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Background: Information regarding left atrial (LA) substrate in conditions predisposing to atrial fibrillation (AF) is limited., Objective: This study sought to characterize the left atrial remodeling that results from chronic atrial stretch caused by atrial septal defect (ASD)., Methods: Eleven patients with hemodynamically significant ASDs and 12 control subjects were studied. The following were evaluated using multipolar catheters: effective refractory period (ERP) at 7 sites, P-wave duration (PWD), conduction time, and inducibility of AF. LA electroanatomic maps were created to determine atrial activation, and regional conduction and voltage abnormalities., Results: Patients with ASDs showed significant LA enlargement (P <0.001), unchanged or prolonged atrial ERPs, increase in LA conduction times (P = 0.03), prolonged PWD (P <0.001), regional conduction slowing (P <0.001), greater number of double potentials or fractionated electrograms (P <0.0001), reduced atrial voltage (P <0.001), and more frequent electrical scar (P = 0.005) compared with control subjects. In addition, patients with ASDs showed a greater propensity for sustained AF with single extrastimuli (4 of 11 vs. 0 of 12, P = 0.04)., Conclusion: ASDs are associated with chronic left atrial stretch, which results in remodeling characterized by LA enlargement, loss of myocardium, and electrical scar that results in widespread conduction abnormalities but with no change or an increase in ERP. These abnormalities were associated with a greater propensity for sustained AF.

Background: Pericardial adipose tissue (PAT) has been shown to be an independent predictor of coronary artery disease. To date its assessment has been restricted to the use of surrogate echocardiographic indices such as measurement of epicardial fat thickness over the right ventricular free wall, which have limitations. Cardiovascular magnetic resonance (CMR) offers the potential to non-invasively assess total PAT, however like other imaging modalities, CMR has not yet been validated for this purpose. Thus, we sought to describe a novel technique for assessing total PAT with validation in an ovine model., Methods: 11 merino sheep were studied. A standard clinical series of ventricular short axis CMR images (1.5T Siemens Sonata) were obtained during mechanical ventilation breath-holds. Beginning at the mitral annulus, consecutive end-diastolic ventricular images were used to determine the area and volume of epicardial, paracardial and pericardial adipose tissue. In addition adipose thickness was measured at the right ventricular free wall. Following euthanasia, the paracardial adipose tissue was removed from the ventricle and weighed to allow comparison with corresponding CMR measurements., Results: There was a strong correlation between CMR-derived paracardial adipose tissue volume and ex vivo paracardial mass (R2 = 0.89, p < 0.001). In contrast, CMR measurements of corresponding RV free wall paracardial adipose thickness did not correlate with ex vivo paracardial mass (R2 = 0.003, p = 0.878)., Conclusion: In this ovine model, CMR-derived paracardial adipose tissue volume, but not the corresponding and conventional measure of paracardial adipose thickness over the RV free wall, accurately reflected paracardial adipose tissue mass. This study validates for the first time, the use of clinically utilised CMR sequences for the accurate and reproducible assessment of pericardial adiposity. Furthermore this non-invasive modality does not use ionising radiation and therefore is ideally suited for future studies of PAT and its role in cardiovascular risk prediction and disease in clinical practice.

Objective: Applanation tonometry evaluation of pulse wave velocity is widely accepted as the 'gold standard' method for noninvasively assessing arterial stiffness. Newer noninvasive tools such as cardiovascular magnetic resonance can also evaluate arterial stiffness, but have not been validated. The aim of this study was to validate cardiovascular magnetic resonance-derived aortic distensibility with pulse wave velocity and to investigate age-related changes in regional aortic distensibility., Methods: Ten young (20-30 years) and ten old (60-70 years) patients underwent applanation tonometry assessment of pulse wave velocity. Cardiovascular magnetic resonance measurements of arterial stiffness were evaluated by aortic distensibility (10-3 mmHg-1) at three separate locations, the ascending aorta, proximal descending aorta and distal descending aorta., Results: Pulse wave velocity correlated strongly with aortic distensibility measurements at each site: ascending aorta R2 = 0.57, proximal descending aorta R2 = 0.60 and distal descending aorta R2 = 0.72. As expected, the old cohort had significantly increased aortic stiffness compared with the young cohort (P < 0.01). Post-hoc comparison showed an increase in proximal stiffness in the old cohort compared with the young cohort (P = 0.018)., Conclusion: Cardiovascular magnetic resonance-derived aortic distensibility is an accurate measure of arterial stiffness and can evaluate regional stiffness through the aorta. Furthermore, our results suggest that aortic stiffening may preferentially occur in the proximal aortic segments in the elderly.

We investigated the ability of fluorodeoxyglucose positron emission tomography (FDG PET) imaging to serially monitor macrophage content in a rabbit model of atherosclerosis. Atherosclerosis was induced in rabbits (n = 8) by a combination of atherogenic diet and balloon denudation of the aorta. At the end of nine months, the rabbits were randomized to a further six months of the same atherogenic diet (progression group) or normal diet (regression group). In vivo uptake of FDG by the thoracic aorta was measured using aortic uptake-to-blood radioactivity ratios at the start and end of the randomized period. A significant increase in FDG uptake of the progression group after continued cholesterol feeding (aortic uptake-to-blood radioactivity: 0.57 +/- 0.02 to 0.68 +/- 0.02, P = 0.001), and a corresponding fall in FDG uptake of the regression group after returning to a normal chow diet (aortic uptake-to-blood radioactivity ratios: 0.67 +/- 0.02 to 0.53 +/- 0.02, P < 0.0001). FDG PET can quantify in vivo macrophage content and serially monitor changes in FDG activity in this rabbit model.

