 1 in the EZE+FENO group). There were no differences in demographic/biochemical characteristics between patients with and without HDL-C reductions.ConclusionsThe incidence of paradoxical HDL-C reductions was low in mixed dyslipidemic patients receiving FENO alone or combined with EZE or EZE/SIMVA.Trial registrationsClinicaltrials.gov: NCT00092560 and NCT00092573

Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway

In the present study, we report that compound C, an inhibitor of a key intracellular energy sensor AMP-activated protein kinase (AMPK), can induce autophagy in cancer cells. The induction of autophagy in U251 human glioma cell line was demonstrated by acridine orange staining of intracellular acidic vesicles, Beclin 1 induction, p62 decrease and conversion of LC3-I to autophagosome-associated LC3-II in the presence of proteolysis inhibitors. The presence of autophagosome-like vesicles was confirmed by transmission electron microscopy. Compound C-mediated inhibition of AMPK and raptor in U251 cells was associated with paradoxical decrease in phosphorylation of AMPK/raptor-repressed mTOR, a major negative regulator of autophagy, and its downstream target p70S6K. The phosphorylation of an mTOR activator Akt and the PI3K-activating kinase Src was also impaired in compound C-treated cells. The siRNA-mediated AMPK silencing did not reduce the activity of the Akt/mTOR/p70S6K pathway and AMPK activators metformin and AIC AR failed to block compound C-induced autophagy. Autophagy inhibitors bafilomycin and chloroquine significantly increased the cytotoxicity of compound C towards U251 cells, as confirmed by increase in lactate dehydrogenase release, DNA fragmentation and caspase-3 activation. Similar effects of compound C were also observed in C6 rat glioma, L929 mouse fibrosarcoma and B16 mouse melanoma cell lines. Since compound C has previously been reported to suppress AMPK-dependent autophagy in different cell types, our findings suggest that the effects of compound C on autophagy might be dose-, cell type- and/or context-dependent. By demonstrating the ability of compound C to induce autophagic response in cancer cells via AMPK inhibition-independent downregulation of Akt/mTOR pathway, our results warrant caution when using compound C to inhibit AMPK-dependent cellular responses, but also support further exploration of compound C and related molecules as potential anticancer agents.

Bepridil Facilitates Early Termination of Spiral-Wave Reentry in Two-Dimensional Cardiac Muscle Through an Increase of Intercellular Electrical Coupling

Bepridil is effective for conversion of atrial fibrillation to sinus rhythm and in the treatment of drug-refractory ventricular tachyarrhythmias. We investigated the effects of bepridil on electrophysiological properties and spiral-wave (SW) reentry in a 2-dimensional ventricular muscle layer of isolated rabbit hearts by optical mapping. Ventricular tachycardia (VT) induced in the presence of bepridil (1 μM) terminated earlier than in the control. Bepridil increased action potential duration (APD) by 5% – 8% under constant pacing and significantly increased the space constant. There was a linear relationship between the wavefront curvature (κ) and local conduction velocity: LCV = LCV0 − D·κ (D, diffusion coefficient; LCV0, LCV at κ = 0). Bepridil significantly increased D and LCV0. The regression lines with and without bepridil crossed at κ = 20 – 40 cm−1, resulting in a paradoxical decrease of LCV at κ > 40 cm−1. Dye transfer assay in cultured rat cardiomyocytes confirmed that bepridil increased intercellular coupling. SW reentry in the presence of bepridil was characterized by decremental conduction near the rotation center, prominent drift, and self-termination by collision with boundaries. These results indicate that bepridil causes an increase of intercellular coupling and a moderate APD prolongation, and this combination compromises wavefront propagation near the rotation center of SW reentry, leading to its drift and early termination.[Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10233FP]

Paradoxical decrease in HDL-cholesterol and apolipoprotein A1 with simvastatin and atorvastatin in a patient with type 2 diabetes

