Chronic Kidney Disease Is Characterized by Expansion of a Distinct Proinflammatory Intermediate Monocyte Subtype and by Increased Monocyte Adhesion to Endothelial Cells.

SIGNIFICANCE STATEMENT: CKD is accompanied by abnormal inflammation, which contributes to progressive loss of functional renal tissue and accelerated cardiovascular disease. Although studies have documented that dysregulation of monocyte maturation and function is associated with CKD and its complications, it is not well characterized. This study reveals that a distinctive human monocyte subtype with high propensity for releasing proinflammatory mediators and activating endothelial cells is increased in adults with CKD compared with adults with high cardiovascular risk and normal kidney function. It also demonstrates that human monocyte adhesion to endothelial layers and responses to specific inflammatory migration signals are enhanced in CKD. These findings offer insights into the mechanisms of CKD-associated intravascular and localized inflammation and may suggest potential targets for therapeutic interventions. BACKGROUND: Cardiovascular disease (CVD) in patients with CKD is associated with increased circulating intermediate monocytes (IMs). Dysregulation of monocyte maturation and function is associated with CKD and its complications, but it is incompletely characterized. METHODS: To explore monocyte repertoire abnormalities in CKD, we studied properties of monocyte subpopulations, including IM subpopulations distinguished by HLA-DR expression level, in individuals with or without CKD. Using flow cytometry, we profiled monocyte populations in blood samples from adults with CKD, healthy volunteers (HVs), and patient controls (PCs) with high CVD risk. Monocyte subpopulations were also derived from single-cell RNA-sequencing profiles of paired blood and biopsy samples from kidney transplant recipients. We quantified intracellular cytokine production, migration, and endothelial adhesion in ex vivo assays of PBMCs. RESULTS: Of four predefined blood monocyte subpopulations, only HLA-DR hi IMs were increased in individuals with CKD compared with HVs and PCs. In HVs and patients with CKD, LPS-stimulated HLA-DR hi IMs isolated from blood produced higher amounts of TNF and IL-1 ß than other monocyte populations. Single-cell analysis revealed four monocyte clusters common to blood and kidneys, including an HLA-DR hi IM-like cluster that was enriched in kidneys versus blood. Migration toward CCL5 and CX3CL1 and adhesion to primary endothelial cell layers were increased in monocyte subpopulations in individuals with CKD compared with HVs. Monocyte adhesion to endothelial cells was partly dependent on CX3CR1/CX3CL1 interaction. CONCLUSIONS: CKD is associated with an increased number of a distinctive proinflammatory IM subpopulation and abnormalities of monocyte migration and endothelial adhesion. Dysregulated monocyte maturation and function may represent targetable factors contributing to accelerated CVD in CKD.

Predictors of Conduction Disturbances Requiring New Permanent Pacemaker Implantation following Transcatheter Aortic Valve Implantation Using the Evolut Series.

(1) Background: Conduction disturbance requiring a new permanent pacemaker (PPM) after transcatheter aortic valve implantation (TAVI) has traditionally been a common complication. New implantation techniques with self-expanding platforms have reportedly reduced the incidence of PPM. We sought to investigate the predictors of PPM at 30 days after TAVI using Evolut R/PRO/PRO+; (2) Methods: Consecutive patients who underwent TAVI with the Evolut platform between October 2019 and August 2022 at University Hospital Galway, Ireland, were included. Patients who had a prior PPM (n = 10), valve-in-valve procedures (n = 8) or received >1 valve during the index procedure (n = 3) were excluded. Baseline clinical, electrocardiographic (ECG), echocardiographic and multislice computed tomography (MSCT) parameters were analyzed. Pre-TAVI MSCT analysis included membranous septum (MS) length, a semi-quantitative calcification analysis of the aortic valve leaflets, left ventricular outflow tract, and mitral annulus. Furthermore, the implantation depth (ID) was measured from the final aortography. Multivariate binary logistic analysis and receiver operating characteristic (ROC) curve analysis were used to identify independent predictors and the optimal MS and ID cutoff values to predict new PPM requirements, respectively; (3) Results: A total of 129 TAVI patients were included (age = 81.3 ± 5.3 years; 36% female; median EuroSCORE II 3.2 [2.0, 5.4]). Fifteen patients (11.6%) required PPM after 30 days. The patients requiring new PPM at 30 days were more likely to have a lower European System for Cardiac Operative Risk Evaluation II, increased prevalence of right bundle branch block (RBBB) at baseline ECG, have a higher mitral annular calcification severity and have a shorter MS on preprocedural MSCT analysis, and have a ID, as shown on the final aortogram. From the multivariate analysis, pre-TAVI RBBB, MS length, and ID were shown to be predictors of new PPM. An MS length of <2.85 mm (AUC = 0.85, 95%CI: (0.77, 0.93)) and ID of >3.99 mm (area under the curve (AUC) = 0.79, (95% confidence interval (CI): (0.68, 0.90)) were found to be the optimal cut-offs for predicting new PPM requirements; (4) Conclusions: Membranous septum length and implantation depth were found to be independent predictors of new PPM post-TAVI with the Evolut platform. Patient-specific implantation depth could be used to mitigate the requirement for new PPM.

