Cardiac chamber volumes and left ventricular mass in people living with HIV and matched uninfected controls.

OBJECTIVES: People living with HIV (PLWH) have increased risk of cardiovascular diseases compared with uninfected populations. We assessed structural cardiac abnormalities and their associated risk factors in well-treated PLWH and uninfected controls using multidetector computed tomography (MDCT). METHODS: People living with HIV and age- and sex-matched uninfected controls underwent MDCT to determine left atrial volume (LAV), left ventricular diastolic volume (LVDV), right ventricular diastolic volume (RVDV) and left ventricular mass (LVM). All outcomes were indexed to body surface area (BSA) (LAVi, LVDVi, RVDVi and LVMi). RESULTS: A total of 592 PLWH and 1184 uninfected controls were included in the study. PLWH had smaller mean (SD) LAVi [40 (8) vs. 41 (9) mL/m2 ; P = 0.002] and LVDVi [61 (13) vs. 65 (14) mL/m2 ; P < 0.001] but larger RVDVi [89 (18) vs. 86 (17) mL/m2 ; P < 0.001] than uninfected controls. HIV was independently associated with 7 mL (95% CI: -10 to -3) smaller LVDV, and with 12 mL (95% CI: 8-16) larger RVDV, and 4 g (95% CI: 1-6) larger LVM after adjustment for cardiovascular risk factors and BSA. Large RVDV in PLWH was not associated with obstructive lung function. CONCLUSIONS: HIV was independently associated with smaller LVDV and larger RVDV and LVM. Alterations in cardiac chamber volumes in PLWH were mainly minor. The clinical impact of these findings is uncertain, but it seems unlikely that alterations in cardiac chamber volumes explain the increased burden of cardiovascular disease previously observed in PLWH.

Plasma levels of ß2-microglobulin are associated with atherosclerosis in patients with systemic lupus erythematosus: a cross-sectional cohort study.

Objective The objective of this paper is to examine the association between plasma levels of ß2-microglobulin (ß2MG), a protein previously associated with atherosclerosis, and the presence of carotid plaque (CP) or coronary artery calcium (CAC) in a cross-sectional cohort study of patients with systemic lupus erythematosus (SLE). Methods Patients with SLE were enrolled between June 2013 and May 2014. The presence of CP and CAC was assessed with ultrasonography and computed tomography scan, respectively. The presence of CP or CAC in the SLE patients was analyzed with respect to plasma levels of ß2MG and renal function expressed as the estimated glomerular filtration rate (eGFR). Results The study cohort consisted of 147 patients, 89% women and 95% Caucasians. The median age was 46 (range: 21-75) years with a median disease duration of 14 years. CP and CAC was observed in 29 (20%) and 57 (39%) of patients, respectively. CP or CAC was seen in 62 (42%) patients and was associated with the highest quartile of plasma ß2MG in patients with eGFR ≥ 90 ml/min/1.73 m2; OR = 18 (95% CI: 1.7-181). ß2MG adjusted for eGFR was also associated with presence of CP or CAC in the total cohort. The exclusion of 25 patients with a prior history of cardiovascular disease did not change the observed associations. Conclusion In this study, we found significant associations between imaging markers of atherosclerosis and high plasma levels of plasma ß2MG. These data suggest that ß2MG is a candidate for further study as a biomarker for atherosclerosis in SLE.

Optimisation of coronary vascular territorial 3D echocardiographic strain imaging using computed tomography: a feasibility study using image fusion.

