Konstantinos Toutouzas

Increased local temperature in human coronary atherosclerotic plaques: an independent predictor of clinical outcome in patients undergoing a percutaneous coronary intervention☆

OBJECTIVES We investigated the midterm clinical significance of human coronary atherosclerotic plaques temperature after a successful percutaneous coronary intervention. BACKGROUND Previous studies have shown an increased temperature in human atherosclerotic plaques. However, the prognostic significance of atherosclerotic plaque temperature in patients undergoing a successful percutaneous intervention is unknown. METHODS We prospectively investigated the relation between the temperature difference (deltaT) between the atherosclerotic plaque and the healthy vessel wall and event-free survival among 86 patients undergoing a successful percutaneous intervention. Temperature was measured by a thermography catheter, as previously validated. The study group consisted of patients with effort angina (EA) (34.5%), unstable angina (UA) (34.5%) and acute myocardial infarction (AMI) (30%). RESULTS The deltaT increased progressively from EA to AMI (0.132 +/- 0.18 degrees C in EA, 0.637 +/- 0.26 degrees C in UA and 0.942 +/- 0.58 degrees C in AMI). The median clinical follow-up period was 17.88 +/- 7.16 months. The deltaT was greater in patients with adverse cardiac events than in patients without events (deltaT: 0.939 +/- 0.49 degrees C vs. 0.428 +/- 0.42 degrees C; p < 0.0001). The deltaT was a strong predictor of adverse cardiac events during the follow-up period (odds ratio 2.14, p = 0.043). The threshold of the deltaT value, above which the risk for an adverse cardiac event was significantly increased, was 0.5 degrees C. The incidence of adverse cardiac events in patients with deltaT > or = 0.5 degrees C was 41%, as compared with 7% in patients with deltaT < 0.5 degrees C (p < 0.001). CONCLUSIONS Increased local temperature in atherosclerotic plaques is a strong predictor of an unfavorable clinical outcome in patients with coronary artery disease undergoing percutaneous interventions.

