Feasibility and Utility of Anatomical and Physiological Evaluation of Coronary Disease With Cardiac CT in Severe Aortic Stenosis (FUTURE-AS Registry): Rationale and Design.

Background: Coronary artery disease (CAD) in patients with severe aortic stenosis (AS) is common and may be associated with worse outcomes. Computed tomography coronary angiography (CTCA) and fractional flow reserve derived from computed tomography (FFRCT) are tools for comprehensive coronary assessment. The utility and safety of CTCA and FFRCT in the work-up for transcatheter aortic valve replacement (TAVR) is not established, especially in an evolving landscape that involves younger TAVR patients. The FUTURE-AS Registry will assess the utility and safety of cardiac-optimized CTCA and FFRCT to evaluate CAD and guide referral for downstream invasive coronary angiography (ICA) in patients with severe AS being considered for TAVR. Methods: FUTURE-AS is an international, prospective, multicenter registry of patients with severe AS referred for TAVR being assessed for CAD with CTCA and FFRCT. The primary end point is the per-patient sensitivity and negative predictive value of CTCA and FFRCT for identifying anatomical and physiologically significant CAD compared to ICA and invasive FFR. The safety end point is the incidence of symptomatic hypotension or bradycardia requiring intervention following the administration of nitroglycerin or ß-blocker medications. Feasibility end points include the incidence of noninterpretable CTCA scans and CTCA scans not adequate for FFR analysis. Other utility end points include specificity, positive predictive value, and accuracy of CTCA and FFRCT. Lastly, the potential of a CTCA and FFRCT guided strategy to defer pre-TAVR ICA will be assessed. Conclusions: FUTURE-AS will characterize the utility, safety, and feasibility of CTCA and FFRCT for coronary assessment pre-TAVR.

Pathological Correlation of a Cardiac Mass with Multimodality Imaging.

Cardiac masses are rarely encountered in clinical practice and can lead to severe hemodynamic consequences. In addition to clinical cues, noninvasive modalities can play an important role in characterization of these masses and therefore their diagnosis and management planning. Here in this case report, we describe the use of various forms of noninvasive imaging techniques to narrow the differential diagnosis and form an operative plan for a cardiac mass later identified as a benign myxoma originating from the right ventricle on histological examination.

Multimodality Imaging of Constrictive Pericarditis: Pathophysiology and New Concepts.

PURPOSE OF REVIEW: The unique pathophysiological changes of constrictive pericarditis (CP) can now be identified with better imaging modalities, thereby helping in its early diagnosis. Through this review, we outline the pathophysiology of CP and its translation into symptomology and various imaging findings which then are used for both diagnosis and guiding treatment options for CP. RECENT FINDINGS: Multimodality imaging has provided us with the capability to recognize early stages of the disease and identify patients with a potential for reversibility and can be treated with medical management. Additionally, peri-procedural planning and prediction of post-operative complications has been made possible with the use of advanced imaging techniques. Advanced imaging has the potential to play a greater role in identification of patients with reversible disease process and provide peri-procedural risk stratification, thereby improving outcomes for patients with CP.

Post-COVID-19 Cardiovascular Evaluation in National Collegiate Athletic Association Division I Athletes.

OBJECTIVE: To evaluate the necessity of cardiac testing after a COVID-19 diagnosis as it relates to myocarditis in collegiate athletes. DESIGN: Cross-sectional retrospective case series. SETTING: National Collegiate Athletic Association Division I University. PATIENTS: One hundred sixty-five collegiate athletes diagnosed with COVID-19 by reverse transcriptase-polymerase chain reaction or immunoglobulin G antibody between August and December 2020 without exclusion. INTERVENTIONS: All participants underwent cardiac workup consisting of serum troponin, electrocardiogram, transthoracic echocardiogram, and cardiac magnetic resonance (CMR). All results were reviewed by team physicians and sports cardiologists. MAIN OUTCOME MEASURES: Prevalence of myocarditis and abnormality on cardiac testing after COVID-19 infection at a single institution. RESULTS: One (0.61% [95% CI, 0.02%-3.3%] asymptomatic athlete had CMR findings of an age-indeterminate myocardial injury with further cardiac testing being otherwise normal. No athlete had CMR abnormalities consistent with acute myocarditis by the modified Lake Louise Criteria. CONCLUSIONS: Occurrence of myocarditis was lower in this population compared with other studies. No student athlete was permanently disqualified from participation because of testing. A stratified, risk-based testing strategy with CMR may be more appropriate than a universal screening strategy.