Current echocardiographic assessments of coronary vascular territories use the 17-segment model and are based on general assumptions of coronary vascular distribution. Fusion of 3D echocardiography (3DE) with multidetector computed tomography (MDCT) derived coronary anatomy may provide a more accurate assessment of left ventricular (LV) territorial function. We aimed to test the feasibility of MDCT and 3DE fusion and to compare territorial longitudinal strain (LS) using the 17-segment model and a MDCT-guided vascular model. 28 patients underwent 320-slice MDCT and transthoracic 3DE on the same day followed by invasive coronary angiography. MDCT (Aquilion ONE, ViSION Edition, Toshiba Medical Systems) and 3DE apical full-volume images (Artida, Toshiba Medical Systems) were fused offline using a dedicated workstation (prototype fusion software, Toshiba Medical Systems). 3DE/MDCT image alignment was assessed by 3 readers using a 4-point scale. Territorial LS was assessed using the 17-segment model and the MDCT-guided vascular model in territories supplied by significantly stenotic and non-significantly stenotic vessels. Successful 3DE/MDCT image alignment was obtained in 86 and 93 % of cases for reader one, and reader two and three, respectively. Fair agreement on the quality of automatic image alignment (intra-class correlation = 0.40) and the success of manual image alignment (Fleiss' Kappa = 0.40) among the readers was found. In territories supplied by non-significantly stenotic left circumflex arteries, LS was significantly higher in the MDCT-guided vascular model compared to the 17-segment model: -15.00 ± 7.17 (mean ± standard deviation) versus -11.87 ± 4.09 (p < 0.05). Fusion of MDCT and 3DE is feasible and provides physiologically meaningful displays of myocardial function.

Prevalence of cerebral and pulmonary thrombosis in patients with cyanotic congenital heart disease.

BACKGROUND: Patients with cyanotic congenital heart disease (CCHD) have a high prevalence of thrombosis, the most frequently described locations being the cerebral and pulmonary vessels. The reported prevalence of both cerebral infarction and pulmonary thrombosis has been highly variable. The aim of this study was to examine the prevalence of both cerebral and pulmonary thrombosis in CCHD according to medical history and imaging. In addition, the role of known erythrocytosis and haemostatic abnormalities as risk factors was evaluated. METHODS AND RESULTS: A cross-sectional descriptive study examining 98 stable adult patients with CCHD with a medical questionnaire, blood samples, MRI of the cerebrum (n=72), multidetector CT imaging (MDCT) of the thorax (n=76) and pulmonary scintigraphy (ventilation/perfusion/single-photon emission computerised tomography/CT) (n=66). The prevalence of cerebral infarction and pulmonary thrombosis according to imaging were 47% and 31%, respectively. Comparing the findings with previous medical history revealed a large under-reporting of thrombosis with only 22% of the patients having a clinical history of stroke and 25% of pulmonary thrombosis. There was no association between the degree of erythrocytosis or haemostatic abnormalities and the prevalence of thrombosis. CONCLUSIONS: Patients with CCHD have a prevalence of both cerebral and pulmonary thrombosis of around 30%-40%, which is much higher than that reported previously. Furthermore, there is a large discrepancy between clinical history and imaging findings, suggesting a high prevalence of silent thrombotic events. Neither erythrocytosis nor haemostatic abnormalities were associated with the prevalence of thrombosis in patients with CCHD. TRIAL REGISTRATION NUMBER: http://www.cvk.sum.dk/CVK/Home/English.aspx (H-KF-2006-4068).

Myocardial perfusion at rest in patients with Diabetes Mellitus Type 1 compared with healthy controls assessed with Multi Detector Computed Tomography.

AIM: Type 1 diabetes mellitus (T1DM) is associated with an increased risk of ischemic heart disease (IHD). The relative contribution of structural and functional abnormalities of the coronary circulation determining clinically manifested IHD remains unknown. The aim of this study was to assess potential differences in myocardial perfusion at rest and coronary atherosclerosis between asymptomatic T1DM patients and healthy controls. METHODS: Left ventricular (LV) myocardial perfusion at rest measured as LV myocardial Attenuation Density/LV blood pool Attenuation Density (MyoAD-ratio) and coronary artery atherosclerosis were evaluated with 320-multidetector computed tomography angiography in 57 asymptomatic T1DM patients and 114 sex and age matched controls. RESULTS: In both groups median age was 53 years (p5,p95: 42,67) and 59.6% were men. Median duration of diabetes in the T1DM group was 35 years (p5,p95: 17,49). Median coronary calcium score was higher in T1DM patients (51 vs. 2, p=0.037) compared with controls. However, a similar frequency of >50% stenosis in one or more coronary arteries was found in T1DM patients and controls (18% vs. 14%, p=0.49). LV myocardial perfusion at rest (MyoAD-ratio) was 18% higher in T1DM patients than controls (0.13 vs. 0.11, p<0.0001). This difference was noted throughout all the LV myocardial segments. In a multiple regression analysis including diabetes, sex, age, cardiovascular risk factors, heart rate, calcium score and coronary stenosis >50%, MyoAD-ratio remained significantly higher in T1DM patients (p=0.0001). CONCLUSIONS: LV myocardial perfusion at rest is higher in T1DM patients compared with controls independent of coronary atherosclerosis and cardiovascular risk factors.