Characterization of non-calcified coronary atherosclerotic plaque by multi-detector row CT: comparison to IVUS.

UNLABELLED: Multi-detector row Computed Tomography (MDCT) permits non-invasive visualization of the coronary arteries. The ability to visualize and, with limitations, to characterize non-calcified coronary atherosclerotic plaque has been described. We investigated the CT attenuation of non-calcified plaques as determined by 16-slice MDCT in comparison to intravascular ultrasound (IVUS). METHODS AND RESULTS: Thirty-two patients were investigated by contrast-enhanced 16-slice CT. In addition, IVUS of one coronary artery (motorized pullback) was performed (LM+LAD: 22, LM+LCX: 4, RCA: 6). At 252 sites within the coronary system, in which non-calcified atherosclerotic plaque could be identified both in MDCT and IVUS, the CT attenuation within the plaque was measured using a centrally placed region of interest and correlated to the appearance of the plaque in IVUS at the corresponding location. The mean CT attenuation within plaque that corresponded to hyper-echogenic appearance in IVUS was 121+/-34HU (n=76). The mean CT attenuation within plaque that corresponded to hypo-echogenic appearance was 58+/-43HU (n=176, p<0.001). However, there was substantial overlap of the density values measured by MDCT in the two groups. CONCLUSIONS: A significant difference of the mean CT attenuation within atherosclerotic lesions of hypo-echogenic and hyper-echogenic appearance in IVUS could be observed. However, we observed substantial overlap of attenuation values between plaque types so that the differentiation of "vulnerable" and "stable" plaques based on their CT attenuation is doubtful.

In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography.

BACKGROUND: The current understanding of the pathophysiology of coronary artery disease is based largely on postmortem studies. Optical coherence tomography (OCT) is a high-resolution ( approximately 10 microm), catheter-based imaging modality capable of investigating detailed coronary plaque morphology in vivo. METHODS AND RESULTS: Patients undergoing cardiac catheterization were enrolled and categorized according to their clinical presentation: recent acute myocardial infarction (AMI), acute coronary syndromes (ACS) constituting non-ST-segment elevation AMI and unstable angina, or stable angina pectoris (SAP). OCT imaging was performed with a 3.2F catheter. Two observers independently analyzed the images using the previously validated criteria for plaque characterization. Of 69 patients enrolled, 57 patients (20 with AMI, 20 with ACS, and 17 with SAP) had analyzable images. In the AMI, ACS, and SAP groups, lipid-rich plaque (defined by lipid occupying > or =2 quadrants of the cross-sectional area) was observed in 90%, 75%, and 59%, respectively (P=0.09). The median value of the minimum thickness of the fibrous cap was 47.0, 53.8, and 102.6 microm, respectively (P=0.034). The frequency of thin-cap fibroatheroma (defined by lipid-rich plaque with cap thickness < or =65 microm) was 72% in the AMI group, 50% in the ACS group, and 20% in the SAP group (P=0.012). No procedure-related complications occurred. CONCLUSIONS: OCT is a safe and effective modality for characterizing coronary atherosclerotic plaques in vivo. Thin-cap fibroatheroma was more frequently observed in patients with AMI or ACS than SAP. This is the first study to compare detailed in vivo plaque morphology in patients with different clinical presentations.

Detection of calcified and noncalcified coronary atherosclerotic plaque by contrast-enhanced, submillimeter multidetector spiral computed tomography: a segment-based comparison with intravascular ultrasound.