Left ventricular mural thrombi with multisystem thrombosis in patients with COVID-19 and myocardial injury: a case series.

BACKGROUND: Cardiovascular and thromboembolic complications have been reported in patients with Coronavirus disease-2019 (COVID-19)-related severe respiratory distress syndrome. Although myocarditis associated with COVID-19 pneumonia has been described, evidence of left ventricular (LV) mural thrombi with other multisystem events has not been reported. CASE SUMMARY: We report two cases with severe COVID-19 pneumonia and myocardial injury with large LV thrombi and other multisystem thrombotic events. The first patient represents an unusual case of large LV apical thrombus without concordant regional wall motion abnormality and mildly reduced LV function. A subsequent inferior ST-elevation myocardial infarction (STEMI) was likely related to either an embolic event or in situ coronary thrombosis. We could not ascertain whether the acute right ventricular dysfunction was due to in situ pulmonary thrombosis or inferior STEMI. The catastrophic cerebrovascular accident was likely an embolic phenomenon. Similarly, the second patient demonstrated multiple large pedunculated thrombi occupying one-third of the LV cavity with moderately reduced LV function. A segmental pulmonary embolism was diagnosed on computed tomography chest, confirming multiple territories of in situ thrombosis. DISCUSSION: COVID-19-related inflammatory cytokine release has been linked to activation of coagulation pathways. Marked elevation of ferritin and C-reactive protein levels in both patients were consistent with evidence of a hyperinflammatory state with 'cytokine storm'. Furthermore, the finding of elevated D-dimer levels lends support to the altered coagulation cascade that plausibly explains the multisystem thrombosis observed in our patients. The direct viral endothelial involvement and subsequent endothelial dysfunction may play an important role in the development of thrombosis in different vascular beds, as seen in our patients.

Treatment with a human recombinant monoclonal IgG antibody against oxidized LDL in atherosclerosis-prone pigs reduces cathepsin S in coronary lesions.

BACKGROUND: Immunization with oxidized LDL (oxLDL) reduces atherosclerosis in rodents. We tested the hypothesis that treatment with a human recombinant monoclonal antibody against oxLDL will reduce the burden or composition of atherosclerotic lesions in hypercholesterolemic minipigs. METHODS AND RESULTS: Thirty-eight hypercholesterolemic minipigs with defective LDL receptors were injected with an oxLDL antibody or placebo weekly for 12weeks. An 18F-fluorodeoxyglucose positron emission tomography (FDG PET) scan (n=9) was performed before inclusion and after 3months of treatment. Blood samples were obtained prior to each injection. Following the last injection all animals were sacrificed, and the heart, aorta, and iliac arteries were removed. The left anterior descending coronary artery was sectioned at 5mm intervals for quantitative and qualitative assessments of atherosclerosis, including immunohistochemical phenotyping of macrophages using a pan-macrophage marker (CD68) and markers for putative pro-atherogenic (cathepsin S) and atheroprotective (CD163) macrophages. Aorta, right coronary artery, and left iliac artery were stained en face with Sudan IV and the amount of atherosclerosis quantified. There was no effect of treatment on plasma lipid profile, vascular FDG-PET signal or the amount of atherosclerosis in any of the examined arteries. However, immunostaining of coronary lesions revealed reduced cathepsin S positivity in the treated group compared with placebo (4.8% versus 8.2% of intima area, p=0.03) with no difference in CD68 or CD163 positivity. CONCLUSIONS: In hypercholesterolemic minipigs, treatment with a human recombinant monoclonal antibody against oxLDL reduced cathepsin S in coronary lesions without any effect on the burden of atherosclerosis or aortic FDG-PET signal.

The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial.

OBJECTIVES: This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques. METHODS: Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was assessed using (18)FDG-PET/CT imaging of the carotid arteries and aorta. Uptake of arterial (18)FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBR ≥ 1.6) at the baseline). RESULTS: Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (ΔTBR index: 0.10 [95% CI: -0.11, 0.30], p = 0.34; ΔTBR AS: -0.01 [-0.31, 0.28], p = 0.93) or hs-CRP (median %ΔCRP [IQR]: 33.83% [153.91] vs. 16.71% [133.45], p = 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%ΔCRP [IQR]: -17.44% [54.68] vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (ΔTBRAS = -0.24 [95% CI: -0.46, -0.01], p = 0.04). CONCLUSIONS: The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation.

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.

Kir1.1 (ROMK) and Kv7.1 (KCNQ1/KvLQT1) are essential for normal gastric acid secretion: importance of functional Kir1.1.