Calcium score of small coronary calcifications on multidetector computed tomography: results from a static phantom study.

INTRODUCTION: Multi detector computed tomography (MDCT) underestimates the coronary calcium score as compared to electron beam tomography (EBT). Therefore clinical risk stratification based on MDCT calcium scoring may be inaccurate. The aim of this study was to assess the feasibility of a new phantom which enables establishment of a calcium scoring protocol for MDCT that yields a calcium score comparable to the EBT values and to the physical mass. MATERIALS AND METHODS: A phantom containing 100 small calcifications ranging from 0.5 to 2.0mm was scanned on EBT using a standard coronary calcium protocol. In addition, the phantom was scanned on a 320-row MDCT scanner using different scanning, reconstruction and scoring parameters (tube voltage 80-135 kV, slice thickness 0.5-3.0mm, reconstruction kernel FC11-FC15 and threshold 110-150 HU). The Agatston and mass score of both modalities was compared and the influence of the parameters was assessed. RESULTS: On EBT the Agatston and mass scores were between 0 and 20, and 0 and 3mg, respectively. On MDCT the Agatston and mass scores were between 0 and 20, and 0 and 4 mg, respectively. All parameters showed an influence on the calcium score. The Agatston score on MDCT differed 52% between the 80 and 135kV, 65% between 0.5 and 3.0mm and 48% between FC11 and FC15. More calcifications were detected with a lower tube voltage, a smaller slice thickness, a sharper kernel and a lower threshold. Based on these observations an acquisition protocol with a tube voltage of 100 kV and two reconstructions protocols were defined with a FC12 reconstruction kernel; one with a slice thickness of 3.0mm and a one with a slice thickness of 0.5mm. This protocol yielded an Agatston score as close to the EBT as possible, but also a mass score as close to the physical phantom value as possible, respectively. CONCLUSION: With the new phantom one acquisition protocol and two reconstruction protocols can be defined which produces Agatston scores comparable to EBT values and to the physical mass.

Left ventricular contractile function after distal protection in primary percutaneous coronary intervention: results from the Drug Elution and Distal Protection in ST-Elevation Myocardial Infarction trial.

BACKGROUND: Coronary intervention (PCI) may result in an increased infarct size. We evaluated the effect of distal protection during PCI for ST-segment elevation myocardial infarction (STEMI) on myocardial function. METHODS: Patients with STEMI were randomly referred within 12 h for PCI with (N = 312) or without distal protection (N = 314). Left ventricular (LV) contractile function was assessed with echocardiography 8 months after PCI. Global LV myocardial wall motion index (WMI) was calculated as the average wall motion score of all myocardial segments. The occurrence of death, nonfatal re-infarction, and stroke 8 months after PCI were also recorded. RESULTS: The occurrence of death, nonfatal re-infarction, and stroke 8 months after PCI was 7.1% after distal protection and 5.7% after conventional treatment (p = 0.17). WMI improved by 4.1% at 8 months in patients treated with distal protection compared to patients receiving conventional PCI (p < 0.01). In myocardium supplied by a culprit artery treated by distal protection regional LV function was 9-11% higher than myocardial regions treated conventionally ( p < 0.02). CONCLUSIONS: Routine use of distal protection during primary PCI is associated with a significant improvement in LV contractile function, with no detectable impact on intermediate term clinical outcome.

Thoracic sympatholysis with epidural blockade assessed by quantitative measurement of cutaneous blood flow.