BACKGROUND: We investigated the ability of multidetector spiral computed tomography (MDCT) to detect atherosclerotic plaque in nonstenotic coronary arteries. METHODS AND RESULTS: In 22 patients without significant coronary stenoses, contrast-enhanced MDCT (0.75-mm collimation, 420-ms rotation) and intravascular ultrasound (IVUS) of one coronary artery were performed. A total of 83 coronary segments were imaged by IVUS (left main, 19; left anterior descending, 51; left circumflex, 4; right coronary, 9). MDCT data sets were evaluated for the presence and volume of plaque in the coronary artery segments. Results were compared with IVUS in a blinded fashion. For the detection of segments with any plaque, MDCT had a sensitivity of 82% (41 of 50) and specificity of 88% (29 of 33). For calcified plaque, sensitivity was 94% (33 of 36) and specificity 94% (45 of 47). Coronary segments containing noncalcified plaque were detected with a sensitivity of 78% (35 of 45) and specificity of 87% (33 of 38), but presence of exclusively noncalcified plaque was detected with only 53% sensitivity (8 of 15). If analysis was limited to the 41 proximal segments (segments 1, 5, 6, and 11 according to American Heart Association classification), sensitivity and specificity were 92% and 88% for any plaque, 95% and 91% for calcified plaque, and 91% and 89% for noncalcified plaque. MDCT substantially underestimated plaque volume per segment as compared with IVUS (24+/-35 mm3 versus 43+/-60 mm3, P<0.001). CONCLUSIONS: The results indicate the potential of MDCT to detect coronary atherosclerotic plaque in patients without significant coronary stenoses. However, further improvements in image quality will be necessary to achieve reliable assessment, especially of noncalcified plaque throughout the coronary tree.

Assessment of coronary remodeling in stenotic and nonstenotic coronary atherosclerotic lesions by multidetector spiral computed tomography.

OBJECTIVES: This study was designed to investigate whether contrast-enhanced multidetector spiral CT (MDCT) permits assessment of remodeling in coronary atherosclerotic lesions. BACKGROUND: With sufficient image quality, MDCT permits noninvasive visualization of the coronary arteries, but its ability to assess remodeling has not been evaluated. METHODS: Out of 102 patients in whom MDCT (16-slice scanner, intravenous contrast, 0.75-mm collimation, 420 ms rotation) was performed before invasive coronary angiography, 44 patients with high-quality MDCT data sets showing atherosclerotic plaque in a proximal coronary artery segment were chosen for evaluation. In multiplanar reconstructions orthogonal to the coronary artery, the cross-sectional vessel area was measured for the respective lesion and for a reference segment proximal to the lesion. The "Remodeling Index" was calculated by dividing the vessel area in the lesion by the reference segment. Results were correlated to the presence of stenosis (>50% diameter reduction) in invasive angiography. In a subset of 13 patients, MDCT measurements were verified by IVUS. RESULTS: Reference vessel area was not significantly different between nonstenotic versus stenotic lesions (20 +/- 8 mm(2), n = 23 vs. 22 +/- 8 mm(2), n = 21). The mean Remodeling Index was significantly higher in nonstenotic than in stenotic lesions (1.3 +/- 0.2 vs. 1.0 +/- 0.2, p < 0.001). In five stenotic lesions, "negative remodeling" (Remodeling Index < or = 0.95) was observed. Cross-sectional vessel areas and Remodeling Indices measured by MDCT correlated closely to IVUS (r(2) = 0.77 and r(2) = 0.82, respectively). CONCLUSIONS: Multidetector spiral CT may permit assessment of remodeling of coronary atherosclerotic lesions in selected data sets of sufficient quality.

Intravascular modalities for detection of vulnerable plaque: current status.

Progress in the diagnosis, treatment, and prevention of atherosclerotic coronary artery disease is dependent on a greater understanding of the mechanisms of coronary plaque progression. Autopsy studies have characterized a subgroup of high-risk, or vulnerable, plaques that result in acute coronary syndromes or sudden cardiac death. These angiographically modest plaques share certain pathologic characteristics: a thin, fibrous cap, lipid-rich core, and macrophage activity. Diagnostic techniques for vulnerable-plaque detection, including serologic markers and noninvasive and invasive techniques, are needed. Recent advances in intravascular imaging have significantly improved the ability to detect high-risk, or vulnerable, plaque in vivo by using various features of plaque vulnerability as methods of identification. The characteristic anatomy of a thin, fibrous cap overlying a lipid pool has promoted high-resolution imaging, such as intravascular ultrasound, optical coherence tomography, and intracoronary magnetic resonance. The lipid-rich core is identifiable by angioscopically detected color changes on the plaque surface or by its unique absorption of energy, or "Raman shift," of its cholesterol core, driving coronary spectroscopy. Finally, temperature heterogeneity arising at foci of plaque inflammation has prompted the development of intracoronary thermography. In this review, we will discuss these techniques, their relative advantages and limitations, and their potential clinical application.