Unfavorable Effects of Passive Smoking on Aortic Function in Men

Among other underlying mechanisms, tobacco smokes effect on the mechanical properties of the arterial wall may play an important role in its catastrophic cardiovascular effects. Previous studies have shown that active smoking influences endothelium-mediated vascular control [1-3], induces coronary artery vasoconstriction [4-7], and increases the stiffness of both muscular and elastic arteries [8-11]. Other investigators have demonstrated that passive smoking is associated with dose-related impairment of endothelium-dependent dilatation and with coronary artery vasoconstriction [12, 13]. The aorta acts as both a conduit and an elastic buffering chamber. By virtue of its elastic properties, this vessel influences left ventricular performance and coronary blood flow [14-23]. Conceivably, any adverse effect of smoking on aortic performance could compromise left ventricular function and coronary blood flow. Previous studies from our laboratory have shown that aortic elastic properties deteriorate acutely during active smoking [24]. In the current study, we investigated aortic elastic properties during passive smoking by using a high-fidelity method suitable for determining the association between aortic pressure and diameter [24-26]. Methods Study Group Potential participants were male patients who underwent diagnostic cardiac catheterization for evaluation of chest pain. Patients with left main-vessel or three-vessel coronary artery disease, arterial hypertension, valvular heart disease, congenital heart disease, left ventricular systolic dysfunction, chronic obstructive pulmonary disease, history of cerebrovascular accident, and diabetes mellitus were excluded from the study. According to these criteria, 16 nonsmokers and 32 current, long-term smokers ( 1 pack per day for 1 year) were enrolled in the study. The nonsmokers were assigned to passive smoking studies, and the smokers were randomly assigned to either active (16 patients) or sham (16 patients) smoking studies. Cardiovascular agents were withheld for at least five half-lives before the study. The institutional ethical committee approved the study protocol, and each patient provided written informed consent. Study Protocol Design The participants did not consume caffeine-containing beverages or meals and refrained from smoking for at least 12 hours before the study. Diagnostic cardiac catheterization and studies of aortic performance were performed during the same catheterization session. After diagnostic catheterization, the participants were allowed to relax in the supine position. An exposure chamber was placed over the heads of the persons in the passive smoking group. Thirty minutes after the last infusion of contrast medium, baseline hemodynamic measurements were obtained. For the passive smoking group, environmental tobacco smoke was then vented into the exposure chamber for 5 minutes; an average carbon monoxide level of 30 parts per million was maintained. The exposure chamber was subsequently removed and patients were allowed to inhale smoke-free room air. Carbon monoxide levels were measured by using a portable carbon monoxide analyzer (Model T15, Langan Products, San Francisco, California). After baseline measurements, the participants in the active smoking group each smoked one filtered cigarette containing 1.0 mg of nicotine under standardized conditions: Every 15 seconds, a puff lasting 5 seconds was taken, and the whole cigarette had to be smoked within 5 minutes. The participants in the sham smoking group performed a similar pattern of inhalation with one unlit cigarette. All variables except cardiac output were measured at baseline and at 1, 2, 3, 4, 5, 10, 15, and 20 minutes after the initiation of passive, active, or sham smoking. Cardiac output was measured by thermodilution at baseline and at 5, 10, and 20 minutes after initiation of passive, active, or sham smoking. Measurement of Aortic Diameters and Pressures Instantaneous aortic diameters were measured at the descending thoracic aorta by a Y-shaped intravascular catheter that was developed in our laboratory and uses sonometry to measure diameter (Figure 1). Aortic pressures were obtained simultaneously at the same point of the aorta by a 3-French catheter-tip micromanometer (Model SPC-330, Millar Instruments, Houston, Texas), as described elsewhere [24-26]. Figure 1. Study instruments. Data Acquisition A VF-1 mainframe (Crystal Biotech, Hopkinton, Massachusetts) was fitted with appropriate modules for measuring aortic diameter and pressure and acquiring an electrocardiogram. Signals were digitized every 5 milliseconds. The digitized data were stored and processed by using Microsoft Excel software (Redmond, Washington). Estimation of Aortic Elastic Properties and Pressure-Diameter Relation The slope of the pressure-diameter loop and aortic distensibility were used as measures of aortic elasticity [24-31]. Statistical Analysis Slope of the Pressure-Diameter Loop The aortic pressure-diameter loop is derived by plotting digitized data for the pressure (ordinate) and the diameter (abscissa) during a single cardiac cycle (Figure 2). The line of this plot during cardiac systole is not identical to the line during cardiac diastole because diameter lags behind pressure as a result of the viscoelastic nature of the aortic wall. Thus, this plot assumes the shape of a clockwise hysteretic loop, the ascending portion of which corresponds to systole and the descending portion of which corresponds to diastole. Multiple loops were obtained for all participants during the study. To characterize the loop, linear regression analysis of pressure versus diameter was done separately in each loop to determine the slope (that is, the regression coefficient b of the following regression equation: pressure = + b x diameter) of the regression line. The slope of this regression line (DeltaP/DeltaD) is an index of aortic elasticity because it gives an inverse measure of the changes in aortic diameter that occur during the cardiac cycle as a response to the changes in distending pressure. With a given change in aortic pressure, a vessel with deteriorated elastic properties responds with a relatively small change in aortic diameter (thus, the slope of the pressure-diameter regression line will be high). In contrast, with a given change in aortic pressure, a vessel with improved elastic properties responds with a relatively large change in aortic diameter (thus, the slope of the pressure-diameter regression line will be low). Figure 2. Representative examples of pressure-diameter loops of three participants (one each from the passive, active, and sham smoking groups). top middle bottom The pressure-diameter loop operates along a hypothetical line of elasticity. Shifting of the pressure-diameter loop to a different hypothetical line of elasticity provides valuable information on the mechanisms involved in the changes in aortic elastic properties (Figure 3). Figure 3. Left. Right. Aortic Distensibility Aortic distensibility was calculated from the following formula: Distensibility = 2Deltad/(d x DeltaP) 106 cm2 dyne1, where d is diastolic aortic diameter, Deltad is the difference between the systolic and diastolic aortic diameters (pulsatile change in aortic diameter), and DeltaP is the difference between the systolic and diastolic aortic pressures (pulse pressure). Large distensibility values represent improved aortic elastic properties, and small values represent deteriorated properties. Data Analysis To obtain individual patient values of aortic pressure and diameter and derived variables at every time point, as well as values of the slope of the pressure-diameter loop regression line, analyses were done on 10 consecutive heartbeats and results were averaged. No values were missing for any variable at any time point. Data are expressed as the mean SD. Repeated-measures analysis of variance (averaged F) was used to detect statistically significant changes in variables within the groups (passive, active, and sham smoking) during the study period, to compare these variables between the passive and sham smoking groups and between the active and sham smoking groups, and to determine whether the time course of these variables differed between the passive and sham smoking groups and between the active and sham smoking groups. To test the univariate homogeneity of variance between the passive and sham smoking groups and between the active and sham smoking groups, the Cochran and Bartlett-Box tests were used. The Box M test was used to assess the equality of the variance-covariance matrices. Greenhouse-Geisser correction was used in the repeated-measures analysis of variance when the Box M test was significant [32]. Normality assumptions, tested by using the Kolmogorov-Smirnoff one-sample test and by calculating the ratio of skewness to the SE of skewness of the sample distribution, were satisfied. P values less than 0.05 were considered statistically significant. Data analysis was done with SPS software, version 7.0 (Chicago, Illinois). Results Baseline Characteristics Three participants in the passive smoking group, three in the active smoking group, and four in the sham smoking group had angiographically normal coronary arteries; the remaining participants had coronary artery disease. Age, baseline hemodynamic measures, and baseline aortic elasticity measures in the three groups are shown in Table 1. Table 1. Baseline Characteristics of the Study Groups* Changes after Passive Smoking Heart Rate, Cardiac Function, and Aortic Pressures Passive smoking was associated with prompt increments in the mean heart rate; cardiac index; and systolic, diastolic, and pulse pressures. Most of these increments occurred during the first 5 minutes. The mean heart rate and cardiac index increased over time in the passive smoking group (peaks at 5 minutes, 76 beats/min [P < 0.001] and 3.6 L/min m2 [P = 0.001]; Table 2) and remained th