BACKGROUND: Quantifying sympathetic activity is difficult. Direct measurement is possible and superior to indirect techniques, but nerves to internal organs are not accessible in humans. Recently, we validated a quantitative technique for measurement of cutaneous blood flow using heat as an indicator. The aim of the study was to investigate whether sympatholysis during thoracic epidural blockade (TEA) may be documented by changes in regional cutaneous blood flow. A secondary aim was to assess whether, during TEA, local heating itself enhances regional blood flow. METHODS: Six patients scheduled for elective coronary artery bypass grafting (CABG) were studied. An epidural catheter was inserted at the T2-3 interspace. Measurements were performed with an electrode, which can measure the local temperature of the skin. The probe is covered with a thermostatically controlled cap to avoid a thermic gradient to air. As a result of the cap, a change in temperature of the central disc depends almost solely on the blood flow in the underlying tissue. Regional cutaneous blood flow rates were measured before and after epidural anesthesia with and without local heating. RESULTS AND COMMENTS: All patients had a sensory blockade covering at least T1-5. Cutaneous blood flow increased in all six patients after blockade (13.6 ml/min/100 g, range 10.6-14.6 vs. 18.4 ml/min/100 g, range 13.9-24.5; P<0.05). Local heating did not further enhance blood flow. CONCLUSION: High TEA is associated with a uniform increase in thoracic cutaneous blood flow, and is suggestive of regional sympatholysis. Quantitative measurements of skin blood flow appear promising for documenting regional sympatholysis during TEA.

Relationship between regional 18F-fluorodeoxyglucose and 13N ammonia uptake in normal myocardium assessed by positron emission tomography: patterns of mismatch and effects of aging.

Increased regional myocardial 18F fluorodeoxyglucose (18FDG) uptake in relation to 13N ammonia (13NH3) uptake--i.e. glucose metabolism-blood flow 'mismatch'--appears to be a strong indicator of myocardial viability in patients with ischemic heart disease (IHD) and regionally reduced contractile function. Reference values of regional 18FDG and 13NH3 uptake have not been determined in healthy subjects with the target age for the development of IHD. We therefore studied healthy middle-aged and old men using positron emission tomography (PET). Twenty-three healthy men aged 51 to 83 years of age were studied. 18FDG and 13NH3 uptake was quantified in 16 myocardial segments with PET and circumferential profile analysis. The relative 18FDG/13NH3 uptake was considerably heterogeneous with 18FDG uptake consistently higher than 13NH3 uptake in the left lateral ventricular wall. This regional 'mismatch' pattern was observed in all subjects, but was most prominent in middle-aged men. The observed age-dependency was the result of a progressive increased in 13NH3 uptake with advancing age in the left ventricular lateral wall. Age-matched reference values of myocardial 18FDG and 13NH3 uptake appears to be important for the discrimination between physiological and pathological glucose metabolism-blood flow mismatch assessed by PET and circumferential profile analysis.

Regional myocardial oxygen consumption estimated by carbon-11 acetate and positron emission tomography before and after repetitive ischemia.

BACKGROUND: Preserved myocardial oxygen consumption estimated by carbon 11-acetate and positron emission tomography (PET) in myocardial regions with chronic but reversibly depressed contractile function in patients with ischemic heart disease have been suggested to be caused by repeated short episodes of acute myocardial ischemia. To evaluate this hypothesis myocardial 11C-acetate PET imaging was performed before and after acute repetitive myocardial ischemia. METHODS AND RESULTS: In open chest dogs (n = 8), the left anterior descending coronary artery was occluded 4 times for 5 minutes alternating with 5 minutes of reperfusion. Before and after repetitive coronary occlusions, oxygen 15 water/oxygen 15 carbon monoxide (blood flow), and 11C-acetate (oxygen consumption) PET imaging were performed. Left ventricular regional systolic wall thickening was measured with sonomicrometry. Forty-five minutes after the ischemic episodes, systolic ventricular wall thickening was decreased by 90%, whereas myocardial blood flow was reduced by 21% compared with baseline values (P < .05). Ninety minutes after the ischemic episodes, estimated oxygen consumption was unaltered compared with the baseline level despite a sustained 70% decrease in the regional contractile function (P < .05). CONCLUSIONS: Oxygen consumption estimated by 11C-acetate PET imaging is preserved after repeated episodes of acute myocardial ischemia despite a severe impairment of contractile function.

Glucose metabolism in reperfused myocardium measured by [2-18F] 2-fluorodeoxyglucose and PET.

