Neal G. Uren

Impaired Coronary Tissue Plasminogen Activator Release Is Associated With Coronary Atherosclerosis and Cigarette Smoking Direct Link Between Endothelial Dysfunction and Atherothrombosis

BackgroundThe aim of the study was to establish the influence of proximal coronary artery atheroma and smoking habit on the stimulated release of tissue plasminogen activator (tPA) from the heart. Methods and ResultsAfter diagnostic coronary angiography in 25 patients, the left anterior descending coronary artery (LAD) was instrumented, and the proximal LAD plaque volume was determined by use of intravascular ultrasound (IVUS). Blood flow and fibrinolytic responses to selective LAD infusion of saline, substance P (10 to 40 pmol/min; endothelium-dependent), and sodium nitroprusside (5 to 20 &mgr;g/min; endothelium-independent) were measured by intracoronary IVUS and Doppler, combined with arterial and coronary sinus blood sampling. Mean plaque burden was 5.5±0.8 mm3/mm vessel (range 0.6 to 13.7 mm3/mm vessel). LAD blood flow increased with both substance P and sodium nitroprusside (P <0.001), although coronary sinus plasma tPA antigen and activity concentrations increased only during substance P infusion (P <0.006 for both). There was a strong inverse correlation between the LAD plaque burden and release of active tPA (r =−0.61, P =0.003). Cigarette smoking was associated with impaired coronary release of active tPA (current smokers, 31±23 IU/min; ex-smokers, 50±33 IU/min; nonsmokers 202±73 IU/min;P <0.05). ConclusionsWe found that both the coronary atheromatous plaque burden and smoking habit are associated with a reduced acute local fibrinolytic capacity of the heart. These important findings provide evidence of a direct link between endogenous fibrinolysis, endothelial dysfunction, and atherothrombosis in the coronary circulation and may explain the greater efficacy of thrombolytic therapy for myocardial infarction in cigarette smokers.

Determinants of Coronary Remodeling in Transplant Coronary Disease A Simultaneous Intravascular Ultrasound and Doppler Flow Study

BACKGROUNDnCoronary remodeling plays a significant role in lumen loss in transplant allograft vasculopathy (TxCAD), but the determinants of remodeling are unknown. We assessed the relationship between remodeling and plaque topography, coronary compliance, and blood flow in TxCAD.nnnMETHODS AND RESULTSnOne artery in each of 27 transplant patients was investigated with simultaneous intravascular ultrasound and coronary flow measurements (basal and hyperemic by Doppler flow wire). At 4 to 8 different cross sections (mean 5.1+/-1. 2), plaque topography (concentric or eccentric) was determined, and total vessel area, lumen area, and intimal/medial area (IMA) were measured. Mean remodeling ratio (vessel area/IMA) in eccentric lesions (E, n=28) was significantly larger than that in concentric lesions (C, n=70) (E 5.87+/-0.93 versus C 3.58+/-0.62; P<0.001), despite similar IMA (E 3.89+/-0.68 versus C 3.90+/-0.41; P=NS) and distribution of imaged segments. Remodeling ratio was consistently larger in eccentric lesions in all 3 vessel segments when analyzed separately, and mean remodeling ratio for each artery was larger in vessels with predominantly eccentric lesions. Coronary compliance ([Delta lumen area/diastolic lumen area]/Delta mean arterial pressure x 10(3)) was also significantly greater in eccentric lesions versus concentric lesions (proximal 1.00+/-0.39 versus 0.22+/-0.04; mid 0.71+/-0.17 versus 0.21+/-0.10; distal 0.43+/-0.13 versus 0. 01+/-0.08; all P<0.01). Coronary flow reserve was also significantly higher in coronary arteries with primarily eccentric lesions (E 2. 49+/-0.64 versus C 1.87+/-0.28; P<0.01).nnnCONCLUSIONSnVessel remodeling in transplant vasculopathy is significantly greater in eccentric lesions than in concentric lesions, possibly due to greater coronary compliance and resistive vessel function.