Aortic stiffness in young patients with heterozygous familial hypercholesterolemia.

BACKGROUND Dyslipidemia is a primary risk factor for the development of atherosclerosis. Aortic distensibility is an important determinant of left ventricular function and coronary blood flow whose possible alterations in patients with dyslipidemia have not been fully investigated. METHODS To assess the effect of dyslipidemia on the elastic properties of the aorta, we studied 60 patients (mean age 37+/-11 years) with heterozygous familial hypercholesterolemia and no manifest arterial disease and compared them with 20 of their normolipidemic siblings (mean age 34+/-10 years). Two indexes of the aortic elastic properties were measured: aortic distensibility was calculated by use of the formula: 2 x (AoS-AoD)/PP x AoD, and aortic stiffness index was calculated by use of the formula: In (SBP/DBP)/(AoS-AoD)/AoD, where AoS and AoD are aortic root end-systolic and end-diastolic diameters, respectively, SBP and DBP are systolic and diastolic arterial pressure, respectively, and PP is pulse pressure. Internal aortic root diameters were measured at 3 cm above the aortic valve by use of two-dimensional guided M-mode transthoracic echocardiography, and arterial pressure was measured simultaneously at the brachial artery by sphygmomanometry. RESULTS The mean aortic systolic and diastolic diameter index did not differ significantly between the two groups. In contrast, aortic distensibility was found to be significantly reduced in subjects with isolated familial hypercholesterolemia compared with that in the control group (2.15+/-1.72 cm2.dynes(-1).10(-6) vs 3.18+/-1.58 cm2.dynes(-1).10(-6), p < 0.02). In addition, the mean aortic stiffness index was double in patients with familial hypercholesterolemia compared with that in normolipidemic subjects. CONCLUSIONS Severe dyslipidemia does not overtly influence aortic dimensions but leads to impairment of aortic elastic properties before the occurrence of clinical manifestations of atherosclerotic disease.

Incremental Predictive Value of Carotid Inflammation in Acute Ischemic Stroke

Background and Purpose— Microwave Radiometry (MWR) allows in vivo noninvasive assessment of internal temperature of tissues. The aim of the present study was to evaluate in patients with ischemic stroke and bilateral carotid plaques (1) whether ipsilateral carotid arteries exhibit higher temperature differences (&Dgr;T), as assessed by MWR; (2) the predictive accuracy of MWR in symptomatic carotid artery identification. Methods— Consecutive patients with recent acute anterior circulation ischemic stroke because of large artery atherosclerosis were included in the study. Carotid arteries of all patients were evaluated by carotid ultrasound and MWR. Results— In total, 50 patients were included in the study. Culprit carotid arteries had higher &Dgr;T compared with nonculprit (0.93±0.58 versus 0.58±0.35°C; P<0.001). The addition of &Dgr;T to a risk prediction model based only on ultrasound plaque characteristics increased its predictive accuracy significantly (c-statistic: 0.691 versus 0.768; Pdif=0.05). Conclusions— Culprit carotid arteries show higher thermal heterogeneity compared with nonculprit carotid arteries in patients with acute ischemic stroke and bilateral carotid plaques. MWR has incremental value in culprit carotid artery discrimination.

