The combination of CTA and perfusion correctly identifies patients with flow limiting CAD defined as ≥50 stenosis by ICA causing a perfusion defect by SPECT/MPI.

The role of cytokines in the pathogenesis of cardiovascular disease is increasingly evident since the identification of immune/inflammatory mechanisms in atherosclerosis and heart failure. In this review, we describe how innate and adaptive immune cascades trigger the release of cytokines and chemokines, resulting in the initiation and progression of atherosclerosis. We discuss how cytokines have direct and indirect effects on myocardial function. These include myocardial depressant effects of nitric oxide (NO) synthase-generated NO, as well as the biochemical effects of cytokine-stimulated arachidonic acid metabolites on cardiomyocytes. Cytokine influences on myocardial function are time-, concentration-, and subtype-specific. We provide a comprehensive review of these cytokine-mediated immune and inflammatory cascades implicated in the most common forms of cardiovascular disease.

BackgroundObesity and its association with reduced life expectancy are well established, with cardiovascular disease as one of the major causes of fatality. Metabolic surgery is a powerful intervention for severe obesity, resulting in improvement in comorbid diseases and in cardiovascular risk factors. This study investigates the relationship between metabolic surgery and long‐term cardiovascular events.Methods and ResultsA cohort of Roux‐en‐Y gastric bypass surgery (RYGB) patients was tightly matched by age, body mass index, sex, Framingham Risk Score, smoking history, use of antihypertension medication, diabetes mellitus status, and calendar year with a concurrent cohort of nonoperated control patients. The primary study end points of major cardiovascular events (myocardial infarction, stroke, and congestive heart failure) were evaluated using Cox regression. Secondary end points of longitudinal cardiovascular risk factors were evaluated using repeated‐measures regression. The RYGB and matched controls (N=1724 in each cohort) were followed for up to 12 years after surgery (overall median of 6.3 years). Kaplan–Meier analysis revealed a statistically significant reduction in incident major composite cardiovascular events (P=0.017) and congestive heart failure (0.0077) for the RYGB cohort. Adjusted Cox regression models confirmed the reductions in severe composite cardiovascular events in the RYGB cohort (hazard ratio=0.58, 95% CI=0.42–0.82). Improvements of cardiovascular risk factors (eg, 10‐year cardiovascular risk score, total cholesterol, high‐density lipoprotein, systolic blood pressure, and diabetes mellitus) were observed within the RYGB cohort after surgery.ConclusionsGastric bypass is associated with a reduced risk of major cardiovascular events and the development of congestive heart failure.

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Purpose Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained. Methods 30,716 individuals underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes. Results 18 subjects had pLOF variants; none had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram (ECG), one had a minor diagnostic criterion, 13 were normal. 184 subjects had VUSs; none had an ARVC diagnosis. In subjects with VUSs, there was no difference in the proportion with major (4%) or minor (13%) ECG diagnostic criteria compared to variant-negative controls. ICD-9 codes showed no difference in defibrillator utilization, electrophysiologic abnormalities or non-ischemic cardiomyopathies in patients with pLOF or VUSs compared to controls. Conclusion pLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.

Purpose:To compare the diagnostic performance of myocardial computed tomographic (CT) perfusion imaging and single photon emission computed tomography (SPECT) perfusion imaging in the diagnosis of anatomically significant coronary artery disease (CAD) as depicted at invasive coronary angiography. Materials and Methods:This study was approved by the institutional review board. Written informed consent was obtained from all patients. Sixteen centers enrolled 381 patients from November 2009 to July 2011. Patients underwent rest and adenosine stress CT perfusion imaging and rest and either exercise or pharmacologic stress SPECT before and within 60 days of coronary angiography. Images from CT perfusion imaging, SPECT, and coronary angiography were interpreted at blinded, independent core laboratories. The primary diagnostic parameter was the area under the receiver operating characteristic curve (A z ). Sensitivity and specificity were calculated with use of prespecified cutoffs.The reference standard was a stenosis of at least 50% at coronary angiography as determined with quantitative methods. Results:CAD was diagnosed in 229 of the 381 patients (60%). The per-patient sensitivity and specificity for the diagnosis of CAD (stenosis 50%) were 88% (202 of 229 patients) and 55% (83 of 152 patients), respectively, for CT perfusion imaging and 62% (143 of 229 patients) and 67% (102 of 152 patients) for SPECT, with A z values of 0.78 (95% confidence interval: 0.74, 0.82) and 0.69 (95% confidence interval: 0.64, 0.74) (P = .001). The sensitivity of CT perfusion imaging for single-and multivessel CAD was higher than that of SPECT, with sensitivities for left main, threevessel, two-vessel, and one-vessel disease of 92%, 92%, 89%, and 83%, respectively, for CT perfusion imaging and 75%, 79%, 68%, and 41%, respectively, for SPECT. Conclusion:The overall performance of myocardial CT perfusion imaging in the diagnosis of anatomic CAD (stenosis 50%), as demonstrated with the A z , was higher than that of SPECT and was driven in part by the higher sensitivity for left main and multivessel disease.q RSNA, 2014