Potassium channels comprise the apical leak pathway supplying extracellular K(+) for exchange with protons by the gastric H(+), K(+)-ATPase and provide potential therapeutic targets for inhibiting gastric acid secretion. The Kir1.1 (ROMK) potassium channel mediates the high capacity K(+) recycling necessary for NaCl reabsorption in the thick ascending limb of the kidney, and this channel exhibits functional and regulatory characteristic well suited for K(+) recycling by gastric parietal cells. We report here that Kir1.1 channels are required for gastric acid secretion and that this channel participates with Kv7.1 (KCNQ1/KvLQT1) in the potassium recycling process. We show that Kir1.1 colocalizes with the ß-subunit of H(+), K(+)-ATPase in gastric parietal cells of Kir1.1 wild-type mice. In Kir1.1-deficient mice, gastric mucosal morphology, as well as parietal cell number, proliferation index, and ultrastructure were normal but secretagogue-stimulated gastric acid secretion in whole stomach and perfused gastric glands was absent. Luminal application of potassium-restored acid secretion in perfused gastric glands from Kir1.1-deficient as well as barium-blocked wild-type mice. In wild-type mice, both luminal Tertiapin-Q, an inhibitor of Kir1.1, as well as XE991, an inhibitor of Kv7.1, reduced proton secretion. We propose that Kir1.1 and Kv7.1 channels collaborate in potassium and current recycling across the apical pole of parietal cells.

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).

Regression of inflammation in atherosclerosis by the LXR agonist R211945: a noninvasive assessment and comparison with atorvastatin.

OBJECTIVES: The aim of this study was to noninvasively detect the anti-inflammatory properties of the novel liver X receptor agonist R211945. BACKGROUND: R211945 induces reversal cholesterol transport and modulates inflammation in atherosclerotic plaques. We aimed to characterize with (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced cardiac magnetic resonance (DCE-CMR) inflammation and neovascularization, respectively, in atherosclerotic plaques with R211945 treatment compared with atorvastatin treatment and a control. METHODS: Twenty-one atherosclerotic New Zealand white rabbits were divided into 3 groups (control, R211945 [3 mg/kg orally], and atorvastatin [3 mg/kg orally] groups). All groups underwent (18)F-FDG-PET/CT and DCE-CMR at baseline and at 1 and 3 months after treatment initiation. Concomitantly, serum metabolic parameters and histology were assessed. For statistical analysis, continuous DCE-CMR and PET/CT outcomes were modeled as linear functions of time by using a linear mixed model, whereas the histological data, animal characteristics data, and nonlinear regression imaging data were analyzed with a 2-tailed Student t test. RESULTS: (18)F-FDG-PET/CT detected a decrease in mean and maximum standard uptake values (SUV) over time in the R211945 group (both p = 0.001), indicating inflammation regression. The atorvastatin group displayed no significant change (p = 0.371 and p = 0.600, respectively), indicating no progression or regression. The control group demonstrated an increase in SUV (p = 0.01 and p = 0.04, respectively), indicating progression. There was a significant interaction between time and group for mean and maximum SUV (p = 0.0003 and p = 0.0016, respectively) . DCE-CMR detected a trend toward difference (p = 0.06) in the area under the curve in the atorvastatin group, suggesting a decrease in neovascularization. There was no significant interaction between time and group (p = 0.6350 and p = 0.8011, respectively). Macrophage and apolipoprotein B immunoreactivity decreased in the R211945 and atorvastatin groups (p < 0.0001 and p = 0.0004, respectively), and R211945 decreased oxidized phospholipid immunoreactivity (p = 0.02). CONCLUSIONS: Noninvasive imaging with (18)F-FDG-PET/CT and DCE-CMR and histological analysis demonstrated significant anti-inflammatory effects of the LXR agonist R211945 compared with atorvastatin. The results suggest a possible role for LXR agonists in the treatment of atherosclerosis.

Pioglitazone modulates vascular inflammation in atherosclerotic rabbits noninvasive assessment with FDG-PET-CT and dynamic contrast-enhanced MR imaging.