Combined analysis of the electrical and mechanical function of the heart holds promise as a means of acquiring a better understanding of a variety of cardiac diseases that ultimately may lead to heart failure. The NOGA XP Cardiac Navigation System is a unique, nonfluoroscopic, catheter-based technology that achieves real-time acquisition of three-dimensional, endoventricular electromechanical maps. Through the provision of point-by-point measurements of endocardial electrical activation and voltage and mechanical shortening, electromechanical mapping has been evaluated for its ability to identify regional myocardial ischemia and characterize tissue viability. A decade of preclinical and clinical research has verified its safety and feasibility and raised the possibility of its application as a diagnostic adjunct to conventional angiography in the catheterization laboratory. However, this role has not yet been realized outside of the research setting. Instead, a more prominent niche for NOGA XP has emerged as a therapeutic tool for guiding direct myocardial interventions, most notably the targeted administration of regenerative therapies (e.g., cells, genes) to the heart. In this review, we discuss the fundamental aspects of this electromechanical mapping system and the evidence for both its diagnostic and therapeutic utility.

Blunt chest-wall trauma is common; however, resultant tricuspid valve rupture is rare and can be subtle in its presentation. Transthoracic echocardiography plays a key role in diagnosis. Herein, we report the case of a 42-year-old woman who sustained substantial chest-wall trauma in a high-speed motor vehicle accident. She presented a week later with symptoms of right-heart failure, secondary to flail tricuspid valve leaflets and torrential tricuspid regurgitation. The case of this patient highlights the importance of early diagnosis and elicits discussion of the mechanisms that can underlie delayed tricuspid valve rupture. Because the clinical diagnosis of tricuspid valve rupture can be difficult, we believe that echocardiography should be used early and, if necessary, repeatedly in all patients who sustain blunt chest-wall trauma.

Background: Percutaneous closure of atrial septal defects (ASDs) should potentially reduce right heart volumes by removing left-to-right shunting. Due to ventricular interdependence, this may be associated with impaired left ventricular filling and potentially function. Furthermore, atrial changes post-ASD closure have been poorly understood and may be important for understanding risk of atrial arrhythmia post-ASD closure. Cardiovascular magnetic resonance (CMR) is an accurate and reproducible imaging modality for the assessment of cardiac function and volumes. We assessed cardiac volumes pre- and post-percutaneous ASD closure using CMR., Methods: Consecutive patients (n = 23) underwent CMR pre- and 6 months post-ASD closure. Steady state free precession cine CMR was performed using contiguous slices in both short and long axis views through the ASD. Data was collected for assessment of left and right atrial, ventricular end diastolic volumes (EDV) and end systolic volumes (ESV). Data is presented as mean +/- SD, volumes as mL, and paired t-testing performed between groups. Statistical significance was taken as p < 0.05., Results: There was a significant reduction in right ventricular volumes at 6 months post-ASD closure (RVEDV: 208.7 +/- 76.7 vs. 140.6 +/- 60.4 mL, p < 0.0001) and RVEF was significantly increased (RVEF 35.5 +/- 15.5 vs. 42.0 +/- 15.2%, p = 0.025). There was a significant increase in the left ventricular volumes (LVEDV 84.8 +/- 32.3 vs. 106.3 +/- 38.1 mL, p = 0.003 and LVESV 37.4 +/- 20.9 vs. 46.8 +/- 18.5 mL, p = 0.016). However, there was no significant difference in LVEF and LV mass post-ASD closure. There was a significant reduction in right atrial volumes at 6 months post-ASD closure (pre-closure 110.5 +/- 55.7 vs. post-closure 90.7 +/- 69.3 mL, p = 0.019). Although there was a trend to a decrease in left atrial volumes post-ASD closure, this was not statistically significant (84.5 +/- 34.8 mL to 81.8 +/- 44.2 mL, p = NS)., Conclusion: ASD closure leads to normalisation of ventricular volumes and also a reduction in right atrial volume. Further follow-up is required to assess how this predicts outcomes such as risk of atrial arrhythmias after such procedures.

A 62-year-old man underwent radiotherapy to the left upper chest for treatment of Pancoast syndrome on a background of previous coronary artery bypass grafting 12 years earlier. Within 1 year, he developed significant stenoses of both the left internal mammary artery (LIMA) graft and ostial left vertebral artery, presumably related to therapeutic radiation exposure. Initially diagnosed using computed tomography coronary angiography, the patient underwent percutaneous coronary intervention and insertion of a drug-eluting stent (DES) to the ostium of the LIMA graft via a left radial approach. He remains clinically well at 6-month follow-up. This is the first reported case in the literature of DES treatment of a radiation-induced vascular stenosis; however, the incidence of cardiovascular disease is elevated in such cases. In patients with a prior history of mantle radiation, consideration should be given to the routine assessment of internal mammary conduits prior to coronary artery bypass surgery.