Endothelial dysfunction, including endothelial hyporesponsiveness to prototypical angiogenic growth factors and eNOS agonists, underlies vascular pathology in many dysmetabolic states. We investigated effects of a saturated free fatty acid, palmitic acid (PA), on endothelial cell responses to VEGF. PA-pretreated endothelial cells had markedly diminished Akt, eNOS, and ERK activation responses to VEGF, despite normal VEGFR2 phosphorylation. PA inhibited VEGF-induced angiogenic cord formation in Matrigel, and PA-treated endothelial cells accumulated early species (C16) ceramide. The serine palmitoyltransferase inhibitor myriocin reversed these defects. Protein phosphatase 2A (PP2A) became more eNOS-associated in PA-treated cells; the PP2A inhibitor okadaic acid reversed PA-induced signaling defects. Mice fed a diet high in saturated fat for 2 to 3 weeks had impaired i) aortic Akt and eNOS phosphorylation to infused VEGF, ii) ear angiogenic responses to intradermal adenoviral-VEGF injection, and iii) vascular flow recovery to hindlimb ischemia as indicated by laser Doppler and αVβ3 SPECT imaging. High-fat feeding did not impair VEGF-induced signaling or angiogenic responses in mice with reduced serine palmitoyltransferase expression. Thus, de novo ceramide synthesis is required for these detrimental PA effects. The findings demonstrate an endothelial VEGF resistance mechanism conferred by PA, which comprises ceramide-induced, PP2A-mediated dephosphorylation of critical activation sites on enzymes central to vascular homeostasis and angiogenesis. This study defines potential molecular targets for preservation of endothelial function in metabolic syndrome.

A ppropriate clinical decisions concerning diagnosis and treatment of coronary artery disease rely on the correct integration of data on coronary anatomy and myocardial perfusion.1 Revascularization of coronary stenosis is only justified if it relieves angina complaints and improves patient outcome, which depends on the extent and severity of inducible myocardial ischemia related to the lesion. 2-5 Clinical Perspective on p 595In clinical practice, conventional coronary angiography (CCA) and single-photon emission tomography myocardial perfusion imaging (single-photon emission computed tomography [SPECT]) are the standard imaging methods for detection and quantification of coronary artery stenosis and myocardial perfusion defects. To define a treatment strategy, physicians must mentally create a correlation map, merging the anatomical data from CCA, a projection-imaging method, with the functional data from SPECT, a mix of projection and tomographic imaging methods, overcoming image foreshortening, differences on image-acquisition times, and differences in spatial and temporal resolution between the methods.Myocardial perfusion defects have also been assigned to vascular territories using left ventricular segmentation models. [6][7][8] This approach is usually applied in research settings, where standardization between different imaging methods is attempted. However, standard assumptions about the vascular territory distribution in myocardial perfusion analysis are frequently inaccurate because of morphologic variability in the Background-Appropriate clinical decisions concerning diagnosis and treatment of coronary artery disease rely on correct integration of data on coronary anatomy and myocardial perfusion. The purpose of this article is to introduce a new left ventricular segmentation model for improved alignment of coronary arterial segments and myocardial perfusion territories, designed for the CORE320 study. Methods and Results-CORE320 is a prospective, multicenter study with a primary objective to evaluate the diagnostic accuracy of 320-row detector computed tomography (CT) to detect coronary artery luminal stenosis and corresponding myocardial perfusion deficits in patients with suspected coronary artery disease compared with the gold standard of conventional coronary angiography and single-photon emission CT myocardial perfusion imaging. We describe a 19-coronary segment and 13-myocardial territory alignment model, its application in both standard and CT image data sets, and the adjudication process of the initial cohort of patients recruited for the CORE320 study. Adjudication committees reviewed the images of the first 101 gold standard and 107 CT data sets. On the basis of the presented model and rules, all cases for adjudication were correctly identified. During image review, 6 (5.9%) gold standard and 9 (8.4%) CT data sets needed further realignment not triggered by the algorithm. Conclusions-We present a vascular territory distribution model developed for the CORE320 multicenter study, which acco...