Josephine Pressacco

Treatment With 5-Lipoxygenase Inhibitor VIA-2291 (Atreleuton) in Patients With Recent Acute Coronary Syndrome

Background—Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor. Methods and Results—In a double-blinded study, 191 patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P<0.0001) in a dose-dependent fashion, with approximately 80% inhibition in >90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291–treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291–treated groups in the 34 of these 60 patients in whom this end point was analyzable (P<0.01). Conclusions—VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.

Imaging Biomarkers in Atherosclerosis Trials

Atherosclerosis and its thrombotic complications are the leading cause of morbidity and mortality in developed countries, and the burden of atherosclerotic disease is expected to increase even further in the coming decades due to soaring obesity rates that feed the diabetes epidemic. There is, therefore, a clear need for new drugs targeting atherosclerosis to add to our current therapeutic armamentarium. Drug approval currently is based on multicenter, randomized, placebo-controlled trials with long-term follow-up in thousands of patients to demonstrate clear benefits in mortality and cardiovascular events and to allow adequate assessment of safety. Cardiovascular drug development has become a hostage to its own success. New drugs must be compared to placebo but on the background of highly effective standard therapy that lowers event rates and necessitates huge sample sizes and long follow-up. Failures of promising new cardiovascular drugs in large clinical trials1 have had catastrophic consequences for the sponsoring pharmaceutical and biotechnological companies. These conditions are inhibiting new drug development and are stimulating a search for alternate methods to assess new compounds. Cardiovascular imaging techniques have been used to fill this need.2 Cardiovascular imaging trials are shorter and require only a fraction of the patients needed for a large events trial because all patients who complete an imaging trial contribute to the end point. Thus, imaging trials are less expensive. By themselves, they are not sufficient for drug approval by regulatory agencies partly because of the limited safety data that can be generated with the study drug given the number of patients involved and duration of exposure. Nevertheless, imaging studies can provide evidence to inform the decision about whether a large outcome trial should proceed. They are therefore currently best suited in phase 2 of drug development. Ideally, imaging studies also should provide useful data regarding the mechanism …

Effects of the tumor necrosis factor-α antagonist adalimumab on arterial inflammation assessed by positron emission tomography in patients with psoriasis: results of a randomized controlled trial.

Background—Psoriasis is a chronic inflammatory disease associated with increased risks of myocardial infarction and stroke. Systemic treatments for moderate to severe psoriasis can reduce skin and joint inflammation; however, their effects on vascular inflammation are unknown. Methods and Results—This randomized, controlled trial included 30 patients with moderate to severe psoriasis and a history, or multiple risk factors, of coronary atherosclerosis. Patients were randomized (2:1) to receive either adalimumab subcutaneously for 4 months or to control nonsystemic treatment (topical therapies or phototherapy). Vascular inflammation was measured in the carotid artery and ascending aorta at baseline and week 15, by 18F-fluorodeoxyglucose uptake on positron emission tomography. The change in target:background ratio in the vessel with highest baseline target:background ratio (primary end point) was significant at week 15 compared with baseline for patients randomized to adalimumab (–0.23 [95% CI, –0.39 to –0.08]; P=0.004) but not for the control group (–0.10 [95% CI, –0.32 to 0.12]; P=0.35). The difference between study arms for this primary end point did not reach statistical significance (–0.13 [95% CI, –0.01 to 0.14]; P=0.32). The change in target:background ratio at week 15 improved with adalimumab compared with controls both in the ascending aorta (–0.26±0.11, P=0.021) and in carotid arteries (–0.32±0.15, P=0.037) when analyzed separately (secondary end points). Changes in other positron emission tomography indices also improved significantly with adalimumab compared with controls in the ascending aorta and carotids. High-sensitivity C-reactive protein decreased by 51% at week 16 with adalimumab compared with 5% in controls (P=0·002). Conclusions—The study did not meet its primary end point because the change in target:background ratio in patients randomized to adalimumab was not different from controls. Although adalimumab may reduce vascular inflammation in patients with moderate to severe psoriasis, this effect is not large enough to be demonstrated in a study with a small sample size. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NTC00940862.