Statins are agents widely used to lower LDL-cholesterol (LDL-C) in primary and secondary prevention of coronary heart disease. The five statins available in the UK (simvastatin, pravastatin, fluvastatin, atorvastatin and rosuvastatin) differ in many of their pharmacologic properties. In addition to lowering LDL-C, statins also increase HDL-cholesterol (HDL-C) moderately. There have been rare reports of significant HDL-C decreases in patients commenced on fibrates and when thiazolidinediones are added to fibrates. This is known as a 'paradoxical HDL-C decrease' as both groups of agents usually increase HDL-C. This phenomenon has never been clearly documented following statin therapy. We now describe a patient with type 2 diabetes who showed this paradoxical fall in HDL-C (baseline HDL-C: 1.8 mmol/L; on simvastatin 40 mg HDL-C 0.6 mmol/L; on atorvastatin 20 mg HDL-C 0.9 mmol/L) with a similar decrease in apolipoprotein A1. No similar decrease was observed with pravastatin and rosuvastatin therapy. This phenomenon appeared to be associated with statin treatment and not a statin/fibrate combination. Our patient clearly demonstrated a paradoxical HDL-C fall with simvastatin and atorvastatin, but not pravastatin or rosuvastatin. Simvastatin and atorvastatin share many pharmacokinetic properties such as lipophilicity while pravastatin and rosuvastatin are relatively hydrophilic and are not metabolized by cytochrome P450 3A4. However, these characteristics do not explain the dramatic reductions in HDL-C observed.

Echocardiographic Brockenbrough–Braunwald–Morrow sign

The Brockenbrough-Braunwald-Morrow sign is the paradoxical decrease in pulse pressure during the post-extrasystole beat seen in patients with hypertrophic obstructive cardiomyopathy. We present a case of intermittent left ventricular outflow tract obstruction and secondary mitral regurgitation resulting from post-extrasystolic potentiation following a premature atrial beat, demonstrating using echocardiography the mechanism behind this sign.

Regulation of the Matriptase-Prostasin Cell Surface Proteolytic Cascade by Hepatocyte Growth Factor Activator Inhibitor-1 during Epidermal Differentiation

Matriptase, a membrane-tethered serine protease, plays essential roles in epidermal differentiation and barrier function, largely mediated via its activation of prostasin, a glycosylphosphatidylinositol-anchored serine protease. Matriptase activity is tightly regulated by its inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1) such that free active matriptase is only briefly available to act on its substrates. In the current study we provide evidence for how matriptase activates prostasin under this tight control by HAI-1. When primary human keratinocytes are induced to differentiate in a skin organotypic culture model, both matriptase and prostasin are constitutively activated and then inhibited by HAI-1. These processes also occur in HaCaT human keratinocytes when matriptase activation is induced by exposure of the cells to a pH 6.0 buffer. Using this acid-inducible activation system we demonstrate that prostatin activation is suppressed by matriptase knockdown and by blocking matriptase activation with sodium chloride, suggesting that prostatin activation is dependent on matriptase in this system. Kinetics studies further reveal that the timing of autoactivation of matriptase, prostasin activation, and inhibition of both enzymes by HAI-1 binding are closely correlated. These data suggest that, during epidermal differentiation, the matriptase-prostasin proteolytic cascade is tightly regulated by two mechanisms: 1) prostasin activation temporally coupled to matriptase autoactivation and 2) HAI-1 rapidly inhibiting not only active matriptase but also active prostasin, resulting in an extremely brief window of opportunity for both active matriptase and active prostasin to act on their substrates.

