Doyeon Hwang

Coronary Flow Reserve and Microcirculatory Resistance in Patients With Intermediate Coronary Stenosis.

BACKGROUND The prognostic impact of microvascular status in patients with high fractional flow reserve (FFR) is not clear. OBJECTIVES The goal of this study was to investigate the implications of coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients who underwent FFR measurement. METHODS Patients with high FFR (>0.80) were grouped according to CFR (≤2) and IMR (≥23 U) levels: group A, high CFR with low IMR; group B, high CFR with high IMR; group C, low CFR with low IMR; and group D, low CFR with high IMR. Patient-oriented composite outcome (POCO) of any death, myocardial infarction, and revascularization was assessed. The median follow-up was 658 days (interquartile range: 503.8 to 1,139.3 days). RESULTS A total of 313 patients (663 vessels) were assessed with FFR, CFR, and IMR. Correlation (r = 0.201; p < 0.001) and categorical agreement (kappa value = 0.178; p < 0.001) between FFR and CFR were modest. Low CFR was associated with higher POCO than high CFR (p = 0.034). There were no significant differences in clinical and angiographic characteristics among groups. Patients with high IMR with low CFR had the highest POCO (p = 0.002). Overt microvascular disease (p = 0.008), multivessel disease (p = 0.033), and diabetes mellitus (p = 0.033) were independent predictors of POCO. Inclusion of a physiological index significantly improved the discriminant function of a predictive model (relative integrated discrimination improvement 0.467 [p = 0.037]; category-free net reclassification index 0.648 [p = 0.007]). CONCLUSIONS CFR and IMR improved the risk stratification of patients with high FFR. Low CFR with high IMR was associated with poor prognosis. (Clinical, Physiological and Prognostic Implication of Microvascular Status; NCT02186093).

Integrated Myocardial Perfusion Imaging Diagnostics Improve Detection of Functionally Significant Coronary Artery Stenosis by 13N-ammonia Positron Emission Tomography

Background—Recent evidence suggests that the diagnostic accuracy of myocardial perfusion imaging is improved by quantifying stress myocardial blood flow (MBF) in absolute terms. We evaluated a comprehensive quantitative 13N-ammonia positron emission tomography (13NH3-PET) diagnostic panel, including stress MBF, coronary flow reserve (CFR), and relative flow reserve (RFR) in conjunction with relative perfusion defect (PD) assessments to better detect functionally significant coronary artery stenosis. Methods and Results—A total of 130 patients (307 vessels) with coronary artery disease underwent both 13NH3-PET and invasive coronary angiography with fractional flow reserve (FFR) measurement. Diagnostic accuracy, optimal cut points, and discrimination indices of respective 13NH3-PET quantitative measures were compared, with FFR as standard reference. The capacity to discern disease with stepwise addition of stress MBF, CFR, and RFR to qualitatively assessed relative PD was also gauged, using the category-free net reclassification index. All quantitative measures showed significant correlation with FFR (PET-derived CFR, r=0.388; stress MBF, r=0.496; and RFR, r=0.780; all P<0.001). Optimal respective cut points for FFR ⩽0.8 and ⩽0.75 were 1.99 and 1.84 mL/min per g for stress MBF and 2.12 and 2.00 for PET-derived CFR. Discrimination indices of quantitative measures that correlated with FFR ⩽0.8 were all significantly higher than that of relative PD (area under the curve: 0.626, 0.730, 0.806, and 0.897 for relative PD, CFR, stress MBF, and RFR, respectively; overall comparison P<0.001). The capacity for functionally significant coronary stenosis was incrementally improved by the successive addition of CFR (net reclassification index=0.629), stress MBF (net reclassification index=0.950), and RFR (net reclassification index=1.253; all P<0.001) to relative PD. Conclusions—Integrating quantitative 13NH3-PET measures with qualitative myocardial perfusion assessment provides superior diagnostic accuracy and improves the capacity to detect functionally significant coronary artery stenosis. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifiers: NCT01621438 and NCT01366404.

PhoB-dependent transcriptional activation of the iciA gene during starvation for phosphate in Escherichia coli

Abstract The IciA protein from Escherichia coli has been shown specifically to inhibit the in vitro initiation of chromosomal DNA replication. However, the in vivo role of IciA has not yet been established. In order to investigate the in vivo function of this protein, expression of the iciA gene was studied by monitoring the β-galactosidase activity specified by an iciA promoter-lacZ fusion inserted into the chromosome. Among the conditions tested (carbon starvation, the stringent response, phosphate starvation, and the SOS response), only phosphate depletion increased iciA expression. Supplementation of phosphate-depleted cultures with inorganic phosphate reduced the β-galactosidase activity to basal levels. Enhanced expression of iciA-lacZ was dependent upon the PhoB protein. PhoB is known to be a transcriptional activator of the Pho regulon, expression of which is activated during phosphate starvation. It was also found that the iciA promoter contains a PhoB protein-binding sequence, termed the Pho box, which is necessary for the activation of genes of the Pho regulon. These results suggest that the iciA gene is a member of the Pho regulon.