Background: There is a paucity of published experience investigating novel treatment strategies in preclinical and clinical studies of nonischemic cardiomyopathy. We set out to validate an ovine model of doxorubicin-induced cardiomyopathy, using cardiac magnetic resonance (CMR) to assess cardiac function., Methods and Results: Ten Merino sheep (51 +/- 8 kg) underwent intracoronary infusions of doxorubicin (1 mg/kg dose) every 2 weeks. Cardiac magnetic resonance was performed at baseline and at 6 weeks after final doxorubicin dose, along with transthoracic echocardiography, measurement of right heart pressure, and cardiac output. After final CMR examination, heart specimens were harvested for histologic analysis. The total dose of doxorubicin administered per animal was 3.8 +/- 0.5 mg/kg. Two animals died prematurely during the study protocol, with evidence of myocarditis. In the remaining 8 sheep, left ventricular ejection fraction dropped from 46.2 +/- 4.7% to 31.3 +/- 8.5% (P < .001), accompanied by reductions in fractional shortening (31.6 +/- 1.8% baseline versus 18.2 +/- 3.9% final, P < .01), cardiac output (3.8 +/- 0.6 L/min versus 3.0 +/- 0.4 L/min, P < .05) and right ventricular ejection fraction (39.5 +/- 5.6% versus 28.9 +/- 9.6%, P < .05). However, significant end-diastolic dilatation of the left ventricle was not observed. Delayed gadolinium uptake was detected by CMR in 2 sheep, in a typical nonischemic pattern. Widespread, multifocal histologic abnormalities consisted of cardiomyocyte degeneration, vasculopathy, inflammatory infiltrates, and replacement fibrosis., Conclusions: Moderate-severe cardiac dysfunction was reproducibly achieved through high-dose intracoronary doxorubicin, with acceptable animal mortality. CMR provides a powerful tool for assessing myocardial function, structural remodeling, and viability in such models.

Aims: To characterize the atrial remodelling in mitral stenosis (MS)., Methods and Results: Twenty-four patients with severe MS undergoing commissurotomy and 24 controls were studied. Electrophysiological evaluation was performed in 12 patients in each group by positioning multi-electrode catheters in both atria to determine the following: effective refractory period (ERP) at 10 sites at 600 and 450 ms; conduction time; conduction delay at the crista terminalis (CT); and vulnerability for atrial fibrillation (AF). P-wave duration (PWD) was determined on the surface ECG. In the remaining 12 patients in each group, electroanatomic maps of both atria were created to determine conduction velocity and identify regions of low voltage and electrical silence. Patients with MS had larger left atria (LA) (P < 0.0001); prolonged PWD (P = 0.0007); prolonged ERP in both LA (P < 0.0001) and right atria (RA) (P < 0.0001); reduced conduction velocity in the LA (P = 0.009) and RA (P < 0.0001); greater number (P < 0.0001) and duration (P< 0.0001) of bipoles along the CT with delayed conduction; lower atrial voltage in the LA (P < 0.0001) and RA (P < 0.0001); and more frequent electrical scar (P = 0.001) compared with controls. Five of twelve with MS and none of the controls developed AF with extra-stimulus (P = 0.02)., Conclusion: Atrial remodelling in MS is characterized by LA enlargement, loss of myocardium, and scarring associated with widespread and site-specific conduction abnormalities and no change or an increase in ERP. These abnormalities were associated with a heightened inducibility of AF.

Cellular therapy for cardiovascular disease heralds an exciting frontier of research. Mesenchymal stromal cells (MSCs) are present in adult tissues, including bone marrow and adipose, from which they can be easily isolated and cultured ex vivo. Although traditional isolation of these cells by plastic adherence results in a heterogeneous composite of mature and immature cell types, MSCs do possess plasticity of differentiation and under appropriate in vitro culture conditions can be modified to adopt cardiomyocyte and vascular cell phenotypic characteristics. In vivo preclinical studies have demonstrated their capacity to facilitate both myocardial repair and neovascularization in models of cardiac injury. The mechanisms underlying these effects appear to be mediated predominantly through indirect paracrine actions, rather than direct regeneration of endogenous cells by transdifferentiation, especially because current transplantation strategies achieve only modest engraftment of cells in the host myocardium. Currently, published clinical trial experience of MSCs as cardiac therapy is limited, and the outcomes of ongoing studies are keenly anticipated. Of relevance to clinical application is the fact that MSCs are relatively immunoprivileged, potentially enabling their allogeneic therapeutic use, although this too requires further investigation. Overall, MSCs are an attractive adult-derived cell population for cardiovascular repair; however, research is still required at both basic and clinical levels to resolve critical areas of uncertainty and to ensure continued development in cell culture engineering and cell transplantation technology.

Cardiac magnetic resonance imaging (MRI) is being utilised increasingly for the purposes of cardiovascular imaging. Limited data suggest a high degree of reproducibility for parameters such as left ventricular (LV) ejection fraction (EF), mass, end-diastolic and end-systolic volumes (EDV and ESV). We sought to investigate reproducibility and establish means for these parameters in a selected normal non-Aboriginal Australian population, using cardiac MRI. Sixty normal volunteers underwent cardiac MRI investigation using a 1.5 T MRI system. Steady state free precession imaging was performed with short axis cine images through the left ventricle obtained. All images were acquired with cardiac gating. Two independent observers then analysed the data set. Data were collected for assessment of left ventricular EF, EDV, ESV, mass and right ventricular volumes. Data are presented as mean+/-S.D. Total imaging time was approximately 15 min. All patients were able to complete the full protocol. Left ventricular parameters: EF 58.5+/-8.0%, LV mass 114.2+/-40.6g, EDV 117.3+/-33.4 mls and ESV 50.0+/-22.2 mls. Right ventricular parameters: EF 45.6+/-11.6%, EDV 163.5+/-52.2 mls and ESV 89.5+/-34.3 mls. Intraclass correlation coefficients for LV: EF 0.84, LV mass 0.84, EDV 0.85 and ESV 0.89. Cardiac MRI provides high quality information about cardiac function with a high level of reproducibility. Cardiac MRI parameters in a normal non-Aboriginal Australian population are provided.