Activation of Integrins by Urea in Perfused Rat Liver

High concentrations of urea were shown to induce a paradoxical regulatory volume decrease response with K(+) channel opening and subsequent hepatocyte shrinkage (Hallbrucker, C., vom Dahl, S., Ritter, M., Lang, F., and Häussinger, D. (1994) Pflügers Arch. 428, 552-560), although the hepatocyte plasma membrane is thought to be freely permeable to urea. The underlying mechanisms remained unclear. As shown in the present study, urea (100 mmol/liter) induced within 1 min an activation of β(1) integrins followed by an activation of focal adhesion kinase, c-Src, p38(MAPK), extracellular signal-regulated kinases, and c-Jun N-terminal kinase. Because α(5)β(1) integrin is known to act as a volume/osmosensor in hepatocytes, which becomes activated in response to hepatocyte swelling, the findings suggest that urea at high concentrations induces a nonosmotic activating perturbation of this osmosensor, thereby triggering a volume regulatory K(+) efflux. In line with this, similar to hypo-osmotic hepatocyte swelling, urea induced an inhibition of hepatic proteolysis, which was sensitive to p38(MAPK) inhibition. Molecular dynamics simulations of a three-dimensional model of the ectodomain of α(5)β(1) integrin in water, urea, or thiourea solutions revealed significant conformational changes of α(5)β(1) integrin in urea and thiourea solutions, in contrast to the simulation of α(5)β(1) in water. These changes lead to an unbending of the integrin structure around the genu, which may suggest activation, whereas the structures of single domains remained essentially unchanged. It is concluded that urea at high concentrations affects hepatic metabolism through direct activation of the α(5)β(1) integrin system.

Strain-Specific Differences in the Impact of Human TRIM5α, Different TRIM5α Alleles, and the Inhibition of Capsid-Cyclophilin A Interactions on the Infectivity of HIV-1

HIV-1 infectivity is strongly restricted by TRIM5α from certain primate species but has been described as being only marginally susceptible to human TRIM5α. In this study, we evaluated the effects of the modulation of human TRIM5α activity (pretreatment of target cells with alpha interferon, expression of a pre-miRNA targeting TRIM5α, and/or overexpression of TRIM5γ), the inhibition of cyclophilin A (CypA)-CA interactions, and the expression of different allelic variants of human TRIM5α on the infectivity of a series of recombinant viruses carrying different patient-derived Gag-protease sequences. We show that HIV-1 displays virus-specific differences in its sensitivity to human TRIM5α and in its sensitivity to different TRIM5α alleles. The effect of inhibiting CypA-CA interactions is also strain specific, and blocking these interactions can either inhibit or improve viral infectivity, depending on the isolate studied. The inhibition of CypA-CA interactions also modulates viral sensitivity to human TRIM5α. In the absence of CypA-CA interactions, most viruses displayed increased sensitivity to the inhibitory effects of TRIM5α on viral replication, but one isolate showed a paradoxical decrease in sensitivity to TRIM5α. Taken together, these findings support a model in which three interlinked factors--capsid sequence, CypA levels, and TRIM5α--interact to determine capsid stability and therefore viral infectivity.

The influence of the obesity paradox and chronic kidney disease on long-term survival in a Japanese cohort with peripheral arterial disease

This study analyzed risk factors for mortality in peripheral arterial disease (PAD), including body mass index (BMI) and estimated glomerular filtration rate (eGFR). Risk factors for long-term survival are unclear in patients with PAD. The origin of the obesity paradox, a paradoxical decrease in mortality with increasing BMI, is also uncertain in these patients. A prospective cohort study was performed in 652 patients (aged 71.3 +/- 9.4 years old) with PAD. The 1-, 5-, 10- and 15-year survival rates were 94.5%, 70.4%, 45.2%, and 21.1%, respectively, in patients with intermittent claudication, and 72.7%, 27.2%, 11.6%, and 5.8%, respectively, in those with critical limb ischemia (CLI). In Cox multivariate analysis, a significant association with all-cause mortality was found for CLI (hazard ratio [HR], 1.931; 95% confidence interval [CI], 1.089-3.422; P = .024), diabetes (HR, 2.111; 95% CI, 1.247-3.572; P = .005), BMI (HR, 0.879; 95% CI, 0.804-0.962; P = .005), and eGFR (HR, 0.985; 95% CI, 0.971-0.998l; P = .028). These parameters were also significant risk factors for cardiovascular mortality. Fibrinogen (HR, 1.003; 95% CI, 1.001-1.005; P = .014) and cerebrovascular disease (HR, 1.730; 95% CI, 1.021-2.930; P = .045) were identified as risk factors for all-cause mortality. The adjusted HR for mortality of BMI <21.5 vs >or=21.5 kg/m(2) was 1.772 (95% CI, 1.378-2.279; P < .001). BMI had positive correlations with triglyceride and albumin concentrations and negative correlations with the fibrinogen level and chronic obstructive pulmonary disease (P = .005). Low BMI, eGFR, CLI, and diabetes are significant risk factors for mortality in PAD. The obesity paradox was verified and may be partly explained by low BMI mediated by malnutrition and systemic inflammation due to PAD or chronic obstructive pulmonary disease.

