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Effect of simvastatin on coronary flow reserve in patients with atherosclerosis and hypercholesterolemia: an intracoronary Doppler study.
Jensen, LO, Thayssen, P, Pedersen, KE, Haghfelt, T
Coronary artery disease. 2006;(1):51-6
Abstract
BACKGROUND Early stages of coronary atherosclerosis are accompanied by a functional impairment of coronary vasodilator capacity and endothelial dysfunction. Reduced coronary flow reserve has been reported in patients with hypercholesterolemia, despite angiographically normal coronary arteries. The aim of the study was to evaluate the effect of simvastatin on coronary flow reserve. METHODS The study was an open non-placebo-controlled serial investigation in which every patient acted as his own control: 36 male patients with hypercholesterolemia and a non-significant coronary artery lesion in a not previously revascularized coronary artery. Intracoronary Doppler measurements were performed. Coronary flow reserve, relative coronary flow reserve and average peak velocity were performed at baseline, after 3 months on a lipid-lowering diet (control period), and after another 12 months of simvastatin 40 mg/day. In the same patient cohort, significant reduction in lesion plaque plus media has been demonstrated by intravascular ultrasound. RESULTS Changes in coronary flow reserve were not influenced by either diet or simvastatin (2.5+/-0.6 vs. 2.6+/-0.5 vs. 2.6+/-0.6, P=ns). Maximum hyperemic flow (34.8+/-12.2 vs. 36.7+/-12.5 vs. 42.5+/-13.1, P<0.001) as well as resting flow (14.3+/-5.3 vs. 14.5+/-4.4 vs. 16.6+/-4.6, P<0.001) increased significantly after 12 months simvastatin therapy. CONCLUSION Despite plaque plus media, regression simvastatin therapy for 12 months does not affect coronary flow reserve obtained using serial intracoronary Doppler studies. Simvastatin, however, increases the hyperemic flow velocity.
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Dietary sodium restriction and beta2-adrenergic receptor polymorphism modulate cardiovascular function in humans.
Eisenach, JH, Schroeder, DR, Pike, TL, Johnson, CP, Schrage, WG, Snyder, EM, Johnson, BD, Garovic, VD, Turner, ST, Joyner, MJ
The Journal of physiology. 2006;(Pt 3):955-65
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Abstract
Dietary Na+ intake influences beta2-adrenergic receptor (beta2AR) responsiveness. While receiving a normal Na+ diet (150 mmol day(-1)), subjects homozygous for glycine at amino acid 16 (Gly16) have greater forearm beta2AR-mediated vasodilatation than subjects homozygous for arginine (Arg16), an effect that is mediated by endothelial NO. We tested the hypothesis that dietary Na+ restriction eliminates genotype differences in forearm and systemic beta2AR-mediated dilatation in these groups. We measured heart rate, mean arterial pressure and cardiac output (CO, acetylene breathing) responses to administration of intravenous terbutaline (TRB) before and after 5 days of low dietary Na+ intake (10 mmol day(-1)) in healthy Gly16 (n = 17; age, 31 +/- 7 year) and Arg16 homozygotes (n = 15; age, 29 +/- 8 year). After the low-Na+ diet, a catheter was placed in the brachial artery to measure forearm blood flow (FBF, plethysmography) responses to administration of isoprenaline (isoproterenol) before and after NO inhibition with NG-mono-methyl-L-arginine (L-NMMA). In the Gly16 group, the low-Na+ diet decreased baseline CO from 6.4 +/- 1.4 to 5.5 +/- 1.2 l min(-1) (P = 0.003, paired t test), tended to decrease stroke volume from 97.0 +/- 20.6 to 86.9 +/- 21.7 ml (P = 0.06) and increased peripheral resistance from 1106 +/- 246 to 1246 +/- 222 dynes s cm(-5) (P = 0.02); significant effects of the low-Na+ diet were not observed in Arg16 subjects. In a repeated measures ANOVA, the responses of all cardiovascular measures to systemic administration of TRB were not influenced by genotype or diet. Additionally, the FBF response to incremental doses of isoprenaline did not differ between genotype groups before or after administration of L-NMMA. We conclude that dietary Na+ restriction blunted the increased forearm NO-mediated beta2AR responsiveness in Gly16 homozygotes observed in a previous study after normal dietary Na+ intake, while baseline CO decreased and peripheral resistance increased in this group. This study provides evidence that dietary Na+ modulates effects of the Arg16Gly polymorphism on cardiovascular function.
