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Beneficial effects of statin treatment on coronary microvascular dysfunction and left ventricular remodeling in patients with acute myocardial infarction.
Ishida, K, Geshi, T, Nakano, A, Uzui, H, Mitsuke, Y, Okazawa, H, Ueda, T, Lee, JD
International journal of cardiology. 2012;(3):442-7
Abstract
BACKGROUND Statin treatment has been shown to improve coronary endothelial function, irrespective of lipid-lowering effects. This study's aim was to elucidate the effects of statin treatment on coronary microvascular dysfunction and left ventricular remodeling in acute myocardial infarction (AMI) patients. METHODS Thirty-five patients undergoing successful reperfusion following AMI were assigned to a statin-treated (Group S, 16) or a non-statin-treated (Group NS, 19) group, according to fasting serum low-density lipoprotein-cholesterol. (13)N-ammonia positron emission tomography was performed to assess myocardial flow reserve (MFR) in the infarct area. RESULTS Infarct sizes and lipid profiles during the chronic period were similar between the two groups. At 2 weeks after AMI onset, mean MFR in the infarct area was significantly higher in Group S than in Group NS (2.34 ± 0.63 vs. 1.91 ± 0.43, p=0.0214). At 6 months post-AMI, Group S had a smaller left-ventricular end-diastolic volume index (69.4 ± 11.7 mL/m(2) vs. 88.5 ± 32.5 mL/m(2), p=0.0328) and higher left-ventricular ejection fraction (67.7 ± 9.2% vs. 59.2 ± 13.3%, p=0.0394) than Group NS. Serum asymmetric dimethylarginine was significantly increased in Group NS at 1 month post-AMI (0.43 ± 0.12 μmol/L (baseline) vs. 0.52 ± 0.14 μmol/L, p=0.0186), but unchanged in Group S. CONCLUSIONS Statin treatment appears to beneficially attenuate left ventricular remodeling after AMI, which may be associated with restoring coronary endothelial function via endogenous nitric oxide.
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Preliminary results of transplantation with kidneys donated after cardiocirculatory determination of death: a French single-centre experience.
Abboud, I, Viglietti, D, Antoine, C, Gaudez, F, Meria, P, Tariel, E, Mongiat-Artus, P, Desgranchamps, F, Roussin, F, Fieux, F, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2012;(6):2583-7
Abstract
BACKGROUND Donation after circulatory determination of death (DCDD), formerly non-heart-beating donation and donation after cardiac death, has been re-introduced into clinical practice in France since June 2006 as a potential solution to organ shortage, but this kidney transplantation programme is not popular yet, mainly because of logistical concerns and uncertainty about the long-term warm ischaemia impact on transplanted kidneys. METHODS Our institution started the DCDD programme in January 2007, following the national 'BioMedicine Agency' protocol. We only considered uncontrolled donors with an initial no-flow period (i.e. delay between collapse and external cardiac massage start) <30 min. A 5-min stand-off period was observed before declaring the death and performing in situ cold perfusion, and since January 2010, normothermic subdiaphragmatic extracorporeal membrane oxygenation. All kidneys were machine-perfused using the hypothermic pulsatile preservation system before transplantation. Morphologic assessment and perfusion indexes were used to assess the suitability for transplantation. RESULTS From January 2007 to December 2010, our team performed 58 kidney transplantations from uncontrolled Maastricht Category I and II donors. Mean recipient age was 47 ± 9 years. Male/female ratio was 45/13. Mean waiting time on transplantation registry was 30 months (4-180). Mean cold ischaemia time was 13 h 40 min (7-18) and pulsatile perfusion time 8 h (1-16). We had three cases (5%) of primary non-function (PNF) and 95% of delayed graft function. There was no increase in biopsy-proven acute rejection incidence (12.7%). Patient and graft survivals were 98 and 91.4%, respectively, at 1 year and 98 and 88%, respectively, at last follow-up. Estimated glomerular filtration rate ( Modification of Diet in Renal Disease formula) was 48 ± 16 mL/min/1.73 m(2) at 1 year and 48 ± 15 mL/min/1.73 m(2) at the last follow-up. CONCLUSIONS DCDD kidneys are a valuable additional source of organs for transplantation. Our results show encouraging outcomes, which give rise to further interest in this donor pool. Respecting the national protocol is crucial to prevent PNF and deleterious warm ischaemia effect on transplanted kidney.
