Eun Kyoung Kim

Mutations in DDX58, which Encodes RIG-I, Cause Atypical Singleton-Merten Syndrome

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

Cardiovascular manifestations of Takayasu arteritis and their relationship to the disease activity: analysis of 204 Korean patients at a single center.

Takayasus arteritis (TA) is primary vasculitis. Cardiac involvements in TA is due to the consequences of the vascular lesions as well as the primary pathology of the heart. The disease activity of TA is known to influence the prognosis of TA. We hypothesized that the cardiovascular involvement of TA is related to the disease activity. We evaluated the cardiovascular manifestations of TA, and we assessed their relation to the disease activity of TA. Two hundred four patients were diagnosed with TA from September, 1994 to March, 2009 according to the diagnostic criteria of the 1990 American College of Rheumatology. Their clinical features and the laboratory, angiographic and echocardiographic findings were retrospectively reviewed. The group with active disease activity was defined as satisfying one of the following criteria: i) an elevated ESR or CRP level, ii) thickened arterial wall with mural enhancement on CT or MR angiography, and iii) carotidynia at the time of the initial diagnosis. One hundred thirty nine patients (69.2%) were classified as the active group. The cardiovascular signs and symptoms were not generally different between the active and inactive groups. The active TA patients had more frequent involvement of the ascending aorta and the aortic arch and its main branches than did the inactive group. The active group showed a higher incidence of significant aortic valve regurgitation and pulmonary hypertension, and a higher level of NT-proBNP. These findings suggest that disease activity plays an important role for the cardiovascular manifestations of TA. The TA patients with higher activity have more cardiovascular morbidity compared to the TA patients with low disease activity.

Noninvasive evaluation of coronary collateral arterial flow by coronary computed tomographic angiography

Background—Coronary collateral flow is an alternative source of myocardial perfusion in patients with totally occluded coronary arteries. Clinical evaluation of collateral flow has been limited by the need of invasive measurements. We investigated whether noninvasive coronary computed tomographic angiography can evaluate the angiographic extent of coronary collateral flow. Methods and Results—We enrolled 325 coronary computed tomographic angiography cases with angiographically confirmed chronic total occlusion (median age, 63 years; men 83%). Transluminal attenuation gradient (TAG), which reflects the kinetics of contrast media in coronary artery, of an entire artery as well as of a distal vessel was assessed to evaluate the flow in entire vessel and distal vessel. TAGs were validated against visually assessed angiographic collateral connection and Rentrop grading. TAG of an entire artery increased consistently according to the angiographic extent of collateral flow (P<0.001). Well-developed collaterals, defined by highest collateral connection and Rentrop grades (n=103), could be predicted by TAG of an entire artery (cutoff, ≥−7.6 Hounsfield units/10 mm; c-statistics, 0.72; sensitivity, 65%; specificity, 73%; positive predictive value, 52%; negative predictive value, 82%). TAG of a distal vessel could discriminate the antegrade (n=143) and retrograde (n=182) flows in distal artery (cutoff, 0.0 Hounsfield unit/10 mm; c-statistics, 0.88; sensitivity, 78%; specificity, 85%; positive predictive value, 87%; negative predictive value, 75%). Conclusions—TAG, an intracoronary attenuation-based analysis of coronary computed tomographic angiography, moderately reflected the functional extent and direction of collateral flow.

Aortic diameter predicts acute type A aortic dissection in patients with Marfan syndrome but not in patients without Marfan syndrome