Three-dimensional forward-viewing intravascular ultrasound imaging of human arteries in vitro

The aim of this work was to investigate the suitability of a novel forward-viewing intravascular ultrasound (IVUS) technique for three-dimensional imaging of severely stenosed or totally occluded vessels, where the conventional side-viewing IVUS systems are of limited use. A stiff 3.8 mm diameter forward-viewing catheter was manufactured to scan a 72 degrees sector ahead of its tip. Conical volume data were acquired by rotating the catheter over 180 degrees by means of a motorised mechanical system. Operating at 30 MHz, the catheter was integrated with an IVUS scanner and a radiofrequency data acquisition system. Postmortem carotid and femoral arteries were scanned in vitro. Correlation of the reconstructed images with histology demonstrated the ability of this forward-viewing IVUS system to visualise healthy lumens, bifurcations, thickened atherosclerotic walls and, most importantly, severe and complete vessel occlusions. A rotating-sector forward-viewing IVUS system is suitable for anatomical assessment of severely diseased vessels in three dimensions.

Influence of differential vascular remodeling on the coronary vasomotor response

OBJECTIVESnArterial remodeling may increase or decrease the luminal encroachment of atherosclerotic plaques in the coronary circulation. However, the factors determining the nature and consequences of the remodeling process remain poorly characterized. The study aims were to assess whether the pattern of vascular remodeling influences the physical and vasomotor responses of the coronary arteries in vivo in man.nnnMETHODSnCoronary vessel area, distensibility and stiffness were determined in positively, negatively and non-remodeled arterial segments using intravascular ultrasound and Doppler flow measurement. Epicardial vasomotor responses were determined following intracoronary boluses of acetylcholine (10(-6) and 10(-4) M), adenosine (24-30 microg) and nitroglycerin (200 microg).nnnRESULTSnFifty-six coronary arterial segments were studied in 25 patients. In comparison to non- and positively remodeled segments, negatively remodeled segments had a higher stiffness index (67+/-16 vs. 33+/-5 and 38+/-8, respectively; P<0.02) and appeared to have lower compliance and distensibility (0.66+/-0.17 vs. 1.65+/-0.54 and 0.94+/-0.18/mmHg; P=NS). Non-remodeled segments had a greater change in vessel area with 10(-6) M acetylcholine (4.9+/-0.8%), compared to positively and negatively remodeled segments (0.6+/-1.8% and -4.9+/-1.8%, respectively, P<0.05). A significant degree of preservation of vasodilatation to 10(-6) M acetylcholine was evident in positively remodeled compared with negatively remodeled segments (P<0.05). Nitroglycerin caused greater vasodilatation in non-remodeled segments (7.2+/-3.8%) than either positively or negatively remodeled segments (4.7+/-0.9 and 3.7+/-0.6%, respectively, P<0.05).nnnCONCLUSIONSnVascular remodeling is an important and major determinant of local epicardial vasomotor responses. Both structural and functional abnormalities are associated with negative remodeling that may contribute to the adverse effects of such lesions.

The progression of thrombus in an ex-vivo shunt model evaluated by intravascular ultrasound radiofrequency analysis.

We tested the ability of ultrasound radiofrequency (RF) signal analysis to characterize thrombus accumulation in a Dacron graft incorporated into the exteriorized arteriovenous shunt in 3 baboons with constant blood flow for 60 min. Thrombus formation was quantified by sequential measurements of 111Indium-labeled platelet deposition. RF signals were acquired every 15 min at 2 sites in the graft, using a 2.9 Fr intravascular ultrasound catheter-based transducer (30 MHz) and digitized at 250 MHz in 8-bit resolution. Regions of interest were placed within a 0.5-mm perimeter adjacent to the graft wall. Integrated backscatter increased significantly (p < 0.001) with increasing platelet deposition. However, mean-to-standard deviation ratio of the RF envelope showed no significant change and the distribution pattern of the RF probability function remained constant and consistent with a Rayleigh scattering process. These results provide a basis for using RF analysis to monitor the time-course of thrombus formation.

A low-dose comprehensive cardiac CT protocol assessing anatomy, function, perfusion, and viability.

Radiation exposure in cardiac imaging is a major healthcare concern and low-dose cardiac imaging has important implications for patients. We describe the application of a low-dose comprehensive cardiac computed tomography protocol that assesses anatomy, function, perfusion and viability with correlations to invasive coronary angiography and magnetic resonance imaging.

The relationship between the basal coronary translesional pressure gradient and fractional flow reserve

Fractional flow reserve (FFR) allows for physiological definition of coronary lesion severity but requires induction of maximal coronary circulation hyperemia with administration of adenosine leading to coronary resistive vessel vasodilatation. However, the hyperemic response to adenosine, and therefore the calculation of FFR, may be affected by dysfunction of the coronary microvasculature. The aim was to define the relationship between basal Pd/Pa and FFR and identify lesion‐independent predictors of the change in Pd/Pa with hyperemia.