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Phase I, first-in-human study of BMS747158, a novel 18F-labeled tracer for myocardial perfusion PET: dosimetry, biodistribution, safety, and imaging characteristics after a single injection at rest.
Maddahi, J, Czernin, J, Lazewatsky, J, Huang, SC, Dahlbom, M, Schelbert, H, Sparks, R, Ehlgen, A, Crane, P, Zhu, Q, et al
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2011;(9):1490-8
Abstract
UNLABELLED (18)F-labeled BMS747158 is a novel myocardial perfusion imaging tracer that targets mitochondrial complex 1. The objectives of this phase I study were to evaluate radiation dosimetry, biodistribution, human safety, tolerability, and early elimination of (18)F activity in urine after injection of a single dose of the tracer at rest in healthy subjects. METHODS Thirteen healthy subjects were injected with 170-244 MBq (4.6-6.6 mCi) of BMS747158 intravenously. Dynamic PET was obtained over the heart for 10 min, followed by sequential whole-body imaging for 5 h. Blood samples and urinary excretion were collected for up to 8 h. Heart rate, electrocardiogram, and blood pressure were monitored before and during imaging. The residence times were determined from multiexponential regression of organ region-of-interest data normalized by injected dose. Absorbed dose estimates for all target organs were determined using MIRD schema with OLINDA/EXM software. RESULTS The organ receiving the largest mean absorbed dose was the kidneys at 0.066 mSv/MBq (0.24 rem/mCi), followed by the heart wall at 0.048 mSv/MBq (0.18 rem/mCi). The mean effective dose was 0.019 mSv/MBq (0.072 rem/mCi). The heart exhibited high and sustained retention of BMS747158 from the earliest images through approximately 5 h after injection. There were no drug-related adverse events, and the tracer was well tolerated in all subjects. Mean urinary excretion was 4.83 percentage injected dose (range, 0.64-12.41 percentage injected dose). CONCLUSION These preliminary data suggest that (18)F-labeled BMS747158 appears to be well tolerated and has a unique potential for myocardial perfusion PET.
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Coronary circulatory function in patients with the metabolic syndrome.
Di Carli, MF, Charytan, D, McMahon, GT, Ganz, P, Dorbala, S, Schelbert, HR
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2011;(9):1369-77
Abstract
UNLABELLED The metabolic syndrome affects 25% of the U.S. population and greatly increases the risk of diabetes and coronary artery disease (CAD). We tested the hypothesis that the metabolic syndrome is associated with impaired coronary vasodilator function, a marker of atherosclerotic disease activity. METHODS Four hundred sixty-two patients at risk for CAD, as defined by a low-density lipoprotein cholesterol ≥ 160 mg/dL with fewer than 2 coronary risk factors, a low-density lipoprotein cholesterol ≥ 130 mg/dL with 2 or more coronary risk factors, or with documented CAD were included. A subset of 234 individuals underwent repeated PET at 1 y. Myocardial blood flow (MBF) and vasodilator reserve were assessed by PET. Modified criteria of the National Cholesterol Education Program, Adult Treatment Panel III were used to characterize the metabolic syndrome. RESULTS Adenosine- and cold-stimulated MBF were similar in patients with and without metabolic syndrome, whereas baseline MBF showed a stepwise increase with increasing features of the syndrome. Consequently, patients with metabolic syndrome showed a lower coronary flow reserve (CFR) (2.5 ± 1.0) than those without metabolic syndrome (3.0 ± 0.9, P = 0.004). Differences in CFR were no longer present after correcting rest flows for the rate-pressure product. Change in MBF and CFR at 1 y were not different across groups of patients with increasing features of the metabolic syndrome. CONCLUSION Patients with metabolic syndrome demonstrate impaired CFR, which is related to the augmentation in resting coronary blood flow caused by hypertension. In high-risk individuals, peak adenosine- and cold-stimulated blood flows are impaired even in the absence of the metabolic syndrome.