OBJECTIVES: We sought to determine the antiatherosclerotic properties of pioglitazone using multimethod noninvasive imaging techniques. BACKGROUND: Inflammation is an essential component of vulnerable or high-risk atheromas. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, possesses potent anti-inflammatory properties. We aimed to quantify noninvasively the anti-inflammatory effects of pioglitazone on atheroma using (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). METHODS: Atherosclerotic plaques were induced in the aorta of 15 New Zealand white rabbits by a combination of a hyperlipidemic diet and 2 balloon endothelial denudations. Nine rabbits continued the same diet, whereas 6 rabbits received pioglitazone (10 mg/kg orally) in addition to the diet. Twelve animals underwent (18)F-FDG-PET/CT, and 15 animals underwent DCE-MRI at baseline, 1 month, and 3 months after treatment initiation. Concomitantly, serum metabolic parameters were monitored. After imaging was completed, aortic histologic analysis and correlation analysis were performed. RESULTS: The (18)F-FDG-PET/CT imaging detected an increase in average standardized uptake value in the control group (p < 0.01), indicating progressive inflammation, whereas stable standardized uptake values were observed in the treatment group, indicating no progression. The DCE-MRI analysis detected a significant decrease in the area under the curve for the pioglitazone group (p < 0.01). Immunohistologic examination of the aortas demonstrated a significant decrease in macrophage and oxidized phospholipid immunoreactivity in the pioglitazone group (p = 0.04 and p = 0.01, respectively) with respect to control animals, underlining the imaging results. Serum metabolic parameters showed no difference between groups. Strong positive correlations between standardized uptake value and macrophage density and between area under the curve and neovessels were detected (r(2) = 0.86 and p < 0.0001, and r(2) = 0.66 and p = 0.004, respectively). CONCLUSIONS: Both (18)F-FDG-PET/CT and DCE-MRI demonstrate noninvasively the anti-inflammatory effects of pioglitazone on atheroma. Both imaging methods seem suited to monitor inflammation in atherosclerosis.

Recombinant high-density lipoprotein formulations.

High-density lipoprotein cholesterol (HDL-C) has emerged as a biomarker of residual cardiovascular disease (CVD) risk in high-risk patients treated with low-density lipoprotein cholesterol (LDL-C)-lowering therapies inclusive of inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase. The evidence for increasing low levels of HDL-C is sparse, and the available data are confounded by metabolic interactions between elevated very low-density lipoprotein (VLDL) and LDL particle concentrations. Despite these limitations, there has been widespread interest in novel strategies that target HDL. One such path has been the development of recombinant HDL formulations that mimic the pre-beta fraction of native HDL, which is the main HDL subclass that mediates cholesterol efflux from lipid-laden macrophages. Various recombinant HDL formulations (apolipoprotein A-1 [apoA-1]-bound phospholipid disks or delipidated HDL particles, mutant apoA-1 proteins, and apoA-1 mimetic peptides) have been investigated in animal studies and some human trials. However, these HDL-modifying therapies require evaluation in clinical trials of atherosclerosis and CVD events. This review presents our current knowledge on novel recombinant therapies, and their future prospects to mitigate atherosclerotic CVD events.

Monitoring of arterial wall remodelling in atherosclerotic rabbits with a magnetic resonance imaging contrast agent binding to matrix metalloproteinases.

AIMS: P947 is a gadolinium-based magnetic resonance imaging (MRI) contrast agent with high affinity for several matrix metalloproteinases (MMPs) involved in arterial wall remodelling. We tested whether the intensity of enhancement detected in vivo in the arterial wall with P947 and MRI correlates with actual tissue MMP-related enzymatic activity measured in a rabbit atherosclerotic model subjected to dietary manipulations. METHODS AND RESULTS: Aortas of 15 rabbits in which atherosclerotic lesions were induced by balloon angioplasty and 4 months of hypercholesterolaemic diet were imaged at 'baseline' with P947-enhanced MRI. Atherosclerotic rabbits were divided into three groups: five rabbits were sacrificed ('baseline' group); five rabbits continued to be fed a lipid-supplemented diet ('high-fat' group); and five rabbits were switched from atherogenic to a purified chow diet ('low-fat' group). Four months later, a second P947-enhanced MRI was acquired in the 10 remaining rabbits. A significantly lower signal was detected in the aortic wall of rabbits from the 'low-fat' group as compared with rabbits from the 'high-fat' group (21 ± 6 vs. 46 ± 3%, respectively; P = 0.04). Such differences were not detected with the contrast agent P1135, which lacks the MMP-specific peptide sequence. In addition, the intensity of aortic wall enhancement detected with MRI after injection of P947 strongly correlated with actual MMP-2 gelatinolytic activity measured in corresponding aortic segments using zymography (r = 0.87). CONCLUSION: P947-enhanced MRI can distinguish dietary-induced variations in MMP-related enzymatic activity within plaques in an experimental atherosclerotic model, supporting its utility as a clinical imaging tool for in vivo detection of arterial wall remodelling.