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Nicorandil administration shows cardioprotective effects in patients with poor TIMI and collateral flow as well as good flow after AMI.
Toyama, T, Seki, R, Hoshizaki, H, Kawaguchi, R, Isobe, N, Adachi, H, Oshima, S, Taniguchi, K, Kasama, S
Annals of nuclear medicine. 2006;(4):277-85
Abstract
BACKGROUND Nicorandil (NCR) has been reported to have cardioprotective effects in patients with AMI. And collateral flow and TIMI flow are also important determinants of final salvaged myocardium in patients with AMI. There is no evidence as to whether TIMI or collateral flow modifies the cardioprotective effects of NCR in patients with AMI. METHODS AND RESULTS We studied 68 initial AMI patients without restenosis which was defined as 50% diameter reduction of the intervention site in the chronic period. On initial CAG, 41 patients with poor flow (collateral: Rentrop 0 or 1 and TIMI 0 or 1) were NCR/Non-NCR = 20/21. Twenty-seven patients with good flow (collateral: Rentrop 2 or 3 or TIMI 2 or 3) were NCR/Non-NCR = 13/14. NCR was administered intravenously (4 mg) via intracoronary injection (2 mg) or continuously (4 mg/h). 99mTc-tetrofosmin (TF) and 123I-BMIPP SPECT were performed in the subacute and chronic (6 Mo) periods. In 20 SPECT segments, summed defect scores (TDS) and regional wall motion (WMS: -1=dyskinesis -4 = normal) of AMI segments using TF-QGS were estimated. In poor flow patients, the following values for NCR patients were higher (p < 0.05) than for Non-NCR patients in the improvement degree of TDS (BMIPP) (NCR: 6.5 +/- 3.9 vs. Non-NCR: 4.0 +/- 3.4), the improvement degree of TDS (TF) (NCR: 5.7 +/- 4.6 vs. Non-NCR: 2.2 +/- 4.6), and delta WMS (NCR: 1.4 +/- 1.1 vs. Non-NCR: 0.9 +/- 1.0). In good flow patients, the following values for NCR patients were better (p < 0.05) than for Non-NCR patients in TDS (BMIPP) (subacute) (NCR: 9.9 +/- 5.2 vs. Non-NCR: 16.5 +/- 10.4) and (chronic) (NCR: 5.1 +/- 5.2 vs. Non-NCR: 12.4 +/- 8.5), WMS (subacute) (NCR: 1.7 +/- 1.3 vs. Non-NCR: 1.0 +/- 1.0), and WMS (chronic) (NCR: 3.0 +/- 1.5 vs. Non-NCR: 2.1 +/- 1.3). CONCLUSION We conclude that the cardioprotective effects of nicorandil administration are observable in both AMI patients with poor collateral and TIMI flow and good flow before reperfusion therapy.
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Age and regional specificity of peak limb vascular conductance in women.