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Caffeine impairs myocardial blood flow response to physical exercise in patients with coronary artery disease as well as in age-matched controls.
Namdar, M, Schepis, T, Koepfli, P, Gaemperli, O, Siegrist, PT, Grathwohl, R, Valenta, I, Delaloye, R, Klainguti, M, Wyss, CA, et al
PloS one. 2009;(5):e5665
Abstract
BACKGROUND Caffeine is one of the most widely consumed pharmacologically active substances. Its acute effect on myocardial blood flow is widely unknown. Our aim was to assess the acute effect of caffeine in a dose corresponding to two cups of coffee on myocardial blood flow (MBF) in coronary artery disease (CAD). METHODOLOGY/PRINCIPAL FINDINGS MBF was measured with (15)O-labelled H2O and Positron Emission Tomography (PET) at rest and after supine bicycle exercise in controls (n = 15, mean age 58+/-13 years) and in CAD patients (n = 15, mean age 61+/-9 years). In the latter, regional MBF was assessed in segments subtended by stenotic and remote coronary arteries. All measurements were repeated fifty minutes after oral caffeine ingestion (200 mg). Myocardial perfusion reserve (MPR) was calculated as ratio of MBF during bicycle stress divided by MBF at rest. Resting MBF was not affected by caffeine in both groups. Exercise-induced MBF response decreased significantly after caffeine in controls (2.26+/-0.56 vs. 2.02+/-0.56, P<0.005), remote (2.40+/-0.70 vs. 1.78+/-0.46, P<0.001) and in stenotic segments (1.90+/-0.41 vs. 1.38+/-0.30, P<0.001). Caffeine decreased MPR significantly by 14% in controls (P<0.05 vs. baseline). In CAD patients MPR decreased by 18% (P<0.05 vs. baseline) in remote and by 25% in stenotic segments (P<0.01 vs. baseline). CONCLUSIONS We conclude that caffeine impairs exercise-induced hyperaemic MBF response in patients with CAD to a greater degree than age-matched controls.
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L-arginine preferentially dilates stenotic segments of coronary arteries thereby increasing coronary flow.
Lauer, T, Kleinbongard, P, Rath, J, Schulz, R, Kelm, M, Rassaf, T
Journal of internal medicine. 2008;(3):237-44
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Abstract
BACKGROUND AND OBJECTIVES Oxidized LDL cholesterol and cytokines increase arginase and decrease nitric oxide (NO) synthase expression in human endothelial cells, leading to a decrease in NO production. In arteriosclerotic plaques, characterized by increased oxidized LDL and cytokine levels, a sustained local NO reduction might enhance sensitivity of the downstream guanylyl cyclase system towards an acute NO increase. We tested whether application of the NO synthase substrate l-arginine (l-arg, 150 micromol min(-1)) or the NO donor isosorbide dinitrate (ISDN; 0.3 mg) preferentially dilates stenotic coronary artery segments (CS) subsequently increasing poststenotic coronary blood flow (CBF) in patients with coronary artery disease (CAD). DESIGN, SETTING AND SUBJECTS Changes in coronary diameter and circumferential surface area were assessed by quantitative coronary angiography (QCA) in a nonstenotic upstream segment, the CS, downstream the CS and in a reference vessel (n = 24). CBF was estimated in a subset of 13 patients by QCA and intracoronary Doppler. RESULTS CS ranged from 62% to 89% (77 +/- 5%). l-arg increased minimal luminal diameter of the stenotic segment from 0.98 +/- 0.06 to 1.14 +/- 0.07 mm (P < 0.05) without affecting other coronary segments. Poststenotic CBF increased by 24 +/- 3%. ISDN dilated all segments again with a predominance of CS (25 +/- 4%) and increased poststenotic CBF by 38 +/- 9%. In a multifactorial anova, a medication with an angiotensin-converting enzyme inhibitor (decreasing inflammation and radical formation) and a ratio of LDL/HDL <3.5 were predictive for an l-arg-induced dilation. CONCLUSION The increase in poststenotic CBF without affecting nondiseased arteries highlights the therapeutic potential of l-arg in patients with CAD.