Platypnea-orthodeoxia is an uncommon condition characterized by the development of hypoxia and breathlessness in the upright posture, relieved by resuming a supine position. First described in 1969, the condition has since been associated with intracardiac and intrapulmonary shunts, liver disease and a host of other conditions. We report an unusual case of episodic breathlessness and hypoxia cured by percutaneous cardiac intervention and discuss the evolving role of cardiac magnetic resonance imaging in the demonstration of functional distortions of cardiac and mediastinal anatomy that may not be as well characterized by other available imaging modalities.

Background: Isolated left ventricular non-compaction (IVNC) was a previously rarely diagnosed condition with an apparent very poor prognosis. However, with high quality cardiac imaging with cardiac magnetic resonance (CMR) becoming increasingly available, it is being increasingly identified. However, asymptomatic patients with a serendipitous diagnosis of IVNC are being discovered, and their prognosis is less clear. We present our consecutive case series of four patients with this condition, and discuss the implications of their clinical presentation in context of the current literature., Methods: Four patients in whom a CMR diagnosis of IVNC was established are presented. All CMR studies were performed on a Siemens Sonata 1.5T MRI scanner and phased array surface coil. ECG gated trueFISP (fast image with steady state precision) images were performed and analysed off-line with proprietary software. Where transthoracic echocardiography (TTE) had been performed it was retrospectively re-assessed for the diagnosis., Results: In none of the four patients was a diagnosis of IVNC confirmed or even suspected until the CMR study. Two of the four patients were asymptomatic and identified serendipitously; aged 21 and 72 years, respectively. The other two presented for the investigation of ventricular dysrhythmias, and one of these had had a previous (incorrect) diagnosis of hypertrophic non-obstructive cardiomyopathy., Conclusions: Isolated left ventricular non-compaction is becoming increasingly identified and the initial poor prognosis described may not represent the true natural history of this condition. The long-term outlook for this asymptomatic cohort of patients with IVNC is unknown, but it may not be as sinister as first thought.

The ability to modify the enzymatic processes involved in promoting atherosclerotic plaque disruption and to serially monitor atherosclerotic evolution could provide novel information in the management of patients with atherosclerosis. We studied the effects of a statin (atorvastatin) and its combination with an acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor (avasimibe) on atherosclerotic regression and plaque stability as measured by matrix metalloproteinase 1 and 3 (MMP-1 and MMP-3) levels. Watanabe Heritable Hyperlipidemic (WHHL) rabbits treated with atorvastatin alone experienced an attenuated increase in atherosclerotic burden versus controls as determined by MR imaging. The mean vessel wall area (VWA) prior to drug therapy was 5.57 +/- 0.01 mm2. The VWA increased to 6.71 +/- 0.03 and 7.16 +/- 0.03 mm2, respectively, in atorvastatin-treated and control groups (p < 0.0001 for both). The combination of atorvastatin and avasimibe induced a significant regression of the previously established atherosclerotic lesions, with the VWA decreasing to 4.54 +/- 0.04 mm2 (p = 0.009). Atorvastatin alone induced a nonsignificant reduction in the percent staining of MMP-1 in atherosclerotic lesions, but the combination treatment with avasimibe led to a significant reduction versus controls (p = 0.005). However, a reduction in MMP-3 staining was significant for rabbits treated with both atorvastatin alone (p = 0.007) and in combination with avasimibe (p = 0.04) versus controls. In this animal model, the addition of avasimibe to atorvastatin has beneficial effects on both atherosclerotic plaque regression and stabilization., (Copyright 2008 S. Karger AG, Basel.)

This paper presents a mathematical model of biological structures in relation to coronary arteries with atherosclerosis. A set of equations has been derived to compute blood flow through these transport vessels with variable axial and radial geometries. Three-dimensional reconstructions of diseased arteries from cadavers have shown that atherosclerotic lesions spiral through the artery. The theoretical framework is able to explain the phenomenon of lesion distribution in a helical pattern by examining the structural parameters that affect the flow resistance and wall shear stress. The study is useful for connecting the relationship between the arterial wall geometries and hemodynamics of blood. It provides a simple, elegant and non-invasive method to predict flow properties for geometrically complex pathology at micro-scale levels and with low computational cost.

Background: Coronary atherosclerosis and its thrombotic complications are the major cause of mortality and morbidity throughout the industrialized world. Thrombosis on disrupted atherosclerotic plaques plays a key role in the onset of acute coronary syndromes. Macrophages density is one of the most critical compositions of plaque in both plaque vulnerability and thrombogenicity upon rupture. It has been shown that macrophages have a high uptake of 18F-FDG (FDG). We studied the correlation of FDG uptake with histopathological macrophage accumulation in atherosclerotic plaques in a rabbit model., Methods: Atherosclerosis was induced in rabbits (n = 6) by a combination of atherogenic diet and balloon denudation of the aorta. PET imaging was performed at baseline and 2 months after atherogenic diet and coregistered with magnetic resonance (MR) imaging. Normal (n = 3) rabbits served as controls. FDG uptake by the thoracic aorta was expressed as concentration (muCi/ml) and the ratio of aortic uptake-to-blood radioactivity. FDG uptake and RAM-11 antibody positive areas were analyzed in descending aorta., Results: Atherosclerotic aortas showed significantly higher uptake of FDG than normal aortas. The correlation of aortic FDG uptake with macrophage areas assessed by histopathology was statistically significant although it was not high (r = 0.48, p < 0.0001). When uptake was expressed as the ratio of aortic uptake-to-blood activity, it correlated better (r = 0.80, p < 0.0001) with the macrophage areas, due to the correction for residual blood FDG activity., Conclusion: PET FDG activity correlated with macrophage content within aortic atherosclerosis. This imaging approach might serve as a useful non-invasive imaging technique and potentially permit monitoring of relative changes in inflammation within the atherosclerotic lesion.