Ridout, SJ, Parker, BA, Proctor, DN
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(6):2067-74
Abstract
The influence of age on limb vasodilator capacity in women is unclear. The objectives of this study were to characterize and compare age-associated changes in forearm and calf peak vascular conductance (VC(peak); a functional index of arterial structure) in women and to identify physiological characteristics predictive of variation in limb-specific VC(peak). Peak conductance (plethysmographic flow/mean arterial pressure), VC(peak) of the forearm (forearm VC(peak)), and calf (calf VC(peak)) after 10 min of arterial occlusion were measured in 58 healthy, normally active women aged 21-79 yr. Aerobic capacity (cycle peak oxygen uptake), arterial health (pulse-wave velocity, ankle-brachial index), total cholesterol, limb-specific tissue composition (dual-energy X-ray absorptiometry), and isometric strength (handgrip, plantar flexion) were also assessed. The relative decline in calf VC(peak) with age (-6.8% per decade, P < 0.001) was greater than the forearm (-4.4% per decade, P = 0.004), in contrast to results previously reported for men (forearm decline > calf decline). Limb VC(peak) per kilogram muscle declined with age in the calf (-6.0% per decade; P = 0.002), but not the forearm (P = 0.12). Age, cholesterol, and regional tissue composition were significant predictors of peak conductance in both limbs; however, age was a stronger predictor of peak conductance in the calf. These results suggest that healthy aging is associated with a linear decline in limb vasodilator capacity in women, but the magnitude of this effect is region specific. Further research will be required to determine whether the decline in lower extremity vasodilator capacity with age explains diminished exercising leg vasodilation in older women.
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Clinical microneedle injection of methyl nicotinate: stratum corneum penetration.
Sivamani, RK, Stoeber, B, Wu, GC, Zhai, H, Liepmann, D, Maibach, H
Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI). 2005;(2):152-6
Abstract
BACKGROUND/PURPOSE In recent years, microneedles were proposed as a method to painlessly deliver drugs past the stratum corneum. Microneedles have been fabricated in several designs, but limited studies have tested microneedle injections in humans. In this work, we compare microneedle injections with topical application (TA) to investigate if microneedles enhance in vivo drug delivery past the stratum corneum. METHOD In vitro tests were used to measure microneedle pressures and injection volumes. In vivo microneedle injections were performed on the volar forearm of 11 healthy volunteers. Two sets of microneedles, pointed and symmetric, were used to develop microneedle/syringe apparatuses that were used to inject approximately 1 microL of 0.1 M methyl nicotinate, and were compared against TA. A Laser Doppler Perfusion Monitor was used to record maximum blood flow and the time to maximum blood flow at the treatment sites. RESULTS Pointed and symmetric microneedle-injected sites showed a significantly faster time to maximum blood flow than TA. The pointed microneedle injections also resulted in a higher maximum blood flux. Volunteers reported feeling pressure but no pain from the microneedles during the injections. CONCLUSION The microneedles aid in bypassing the stratum corneum and enhance drug delivery through it. The design of the microneedle influences its delivery capabilities, because the pointed microneedles seem to be less susceptible to clogging during the injection.
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An improved model for the measurement of myocardial perfusion in human beings using N-13 ammonia.
Hickey, KT, Sciacca, RR, Chou, RL, Rodriguez, O, Bokhari, S, Bergmann, SR
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2005;(3):311-7
Abstract
BACKGROUND Oxygen 15 water and nitrogen 13 ammonia are widely used for the quantitative measurement of myocardial perfusion with positron emission tomography. However, blood flow obtained with N-13 ammonia by use of the conventional 2-compartment model frequently underestimates flow by 30% to 50% compared with O-15 water. We hypothesized that this discrepancy is a result of the model configuration of N-13 ammonia and investigated changes to the mathematical model to determine whether more accurate measurements of perfusion could be obtained. METHODS AND RESULTS Twelve healthy volunteers were sequentially studied with O-15 water and N-13 ammonia at rest and during maximal coronary vasodilation with adenosine. Perfusion measurements obtained with the conventional and modified models were compared with values obtained with O-15 water. The conventional N-13 ammonia model underestimated flow by 37% +/- 16% at rest and by 20% +/- 24% with stress when compared with flows obtained with O-15 water. The modified model yielded flow values closer to the line of identity than the conventional model (y = 1.07x + 0.04 vs y = 0.69x + 0.08; respectively; P < .01). CONCLUSIONS Model changes made N-13 ammonia myocardial blood flow estimates more comparable to those obtained with O-15 and may allow for better comparison of flows obtained with these two tracers in the future. Further efforts are warranted to evaluate the accuracy of flow models in human subjects.