OBJECTIVE: [2-18F] 2-fluorodeoxyglucose (FDG) is widely used to trace glucose metabolism for cardiac imaging with positron emission tomography. Because the transport and phosphorylation rates differ for glucose and FDG, a lumped constant (LC) is used to correct for these differences. The effects of ischemia and reperfusion on the LC in vivo are unknown. To determine the validity of FDG as a tracer of glucose metabolism in post-ischemic myocardium in vivo, the relationship between glucose uptake (GU) and FDG metabolic rate (FDG-MR) was assessed early post-reperfusion following a transient ischemic event. METHODS: FDG metabolic rate, measured with FDG and PET, was compared to invasive measurements of substrate metabolism in reperfused and global myocardium of dogs subjected to 25 min ischemia and 2 h reperfusion. RESULTS: The FDG metabolic rate was decreased 20 +/- 4% in reperfused relative to remote myocardium. Glucose oxidation and lactate uptake were also decreased in reperfused relative to global myocardium, by 26 +/- 6% and 60 +/- 8% respectively. Glucose uptake did not differ significantly between reperfused and global myocardium. A linear correlation between FDG metabolic rate and glucose uptake was found in both reperfused and remote myocardium. Estimates of the LC from the slopes of the regression lines were similar in reperfused and remote myocardium, 1.25 and 1.44 respectively, and did not differ significantly from the LC determined in control dogs, 1.1. CONCLUSIONS: We conclude that the FDG metabolic rate continues to correlate well with glucose metabolism in reperfused myocardium. While FDG metabolic rate was modestly decreased in the absence of a significant change in glucose uptake, large alterations in the LC are not found 2 h post-reperfusion in vivo.

[Cardiac scanning with positron emission tomography--PET. Clinical use and research aspect]. / Hjertescanning med positronemissionstomografi--PET. Klinisk anvendelse og forskningsmaessig betydning.

Assessment of regional myocardial glucose metabolism and regional myocardial perfusion has become possible with positron emission tomography (PET). These parameters are of importance in distinguishing viable from fibrotic myocardium in patients with ischaemic heart disease. PET scanning appears to be the method of choice in these patients, which has led to an increased clinical application of PET as a method usable to select patients with severe heart disease before potential revascularisation. In the present review, PET technology is briefly described, together with an overview of the scientific evidence supporting the clinical application of cardiac PET. Finally, its applications in the fields of pathophysiology and pharmacology are briefly described.

Fluorodeoxyglucose uptake in dysfunctional myocardium subtended by an occluded coronary artery. Relation to dobutamine contractile reserve and Sestamibi uptake.

BACKGROUND: Myocardial segments with impaired function may have the potential for functional recovery. Augmented exogenous glucose uptake in relation to blood flow estimated by [2-18F]2-fluorodeoxyglucose (FDG) and positron emission tomography (PET) frequently indicates functional reversibility. The spectrum of FDG uptake levels in relation to Sestamibi uptake and dobutamine contraction reserve in areas with impaired function subtended by an occluded coronary artery has never been reported. METHODS AND RESULTS: Seventeen patients with stable angina pectoris and dysfunctional myocardium subtended by an occluded coronary artery were studied with FDG-PET, low-dose dobutamine echocardiography and Sestamibi-Single Photon Emission Computerized Tomography. In a 16 segment model dysfunctional myocardial segments showed a normally distributed FDG uptake ranging from 34% to 150% when normalized to peak segmental Sestamibi uptake. Low FDG uptake was associated with both lack of dobutamine induced contractile reserve and low Sestamibi uptake (in 73% of the segments) whereas high FDG uptake displayed both contractile reserve and Sestamibi uptake (57%). Segments with intermediate FDG uptake had either contractile reserve or a preserved Sestamibi uptake (62%). CONCLUSION: Dysfunctional myocardium subtended by an occluded coronary artery represents a continuum of metabolic states with a high degree of heterogeneity with regard to contractile reserve and Sestamibi uptake.

Dual spillover problem in the myocardial septum with nitrogen-13-ammonia flow quantitation.