Effects of the TNF alpha Antagonist Adalimumab on Arterial Inflammation Assessed by Positron Emission Tomography in Patients with Psoriasis: Results of a Randomized Controlled Trial

Background—Psoriasis is a chronic inflammatory disease associated with increased risks of myocardial infarction and stroke. Systemic treatments for moderate to severe psoriasis can reduce skin and joint inflammation; however, their effects on vascular inflammation are unknown. Methods and Results—This randomized, controlled trial included 30 patients with moderate to severe psoriasis and a history, or multiple risk factors, of coronary atherosclerosis. Patients were randomized (2:1) to receive either adalimumab subcutaneously for 4 months or to control nonsystemic treatment (topical therapies or phototherapy). Vascular inflammation was measured in the carotid artery and ascending aorta at baseline and week 15, by 18F-fluorodeoxyglucose uptake on positron emission tomography. The change in target:background ratio in the vessel with highest baseline target:background ratio (primary end point) was significant at week 15 compared with baseline for patients randomized to adalimumab (–0.23 [95% CI, –0.39 to –0.08]; P=0.004) but not for the control group (–0.10 [95% CI, –0.32 to 0.12]; P=0.35). The difference between study arms for this primary end point did not reach statistical significance (–0.13 [95% CI, –0.01 to 0.14]; P=0.32). The change in target:background ratio at week 15 improved with adalimumab compared with controls both in the ascending aorta (–0.26±0.11, P=0.021) and in carotid arteries (–0.32±0.15, P=0.037) when analyzed separately (secondary end points). Changes in other positron emission tomography indices also improved significantly with adalimumab compared with controls in the ascending aorta and carotids. High-sensitivity C-reactive protein decreased by 51% at week 16 with adalimumab compared with 5% in controls (P=0·002). Conclusions—The study did not meet its primary end point because the change in target:background ratio in patients randomized to adalimumab was not different from controls. Although adalimumab may reduce vascular inflammation in patients with moderate to severe psoriasis, this effect is not large enough to be demonstrated in a study with a small sample size. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NTC00940862.

Simultaneous MR arteriography and venography with blood pool contrast agent detects deep venous thrombosis in suspected arterial disease.

OBJECTIVE The purpose of this study was to investigate the prevalence of incidental deep venous thrombosis (DVT) in patients with clinically suspected peripheral arterial occlusive disease (PAOD) using contrast-enhanced MR angiography (MRA) with a blood pool contrast agent. SUBJECTS AND METHODS Two hundred fifty-nine MRA examinations with blood pool contrast agent in 245 consecutive patients (161 men; age range, 36-92 years), yielding a total of 4102 assessable arterial and venous vessel segments, were assessed with regard to the rate of incidentally observed acute and organized DVT and arterial stenosis grades. Incidental DVT was confirmed using duplex ultrasound. Contralateral nondiseased veins served as internal controls. The relationship between PAOD stages and acute and organized DVT was investigated using chi-square tests and a Mann-Whitney U test. RESULTS Arterial stenosis grading using MRA with blood pool contrast agent revealed less than 50% luminal stenosis in 78% of segments (3199/4102), 50% or greater stenosis in 8% of segments (317/4102), and occlusion in 14% of segments (586/4102). Incidental DVT was observed in 26 of 245 patients (11%) (acute DVT was seen in 10 patients and 26 segments; organized DVT was seen in 17 patients and 35 segments; and one patient had both acute and organized DVT). All incidentally diagnosed cases of DVT were confirmed by duplex ultrasound. Internal controls revealed no false-positive or -negative findings (26 patients and 172 segments). Incidental acute DVT was significantly more common among patients without arterial stenosis greater than 50% (p < 0.05). Otherwise, there was no significant relationship between Fontaine PAOD stages and the occurrence of acute (p = 0.688) or organized (p = 0.995) DVT. CONCLUSION Incidental DVT was prevalent in 11% of patients with clinically suspected PAOD. MRA with blood pool contrast agent has a potential role in the simultaneous assessment of arteries and veins and can detect concomitant venous disease affecting therapeutic management.

Evaluation of Adult Congenital Heart Disease by Cardiac Magnetic Resonance Imaging

Cardiovascular magnetic resonance (CMR) imaging plays an essential role in the evaluation and follow-up of adult congenital heart disease (ACHD), providing safe, high-resolution imaging of some of the most complex anatomies encountered. Unlimited by acoustic windows and capable of tissue characterization, CMR is devoid of ionizing radiation and provides superior three-dimensional spatial resolution to transthoracic echocardiography and superior temporal resolution to computed tomography, making it the gold standard for various cardiac and great vessel imaging indications in ACHD. In this state-of-the art review, we provide an overview of CMR examination methods and detail the various approaches and classical findings in the more common forms of ACHD. Although this review touches upon technical aspects of CMR imaging in ACHD, it is primarily geared toward the adult congenital caregiver (i.e., clinical, interventional, or surgical), highlighting relevant practical considerations. To enhance the clinical utility of this review, numerous examples with intraoperative correlates are provided to highlight our imaging approaches for various defects. As CMR image acquisition may be time consuming and requires patient collaboration (e.g., intermittent breath holding), a systemic approach is required to maximize efficiency. A thorough knowledge of ACHD anatomy and natural history is essential in maximizing image interpretation. Proficient scanning is further enabled by clearly outlined study objectives with prior documentation of interventional and surgical procedures, where applicable.