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Comparison of effect between nitrates and calcium channel antagonist on vascular function in patients with normal or mildly diseased coronary arteries.
Ninomiya, Y, Hamasaki, S, Saihara, K, Ishida, S, Kataoka, T, Ogawa, M, Orihara, K, Oketani, N, Fukudome, T, Okui, H, et al
Heart and vessels. 2008;(2):83-90
Abstract
The comparative long-term antianginal efficacy of long-acting nitrates versus calcium channel antagonists remains unclear. The goal of the present study was to compare the coronary endothelial cell function and coronary artery vasoconstriction between patients with normal or mildly diseased coronary arteries treated with long-acting nitrates or calcium channel antagonists. Forty-two patients suspected to have angina pectoris and with normal or mildly diseased coronary arteries underwent Doppler flow study of the left anterior descending coronary artery. All patients were suspected to have angina pectoris and were receiving either long-acting nitrates (n = 18; Nitrates group) or calcium channel antagonists (n = 24; Ca-antagonists group) for at least 1 year. Vascular reactivity was assessed by intracoronary administration of papaverine, acetylcholine (Ach), and nitroglycerin using a Doppler guidewire. Segments that showed the greatest constrictive response to Ach were used for assessment of vasoconstriction. The percent increase in coronary blood flow (CBF) and coronary artery diameter (CAD) induced by Ach was significantly smaller in the Nitrates group than in the Ca-antagonists group (33% +/- 74% vs 83% +/- 77%, P < 0.05; -3% +/- 16% vs 11% +/- 12%, P < 0.01, respectively). The percent diameter reduction in the region of greatest constrictive response to Ach was significantly greater in the Nitrates group than in the Ca-antagonists group (44% +/- 39% vs 15% +/- 32%, P < 0.02). Long-term treatment with long-acting nitrates may produce less favorable effects on coronary endothelial function and the constrictive response to Ach when compared with long-acting calcium channel antagonists in patients with normal or mildly diseased coronary arteries.
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Comparison of coronary flow reserve and fractional flow reserve in patients with versus without diabetes mellitus and having elective percutaneous coronary intervention and abciximab therapy (from the PREDICT Trial).
Kini, AS, Kim, MC, Moreno, PR, Krishnan, P, Ivan, OC, Sharma, SK
The American journal of cardiology. 2008;(6):796-800
Abstract
Patients with diabetes mellitus (DM) have poor long-term outcome after percutaneous coronary intervention (PCI) partly because of microvascular disease and distal embolization. Microvascular obstruction can be assessed by measuring coronary flow reserve (CFR). The Prediction of CK-MB RElease During Successful Stenting Correlating with Indicators of Microvascular ObstruCTion (PREDICT) trial compared the CFR in patients with versus without DM during PCI. Patients undergoing elective PCI were prospectively enrolled according to diabetic (n = 36) and nondiabetic (n = 36) status. All patients received drug-eluting stent with abciximab and were followed for 30-day major adverse cardiac events. CFR and FFR (fractional flow reserve) before and after stenting were measured before and after intracoronary adenosine bolus. Procedural success, MB enzyme of creatine-kinase (CK-MB), troponin I, and high-sensitive C-reactive protein elevation, vascular complications, and major adverse cardiac events were not different. FFR before stenting was 0.77 +/- 0.03 in patients with DM versus 0.76 +/- 0.02 in patients without DM (p = 0.69). FFR after stenting was 0.97 +/- 0.03 and 0.99 +/- 0.01 (p = 0.26), respectively. CFR before stenting was 1.36 +/- 0.31 in patients with DM versus 1.49 +/- 0.25 in patients without DM (p = 0.064). However, CFR after stenting was significantly lower in patients with versus without DM (1.89 +/- 0.30 versus 2.44 +/- 0.67, p <0.001, respectively). CFR after stenting only moderately correlated with CK-MB and high-sensitive C-reactive protein after PCI but did not correlate with 30-day major adverse cardiac events. In conclusion, patients with DM have significantly lower CFR after stenting despite equivalent FFR and myonecrosis compared with patients without DM, indicating greater microvascular obstruction after PCI despite abciximab.
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NO metabolite flux across the human coronary circulation.