Coronary in-stent restenosis following beta brachytherapy: a histopathological examination.

Two cases of in-stent restenosis of a coronary artery bypass vein graft following beta (beta) brachytheraphy are presented. Previously unreported histopathology of directed atherectomy specimens of such restenotic lesions and a discussion of their proposed significance form the basis of this report.

Through the looking glass: primary epithelioid angiosarcoma in the left atrium, a unique site for a rare malignancy.

Malignant cardiac tumours occurring on the left side are vanishingly rare entities. We describe a case of a 73-year-old male who underwent surgery for a left-sided cardiac tumour following initial presentation with transient ischaemic attacks. In addition to the unusual presentation and subsequent metastatic pattern to the femur, the tumour's pathological diagnosis was that of an epithelioid variant of an angiosarcoma which has not been previously described in this anatomical location.

Diagnostic accuracy of optical coherence tomography and integrated backscatter intravascular ultrasound images for tissue characterization of human coronary plaques.

OBJECTIVES: The purpose of the present study was to validate the diagnostic accuracy of optical coherence tomography (OCT), integrated backscatter intravascular ultrasound (IB-IVUS), and conventional intravascular ultrasound (C-IVUS) for tissue characterization of coronary plaques and to evaluate the advantages and limitations of each of these modalities. BACKGROUND: The diagnostic accuracy of OCT for characterizing tissue types is well established. However, comparisons among OCT, C-IVUS, and IB-IVUS have not been done. METHODS: We examined 128 coronary arterial sites (42 coronary arteries) from 17 cadavers; IVUS and OCT images were acquired on the same slice as histology. Ultrasound signals were obtained using an IVUS system with a 40-MHz catheter and digitized at 1 GHz with 8-bit resolution. The IB values of the ultrasound signals were calculated with a fast Fourier transform. RESULTS: Using histological images as a gold standard, the sensitivity of OCT for characterizing calcification, fibrosis, and lipid pool was 100%, 98%, and 95%, respectively. The specificity of OCT was 100%, 94%, and 98%, respectively (Cohen's kappa = 0.92). The sensitivity of IB-IVUS was 100%, 94%, and 84%, respectively. The specificity of IB-IVUS was 99%, 84%, and 97%, respectively (Cohen's kappa = 0.80). The sensitivity of C-IVUS was 100%, 93%, and 67%, respectively. The specificity of C-IVUS was 99%, 61%, and 95%, respectively (Cohen's kappa = 0.59). CONCLUSIONS: Within the penetration depth of OCT, OCT has a best potential for tissue characterization of coronary plaques. Integrated backscatter IVUS has a better potential for characterizing fibrous lesions and lipid pools than C-IVUS.

Intravascular optical coherence tomography: cellular imaging.

The vast majority of acute coronary events are attributed to rupture or erosion of high-risk or vulnerable plaques. Novel imaging techniques are being actively sought that can detect quiescent vulnerable features within coronary plaque and thereby identify populations at risk, monitor plaque progression, and target therapy appropriately. Optical coherence tomography is an intravascular imaging modality capable of detecting and characterizing coronary plaque in vivo. Recently, optical coherence tomography quantification of macrophage infiltration within atherosclerotic plaque ex vivo was demonstrated. Application of this technique to clinical practice yields a hybrid image incorporating plaque morphology with a measure of biologic activity. In a recently conducted clinical study assessing macrophage distributions in patients, evidence supporting both the vulnerable plaque model and the hypothesis of multifocal inflammatory risk, linked by the common thread of increased macrophage infiltration, has been found. These results suggest that elevated multifocal coronary macrophage content, present both in culprit lesions and at remote sites, serves as a background for heightened risk. Superimposed on this inflammatory background, local increases in macrophage content, particularly at the cap surface and at areas at high risk for rupture, further promote the instability of individual lesions.

Catheter-based ventricle-coronary vein bypass.