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L-arginine-mediated vasoreactivity in patients with a risk of stroke.
Zimmermann, C, Wimmer, M, Haberl, RL
Cerebrovascular diseases (Basel, Switzerland). 2004;(2-3):128-33
Abstract
OBJECTIVES L-arginine is the substrate for nitric oxide (NO) production and has been shown to induce an endothelium-dependent increase in cerebral blood flow in humans. We studied the hypothesis that L-arginine-mediated vasoreactivity is impaired in patients with cardiovascular risk factors and a risk of stroke. METHODS 55 patients with cardiovascular risk factors (mean age 63.0 +/- 8.5 years) were included in the study. 45 of them had a history of previous minor stroke or transient ischemic attack (TIA) while 10 patients had cardiovascular risk factors but no previous cerebral ischemic event. Endothelium-dependent changes in cerebral blood flow during the infusion of 30 g L-arginine were assessed by continuous transcranial Doppler sonography of both middle cerebral arteries, intima-media thickness (IMT) of the common carotid artery, by Duplex sonography. Associations between risk factors, IMT, L-arginine reactivity and previous cerebrovascular events were analyzed by stepwise multiple linear regression analysis and patient groups were compared. RESULTS Normal young volunteers showed an L-arginine-mediated increase in mean flow velocity of 22 +/- 8%; L-arginine reactivity of the 55 patients was 28 +/- 10%. Patients with a history of stroke or TIA had significantly higher flow velocity responses to L-arginine (29 +/- 10%) than patients with cardiovascular risk factors but no previous cerebrovascular event (21 +/- 8%, p < 0.05). Stepwise multiple linear regression analysis showed a significant association of enhanced L-arginine reactivity with previous stroke/TIA (p < 0.001) and elevated fibrinogen levels (p < 0.05) but not with age, IMT, hypertension, cholesterol or other risk factors. The same regression model showed an association between IMT and previous stroke/TIA (p < 0.001) and serum cholesterol levels (p < 0.05) but not L-arginine reactivity. CONCLUSIONS L-arginine reactivity of the cerebral vessels may be assessed by Doppler sonography and was enhanced in patients with a history of stroke or TIA. It was independent of IMT of the carotid arteries. We conclude that enhanced L-arginine reactivity is a potential marker for cerebral endothelial dysfunction and an independent indicator for an increased risk of stroke.
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Effective flow performances and dialysis doses delivered with permanent catheters: a 24-month comparative study of permanent catheters versus arterio-venous vascular accesses.