Rogers, SC, Khalatbari, A, Datta, BN, Ellery, S, Paul, V, Frenneaux, MP, James, PE
Cardiovascular research. 2007;(2):434-41
Abstract
OBJECTIVES The theory of a red blood cell derived nitric oxide (NO) reserve conserving NO bioactivity and delivering NO as a function of oxygen demand has been the subject of much interest. We identified the human coronary circulation as an ideal model system in which to analyse NO metabolites because of its large physiological oxygen gradient. Our objective was to identify whether oxygen drove apportion between various NO metabolite species across a single vascular bed. METHODS Plasma and red blood cell NO metabolites were assessed from the left main coronary artery, coronary sinus and pulmonary artery (providing cross heart and cross pulmonary analysis) of healthy subjects under resting conditions and following administration of an inhibitor of NO biosynthesis. Physiological parameters and angiographic data were monitored throughout the study. RESULTS Under baseline conditions we observed significant metabolite flux upon the transit of blood across the coronary and pulmonary vascular beds. Whilst there was no net loss of NO through the coronary circulation (p=0.0759), plasma nitrite/protein NO (excluding nitrate) (p=0.0279) and red blood cell sulphanilamide labile signal (p=0.0143) decreased whereas haemoglobin-bound NO increased three-fold (p=0.005). These changes across the coronary circulation were reversed through the pulmonary circuit with red blood cell sulphanilamide labile signal (p=0.0143) and plasma nitrite/protein NO (p=0.0279) increasing and haemoglobin-bound NO decreasing. Blockade of NO synthesis increased mean arterial blood pressure (p<0.01) and reduced coronary artery diameter (p<0.05), however we observed similar apportion of NO metabolites across the heart and lung with no net loss or gain in total NO metabolites. CONCLUSIONS For the first time in human subjects across the resting coronary circulation we reveal significant re-apportionment of NO between metabolite species which correlate with haemoglobin oxygen saturation. These changes occur even within the transit time of blood across this single vascular bed. We demonstrate no net loss/gain of NO from the total metabolite pool across the coronary circulation even where NO biosynthesis is inhibited.
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Beneficial effects of atorvastatin on myocardial regions with initially low vasodilatory capacity at various stages of coronary artery disease.
Wielepp, P, Baller, D, Gleichmann, U, Pulawski, E, Horstkotte, D, Burchert, W
European journal of nuclear medicine and molecular imaging. 2005;(12):1371-7
Abstract
PURPOSE The aim of this study was to analyse non-invasively the regional effect of therapy with an HMG-CoA reductase inhibitor on myocardial blood flow in patients with coronary artery disease (CAD) with special reference to segments with initially substantially impaired vasodilation. METHODS The study included 26 patients with untreated hypercholesterolaemia. Coronary angiography revealed CAD in nine patients with stenosis >50% and wall irregularities or minimal stenosis <30% in 17 patients. Before and 4.6+/-1.8 months after atorvastatin therapy, ( 13)N-ammonia positron emission tomography (PET) studies were performed at rest and under pharmacological stress. Minimum coronary vascular resistance (MCR) and coronary flow reserve (CFR) were determined. Segments were divided into those with normal or near-normal (MBF during adenosine > or =2.0 ml/min/g) and those with abnormal (MBF<2.0 ml/min/g) vasodilator flow response. In CAD patients, 156 segments were analysed, 85 of which had abnormal MBF; in the non-obstructive group, 59 of 297 segments had abnormal MBF. RESULTS LDL cholesterol decreased after atorvastatin therapy from 186+/-43 mg/dl to 101+/-26 mg/dl (p<0.001). In normal segments no significant changes in MBF, CFR and MCR were found. However, initially abnormal segments showed significant improvements in MCR (15%, p<0.0001) and MBF during adenosine (30%, p<0.0001) after therapy. CONCLUSION The improvement in regional coronary vasodilator function after atorvastatin in patients with coronary atherosclerosis may be caused, at least in part, by increased flow-mediated (endothelium-dependent) dilation of the total arteriolar and arterial vascular system. These data further support the concept of non-invasive management of stable CAD by statin therapy and life-style modification guided by PET.