The goal of this study was to investigate the feasibility of a catheter-based ventricle-to-coronary vein bypass (VPASS) in order to achieve retrograde myocardial perfusion by a conduit (VSTENT) from the left ventricle (LV) to the anterior interventricular vein (AIV). Percutaneous coronary venous arterialization has been proposed as a potential treatment strategy for otherwise untreatable coronary artery disease. In an acute setting, the VSTENT implant was deployed percutaneously using the VPASS procedure in five swine. Coronary venous flow and pressure patterns were measured before and after VSTENT implant deployment with and without AIV and left anterior descending artery (LAD) occlusion. In a separate chronic pilot study, the VPASS procedure was completed on two animals that had a mid-LAD occlusion or LAD stenosis. At day 30 post-VPASS procedure, left ventriculography and magnetic resonance imaging (MRI) were performed to assess the patency and myocardial viability of the VSTENT implants. Pre-VSTENT implantation, the mid-AIV systolic wedge pressure was significantly lower than LV systolic pressure during AIV blockage (46 +/- 19 vs. 90 +/- 16 mm Hg; P < 0.01). The VSTENT implant deployment was performed without complication and achieved equalization of the AIV and LV systolic pressures and creation of retrograde flow in the distal AIV (maximal flow velocity: 37 +/- 7 cm/sec). At day 30 post-VPASS procedure, left ventriculography showed VSTENT implant patency. MRI perfusion images demonstrated myocardial viability even with an LAD occlusion. Coronary retrograde perfusion using the VPASS procedure is feasible and may represent a potential technique for end-stage myocardial ischemia.

Catheter-based antegrade intracoronary viral gene delivery with coronary venous blockade.

The purpose of this study is to evaluate the feasibility of percutaneous antegrade myocardial gene transfer (PAMGT). A consistent and safe technique for in vivo gene transfer is required for clinical application of myocardial gene therapy. PAMGT with concomitant coronary venous blockade was performed in 12 swine. The myocardium was preconditioned with 1 min of occlusion of the left anterior descending and left circumflex arteries. The anterior interventricular vein was occluded during left anterior descending artery delivery, and the great cardiac vein at the entrance of the middle cardiac vein was occluded during left circumflex artery delivery. With arterial and venous balloons inflated (3 min) and after adenosine (25 mug) injection, PAMGT was performed by antegrade injection of an adenoviral solution (1 ml of 10(11) plaque-forming units in each coronary artery) carrying beta-galactosidase or saline through the center lumen of the angioplasty balloon. In one set of animals, PAMGT was performed with selective coronary vein blockade (n = 9); in another set of animals, PAMGT was performed without coronary vein blockade (n = 5). At 1 wk after gene delivery, the animals were killed. Quantitative beta-galactosidase analysis was performed in the left and right ventricular walls. PAMGT was successfully performed in all animals with and without concomitant occlusion of the coronary veins. Quantitative beta-galactosidase analysis showed that PAMGT with coronary blockade was superior to PAMGT without coronary blockade. beta-Galactosidase activity increased significantly in the beta-galactosidase group compared with the saline group: 1.34 +/- 0.18 vs. 0.81 +/- 0.1 ng (P

Targeting signaling pathways in heart failure by gene transfer.

Congestive heart failure represents an enormous clinical problem demanding effective therapeutic approaches. The varied etiologies of heart failure include abnormalities of ion handling, cellular signaling, neurohormonal control, and apoptosis, all of which are potentially amenable to genetic manipulation. Gene therapy holds the promise of retarding the progression, preventing, and perhaps reversing heart failure. Advances in our knowledge of possible targets, vectors, and delivery techniques have revolutionized this field in recent years, bringing us close to clinical application.

Toward a new blood vessel.

Strategies to treat atherosclerotic coronary artery disease include coronary artery bypass grafting (CABG), in which grafts are used to bypass atherosclerotic vessels and restore blood flow to the ischemic myocardium. The grafts used include healthy arteries or veins harvested from a separate site. Results with arterial grafts have been superior to venous grafts; promoting the practice of total arterial revascularization using only arterial grafts. Suitable arterial grafts, however, are scarce and harvest procedures add to morbidity and cost. Tissue engineering combines the principles of engineering with life sciences for the development of biological substitutes and restore, maintain or improve tissue function. Advances in this field have included the development of tissue-engineered blood vessels, with the potential to serve as arterial grafts, conduits or fistulae. This review describes the history of tissue engineering arteries, the techniques used, and progress to date. The source of cells and the future direction of this field are explored.