UNLABELLED: Conventional cardiac PET modeling techniques for [13N]ammonia flow determination do not fully account for the effects of spillover of activity from the right ventricle (RV) onto the activity in the myocardial septum. The purpose of this study was to investigate and to quantitatively account and correct for this effect. METHODS: Simulations were performed to determine the error introduced by conventional quantitation using septal time-activity curves, which only account for left ventricle (LV) spillover. Furthermore, we explored two separate methods to account for the dual spillover problem: direct estimation of the RV and LV spillover fractions incorporated into the [13N]ammonia model by using the LV and RV input functions in the fit and estimation of the relative dispersion and time shift between the LV and RV input functions by fitting using only the LV input function. The simulated curves were fitted using a two-compartment [13N]ammonia model. Flow estimates from the conventional model and the models including either of the two correction procedures were compared with canine microsphere data. RESULTS: The influence of RV spillover on flow estimation in the septum is determined by several parameters (e.g., dispersion between the RV and LV input function). Depending on the value of these parameters, the septal flow may be underestimated by 0%-30%. The applied methods for correction of the dual spillover problem were comparable and allow for more accurate quantitation in the septum. The canine microsphere data revealed that flow underestimation in the septum is small but significant. CONCLUSION: Dual spillover in the myocardial septum can introduce significant errors in the estimation of flow by the conventional [13N]ammonia model fitting method, which does not properly account for the RV spillover. Adjusting for the RV spillover in one of the two proposed methods allows for more accurate quantitation of myocardial septal flow with [13N]ammonia PET data.

Regulation of pyruvate dehydrogenase activity and glucose metabolism in post-ischaemic myocardium.

Pyruvate dehydrogenase (PDH) is regulated both by covalent modification and through modulation of the active enzyme by metabolites. In the isolated heart, post-ischaemic inhibition of PDH, leading to uncoupling of glycolysis and glucose oxidation and a decrease in cardiac efficiency, has been described. In vivo, post-ischaemic reperfusion leads to metabolic abnormalities consistent with PDH inhibition, but the effects of ischaemia/reperfusion on PDH are not well characterized. We therefore investigated PDH regulation following transient ischaemia in vivo. In 33 open-chest dogs, the left anterior descending (LAD) was occluded for 20 min followed by 4 h reperfusion. In 17 dogs, dichloroacetate (DCA) was injected prior to reperfusion, while 16 dogs served as controls. In dogs without DCA, glucose oxidation and lactate uptake were lower in reperfused than in remote tissue, suggesting reduced flux through PDH. However, percent active and total PDH measured in myocardial biopsies were similar in both territories, excluding covalent enzyme modification or loss of functional enzyme. DCA activated PDH activity similarly in both regions and abolished differences in glucose oxidation and lactate uptake. Thus, decreased PDH flux in reperfused myocardium does not result from covalent modification or loss of total enzyme activity, but more likely from metabolite inhibition of the active enzyme. DCA leads to essentially complete activation of PDH, increases overall glucose utilization and abolishes post-ischaemic inhibition of glucose oxidation.

Simultaneous measurement of myocardial oxygen consumption and blood flow using [1-carbon-11]acetate.

UNLABELLED: [1-Carbon-11]acetate has been used as a tracer for oxidative metabolism with PET. The aim of this study was to validate, in humans, a previously proposed two-compartment model for [1-11C]acetate for the noninvasive measurement of myocardial oxygen consumption (MVO2) and myocardial blood flow (MBF) with PET. METHODS: Twelve healthy volunteers were studied with [13N]ammonia, [1-11C]acetate and PET. Myocardial oxygen consumption was invasively determined by the Fick method from arterial and coronary sinus O2 concentrations and from MBF obtained by [13N]ammonia PET. RESULTS: Directly measured MVO2 ranged from 5.2 to 11.1 ml/100g/min, and MBF ranged from 0.48 to 0.88 ml/g/min. Oxidative flux through the tricarboxylic acid cycle, reflected by the rate constant k2, which correlated linearly with measured MVO2 [k2 = 0.0071 + 0.0074(MVO2); r = 0.74, s.e.e. = 0.015]. With this correlation, MVO2 could be estimated from the model-derived k2 value by MVO2 = 135(k2) - 0.96. The slope of this relationship was close to that previously obtained in rats and implies that the tricarboxylic acid cycle intermediate metabolite pool sizes are comparable. The net extraction (K1) of [1-11C]acetate, measured by PET, from blood into myocardium correlated closely with MBF by K1 = 0.15 + 0.73(MBF) (r = 0.93, s.e.e. = 0.033) and, thus, provided noninvasively obtainable measures of blood flow. CONCLUSION: The proposed compartment model for [1-11C]acetate fits the measured kinetics well and, with proper calibration, allows estimation of absolute MVO2 rather than only an index of oxidative metabolism. Furthermore, [1-11C]acetate-derived estimates of MBF are feasible.