Concordance Between an Electroanatomic Mapping System and Cardiac MRI in Arrhythmogenic Right Ventricular Cardiomyopathy

A 29‐year‐old man presenting with syncopal ventricular tachycardia was diagnosed with arrhythmogenic right ventricular (RV) cardiomyopathy. Cardiac magnetic resonance imaging (MRI) revealed an unequivocal dyskinetic segment at the basal portion of the RV lateral free wall. Three‐dimensional electroanatomic voltage mapping using the EnSite NavX™ system recorded a low voltage area corresponding to the diseased portion of the right ventricle identified by MRI. This report describes concordance between cardiac MRI and this novel mapping system in arrhythmogenic RV cardiomyopathy.

Evaluation of coronary atheroma by 64-slice multidetector computed tomography: Comparison with intravascular ultrasound and angiography

BACKGROUND Recent improvements in multidetector computed tomography (MDCT) with 64-slice scanners have allowed acquisition of a coronary study in 5 s to 6 s, with good temporal and spatial resolution. Previous studies have reported an underestimation of plaque burden by MDCT. Whether shorter scan times can allow correct assessment of plaque volume requires comparison with intravascular ultrasound (IVUS). METHODS Patients (n=30) scheduled for coronary angiography also underwent MDCT and IVUS examinations within 96 h. MDCT examination was performed with a 64-slice scanner. Nitroglycerin was administered before all imaging procedures. MDCT, quantitative coronary angiography (QCA) and IVUS analyses were performed by observers blinded to other results. Plaque volumes were determined by MDCT and IVUS in one vessel, and maximum percentage diameter stenosis was identified in each coronary segment by MDCT and QCA. RESULTS The mean (+ or - SD) plaque volume was determined to be 179.1 + or - 78.9 mm(3) by MDCT and 176.1 + or - 87.9 mm(3) by IVUS. There was a strong positive correlation for plaque volume between MDCT and IVUS (r=0.84, P<0.0001). Percentage diameter stenosis assessed by MDCT and QCA also correlated well (r=0.88 per patient and r=0.87 per vessel, P<0.0001 for both). The maximum percentage diameter stenosis per vessel was 38.1 + or - 30.2% with MDCT and 34.1 + or - 27.6% with QCA. The sensitivity and specificity of MDCT in detecting stenoses above 50% per vessel were 100% and 91.0%, respectively. CONCLUSIONS Plaque volumes measured by 64-slice MDCT and IVUS correlate well, without systematic underestimation. The sensitivity and specificity of MDCT to detect stenoses greater than 50% by QCA are excellent with the administration of nitroglycerin before imaging.

Atherosclerosis Imaging and the Canadian Atherosclerosis Imaging Network

Atherosclerosis exacts a large toll on society in the form of cardiovascular morbidity, mortality, and resource use and is exacerbated by the epidemics of obesity and diabetes. Consequently, there is a critical need for more-effective methods of diagnosis, treatment, and prevention of the complications of atherosclerosis. Careful and well-conducted large population studies are needed in order to truly understand the natural history of the disease, its imaging biomarkers, and their links to patient outcomes. The Canadian Atherosclerosis Imaging Network (CAIN) is a unique research network funded by the Canadian Institutes of Health Research and the Canada Foundation for Innovation and designed to address these needs and to enable large population-based imaging studies. The central objective of CAIN is to move innovations in imaging toward their broad application in clinical research and clinical practice for the improved evaluation of cardiac and neurologic vascular disease. CAIN is established as an international resource for studying the natural history, progression, and regression of atherosclerosis, as well as novel therapeutic interventions aimed at atherosclerosis. The network represents Canadas leading atherosclerosis imaging experts, embodying both basic imaging science and clinical imaging research. The network is improving methods of detection and treatment of atherosclerosis and, through a better understanding of the underlying disease itself, improving strategies for disease prevention. The benefits are expected to appear in the next 2 to 3 years. CAIN will drive innovation in imaging technology within the field of cardiology and neurology and improve health outcomes in Canada and worldwide.

Coronary artery noninvasive imaging in adult Kawasaki disease

Coronary artery aneurysms, stenoses, and thromboses are significant complications of Kawasaki disease (KD). While appearing in childhood, coronary complications are often left unrecognized until early and mid-adulthood. Along with the increasing capacity of noninvasive coronary artery imaging modalities, especially computed tomography and magnetic resonance, radiologists are more likely to face the diagnosis of KD in adults. This article will review the clinical aspects of KD for radiologists and will compare coronary imaging modalities in the diagnosis of KD.