Paradoxical Severe Decrease in High-Density Lipoprotein Cholesterol Due to Rosiglitazone-Fenofibrate Interaction

To determine whether the marked decrease in high-density lipoprotein cholesterol (HDL-C) occasionally associated with combination fibrate-thiazolidinedione therapy results from interaction between the 2 drugs or is solely the result of fibrate administration, a previously recognized cause. We prospectively followed the clinical course of 2 patients receiving fenofibrate and rosiglitazone and reviewed the relevant literature, searching PubMed for reports describing striking reductions in HDL-C associated with fibrate administration alone and in conjunction with rosiglitazone and statins. Additional references were obtained from the bibliography of each identified article. Each of the 2 patients demonstrated a Drug Interaction Probability Score score of 9, indicating a highly probable likelihood of interaction. Critical review of all reported cases of concurrent fenofibrate-rosiglitazone-associated decreases in HDL-C failed to show conclusive evidence that the HDL-C decrease could be due to an interaction between the 2 drugs as opposed to either drug being given alone. In at least some patients who experience marked HDL-C decrease when given a combination of fenofibrate and rosiglitazone, this severe adverse effect is the result of a drug interaction between the 2 pharmaceutical agents and is not reproduced by the administration of either drug singly.

Paradoxical Decrease in High-Density Lipoprotein Cholesterol with Fenofibrate: A Quite Rare Phenomenon Indeed

Some recent clinical reports have suggested that paradoxical decreases in high-density lipoprotein cholesterol (HDL-C) levels after fenofibrate treatment may be quite common. These appear to occur mainly in patients with combined fibrate/statin therapy and possibly in those with low baseline HDL-C. Reports on HDL-C reductions after fenofibrate are possibly supported by the disappointing results in terms of HDL-C responses from the recent FIELD study. A survey on 581 patients treated for 1 year or longer was carried out in our Clinical Center. This indicated that paradoxical HDL-C reductions are a relatively uncommon phenomenon. Not more than 15.3% of the present series showed an HDL-C reduction, mostly of a modest degree. Further, reductions of HDL-C appear to occur mainly in individuals with significant HDL-C elevations (>50 mg/dL), almost never in patients with low HDL-C. Otherwise, there seems to be no impact of a previous diagnosis of diabetes or hypertension on the HDL-C changes. From a very recent pharmacogenomic study on the apo A1/C3/A4/A5 gene cluster, genetic influences appear only to reduce the positive impact of fenofibrate on HDL-C, but do not indicate any risk of occurrence of HDL-C reductions. Also based on our very long experience with this drug, it appears that fenofibrate raises HDL-C levels in the vast majority of treated patients, with a particularly dramatic effect in individuals with low HDL-C and hypertriglyceridemia.