OBJECTIVESnAmong the parameters for surveillance of patients at risk of acute type A aortic dissection, the aortic size has been considered a cardinal factor. Preventive surgery of the aorta in asymptomatic patients on the basis of size alone is still controversial in patient populations lacking other risk factors for aortic dissection. The aim of the present study was to assess the value of the aortic diameter as a current criterion for elective aortic surgery to prevent the development of aortic dissection in patients without and with Marfan syndrome (MFS).nnnMETHODSnWe reviewed the data from patients diagnosed with acute type A aortic dissection from December 1994 to March 2009 at our institute. A total of 237 patients who presented with acute type A aortic dissection were enrolled, of whom 31 were diagnosed with MFS.nnnRESULTSnThe maximal ascending aorta size was 46.7 mm (range, 42.9-51.6) in non-MFS patients and 58.5 mm (range, 43.8-64.9) in MFS patients (Pxa0<xa0.001). Two thirds (74%) of the MFS patients had a maximal aortic root size of ≥45 mm. However, 87% of the 206 non-MFS patients had an aortic diameter <55 mm. Non-MFS patients presenting with an aortic size <55 mm developed aortic dissection at a younger age and had a higher body mass index than those with an aortic size ≥55 mm.nnnCONCLUSIONSnType A aortic dissection occurs in smaller aortas in non-MFS patients compared with those with MFS.

Peripheral Artery Disease in Korean Patients Undergoing Percutaneous Coronary Intervention: Prevalence and Association with Coronary Artery Disease Severity

Peripheral artery disease (PAD) is an important marker for the risk stratification of patients with coronary artery disease (CAD). We investigated the prevalence of PAD in patients undergoing percutaneous coronary intervention (PCI) with CAD and the relationship between ankle-brachial pressure index (ABPI) and CAD severity. A total of 711 patients undergoing PCI for CAD from August 2009 to August 2011 were enrolled. PAD diagnosis was made using the ABPI. The prevalence of PAD was 12.8%. In PAD patients, mean values of right and left ABPI were 0.71 ± 0.15 and 0.73 ± 0.15. Patients with PAD had a higher prevalence of left main coronary disease (14.3% vs 5.8%, P = 0.003), more frequently had multivessel lesions (74.9% vs 52.1%, P < 0.001) and had higher SYNTAX score (18.2 ± 12.3 vs 13.1 ± 8.26, P = 0.002). Using multivariate analysis, we determined that left main CAD (OR, 2.954; 95% CI, 1.418-6.152, P = 0.004) and multivessel CAD (OR, 2.321; 95% CI, 1.363-3.953, P = 0.002) were both independently associated with PAD. We recommend that ABPI-based PAD screening should be implemented in all patients undergoing PCI with CAD, especially in severe cases.

A protective role of early collateral blood flow in patients with ST-segment elevation myocardial infarction

UNLABELLEDnConflict persists regarding whether the presence of early collateral blood flow to the infarct-related artery has an effective role in reducing infarct size and improving myocardial salvage in patients with ST-segment elevation myocardial infarction (STEMI). We sought to investigate the impact of the collateral circulation on myocardial salvage and infarct size in STEMI patients.nnnMETHODSnIn 306 patients who were diagnosed with STEMI and underwent cardiac magnetic resonance within 1 week after revascularization, initial collateral flow to the infarct-related artery was assessed by coronary angiography. Using cardiac magnetic resonance imaging, myocardial infarct size and salvage were measured.nnnRESULTSnAmong 247 patients with preprocedural Thrombolysis in Myocardial Infarction flow 0/1, 54 (22%) patients had good collaterals (Rentrop grade ≥ 2, Collateral Connection Score ≥ 2). Infarct size and area at risk were significantly smaller in patients with good collaterals than those with poor collaterals (infarct size: 17.1 ± 10.1 %LV vs 21.8 ± 10.5 %LV, P = .003, area at risk: 33.8 ± 16.8 %LV vs 38.8 ± 15.5 %LV, P = .039). There was a significant difference of myocardial salvage index between 2 groups (50.9% ± 15.0% vs 43.8% ± 18.5%, P = .005). Poor collateralization was an independent predictor for large infarct size (odd ratio 2.48 [1.28-4.80], P = .007).nnnCONCLUSIONSnIn patients with STEMI, the presence of well-developed collaterals to occluded coronary artery from the noninfarct vessel and its extent were independently associated with reduced infarct burden and improved myocardial salvage. Our results help explain why MI patients with well-developed collateralization have reduced mortality and morbidity.