Positive coronary artery remodeling is associated with unstable coronary syndromes. Serum inflammatory markers, including high-sensitivity CRP (hsCRP), can predict future risk of acute coronary events in patients with stable coronary artery disease. We sought to elucidate the relationship of specific serum inflammatory markers with intravascular ultrasound (IVUS) estimation of coronary artery remodeling in patients with stable coronary artery disease. Thirty-one sequential patients at our institution undergoing IVUS-assisted percutaneous coronary intervention (PCI) with stable coronary artery disease were enrolled. Automated IVUS pullback and offline analysis were performed in all patients. Images were analyzed for vessel wall area (VWA) and lumen area (LA), at the culprit lesion and at a proximal reference site, and the remodeling index (RI) was calculated. Positive and negative remodeling were defined as a RI of > 1.05 and < 0.95, respectively. ELISA essays were performed for soluble VCAM-1, ICAM-1 and E-selectin. The distribution of data followed a lognormal distribution. By defining arterial remodeling as simply positive or negative, significant differences were identified for log E-selectin only (1.80 +/- 0.04 versus 1.62 +/- 0.05, respectively; p = 0.02). The RI correlation coefficient was 0.38 (p = 0.04) for log sVCAM-1 and 0.42 (p = 0.02) for log sICAM-1. The log E-selection and RI correlation coefficient, although weaker at 0.32, showed a trend toward significance (p = 0.08). There was no significant correlation between log hsCRP and RI (p = 0.42). Using step-wise multivariate analysis, log sVCAM-1 only remained an independent predictor of the RI (p = 0.03). Positive coronary artery remodeling correlates with serological markers of inflammation in patients with stable coronary artery disease.

Background: Evidence for statin therapy in prevention of coronary artery disease is overwhelming. In spite of theoretical benefits, any additional advantage of its early introduction in the management of acute coronary syndrome is, however, uncertain. We therefore investigated differences between plasma levels of the systemic inflammatory markers intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, C-reactive protein and interleukin-6 in patients presenting with unstable angina or acute myocardial infarction, and assessed whether the 30-day levels of these markers are influenced by early instigation of the HMG-CoA reductase inhibitor pravastatin., Materials and Methods: 170 (134 male) patients presenting with acute coronary syndrome, but without previous statin therapy, participated. Blood was taken within 24 h of onset of ischaemic pain and again at 30 days. In all, 87 (71 male) participants were treated with pravastatin (20-40 mg daily) and 83 (63 male) with a matched placebo., Results: At presentation, interleukin-6 was higher in males than in females (P=0.008) and lower in those with a pre-existing history of myocardial infarction (P=0.038). C-reactive protein and interleukin-6 were greater in myocardial infarction, but this difference was lost at 30 days. Thirty-day changes in all parameters were inversely related to level at presentation but not to treatment with pravastatin. Hypertension (P=0.011) and smoking (P=0.042) were associated with elevation of C-reactive protein with no difference between unstable angina or acute myocardial infarction. The effect of these individual factors was cumulative., Conclusions: Interleukin-6 was greater in acute myocardial infarction than in unstable angina; E-selectin was positively associated with a previous myocardial infarction and inversely related to age. We found no effect of early introduction of pravastatin on systemic inflammatory markers 30 days after acute coronary syndrome.

Objective: This study investigates effects of short-term administration of high-density lipoproteins (HDL) and a statin on atherosclerosis in cholesterol-fed rabbits. Effects of HDL apolipoprotein and phospholipid composition have also been investigated., Methods and Results: Aortic atherosclerosis was established over 17 weeks in 46 rabbits by balloon denudation and cholesterol feeding. During the past 5 days of the cholesterol-feeding period, animals received: (1) no treatment; (2) oral atorvastatin 5 mg/kg on each of the 5 days; or (3) infusions of HDL (8 mg/kg apolipoprotein A-I) on days 1 and 3 of the treatment phase. After euthanization, lesion size and composition were assessed by histological and immunohistochemical analysis. HDL (but not atorvastatin) reduced lesion size by 36% (P<0.05). The ratio of smooth muscle cells to macrophages in the lesions increased 2.6-fold in animals infused with HDL (P<0.05) and 4-fold in those receiving atorvastatin (P<0.01). HDL and atorvastatin reduced matrix metalloproteinase (MMP)-9 expression by 42% (P<0.05) and 45% (P<0.03), respectively. HDL increased thrombomodulin expression 2-fold (P<0.03). The beneficial effects on lesion area and plaque cellular composition were influenced by HDL phospholipid and apolipoprotein composition., Conclusions: Infusing small amounts of HDL rapidly reduces lesion size and is comparable to atorvastatin in promoting a stable plaque phenotype.