Effects of cardiac allograft vasculopathy on myocardial blood flow, vasodilatory capacity, and coronary vasomotion.

BACKGROUND: Coronary vasculopathy is the third leading cause of death 1 year after cardiac allograft transplantation. This study was designed to assess the hemodynamic effects of transplant vasculopathy on myocardial blood flow and vasomotion. METHODS AND RESULTS: Thirty-two patients were studied 1 to 2 years after cardiac transplantation by use of positron emission tomography (n = 32), intravascular ultrasound (n = 26), coronary angiography (n = 32), and endomyocardial biopsy (n = 32). Twenty healthy individuals served as control subjects. Quantitative intravascular ultrasound was used to compute coronary lumen area, intimal thickness, and intimal index [Intima Area/(Intima + Lumen Area)]. Myocardial blood flow was quantified with the use of 13N-ammonia/positron emission tomography. Mean myocardial blood flow was higher in the transplant patients than in control subjects (0.94 +/- 0.26 versus 0.68 +/- 0.16 mL.min-1.g-1 P < .0005). Cold increased myocardial blood flow to 0.79 +/- 0.18 mL.min-1.g-1 in control subjects but not in patients (0.98 +/- 0.36 mL.g-1.min-1). Hyperemic myocardial blood flow was lower in patients than in control subjects (1.69 +/- 0.78 versus 2.30 +/- 0.32 mL.min-1.g-1; P < .05) and was inversely related to maximal intimal thickness and intimal index (all P < .05). The myocardial flow reserve was reduced in patients (1.82 +/- 0.55 versus 3.45 +/- 1.03; P < .0001). CONCLUSIONS: The degree of intimal thickening is correlated with abnormalities in coronary function in patients with diffuse cardiac allograft vasculopathy. The reduction in vasodilatory capacity and the abnormal blood flow response to cold suggest abnormalities in endothelium-dependent and -independent coronary vasodilation in transplant recipients.

Inhibition of glyceraldehyde-3-phosphate dehydrogenase in post-ischaemic myocardium.

OBJECTIVE: Myocardial reperfusion following brief period of ischaemic is associated with prolonged, reversible periods of metabolic dysfunction. As the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is inhibited in vitro by reactive oxygen species, we hypothesized that production of reactive oxygen species during reperfusion would lead to inhibition of GAPDH in post-ischaemic myocardium. METHODS: Anaesthetized closed-chest-dogs were subjected to 20 min balloon occlusion of the left anterior descending coronary artery. Biopsy samples were taken after 3 and 24 h of reperfusion, to determine the activity of GAPDH and the concentrations of glycolytic intermediates in post-ischaemic and remote, non-ischaemic territories. RESULTS: A significant reduction in GAPDH activity was observed in post-ischaemic relative to remote tissue after 3 h reperfusion (4.8 +/- 0.5 vs. 2.9 +/- 0.2 mumol/min/mg protein; P < 0.01). Western blotting revealed no reduction in the levels of GAPDH protein. Analysis of enzyme kinetics showed the loss of activity to be associated with decreased Vmax (5.9 +/- 0.5 vs. 3.2 +/- 0.2 mumol/min/mg protein; P < 0.01) with no significant change in the Km for glyceraldehyde-3-phosphate (GAP). Incubation of the inhibited enzyme under both mild and strong reducing conditions failed to reactivate the enzyme. The acute reduction in enzyme activity in post-ischaemic tissue was accompanied by regional differences in glycolytic intermediates, notably a twofold accumulation of GAP (P < 0.05), and a reduction in the glucose metabolic rate (GMR) determined by positron emission tomography and [18F]2-fluorodeoxyglucose. By 24 h reperfusion, no regional differences in GAPDH activity, reaction Vmax or Km, GAP concentrations or GMR were detectable. CONCLUSIONS: These results suggest that inhibition of GAPDH activity may represent an important point at which glycolysis is limited during reperfusion, and further, that the mechanisms of enzyme inhibition do not involve simple oxidation or S-thiolation of critical active site thiol groups.