Subclinical atherosclerosis in adolescents and young adults and the risk of cardiovascular disease: The Strong Heart Family Study (SHFS).

BACKGROUND AND AIMS: Rates of cardiovascular disease (CVD) among American Indians (AI) have been increasing. Although we have observed an association between atherosclerosis and CVD in older adults, the potential association among young AI is unclear. Therefore, we aim to describe the prevalence of atherosclerosis among young AI and determine its association with CVD and all-cause mortality. METHODS AND RESULTS: We evaluated AI participants from the Strong Heart Family Study (SHFS), who were <40 years old and CVD free at the baseline examination, 2001-2003 (n = 1376). We used carotid ultrasound to detect baseline atherosclerotic plaque. We identified CVD events and all-cause mortality through 2019, with a median follow-up of 17.8 years. We used shared frailty Cox Proportional Hazards models to assess the association between atherosclerosis and time to CVD event or all-cause mortality, while controlling for covariates. Among 1376 participants, 71 (5.2%) had atherosclerosis at baseline. During follow-up, 120 (8.7%) had CVD events and 104 (7.6%) died from any cause. CVD incidence was higher in participants who had baseline atherosclerosis (13.51/1000 person-years) than in those who did not (4.95/1000 person-years, p = 0.0003). CVD risk and all-cause mortality were higher in participants with atherosclerosis, while controlling for covariates (CVD HR = 1.85, 95%CI = 1.02-3.37, p = 0.0420; all-cause mortality HR = 2.04, 95%CI = 1.07-3.89, p = 0.0291). CONCLUSIONS: Among young AI, atherosclerosis was independently associated with incident CVD and all-cause mortality later in life. Thus, atherosclerosis begins early in life and interventions in adolescents and young adults to slow the progression of disease could prevent or delay CVD events later in life.

Increased arterial inflammation in individuals with stage 3 chronic kidney disease.

PURPOSE: While it is well known that patients with chronic kidney disease (CKD) are at increased risk for the development and progression of atherosclerosis, it is not known whether arterial inflammation is increased in mild CKD. The aim of this study was to compare arterial inflammation using 18F-FDG PET/CT in patients with CKD and in matched controls. METHODS: This restrospective study included 128 patients undergoing FDG PET/CT imaging for clinical indications, comprising 64 patients with stage 3 CKD and 64 control patients matched by age, gender, and cancer history. CKD was defined according to guidelines using a calculated glomerular filtration rate (eGFR). Arterial inflammation was measured in the ascending aorta as FDG uptake on PET. Background FDG uptake (venous, subcutaneous fat and muscle) were recorded. Coronary artery calcification (CAC) was assessed using the CT images. The impact of CKD on arterial inflammation and CAC was then assessed. RESULTS: Arterial inflammation was higher in patients with CKD than in matched controls (standardized uptake value, SUV: 2.41 ± 0.49 vs. 2.16 ± 0.43; p = 0.002). Arterial SUV correlated inversely with eGFR (r = -0.299, p = 0.001). Venous SUV was also significantly elevated in patients with CKD, while subcutaneous fat and muscle tissue SUVs did not differ between groups. Moreover, arterial SUV remained significantly elevated in patients with CKD compared to controls after correcting for muscle and fat background, and also remained significant after adjusting for clinical risk factors. Further, CKD was associated with arterial inflammation (SUV) independent of the presence of subclinical atherosclerosis (CAC). CONCLUSION: Moderate CKD is associated with increased arterial inflammation beyond that of controls. Further, the increased arterial inflammation is independent of presence of subclinical atherosclerosis. Current risk stratification tools may underestimate the presence of atherosclerosis in patients with CKD and thereby the risk of cardiovascular events.

HIF-1α and PFKFB3 Mediate a Tight Relationship Between Proinflammatory Activation and Anerobic Metabolism in Atherosclerotic Macrophages.