Objectives: This study sought to compare the effects of aggressive and conventional lipid lowering by two different dosages of the same statin on early human atherosclerotic lesions using serial noninvasive magnetic resonance imaging (MRI)., Background: Regression of atherosclerotic lesions by lipid-lowering therapy has been reported., Methods: Using a double-blind design, newly diagnosed hypercholesterolemic patients (n = 51) with asymptomatic aortic and/or carotid atherosclerotic plaques were randomized to 20 mg/day (n = 29) or 80 mg/day (n = 22) simvastatin. Mean follow-up was 18.1 months. A total of 93 aortic and 57 carotid plaques were detected and sequentially followed up by MRI every six months after lipid-lowering initiation. The primary MRI end point was change in vessel wall area (VWA) as a surrogate for atherosclerotic burden., Results: Both statin doses reduced significantly total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) versus baseline (p < 0.001). Total cholesterol decreased by 26% versus 33% and LDL-C by 36% versus 46% in the conventional (20 mg) versus aggressive (80 mg) simvastatin groups, respectively. Although the simvastatin 80-mg group had significantly higher baseline TC and LDL-C levels, both groups reached similar absolute values after treatment. A significant reduction in VWA was already observed by 12 months. No difference on vascular effects was detected between the randomized doses. Post-hoc analysis showed that patients reaching mean on-treatment LDL-C < or = 100 mg/dl had larger decreases in plaque size., Conclusions: Effective and protracted lipid-lowering therapy with simvastatin is associated with a significant regression of atherosclerotic lesions. No difference in vessel wall changes was seen between high and conventional doses of simvastatin. Changes in vessel wall parameters are more related to LDL-C reduction rather than to the dose of statin.

Objectives: The purpose of this research was to compare the Thrombolysis In Myocardial Infarction (TIMI) frame count (CTFC) with coronary flow velocity reserve (CFVR) in patients undergoing percutaneous coronary intervention (PCI)., Background: The relationship between CTFC and CFVR has not been adequately assessed in patients with coronary artery disease., Methods: We studied 62 patients who underwent successful non-emergent PCI. All patients had Doppler evaluation of CFVR, CTFC, and quantitative coronary angiography. In an additional 17 patients, a frame count reserve was calculated as baseline CTFC/CTFC at peak hyperemia, induced by intracoronary adenosine after PCI., Results: The CTFC decreased from 27 +/- 13 to 18 +/- 8, and CFVR increased from 1.5 +/- 0.4 to 2.6 +/- 0.7 (both p < 0.0001). The pre-PCI CTFC and the CFVR were closely related to minimal lumen diameter (p < 0.0001). After PCI, there was no correlation between CFVR and CTFC. In addition, no relationship was observed between CFVR and the frame count reserve., Conclusions: There was no significant correlation between CFVR and CTFC in patients undergoing coronary intervention. The relative utility of these measures in predicting outcomes in this setting requires further evaluation, but CTFC (or frame count reserve) does not appear to be an adequate surrogate measure of Doppler-derived CFVR.

Advances in coronary angiographic imaging have been recently realized with the advent of so-called flat panel technology. However, some of the limitations of coronary angiography, including the so-called pseudo-thrombus appearance of focal highly calcific coronary artery lesions remain. This case highlights the utility of intravascular ultrasound in determining the pathobiology of coronary artery lesions in select cases.

Objectives: The purpose of the current study was to assess the effect of angiotensin-converting enzyme inhibitor (ACEI) therapy in facilitating cardioversion from persistent atrial fibrillation (AF) and maintaining sinus rhythm., Background: Pharmacologic therapy and electrical cardioversion for AF are often unsuccessful in maintaining long-term sinus rhythm., Methods: The current study, a 1-year, prospective follow-up, comprised 47 patients with persistent AF undergoing electrical cardioversion. Patients receiving ACEI were compared with those receiving other medications. The study end point was the number of defibrillation attempts required for atrial defibrillation and the number of hospital admissions. A secondary end point was change in signal-averaged P-wave duration (SAPD) 1 year after successful electrical cardioversion., Results: Of those admitted and requiring electrical defibrillation, the number of defibrillation attempts required for successful cardioversion was significantly less in the ACEI group (P <.001). The incidence rate ratio for admissions comparing recipients of ACEI with others was 0.14 (P =.03). Patients receiving ACEI therapy had significantly lower SAPD at 1 year when compared with the no-ACEI group (135 ms +/- 3 vs 150 ms +/- 2, P =.002)., Conclusions: The use of long-term ACEI therapy facilitated electrical defibrillation in patients with persistent AF. ACEI therapy also reduced SAPD, suggesting amelioration of the arrhythmogenic substrate. Furthermore, we confirmed that SAPD is prolonged in patients with persistent AF.

Objective: Experimental evidence indicates that ATP-sensitive potassium (K(ATP)) channels regulate coronary blood flow (CBF). However, their contribution to human coronary metabolic vasodilation is unknown., Methods and Results: Seventeen patients (12 male, age 58+/-10 years) were studied. Coronary hemodynamics were assessed before and after K(ATP) channel inhibition with subselective intracoronary glibenclamide infused at 40 microg/min in an angiographically smooth coronary artery after successful percutaneous coronary intervention to another vessel. Metabolic vasodilation was induced by 2 minutes of rapid right ventricular pacing. Coronary blood velocity was measured with a Doppler guidewire and CBF calculated. The time course of hyperemia was recorded for 2 minutes after pacing, and hyperemic volume was estimated from the area under the flow-versus-time curve (AUC). Compared with vehicle infusion (0.9% saline), glibenclamide reduced resting CBF by 9% (P=0.04) and increased resting coronary vascular resistance (CVR) by 15% (P=0.03). Glibenclamide reduced pacing-induced peak CBF (50.8+/-6.8 versus 42.0+/-5.4 mL/min, P=0.001), peak CBF corrected for baseline flow (25.1+/-4.6 versus 17.6+/-3.1 mL/min, P=0.01), and increased minimum CVR (2.6+/-0.3 versus 3.1+/-0.3 mm Hg/mL per minute, P=0.002). Compared with vehicle, glibenclamide reduced total AUC at 2 minutes (3535+/-397 versus 3027+/-326 mL, P=0.001)., Conclusions: Vascular K(ATP) channels appear to be involved in functional coronary hyperemia after metabolic stimulation.