Clinical Features of Right-Sided Infective Endocarditis Occurring in Non-Drug Users

Right-sided infective endocarditis (RIE) occurs predominantly in intravenous drug users in western countries, and it has a relatively good prognosis. Clinical features and prognosis of RIE occurring in non-drug users are not well known. We investigated the clinical findings of RIE in non-drug users. We retrospectively reviewed 345 cases diagnosed with IE. Cases with RIE or left-sided infective endocarditis (LIE) defined by the vegetation site were included and cases having no vegetation or both-side vegetation were excluded. Clinical findings and in-hospital outcome of RIE were compared to those of LIE. Among the 245 cases, 39 (16%) cases had RIE and 206 (84%) cases had LIE. RIE patients were younger (40±19 yr vs 50±18 yr, P=0.004), and had a higher incidence of congenital heart disease (CHD) (36% vs 13%, P<0.001) and central venous catheter (CVC) (21% vs 4%, P=0.001) compared to LIE patients. A large vegetation was more common in RIE (33% vs 9%, P<0.001). Staphylococcus aureus was the most common cause of RIE, while Streptococcus viridans were the most common cause of LIE. In-hospital mortality and cardiac surgery were not different between the two groups. CHD and use of CVC were common in non-drug users with RIE. The short-term clinical outcome of RIE is not different from that of LIE. Graphical Abstract

Noninvasive Discrimination of Coronary Chronic Total Occlusion and Subtotal Occlusion by Coronary Computed Tomography Angiography.

OBJECTIVESnThe aim of this study was to investigate whether noninvasive discrimination of chronic total occlusion (CTO), a complete interruption of coronary artery flow, and subtotal occlusion (STO), a functional total occlusion, is feasible using coronary computed tomography angiography (CTA).nnnBACKGROUNDnCTO and STO may be different in pathophysiology and clinical treatment strategy.nnnMETHODSnWe included 486 consecutive patients (median age 63 years, 82% male) who showed a total of 553 completely occluded coronary arteries in coronary CTA. The length of occlusion, side branches, shape of proximal stump, and collateral vessels were measured as anatomical findings. Transluminal attenuation gradient, which reflects intraluminal contrast kinetics and functional extent of collateral flow, was measured as a physiological surrogate. All patients were followed by invasive coronary angiography.nnnRESULTSnCoronary arteries with CTO showed longer occlusion length (cutoff ≥ 15 mm), higher distal transluminal attenuation gradient (cutoff ≥-0.9 Hounsfield units [HU]/10 mm), more frequent side branches, blunted stump, cross-sectional calcification ≥ 50%, and collateral vessels compared with arteries with STO (p < 0.001, all). The combination of these findings could distinguish CTO from STO (c-statistics = 0.88 [95% confidence interval: 0.94 to 0.90], sensitivity 83%, specificity 77%, positive predictive value 55%, negative predictive value 93%; p < 0.001). Percutaneous coronary intervention (PCI) was attempted in 342 arteries and was successful in 279 arteries (82%). The computed tomography findings could predict the unsuccessful PCI (c-statistics = 0.70 [95% confidence interval: 0.65 to 0.75], sensitivity 63%, specificity 73%, positive predictive value 91%, negative predictive value 31%; p < 0.001).nnnCONCLUSIONSnNoninvasive coronary CTA could discern CTO from STO, and also could predict the success of attempted PCI.

Long-term effects of ischemic postconditioning on clinical outcomes: 1-year follow-up of the POST randomized trial

BACKGROUNDnIn the Effects of Postconditioning on Myocardial Reperfusion in Patients with ST-segment Elevation Myocardial Infarction (POST) trial, ischemic postconditioning failed to improve myocardial reperfusion. However, long-term effects of ischemic postconditioning on clinical outcomes are not known in patients with ST-segment elevation myocardial infarction.nnnMETHODSnA total of 700 patients undergoing primary percutaneous coronary intervention (PCI) were randomly assigned to the postconditioning group or the conventional primary PCI group in a 1:1 ratio. Postconditioning was performed immediately after restoration of coronary flow by balloon occlusion 4 times for 1 minute. Complete follow-up data for major clinical events at 1 year were available in 695 patients (99.3%), and analyses were done by the intention to treat principle. The primary outcome was a composite of death, myocardial infarction, severe heart failure, or stent thrombosis at 1 year.nnnRESULTSnAt 1 year, a composite of death, myocardial infarction, severe heart failure, or stent thrombosis occurred in 21 patients (6.1%) in the postconditioning group and 16 patients (4.6%) in the conventional PCI group (hazard ratio [HR] 1.32, 95% CI 0.69-2.53, P = .40). The risk of death (4.9% vs 3.7%, HR 1.32, 95% CI 0.64-2.71, P = .46), heart failure (2.6% vs 2.3%, HR 1.13, 95% CI 0.44-2.94, P = .80), and stent thrombosis (2.3% vs 1.7%, HR 1.34, 95% CI 0.46-3.85, P = .59) did not differ significantly between the 2 groups.nnnCONCLUSIONSnIschemic postconditioning does not seem to improve the 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction undergoing primary PCI.