Canaud, B, Leray-Moragues, H, Kerkeni, N, Bosc, JY, Martin, K
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2002;(7):1286-92
Abstract
BACKGROUND Permanent venous catheters have emerged as a long-term vascular access option for renal replacement therapy in end-stage renal disease patients. The design and venous location of catheter devices bear intrinsic flow limitations that may negatively affect the adequacy of dialysis and the patient outcome. There is limited data comparing the long-term dialysis adequacy delivered with permanent catheters vs arterio-venous vascular accesses (AVA). METHODS To explore this problem, we conducted a prospective 24-month trial comparing the flow performances and dialysis dose (Kt/Vdp) deliveries of both access options in a group of 42 haemodialysis patients during two study phases. During the first 12 months the patients completed a treatment period by means of permanent dual silicone catheters (DualKT). Then they were transferred to an AVA (40 native arterio-venous fistulas and two PTFE grafts) and monitored for an additional 12-month period. Assessments of flow adequacy and dialysis quantification were performed monthly. RESULTS Dialysis adequacy was achieved in all cases. No patient had to be transferred prematurely to the AVA because of catheter failure. Three catheters had to be replaced due to bacteraemia in three patients. The mean effective blood flow rates achieved were 316+/-3.5 ml/min and 340+/-3.3 ml/min with DualKT and AVA, respectively, for a pre-set machine blood flow of 348+/-2.2 ml/min. Recirculation rates evaluated with the 'slow blood flow' method were 8.6+/-0.6 and 12.1+/-0.8% for DualKT and AVA using mean values of the solute markers urea and creatinine. Due to the possibility of a comparison veno-venous vs arterio-venous blood circulation, a corrected arterio-venous access recirculation could be derived from the difference between the two, which was around 3%. The blood flow resistance of the DualKT was slightly higher than with AVA as indicated by venous pressure differences. Kt/Vdp delivered was 1.37+/-0.02 and 1.45+/-0.02 with DualKT and AVA access respectively. The loss of dialysis efficacy using catheters was estimated at 6%. However, in all cases Kt/Vdp values remained above the recommended values (Kt/Vdp > or = 1.2). Protein nutritional state, as well as conventional clinical and biochemical markers of dialysis adequacy, remained in the optimal range. CONCLUSION Permanent venous catheters provide adequate haemodialysis on a long-term basis. Flow performances and dialysis doses are slightly reduced (5-6%) when compared with AVA. Regular assessment of dialysis performance is strongly recommended to assure dialysis adequacy. Lengthening dialysis time may represent a simple and efficient tool to compensate for reduced flow performances with catheter use.
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Estrogen replacement therapy in postmenopausal women augments reactive hyperemia in the forearm by reducing angiotensin converting enzyme activity.
Sanada, M, Higashi, Y, Nakagawa, K, Sasaki, S, Kodama, I, Sakashita, T, Tsuda, M, Ohama, K
Atherosclerosis. 2001;(2):391-7
Abstract
The precise mechanism of the vasoprotective effect of estrogen replacement therapy in postmenopausal women is not fully understood. The present study sought to determine the role of nitric oxide (NO) and angiotensin-converting enzyme (ACE) in the vasodilator response of the forearm vessels induced by estrogen administration to postmenopausal women. Subjects were divided into two groups. One group received conjugated equine estrogen (0.625 mg daily) orally for 3 months (n=26), while the other received no treatment (control group, n=10). Forearm blood flow was measured by strain-gauge plethysmography. The concentrations of nitrite/nitrate (metabolites of NO), ACE activity, and lipid parameters were measured. Basal forearm blood flow, body weight, blood pressure, and heart rate were similar at baseline in both groups. After 3 months of estrogen administration, the maximal forearm blood flow response during reactive hyperemia and the serum level of nitrite/nitrate each showed a significant increase over baseline values: from 23.6+/-2.0 to 36.5+/-3.1 ml/min per 100 ml tissue (P<0.01), and from 24.8+/-2.3 to 38.6+/-3.6 micromol/l (P<0.01), respectively. Plasma levels of ACE activity were significantly reduced from baseline after 3 months of estrogen treatment (from 12.2+/-0.6 to 10.9+/-0.6 IU/l, P<0.01). No changes were seen in controls. The change in forearm blood flow after sublingual nitroglycerin was similar at baseline versus after 3 months of estrogen administration. The increase in the serum level of nitrite/nitrate after 3 months of estrogen therapy showed a significant inverse correlation (r=0.52, P<0.01) with the reduction in the plasma level of ACE activity. There was no significant correlation between the increase in serum nitrite/nitrate and any change in serum lipids, blood pressure, or other parameters. The administration of oral estrogen to postmenopausal women for 3 months increased the NO-mediated forearm endothelium-dependent vasodilatation. This was likely due, at least in part, to ACE inhibition. The latter may be one mechanism by which ERT provides its well-known cardiovascular benefit.