The human cardiovascular system is regulated by haemodynamic, neurohumoral and structural mechanisms. The endothelium and the neurohumoral system play a key role in modulating both vascular tone and structure by producing vasoactive substances, and in the modulation of blood cell adhesion. Although the neurohormonal systems are essential in vascular homeostasis, they become maladaptive in conditions such as hypertension, coronary disease and heart failure. The clinical success of blocking the renin-angiotensin system by angiotensin converting enzyme (ACE)-inhibitors and the sympathetic nerve system by beta-blockers demonstrates the importance of neurohumoral blockade. The inadequate effect of angiotensin converting enzyme (ACE) or neutral endopeptidase (NEP) inhibitor monotherapy seen in some patients treated for hypertension or congestive heart failure, and the promising effect seen after their combination, led to the development of drugs that simultaneously inhibit both enzyme systems. Neutral endopeptidase, like ACE, is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site to ACE. NEP is the major enzymatic pathway for degradation of natriuretic peptides. The natriuretic peptide system can be viewed as the endogenous inhibitor of the renin angiotensin system. The dual metalloprotease inhibitors of ACE and NEP, called vasopeptidase inhibitors therefore represent a new and attractive therapeutic strategy for the treatment of cardiovascular disease. The ability to add incremental benefit over already proven therapy, with an acceptable side-effect profile however, is questionable in this new class of agents.

Objective: MRI is being used to characterize the composition of atherosclerotic plaques. However, the resolution achievable using surface radiofrequency coils is limited by the signal to noise ratio. We studied the utility of a new intravascular (IV) MRI probe for high-resolution in vivo imaging of atherosclerotic lesions., Methods and Results: Balloon-injured Watanabe heritable hyperlipidemic rabbits served as the experimental model of atherosclerosis. The newly developed IV MRI probe is 1.3 mm in diameter and can be positioned over a guidewire. MRI was performed with both an external phased-array coil and the IV MR coil. MR observations were correlated with histopathology. After MRI, the animals were killed and analysis of agreement between MR and histopathology was performed. The IV MR coil allows aortic images to be obtained with 156x156 micro m(2) in-plane resolution versus 352x352 micro m(2) when used with the external phased-array coil. No significant motion artifacts were noted, despite the continuation of arterial blood flow during image acquisition around the IV probe. The different components of the atherosclerotic lesions (lipid core and fibrous cap) were easily identified. There was an excellent agreement between MRI with the IV coil and histopathology by simple linear regression for both the mean wall thickness (r=0.88, slope 0.82, P<0.0001) and vessel wall area (r=0.86, slope 1.08, P<0.0001)., Conclusions: The new nonobstructive design for this intravascular coil provides great promise for additional work in high-resolution MRI characterization of atherosclerotic plaques in vivo. The ability to position the probe with a guidewire allows its placement under fluoroscopic or MRI guidance, whereas its size is compatible with human coronary arteries.

Background: Statins are widely used to treat hypercholesterolemia and atherosclerotic disease. Noninvasive MRI allows serial monitoring of atherosclerotic plaque size changes. Our aim was to investigate the effects of lipid lowering with simvastatin on atherosclerotic lesions., Methods and Results: A total of 44 aortic and 32 carotid artery plaques were detected in 21 asymptomatic hypercholesterolemic patients at baseline. The effects of statin on these atherosclerotic lesions were evaluated as changes versus baseline in lumen area (LA), vessel wall thickness (VWT), and vessel wall area (VWA) by MRI. Maximal reduction of plasma total and LDL cholesterol by simvastatin (23% and 38% respectively; P<0.01 versus baseline) was achieved after approximately 6 weeks of therapy and maintained thereafter throughout the study. Significant (P<0.01) reductions in maximal VWT and VWA at 12 months (10% and 11% for aortic and 8% and 11% for carotid plaques, respectively), without changes in LA, have been reported. Further decreases in VWT and VWA ranging from 12% to 20% were observed at 18 and 24 months. A slight but significant increase (ranging from 4% to 6%) in LA was seen in both carotid and aortic lesions at these later time points., Conclusion: The present study demonstrates that maintained lipid-lowering therapy with simvastatin is associated with significant regression of established atherosclerotic lesions in humans. Our observations indicate that lipid-lowering therapy is associated with sustained vascular remodeling and emphasize the need for longer-term treatment.

Background: Atherosclerosis is an inflammatory process in which adhesion molecules play an intimate role in both the initiation and progression of lesions. It is postulated that they also play a role in the presentation of acute coronary syndromes and that plasma levels thereafter may be of potential prognostic significance. The stability of sample levels under different laboratory conditions is unknown., Methods: Stability of plasma levels was assessed in six healthy subjects under four different laboratory conditions. The time course of levels was studied in 57 patients with acute chest pain, 21 of non-cardiac aetiology, 23 unstable angina and 13 acute myocardial infarction, at mean times of 2.3, 8.2 and 17.3 h after the onset of pain. Samples were assayed for intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, E-selectin and C-reactive protein (CRP)., Results: ICAM-1, VCAM-1, P-selectin and E-selectin levels did not differ under different laboratory conditions. Levels were similar at presentation in patients with acute chest pain of non-cardiac aetiology, unstable angina or acute myocardial infarction (median levels ICAM-1 269 microg/l, VCAM-1 379 microg/l, P-selectin 167 microg/l and E-selectin 53 microg/l). Levels did not change in the 24 h following the onset of pain. CRP levels did not differ at presentation between groups (median level 2.1 mg/l), but rose more than 12 h after the onset of pain in the group with acute myocardial infarction (P < 0.05)., Conclusion: Adhesion molecule levels are stable under normal laboratory sample handling conditions. Levels do not change in the 24 h following the onset of chest pain of non-cardiac or acute ischaemic aetiology.