Ischemic Postconditioning during Primary Percutaneous Coronary Intervention: The POST Randomized Trial

Background— Ischemic postconditioning has been reported to reduce infarct size in patients with ST-segment–elevation myocardial infarction. However, cardioprotective effects of postconditioning have not been demonstrated in a large-scale trial. Methods and Results— We performed a multicenter, prospective, randomized, open-label, blinded end-point trial. A total of 700 patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment–elevation myocardial infarction within 12 hours after symptom onset were randomly assigned to the postconditioning group or to the conventional primary PCI group in a 1:1 ratio. Postconditioning was performed immediately after restoration of coronary flow as follows: The angioplasty balloon was positioned at the culprit lesion and inflated 4 times for 1 minute with low-pressure (<6 atm) inflations, each separated by 1 minute of deflation. The primary end point was complete ST-segment resolution (percentage resolution of ST-segment elevation >70%) measured at 30 minutes after PCI. Complete ST-segment resolution occurred in 40.5% of patients in the postconditioning group and 41.5% of patients in the conventional PCI group (absolute difference, −1.0%; 95% confidence interval, −8.4 to 6.4; P=0.79). The rate of myocardial blush grade of 0 or 1 and the rate of major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) at 30 days did not differ significantly between the postconditioning group and the conventional PCI group (17.2% versus 22.4% [P=0.20] and 4.3% versus 3.7% [P=0.70], respectively). Conclusion— Ischemic postconditioning did not improve myocardial reperfusion in patients with ST-segment–elevation myocardial infarction undergoing primary PCI with current standard practice. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00942500.Background —Ischemic postconditioning has been reported to reduce infarct size in patients with ST-segment elevation myocardial infarction (STEMI). However, cardioprotective effects of postconditioning have not been demonstrated in a large-scale trial. nnMethods and Results —We performed a multicenter, prospective, randomized, open-label, blinded endpoint trial. A total of 700 patients undergoing primary percutaneous coronary intervention (PCI) for STEMI within 12 hours after symptom onset were randomly assigned to the postconditioning group or the conventional primary PCI group in a 1:1 ratio. Postconditioning was performed immediately after restoration of coronary flow as follows: the angioplasty balloon was positioned at the culprit lesion, and inflated 4 times for 1 minute with low-pressure ( 70%) measured at 30 minutes after PCI. Complete ST-segment resolution occurred in 40.5% of patients in the postconditioning group and 41.5% of patients in the conventional PCI group (absolute difference, -1.0%; 95% confidence interval, -8.4% to 6.4%; P =0.79). The rate of myocardial blush grade of 0 or 1 and the major adverse cardiac events (a composite of death, myocardial infarction, severe heart failure, or stent thrombosis) at 30 days did not differ significantly between the postconditioning group and the conventional PCI group (17.2% versus 22.4%, P =0.20, and 4.3% versus 3.7%, P =0.70, respectively). nnConclusions —Ischemic postconditioning did not improve myocardial reperfusion in patients with STEMI undergoing primary PCI with current standard practice. nnClinical Trial Registration Information —http://ClinicalTrials.gov. Identifier: [NCT00942500][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00942500&atom=%2Fcirculationaha%2Fearly%2F2013%2F09%2F25%2FCIRCULATIONAHA.113.001690.atom