OBJECTIVE: Although it is accepted that macrophage glycolysis is upregulated under hypoxic conditions, it is not known whether this is linked to a similar increase in macrophage proinflammatory activation and whether specific energy demands regulate cell viability in the atheromatous plaque. APPROACH AND RESULTS: We studied the interplay between macrophage energy metabolism, polarization, and viability in the context of atherosclerosis. Cultured human and murine macrophages and an in vivo murine model of atherosclerosis were used to evaluate the mechanisms underlying metabolic and inflammatory activity of macrophages in the different atherosclerotic conditions analyzed. We observed that macrophage energetics and inflammatory activation are closely and linearly related, resulting in dynamic calibration of glycolysis to keep pace with inflammatory activity. In addition, we show that macrophage glycolysis and proinflammatory activation mainly depend on hypoxia-inducible factor and on its impact on glucose uptake, and on the expression of hexokinase II and ubiquitous 6-phosphofructo-2-kinase. As a consequence, hypoxia potentiates inflammation and glycolysis mainly via these pathways. Moreover, when macrophages' ability to increase glycolysis through 6-phosphofructo-2-kinase is experimentally attenuated, cell viability is reduced if subjected to proinflammatory or hypoxic conditions, but unaffected under control conditions. In addition to this, granulocyte-macrophage colony-stimulating factor enhances anerobic glycolysis while exerting a mild proinflammatory activation. CONCLUSIONS: These findings, in human and murine cells and in an animal model, show that hypoxia potentiates macrophage glycolytic flux in concert with a proportional upregulation of proinflammatory activity, in a manner that is dependent on both hypoxia-inducible factor -1α and 6-phosphofructo-2-kinase.

Arterial inflammation in bronchial asthma.

BACKGROUND: Bronchial asthma is a chronic inflammatory condition associated with increased cardiovascular (CV) events. Here, we assess arterial inflammation, using 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging (FDG-PET/CT), in patients with bronchial asthma and low to intermediate Framingham risk scores (FRS). METHODS: A total of 102 patients underwent FDG-PET/CT imaging for clinical indications. Thirty-four patients (mean age 54.9 ± 16.1) with mild asthma and no known atherosclerotic disease were compared to 2 non-asthmatic groups. The first control group (n = 34) were matched by age, gender, and FRS. The second control group (n = 34) had clinical atherosclerosis and were matched by gender. Thereafter, arterial FDG uptake on PET images was determined, while blinded to patient identifiers. RESULTS: Target-to-background-ratio (TBR) in the aorta was higher in asthmatics vs non-asthmatic FRS-matched controls (1.96 ± 0.26 vs 1.76 ± 0.20; P < .001). The aortic TBR remained elevated in asthmatics vs non-asthmatic controls after adjusting traditional CV risk factors (P < .001). An inverse correlation was observed between FDG uptake and lung function, FEV1 (P = .02) and peak flow (P = .03). CONCLUSIONS: Bronchial asthma is associated with increased arterial inflammation beyond that estimated by current risk stratification tools. Further studies are required to evaluate whether attenuation of systemic inflammation will decrease CV events.

Access to cardiac PET/CT by sarcoidosis patients and cost-effectiveness analysis of cardiac PET/MR compared to the standard of care.

IMPORTANCE: Cardiac sarcoidosis is associated with a high mortality rate. Given multiple barriers to obtaining cardiac PET imaging, we suspect individuals with access to this imaging modality are not representative of the Sarcoid patient population, which in the United States are predominantly Black females. OBJECTIVE: To evaluate the demographics of patients with cardiac PET access and the cost-effectiveness of cardiac PET/MR imaging relative to standard of care. DESIGN: This is a retrospective, observational study. The demographic information of patients with suspected cardiac sarcoidosis and cardiac PET/CT imaging within a national registry of sarcoidosis were reviewed (n = 4561). An individual-level, continuous, time-state transition model was used for the evaluation of long-term cost-effectiveness for the combined cardiac PET/MR compared to standard of care cardiac MR followed by cardiac PET/CT. RESULTS: Patients who underwent cardiac PET in the national registry had 88.35% higher odds of being male (p < 0.001) and 43.82% higher odds of being White (p = 0.003) than their counterparts who did not have cardiac PET imaging. Combined cardiac PET/MR had overall lower total lifetime costs ($8761 vs $10,777) and overall improved expected quality of life-years compared to the standard of care (0.77 vs 0.69). CONCLUSION AND RELEVANCE: The findings suggest that patients with access to cardiac PET/CT are not representative of the patient population most likely to have cardiac sarcoidosis in this limited study evaluation. Universal insurance coverage should be considered for Cardiac PET imaging as same day cardiac PET and MR imaging has potential long-term cost and quality of life benefit.