Prophylaxis of contrast-induced nephropathy in patients undergoing coronary angiography.

Contrast-induced nephropathy (CIN) is a common complication of cardiac catheterization, reported to result in a 15% incidence of acute renal failure. Convincing evidence supports the prophylactic use of prehydration and low volumes of contrast medium. Recently, the antioxidant acetylcysteine has been shown to have a potential preventive role. The aim of this study was to examine the hypothesis that acetylcysteine prevents CIN. Patients undergoing cardiac catheterization with a serum creatinine >/= 1.5 mg/dl were prospectively randomized to receive acetylcysteine or placebo. A total of five doses of acetylcysteine 600 mg b.i.d. or placebo was administered, commencing on the day of the procedure. All patients were prehydrated with 0.45% saline and during the catheterization a nonionic low-osmolality contrast medium was used. Serum creatinine and urea were measured at 24, 48, and 72 hr postprocedure. A total of 43 patients were studied. There was no significant difference between the groups in terms of baseline characteristics, including baseline renal function. No adverse events were experienced with acetylcysteine treatment. Serum creatinine levels at 48 and 72 hr remained largely unchanged in the acetylcysteine group but continued to rise at 48 and 72 hr in the placebo group. By 72 hr, the incidence of CIN, defined as a 25% increase in baseline creatinine, was significantly lower in the acetylcysteine arm compared to placebo (5% for acetylcysteine vs. 32% for placebo; P = 0.046). In patients with mild to moderate renal impairment undergoing cardiac catheterization, prophylactic treatment with oral acetylcysteine reduces the incidence of contrast-induced nephropathy.

Mechanical analysis of atherosclerotic plaques based on optical coherence tomography.

Finite element analysis is a powerful tool for investigating the biomechanics of atherosclerosis and has thereby provided an improved understanding of acute myocardial infarction. Structural analysis of arterial walls is traditionally performed using geometry contours derived from histology. In this paper we demonstrate the first use of a new imaging technique, optical coherence tomography (OCT), as a basis for finite element analysis. There are two primary benefits of OCT relative to histology: 1) imaging is performed without excessive tissue handling, providing a more realistic geometry than histology and avoiding structural artifacts common to histologic processing, and 2) OCT imaging can be performed in vivo, making it possible to study disease progression and the effect of therapeutic treatments in animal models and living patients. Patterns of mechanical stress and strain distributions computed from finite element analysis based on OCT were compared with those from modeling based on "gold standard" histology. Our results indicate that vascular structure and composition determined by OCT provides an adequate basis for investigating the biomechanical factors relevant to atherosclerosis and acute myocardial infarction.

Focal and multi-focal plaque macrophage distributions in patients with acute and stable presentations of coronary artery disease.

OBJECTIVES: This study was designed to utilize optical coherence tomography (OCT) images of coronary atherosclerotic plaque macrophages to investigate the relationship between macrophage distributions and clinical syndrome. BACKGROUND: The relative significance of focal macrophage infiltration and generalized coronary inflammation for predicting acute coronary events is a currently a source of considerable controversy in cardiology. Lack of a high-resolution cross-sectional imaging modality has limited macrophage evaluation in vivo. METHODS: Intracoronary OCT imaging was performed at culprit and non-culprit plaques in patients presenting with stable angina pectoris, unstable angina pectoris,and ST-segment elevation myocardial infarction. Macrophage densities were quantified from these images and analyzed with respect to the clinical presentations of the patients under investigation. RESULTS: A significantly greater macrophage density was found in unstable patients, both for fibrous and lipid-rich plaques (p = 0.025 and p = 0.002, respectively). Within each patient, the macrophage densities at culprit and non-culprit lesions correlated significantly (r = 0.66, y = 0.88x + 0.43, p = 0.01). Sites of plaque rupture demonstrated a greater macrophage density than non-ruptured sites (6.95 +/- 1.60%, 5.29 +/- 1.17%; p = 0.002). Surface macrophage infiltration was a stronger predictor of unstable clinical presentation than subsurface infiltration for culprit lesions (p = 0.035) but not for remote lesions (p = 0.80). CONCLUSIONS: Our results demonstrate that increases in both multi-focal and focal macrophage densities are highly correlated with symptom severity. By providing a means of detecting increases in plaque macrophage content before an acute event, this technique may aid in determining prognosis and guiding preventive therapy.