Prevalence and predictors of culprit plaque rupture at OCT in patients with coronary artery disease: a meta-analysis

AIMS The prevalence of plaque rupture at the culprit lesion identified by optical coherence tomography (OCT) in different clinical subset of patients undergoing coronary angiography and its clinical predictors remain to be defined. METHODS All studies including patients with OCT evaluation of the culprit coronary plaque were included. The prevalence of culprit plaque rupture (CPR) and thin-cap fibro-atheroma (TCFA) were the primary endpoints. The factors associated with these findings were studied in a subset of patients with different clinical presentations [ST-elevation myocardial (STEMI) vs. nonST-elevation myocardial infarction (NSTEMI) vs. unstable angina (UA) vs. stable angina pectoris (SAP)]. RESULTS One hundred and fifty citations were initially appraised at the abstract level and 23 full-text studies were assessed. The mean prevalence of CPR and TCFA was 48.1% (40.5-55.8) and 48.7% (37.4-60.1), respectively. The prevalence of CPR and TCFA were higher in STEMI (70.4 and 76.6%) than in NSTEMI (55.6 and 56.3%) and UA (39.1 and 52.9%) or SAP (6.2 and 22.8%). In the overall population at meta-regression analysis, TCFA and current smoking were the only predictors of CPR (B 3.6:2.0-5.1, P < 0.001 and 0.06:0.02-0.1, P = 0.002, respectively). The factors associated with CPR were different depending on clinical presentation. Hypertension was the only clinical predictor for STEMI (B 3.3: 1.2.-5.3 P = 0.001), while advanced age (B 0.12: 0.02-0.22, P = 0.021), diabetes mellitus (B 0.04: 0.01-0.08, P = 0.012), and hyperlipidaemia (B 0.07:0.02-0.11, P = 0.005) were the predictors in NSTEMI and UA. No clinical predictor was found in SA. CONCLUSIONS Our analysis showed high rates of CPR and TCFA detected by OCT in CAD patients, especially in those with ACS, although their prevalence is not negligible in stable patients. TCFA seems to be a strong predictor of CPR in all the ACS scenarios.

Association of inflammatory markers with angiographic severity and extent of coronary artery disease

Inflammatory processes play a pivotal role in the pathogenesis of atherosclerosis and mediate many of the stages of atheroma development, from initial leukocyte recruitment to eventual rupture of the unstable atherosclerotic plaque. Several systemic inflammatory markers reflect different degrees of inflammation and have been indicated as independent risk factors in cardiovascular disease, especially in unstable coronary syndromes. However, whether elevated levels of circulating inflammatory markers play a role in the extent and severity of atherosclerosis remains controversial. The present review summarizes our current understanding of the relationship between inflammatory markers and the presence and extent of coronary atherosclerosis, in order to assess the potential utility of these markers in identifying patients with higher levels of atherosclerotic burden.

First In Vivo Application of Microwave Radiometry in Human Carotids: A New Noninvasive Method for Detection of Local Inflammatory Activation

OBJECTIVES This study investigated whether temperature differences: 1) can be measured in vivo noninvasively by microwave radiometry (MR); and 2) are associated with ultrasound and histological findings. BACKGROUND Studies of human carotid artery samples showed increased heat production. MR allows in vivo noninvasive measurement of internal temperature of tissues. METHODS Thirty-four patients undergoing carotid endarterectomy underwent screening of carotid atherosclerosis by ultrasound and MR. Healthy volunteers were enrolled as a control group. During ultrasound study, plaque texture, plaque surface, and plaque echogenicity were analyzed. Temperature difference (ΔT) was assigned as maximal minus minimum temperature. Association of thermographic with ultrasound and histological findings was performed. RESULTS ΔT was higher in atherosclerotic carotid arteries compared with the carotid arteries of controls (p < 0.01). Fatty plaques had higher ΔT compared with mixed and calcified (p < 0.01) plaques. Plaques with ulcerated surface had higher ΔT compared with plaques with irregular and regular surface (p < 0.01). Heterogeneous plaques had higher ΔT compared with homogenous (p < 0.01). Specimens with thin fibrous cap and intense expression of CD3, CD68, and vascular endothelial growth factor (VEGF) had higher ΔT compared with specimens with thick cap and low expression of CD3, CD68, and VEGF (p < 0.01). CONCLUSIONS MR provides in vivo noninvasive temperature measurements of carotid plaques, reflecting plaque inflammatory activation.

New balloon-thermography catheter for in vivo temperature measurements in human coronary atherosclerotic plaques: A novel approach for thermography?