A case series on inflammatory cardiomyopathy and suspected cardiac sarcoidosis: role of cardiac PET in management.

BACKGROUND: Presentation of life-threatening arrhythmias concomitantly with a new-onset non-ischaemic cardiomyopathy raises concern for an inflammatory cardiomyopathy such as cardiac sarcoidosis or cardiac manifestations of connective tissue disease. Comprehensive workup for specific aetiologies may be unrevealing except for signs of myocardial inflammation identified on cardiac positron emission tomography (PET). Here, we present five cases of such subjects and their clinical course. CASE SUMMARY: We collected clinical, imaging, pathological, and follow-up data of five subjects presenting with arrhythmias and unexplained new-onset cardiomyopathy. Mean age was 56.2 ± 5.8 years. Three subjects presented with ventricular tachycardia and two with atrial arrhythmias. Echocardiography showed a mean left ventricular ejection fraction of 37 ± 9%. Significant coronary artery disease was ruled out in all cases as the cause of the cardiomyopathy. All patients underwent cardiac magnetic resonance imaging (MRI) and PET scan at presentation and follow-up. In all patients, cardiac MRI revealed hyperenhancement in epicardial and mid-myocardial pattern in a non-coronary distribution, while PET scan revealed fluorodeoxyglucose (FDG) mismatch defects in multiple foci in a non-coronary distribution. Right ventricular biopsy was obtained in all patients and revealed interstitial fibrosis and cardiomyocyte hypertrophy. On median follow-up of 210 days, all subjects had improvement in both heart failure symptoms and arrhythmias and repeat PET in four out of five patients showed decreased inflammation. DISCUSSION: A high level of suspicion for inflammatory cardiomyopathy is needed in patients presenting with new unexplained cardiomyopathy and arrhythmias. A cardiac FDG-PET should be considered for diagnosis if cardiac inflammation is in the differential. This can inform further decisions regarding targeted immunomodulation therapy that may be helpful in this cohort.

Left atrial thrombus despite continuous direct oral anticoagulant or warfarin therapy in patients with atrial fibrillation: insights into rates and timing of thrombus resolution.

PURPOSE: Left atrial thrombus (LAT) may be detected by transesophageal echocardiography (TEE) in patients with atrial fibrillation (AF) or flutter (AFL) despite continuous anticoagulation therapy. We sought to examine the rates and timing of LAT resolution in response to changes in anticoagulation regimen. METHODS: A retrospective study of 1517 consecutive patients on ≥ 4 weeks continuous oral anticoagulation (OAC) undergoing TEE prior to either direct current cardioversion or catheter ablation for AF or AFL was performed. Patients who had LAT on index TEE imaging and had follow-up TEEs were analyzed. RESULTS: Despite ≥ 4 weeks of continuous anticoagulation therapy, 63 (4.2%) patients had LAT. Forty-four patients (median age 67 [IQR 58, 74]; 33 [75%] male; 25 [57%] on direct oral anticoagulant [DOAC]) had follow-up TEEs performed. Upon detection of LAT on index TEE, 8 patients switched from warfarin to a DOAC, 21 patients switched from a DOAC to warfarin or another DOAC, and 15 patients remained on the same OAC. Over median 4.2 months (IQR 2.9, 6.6), LAT resolution was seen in 25 (57%) patients. Of the 25 patients who had LAT resolution, 7 (28%) required TEE imaging > 6 months after index TEE to show clearance of thrombus. Rates of LAT resolution were similar between patients who had alterations in OAC and those who did not (52 vs. 60%; P = 0.601). CONCLUSIONS: After initial detection of left atrial thrombus despite uninterrupted anticoagulation for atrial fibrillation or flutter, > 40% patients have persistent clot despite additional extended anticoagulation.

Left atrial thrombus and dense spontaneous echocardiographic contrast in patients on continuous direct oral anticoagulant therapy undergoing catheter ablation of atrial fibrillation: Comparison of dabigatran, rivaroxaban, and apixaban.