Background: Modification or stabilization of atherosclerotic plaques has been proposed as the mechanism responsible for the beneficial clinical effect of lipid-lowering therapies. An imaging modality able to quantify atherosclerotic plaque composition could potentially allow not only the identification of these vulnerable atherosclerotic lesions, but also monitoring of the effects of therapeutic interventions on plaque composition. Our aim was to monitor changes in burden and composition of atherosclerotic plaques in a rabbit model of complex atherosclerosis using serial noninvasive magnetic resonance imaging (MRI)., Methods and Results: Aortic atherosclerotic lesions were induced in rabbits and the animals randomized to continue an atherogenic diet (atherosclerosis progression) or resume normal chow (atherosclerosis regression) for 6 months. MRI of the aorta was performed at 3 time points in each rabbit, as follows: baseline, after atherosclerosis induction (9 months old), and after atherosclerosis regression or progression (15 months old). Histopathologic correlation with MRI was performed. There was a significant (P<0.0001) reduction in atherosclerotic burden in the regression group, and an increase in the progression group. There was a significant (P<0.001) reduction in the lipidic component of plaques in the regression group, and an increase in the progression group. A small, nonsignificant increase in the fibrotic plaque components was noted in the regression group, but a significant decrease in the fibrotic composition of lesions in the progression group. A significant correlation (P<0.001) was found between MRI and histopathology for atherosclerotic burden and plaque composition., Conclusions: These findings indicate that serial noninvasive MRI can monitor changes in atherosclerotic plaque composition under conditions of atherosclerotic progression and regression.

Experimental data suggest that vascular ATP-sensitive potassium (K(ATP)) channels regulate coronary blood flow (CBF), but their role in regulating human CBF is unclear. We sought to determine the contribution of K(ATP) channels to resting conduit vessel and microvascular function in the human coronary circulation. Twenty-five patients (19 male/6 female, aged 56 +/- 12 years) were recruited. Systemic and coronary hemodynamics were assessed in 20 patients before and after K(ATP) channel inhibition with graded intracoronary glibenclamide infusions (4, 16, and 40 microg/min), in an angiographically smooth or mildly stenosed coronary artery following successful elective percutaneous coronary intervention to another vessel. Coronary blood velocity was measured with a Doppler guidewire and CBF calculated. Adenosine-induced hyperemia was determined following bolus intracoronary adenosine injection (24 microg). Time control studies were undertaken in 5 patients. Compared with vehicle infusion (0.9% saline), glibenclamide reduced resting conduit vessel diameter from 2.5 +/- 0.1 to 2.3 +/- 0.1 mm (P<0.01), resting CBF by 17% (P=0.05), and resting CBF corrected for rate pressure-product by 18% (P=0.01) in a dose-dependent manner. A corresponding 24% increase in coronary vascular resistance was noted at the highest dose (P<0.01). No alteration to resting CBF was noted in the time control studies. Glibenclamide reduced peak adenosine-induced hyperemia (P=0.01) but did not alter coronary flow reserve. Plasma insulin increased from 5.6 +/- 1.2 to 7.6 +/- 1.3 mU/L (P=0.02); however, plasma glucose was unchanged. Vascular K(ATP) channels are involved in the maintenance of basal coronary tone but may not be essential to adenosine-induced coronary hyperemia in humans.

Atherosclerotic disease and its thrombotic complications remain the leading causes of mortality and morbidity in Western society. In Australia, cardiovascular disease is responsible for one in every 2.4 (41%) deaths and is the leading single cause of mortality. The crucial final common process for the conversion of a non-occlusive, often clinically silent, atherosclerotic lesion to a potentially fatal condition is plaque disruption. The mortality associated with atherosclerotic disease relates to the acute coronary syndromes, including acute myocardial infarction, unstable angina pectoris and sudden cardiac death. There is substantial clinical, experimental and postmortem evidence demonstrating the role acute thrombosis upon a disrupted atherosclerotic plaque plays in the onset of acute coronary syndromes. Atherosclerotic plaque composition, rather than the stenotic severity, appears to be central in determining risk of both plaque rupture and subsequent thrombogenicity. In particular, a large lipid core and a thin fibrous cap render an atherosclerotic lesion susceptible or vulnerable to these complications. We are currently limited in our ability to accurately identify patients at risk for an acute coronary event. The armamentarium of diagnostic investigations, both non-invasive and invasive, currently clinically available is only able to provide us with data related to the stenotic severity of a coronary artery. The non-invasive testing includes stress-induced (exercise or pharmacological) ischaemic changes in electrical repolarisation, wall motion or myocardial radioactive-tracer uptake. The invasive test of coronary angiography, although the current 'gold standard' for the detection of coronary atherosclerotic disease, provides us with no data about the composition of the atherosclerotic lesion. However, the vast majority of acute coronary events involve a non-critically stenosed atherosclerotic lesion, and thus with currently available means of identification, these lesions would be undetected by stress testing/imaging techniques. Given the critical role that atherosclerotic lesion composition has been shown to play in the risk of both plaque rupture and subsequent thrombogenicity and, consequently, an acute coronary event, new detection techniques need to be investigated for the task of documenting atherosclerotic lesion composition. In the present review we will focus on the status of imaging modalities available for coronary artery imaging and how they may advance our understanding and management of patients with and at risk of coronary artery disease in the new millennium.