A Novel Technology for Assessing Cerebral Blood Flow at Altitude

Most current assessments of cerebral hemodynamics at altitude rely on transcranial dopplers (TCDs). This technology does not monitor cerebral blood flow (CBF), per se, but rather blood flow velocity. Equating CBF to blood flow velocity is predicated on multiple assumptions that remain unproven at altitude, such as constant diameter of medium-sized arteries. An increase in middle cerebral artery velocity as measured by TCD is interpreted as evidence of vasospasm within the context of subarachnoid hemorrhage, for example, but vasodilation within the context of ascent to altitude. Current techniques to directly assess CBF, such as Xenon CT (XeCT), are either too cumbersome or too expensive to allow serial measurements to assess the temporal dynamics of changes in CBF during ascent to high altitude. We present a human feasibility study of a technique, previously validated in animal models, that allows measurement of CBF that is uniquely suited to investigation of blood flow changes at altitude. Near infrared spectroscopy coupled with intravenous injection of indocyanin green dye (ICG-NIRS) was used to measure a CBF index in 3 patients undergoing laparoscopic surgery to assess feasibility of this technique in humans. Two of the 3 patients exhibited an increase in CBF index of 40% and 59%, during insufflation of CO2. The third patient exhibited a paradoxical decrease in CBF index of 39%. The combination of ICG-NIRS and determination of CBF index is a promising, minimally invasive, portable and straightforward technique to provide repeated quantitative information regarding changes in CBF. This method is well suited to use in the alpine environment. Further refinements in technique and equipment, as well as formal validation studies in humans, are needed to increase the utility of ICG-NIRS.

HDL Cholesterol Reduction during Rosiglitazone and Fenofibrate Treatment in a Type 2 Diabetes Mellitus Patient with Dyslipidemia

Thiazolidinediones (TZD), which are widely used as insulin sensitizers, and fibrates, which are lipid-lowering drugs, are used in the treatment of dyslipidemia that commonly accompanies diabetes. Several reports suggest elevated levels of high-density lipoprotein (HDL) cholesterol, but the paradoxical reduction of HDL cholesterol level during single or combined TZD and fibrate therapies has been occasionally reported. Herein, we report a case of paradoxical decrease in HDL cholesterol and apolipoprotein A-1 levels during rosiglitazone and fenofibrate treatment for the first time in Korea. The patient was a 56-yr-old man presenting with type 2 diabetes mellitus and dyslipidemia. His HDL cholesterol and apolipoprotein A-1 levels returned to normal after the cessation of fenofibrate therapy. Since diabetes is an established risk factor of cardiovascular diseases, low HDL cholesterol can be a key cause of concern for patients with diabetes. Therefore, HDL cholesterol level should be determined before and after starting TZD and/or fibrate therapy in diabetic patients.

Abstract 4928: Coronary Flow Reserve is Reduced in Pulmonary Arterial Hypertension Patients

Background: Pump function of the right ventricle, which is a major determinant of prognosis in pulmonary arterial hypertension (PAH), is much influenced by coronary perfusion. Acute studies in animals exhibited paradoxical coronary flow decrease under excessive pressure overload. However, little is known about human or chronic coronary flow reserve (CFR) in PAH. Methods: Coronary flow measurement with pulse Doppler was performed for 19 PAH consecutive patients (right ventricular systolic pressure RVSP 89.7±22.7 mmHg; age 22.0±5.5 year; 10 females, data are mean±SD). The control state blood velocity was recorded in distal right coronary artery (RCA). The maximal blood velocity was recorded at the same site, on continuous infusion of adenosine triphosphate (150ng/kg/min). CFR was defined as the ratio of peak adenosine/baseline flow velocity. RVSP was adopted from the most adjacent catheterization. Coronary arterial lesions were excluded with coronary angiogram. Results: RCA flow signals were achieved in 17/19. Systolic flow signals were observed in 2/17. RCA diastolic peak velocity in basal condition was somewhat higher than reported in normal subjects (29.9±11.4 cm/sec) and positively correlated with right ventricular systolic pressure (RVSP) with significance (R^2 = .236; p&lt;0.05). CFR of RCA ranged 1.55– 4.16 (2.46±0.82) and was below 2.0 in 7/17. It negatively correlated with RVSP (R^2 = .383; P &lt; 0.01). Conclusion: Peak flow velocity of RCA in PAH correlated with RVSP, in reply to greater energy demand of RV. CFR of RCA was low and negatively correlated with RVSP, which may suggest poor energy supply reserve in PAH patients.