BACKGROUND: Left atrial thrombus (LAT) and dense spontaneous echocardiographic contrast (SEC) detected by transesophageal echocardiography (TEE) in patients on continuous direct oral anticoagulants (DOAC) therapy before catheter ablation of atrial fibrillation (AF) or atrial flutter (AFL) have been described. OBJECTIVE: We sought to compare rates of TEE-detected LAT and dense SEC among patients taking different DOACs. METHODS: We evaluated 609 consecutive patients from 3 tertiary hospitals (median age 65 years; interquartile range 58-71 years; 436 (72%) men) who were on ≥4 weeks of continuous DOAC therapy (dabigatran, n = 166 [27%]; rivaroxaban, n = 257 [42%]; or apixaban, n = 186 [31%]) undergoing TEE before catheter ablation of AF/AFL. Demographic, clinical, and TEE data were collected for each patient. RESULTS: Despite ≥4 weeks of continuous DOAC therapy, 17 patients (2.8%) had LAT and 15 patients (2.5%) had dense SEC detected by TEE. The rates of LAT were 3.0%, 3.5%, and 1.6% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .482). The rates of dense SEC were 1.2%, 3.5%, and 2.2% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .299). Congestive heart failure (odds ratio 4.4; 95% confidence interval 1.6-12; P = .003) and moderate/severe left atrial enlargement (odds ratio 3.1; 95% confidence interval 1.1-8.6; P = .026) were independent predictors of LAT. CONCLUSION: In this study, ∼3% of patients on continuous DOAC therapy had LAT detected before catheter ablation of AF/AFL. Specific DOAC therapy did not significantly affect the rates of LAT detection.

Role of Cardiac PET in Clinical Practice.

OPINION STATEMENT: Early identification of atherosclerosis and at-risk lesions plays a critical role in reducing the burden of cardiovascular disease. While invasive coronary angiography serves as the gold standard for diagnosing coronary artery disease, non-invasive imaging techniques provide visualization of both anatomical and functional atherosclerotic processes prior to clinical presentation. The development of cardiac positron emission tomography (PET) has greatly enhanced our capability to diagnose and treat patients with early stages of atherosclerosis. Cardiac PET is a powerful, versatile non-invasive diagnostic tool with utility in the identification of high-risk plaques, myocardial perfusion defects, and viable myocardial tissue. Cardiac PET allows for comparisons of myocardial function both at time of rest and stress, providing accurate assessments of both myocardial perfusion and viability. Furthermore, novel PET techniques with unique radiotracers yield clinically relevant data on high-risk plaques in active progressive atherosclerosis. While PET exercise stress tests were previously difficult to perform given short radiotracer half-life, the development of the novel radiotracer Flurpiridaz F-18 provides a promising future for PET exercise stress imaging. In addition, hybrid imaging with computed tomography angiography (CTA) and cardiac magnetic resonance (CMR) provides integration of cardiac function and structure. In this review article, we discuss the principles of cardiac PET, the clinical applications of PET in diagnosing and prognosticating patients at risk for future cardiovascular events, compare PET with other non-invasive cardiac imaging modalities, and discuss future applications of PET in CVD evaluation and management.

Role of molecular imaging with positron emission tomographic in aortic aneurysms.

Aortic aneurysms (AA) are often asymptomatic before the occurrence of acute, potentially fatal complications including dissection and/or rupture. Beyond aortic size, the ability to assess aortic wall characteristics and processes contributing to aneurysm development may allow improved selection of patients who may benefit from prophylactic surgical intervention. Current risk stratification for aneurysms relies upon routine noninvasive imaging of aortic size without assessing the underlying pathophysiologic processes, including features such as inflammation, which may be associated with aneurysm development and progression. The use of molecular imaging modalities with positron emission tomographic (PET) scan allows characterization of aortic wall inflammatory activity. Elevated uptake of Fuorine-2-deoxy-D-glucose (FDG), a radiotracer with elevated avidity in highly-metabolic cells, has been correlated with the development and progression of both abdominal and thoracic AA in a number of animal models and clinical studies. Other novel PET radiotracers targeting matrix metalloproteinases (MMPs), mitochondrial translocator proteins (TSPO) and endothelial cell adhesion molecules are being investigated for clinical utility in identifying progression of disease in AA. By further defining the activation of molecular pathways in assessing aortic regions at risk for dilatation, this imaging modality can be integrated into future clinical decision-making models.