Although ex vivo studies showed marked thermal heterogeneity in atheromatic plaques, in in vivo human studies trivial temperature variations are recorded due to the cooling effect of blood flow. We investigated a new balloon‐thermogaphy catheter for temperature measurements during coronary flow interruption. A thermistor probe is positioned at the distal segment of the catheter. At the opposite site of the thermistor, a balloon is placed. By inflation of the balloon, coronary flow is interrupted. Ten patients with effort angina were studied. Coronary flow velocity was continuously recorded. Temperature was recorded at the proximal vessel wall and at the lesion before, during, and after complete interruption of blood flow by inflation of the balloon. ΔTp was assigned as the difference between the background temperature and the maximal temperature during and after balloon inflation. ΔTl was assigned as the difference between the atherosclerotic plaque and the proximal vessel wall. The procedure was not complicated. ΔTp during and after balloon inflation was 0.01 ± 0.01°C and −0.003 ± −0.01°C (P < 0.001), respectively. ΔTl was 0.07 ± 0.04°C at baseline, 0.17 ± 0.06°C (59.3% ± 11.8% increase) during, and 0.07 ± 0.05°C after flow interruption (P < 0.001). ΔTl was greater than ΔTp during and after impairment of flow (P < 0.001). In vivo atherosclerotic plaque temperature recording seems to be feasible with this new balloon‐thermography catheter. This device may introduce a new approach for the detection of thermal heterogeneity in plaques by addressing the issue of cooling effect of blood flow. Cathet Cardiovasc Intervent 2003;58:344‐350.

Inflammatory markers and plaque morphology: An optical coherence tomography study

BACKGROUND OCT with its unique image resolution is the ideal method to detect culprit lesion characteristics in different clinical presentations. The identification of inflammatory markers related to plaque characteristics may be of clinical importance. METHODS Thirty-two patients with acute coronary syndromes (ACS) and fourteen patients with stable angina pectoris (SAP) were enrolled in this study. Culprit lesion morphology was assessed by optical coherence tomography (OCT) in patients with ACS and SAP. The possible relations between serum levels of high sensitivity-C reactive protein (hs-CRP) and interleukin-18 (IL-18) with plaque characteristics were investigated in those patients. RESULTS Plaque rupture and thin-cap fibroatheroma (TCFA) were detected more frequently in ACS patients compared with SAP patients, (78.6% vs. 14.3%, p<0.001, 92.9% vs. 14.3%, p<0.001, respectively). Higher levels of serum hs-CRP and IL-18 were found in patients with plaque rupture vs. those with no plaque rupture (median value: 19.2mg/L vs. 1.6 mg/L, p<0.001 and 219.5 pg/ml vs. 127.5 pg/ml, p=0.001 respectively), and TCFA vs. those without TCFA (median value: 15.2mg/L vs. 1.6 mg/L, p=0.004 and 209.0 pg/ml vs.153.2 pg/ml, p=0.03 respectively). Serum hs-CRP was the only independent predictor of plaque rupture (p=0.02, odds ratio 1.1, 95% confidence interval 1.0 to 1.2). A cut-off value of hs-CRP>4.5mg/L could detect ruptured plaque with a sensitivity of 91.7% and a specificity of 77.8%. CONCLUSIONS OCT detected plaque rupture and TCFA more frequent in ACS patients compared with SAP. Elevated hs-CRP and IL-18 were positively related to plaque instability and rupture.

A new dedicated stent and delivery system for the treatment of bifurcation lesions: Preliminary experience

We report the first clinical experience in eight patients with a new stent and delivery system specifically designed for the treatment of bifurcational lesions. The device (AST SLK‐View system) consists of a premounted stent and a delivery system. The stent has a side aperture, which orients toward the ostium of the side branch. The system allows deployment of the stent while the access to both main and side branches is maintained by two wires. We evaluated this system in nine bifurcations. The location of bifurcations was left descending artery/diagonal branch in four lesions, left circumflex/obtuse marginal branch in three lesions, and postero‐lateral branch/posterior descending artery in two lesions. Predilation was performed in six lesions of the main branches and in five lesions of the side branches. The stent was effectively delivered to all bifurcations except for one, in which the target lesion was located at a distal segment and the device could not be delivered. Following stent implantation in the main branch, two lesions at the side branches were treated by stent, while the other lesions were treated by balloon angioplasty without difficulty. Final kissing balloon was performed in four bifurcation lesions. No adverse event was observed during 1 month of clinical follow‐up. Treatment of bifurcation lesions with this new dedicated device appears to be feasible. This new device may introduce a new approach for the treatment of coronary bifurcation lesions. Cathet Cardiovasc Intervent 2003;58:34–42.