Cine-CMR partial voxel segmentation demonstrates increased aortic stiffness among patients with Marfan syndrome.

BACKGROUND: Standard cine-cardiac magnetic resonance (CMR) imaging is commonly used to evaluate cardiac structure, geometry and function. Prior studies have shown that automated segmentation via partial voxel interpolation (PVI) accurately quantifies phantom-based cardiac chamber volumes and necropsy left ventricular myocardial mass. Despite this, the applicability and usefulness of PVI in the determination of physiologic parameters of the aorta such as aortic stiffness has yet to be investigated. METHODS: Routine CMR was conducted with a 1.5T (GE) scanner with pulse sequences similar to that of standard CMR (parameters: TR 3.4 msec, TE 1.14 msec, flip angle 60°, temporal resolution ~30-40 msec). Views were obtained in standard cardiac-oriented longitudinal or axial views (2, 3 and 4 chambers). Within non-dilated regions of the descending thoracic aorta, aortic area was quantified via a novel PVI automated process (LV-METRIC), which discerns relative amounts of blood pool in each voxel. Aortic stiffness, as calculated from brachial artery pulse pressure and aortic area at maximal and minimal dimensions, was evaluated in 60 total segments (one segment per patient). All segments were in the descending aorta and were not aneurysmal. RESULTS: Sixty patients in total were studied, including 50 that had genetically-related aortic disorder [35 bicuspid aortic valve (BAV), 15 Marfan syndrome (MFS)]. Ten normal controls without aortic disease were included for comparison purposes. All patients (n=60) had evaluable CMR images for assessment of the descending aorta with use of automated segmentation. Patients with BAV and MFS were similar to controls in age, systolic blood pressure, brachial artery pulse pressure, smoking status or hypercholesterolemia (all P=NS). There were more women (P<0.001), lower body mass index (P=0.008), and greater height (P<0.001) in the MFS cohort compared to BAV and controls. Descending aortic area in either systole (maximal) or diastole (minimal) was similar among all three cohorts. However, change in aortic area (ΔArea) throughout the cardiac cycle was substantially lower in MFS than control subjects (P<0.001). In contrast, change in aortic area throughout the cardiac cycle was not significantly different between BAV vs. controls (P=0.62). Aortic stiffness was increased among MFS patients versus control subjects (P=0.014). When comparing MFS to BAV subjects, a comparable trend was observed (P=0.09). No statistical difference was evident in aortic stiffness in patients with BAV versus control subjects (P=0.29). CONCLUSIONS: The application of PVI to standard CMR imaging can assess abnormal descending aorta functional indices in normal caliber segments in MFS subjects. Future prospective studies with larger subject populations are warranted to further determine the overall utility of automated aortic segmentation as a possible early biomarker of aortic dysfunction before overt dilatation.

Coronary Plaque Morphology and the Anti-Inflammatory Impact of Atorvastatin: A Multicenter 18F-Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Study.

BACKGROUND: Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM. METHODS AND RESULTS: In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent 18F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation (18F-fluorodeoxyglucose uptake, expressed as target-to-background ratio) was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast-enhanced computed tomographic angiography was performed to characterize the presence of HRM (defined as noncalcified or partially calcified plaques) in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM (mean±SEM: 1.95±0.43 versus 1.67±0.32 for LMCA with versus without HRM, respectively; P=0.04). Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM (12 week-baseline Δtarget-to-background ratio [95% confidence interval]: -0.18 [-0.35 to -0.004] versus 0.09 [-0.06 to 0.26]; P=0.02). Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low-density lipoprotein and statin dose (ß=-0.27; P=0.038). CONCLUSIONS: In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00703261.

GM-CSF Enhances Macrophage Glycolytic Activity In Vitro and Improves Detection of Inflammation In Vivo.

UNLABELLED: (18)F-FDG accumulates in glycolytically active tissues and is known to concentrate in tissues that are rich in activated macrophages. In this study, we tested the hypotheses that human granulocyte-macrophage colony-stimulating factor (GM-CSF), a clinically used cytokine, increases macrophage glycolysis and deoxyglucose uptake in vitro and acutely enhances (18)F-FDG uptake within inflamed tissues such as atherosclerotic plaques in vivo. METHODS: In vitro experiments were conducted on human macrophages whereby inflammatory activation and uptake of radiolabeled 2-deoxyglucose was assessed before and after GM-CSF exposure. In vivo studies were performed on mice and New Zealand White rabbits to assess the effect of GM-CSF on (18)F-FDG uptake in normal versus inflamed arteries, using PET. RESULTS: Incubation of human macrophages with GM-CSF resulted in increased glycolysis and increased 2-deoxyglucose uptake (P < 0.05). This effect was attenuated by neutralizing antibodies against tumor necrosis factor-α or after silencing or inhibition of 6-phosphofructo-2-kinase. In vivo, in mice and in rabbits, intravenous GM-CSF administration resulted in a 70% and 73% increase (P < 0.01 for both), respectively, in arterial (18)F-FDG uptake in atherosclerotic animals but not in nonatherosclerotic controls. Histopathologic analysis demonstrated a significant correlation between in vivo (18)F-FDG uptake and macrophage staining (R = 0.75, P < 0.01). CONCLUSION: GM-CSF substantially augments glycolytic flux in vitro (via a mechanism dependent on ubiquitous type 6-phosphofructo-2-kinase and tumor necrosis factor-α) and increases (18)F-FDG uptake within inflamed atheroma in vivo. These findings demonstrate that GM-CSF can be used to enhance detection of inflammation. Further studies should explore the role of GM-CSF stimulation to enhance the detection of inflammatory foci in other disease states.

Prevalence of Left Atrial Thrombus Detection by Transesophageal Echocardiography: A Comparison of Continuous Non-Vitamin K Antagonist Oral Anticoagulant Versus Warfarin Therapy in Patients Undergoing Catheter Ablation for Atrial Fibrillation.

OBJECTIVES: The purpose of this study is to determine whether patients on ≥4 weeks of continuous non-vitamin K antagonist oral anticoagulant (NOAC) therapy require transesophageal echocardiography (TEE) before catheter ablation of atrial fibrillation (AF) or atrial flutter and to compare rates of left atrial (LA) thrombus and dense spontaneous echocardiographic contrast (SEC) in patients on NOAC versus warfarin therapy. BACKGROUND: The impact of NOAC therapy on the rates of LA thrombus detection by TEE in patients undergoing catheter ablation of AF is unknown. METHODS: Initial TEEs for 388 patients (median age, 65 years; 74% male) on ≥4 weeks of continuous NOAC (n = 183) or warfarin therapy (n = 205) undergoing catheter ablation of AF and flutter were reviewed. RESULTS: After ≥4 weeks of therapy, the prevalence of LA thrombus and LA thrombus/dense SEC among patients on NOACs was 4.4% and 6.0%, respectively, which was comparable with that of patients on warfarin. LA thrombus rates among patients on dabigatran, rivaroxaban, and apixaban were 5.4%, 4.8%, and 0%, respectively (p = 0.46). Predictors of LA thrombus were congestive heart failure (odds ratio [OR]: 5.38; 95% confidence interval [CI]: 1.79 to 16.2; p = 0.003); and persistent AF (OR: 3.27; 95% CI: 1.06 to 10.2; p = 0.040). CONCLUSIONS: Despite ≥4 weeks of anticoagulation, the rate of LA thrombus in patients on NOACs before catheter ablation of AF or atrial flutter was 4.4%. This suggests that continuous NOAC therapy does not eliminate the need for TEE before catheter ablation of AF.

Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans.

OBJECTIVES: This study sought to determine whether splenic activation after acute coronary syndrome (ACS) is linked to leukocyte proinflammatory remodeling and whether splenic activity independently predicts the risk of cardiovascular disease (CVD) events. BACKGROUND: Pre-clinical data suggest the existence of a cardiosplenic axis, wherein activation of hematopoietic tissues (notably in the spleen) results in liberation of proinflammatory leukocytes and accelerated atherosclerotic inflammation. However, it is presently unknown whether a cardiosplenic axis exists in humans and whether splenic activation relates to CVD risk. METHODS: (18)F-fluorodeoxyglucose ((18)FDG)-positron emission tomography (PET) imaging was performed in 508 individuals across 2 studies. In the first study, we performed FDG-PET imaging in 22 patients with recent ACS and 22 control subjects. FDG uptake was measured in spleen and arterial wall, whereas proinflammatory gene expression of circulating leukocytes was assessed by quantitative real-time polymerase chain reaction. In a second study, we examined the relationship between splenic tissue FDG uptake with subsequent CVD events during follow-up (median 4 years) in 464 patients who previously had undergone FDG-PET imaging. RESULTS: Splenic activity increased after ACS and was significantly associated with multiple indices of inflammation: 1) up-regulated gene expression of proinflammatory leukocytes; 2) increased C-reactive protein; and 3) increased arterial wall inflammation (FDG uptake). Moreover, in the second study, splenic activity (greater than or equal to the median) was associated with an increased risk of CVD events (hazard ratio [HR]: 3.3; 95% confidence interval [CI]: 1.5 to 7.3; p = 0.003), which remained significant after adjustment for CVD risk factors (HR: 2.26; 95% CI: 1.01 to 5.06; p = 0.04) and for arterial FDG uptake (HR: 2.68; 95% CI: 1.5 to 7.4; p = 0.02). CONCLUSIONS: Our findings demonstrate increased splenic metabolic activity after ACS and its association with proinflammatory remodeling of circulating leukocytes. Moreover, we observed that metabolic activity of the spleen independently predicted risk of subsequent CVD events. Collectively, these findings provide evidence of a cardiosplenic axis in humans similar to that shown in pre-clinical studies.

High-dose atorvastatin reduces periodontal inflammation: a novel pleiotropic effect of statins.

OBJECTIVES: The purpose of this study was to test whether high-dose statin treatment would result in a reduction in periodontal inflammation as assessed by (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT). BACKGROUND: Periodontal disease (PD) is an independent risk factor for atherosclerosis. METHODS: Eighty-three adults with risk factors or with established atherosclerosis and who were not taking high-dose statins were randomized to atorvastatin 80 mg vs. 10 mg in a multicenter, double-blind trial to evaluate the impact of atorvastatin on arterial inflammation. Subjects were evaluated using FDG-PET/CT at baseline and at 4 and 12 weeks. Arterial and periodontal tracer activity was assessed while blinded to treatment allocation, clinical characteristics, and temporal sequence. Periodontal bone loss (an index of PD severity) was evaluated using contrast-enhanced CT images while blinded to clinical and imaging data. RESULTS: Seventy-one subjects completed the study, and 59 provided periodontal images for analysis. At baseline, areas of severe PD had higher target-to-background ratio (TBR) compared with areas without severe PD (mean TBR: 3.83 [95% confidence interval (CI): 3.36 to 4.30] vs. 3.18 [95% CI: 2.91 to 3.44], p = 0.004). After 12 weeks, there was a significant reduction in periodontal inflammation in patients randomized to atorvastatin 80 mg vs. 10 mg (ΔTBR 80 mg vs. 10 mg group: mean -0.43 [95% CI: -0.83 to -0.02], p = 0.04). Between-group differences were greater in patients with higher periodontal inflammation at baseline (mean -0.74 [95% CI: -1.29 to -0.19], p = 0.01) and in patients with severe bone loss at baseline (-0.61 [95% CI: -1.16 to -0.054], p = 0.03). Furthermore, the changes in periodontal inflammation correlated with changes in carotid inflammation (R = 0.61, p < 0.001). CONCLUSIONS: High-dose atorvastatin reduces periodontal inflammation, suggesting a newly recognized effect of statins. Given the concomitant changes observed in periodontal and arterial inflammation, these data raise the possibility that a portion of that beneficial impact of statins on atherosclerosis relate to reductions in extra-arterial inflammation, for example, periodontitis. (Evaluate the Utility of 18FDG-PET as a Tool to Quantify Atherosclerotic Plaque; NCT00703261).