Clinical implications of three-vessel fractional flow reserve measurement in patients with coronary artery disease

Aims There are limited data on the clinical implications of total physiologic atherosclerotic burden assessed by invasive physiologic studies in patients with coronary artery disease. We investigated the prognostic implications of total physiologic atherosclerotic burden assessed by total sum of fractional flow reserve (FFR) in three vessels (3V-FFR). Methods and results A total of 1136 patients underwent FFR measurement in three vessels (3V FFR-FRIENDS study, NCT01621438). The patients were classified into high and low 3V-FFR groups according to the median value of 3V-FFR (2.72). The primary endpoint was major adverse cardiac events (MACE, a composite of cardiac death, myocardial infarction and ischaemia-driven revascularization) at 2 years. Mean angiographic percent diameter stenosis and FFR were 43.7 ± 19.3% and 0.90 ± 0.08, respectively. There was a negative correlation between 3V-FFR and estimated 2-year MACE rate (P < 0.001). The patients in low 3V-FFR group showed a higher risk of 2-year MACE than those in the high 3V-FFR group [(7.1% vs. 3.8%, hazard ratio (HR) 2.205, 95% confidence interval (CI) 1.201-4.048, P = 0.011]. The higher 2-year MACE rate was mainly driven by the higher rate of ischaemia-driven revascularization in the low 3V-FFR group (6.2% vs. 2.7%, HR 2.568, 95% CI 1.283-5.140, P = 0.008). In a multivariable adjusted model, low 3V-FFR was an independent predictor of MACE (HR 2.031, 95% CI 1.078-3.830, P = 0.029). Conclusion Patients with high total physiologic atherosclerotic burden assessed by 3V-FFR showed higher risk of 2-year clinical events than those with low total physiologic atherosclerotic burden. The difference was mainly driven by ischaemia-driven revascularization for both functionally significant and insignificant lesions at baseline. Three-vessel FFR might be used as a prognostic indicator in patients with coronary artery disease. Clinical trial registration 3V FFR-FRIENDS study (https://clinicaltrials.gov/ct2/show/NCT01621438, NCT01621438).

Chronic Kidney Disease in the Second-Generation Drug-Eluting Stent Era : Pooled Analysis of the Korean Multicenter Drug-Eluting Stent Registry

OBJECTIVES The purpose of this study was to evaluate the clinical impact of chronic kidney disease (CKD) on clinical outcomes in contemporary practice of percutaneous coronary intervention (PCI) using second-generation drug-eluting stents (DES). BACKGROUND Although second-generation DES have improved the safety and efficacy issues in PCI, data regarding the performance of second-generation DES in patients with CKD are still limited. METHODS We performed a patient-level pooled analysis on 12,426 patients undergoing PCI using second-generation DES from the Korean Multicenter Drug-Eluting Stent Registry. Endpoints were stent-oriented outcomes (target lesion failure [TLF]) and patient-oriented composite outcomes (POCO) during a median follow-up of 35 months. CKD patients were stratified by the estimated glomerular filtration rate (eGFR) from mild CKD to end-stage renal disease patients, and by the coexistence of diabetes mellitus (DM). RESULTS A total of 2,927 patients had CKD (23.6%), who showed a significantly higher risk of TLF (adjusted hazard ratio [HRadjust]: 1.50; 95% confidence interval [CI]: 1.21 to 1.86) and POCO (HRadjust 1.34; 95% CI: 1.17 to 1.55) compared to patients with preserved renal function. Stratified analysis by eGFR showed that TLF was not increased in the mild to moderate CKD, whereas severe CKD and dialysis-dependent patients showed significantly higher risk of TLF (HRadjust 2.44; 95% CI: 1.54 to 3.86; HRadjust 3.58; 95% CI: 2.52 to 5.08, respectively). The eGFR threshold of increased clinical events was 40 to 45 ml/min/1.73 m2. Among CKD patients, DM CKD patients showed a higher incidence of TLF compared to non-DM CKD patients (HRadjust: 1.82; 95% CI: 1.32 to 2.52), driven by the increase in target vessel-related events. CONCLUSIONS In the era of second-generation DES, CKD patients were at a significantly higher risk of clinical outcomes only in severe CKD and end-stage renal disease patients.

Incremental Prognostic Value of Brachial-Ankle Pulse Wave Velocity to Single-Photon Emission Computed Tomography in Patients with Suspected Coronary Artery Disease.

AIM Arterial stiffness assessed by brachial-ankle pulse wave velocity (baPWV) is predictive of cardiovascular events. This study was designed to investigate whether baPWV has an additional prognostic value to single-photon emission computed tomography (SPECT) in patients with suspected coronary artery disease (CAD). METHODS A total of 350 subjects (age, 66.2 ± 10.5 years, 53.4% male) with suspected CAD undergoing myocardial SPECT and baPWV within 30 days were retrospectively analyzed. Cardiovascular events, including cardiovascular death, acute coronary syndrome and ischemic stroke, were assessed. Both fixed and reversible perfusion defects on SPECT were considered abnormal myocardial perfusion imaging (MPI) findings. RESULTS During the median follow-up period of 441 days (interquartile range 169-719 days), cardiovascular events occurred in 21 patients (6.0%). In multivariable Cox regression analysis, abnormal MPI [hazard ratio (HR), 2.67; 95% confidence interval (CI), 1.21-10.37; p=0.024] and high baPWV (≥ 1,790 cm/s) (HR, 2.03; 95% CI, 1.08-6.38; p=0.007) were independent predictors of clinical events even after adjusting for possible confounders. Also, high baPWV had an incremental prognostic value to traditional risk factors and abnormal MPI in predicting cardiovascular events (overall Chi-square, from 24.08 to 27.42; p ＜ 0.001). Kaplan-Meier survival curves stratified by baPWV and MPI proved significantly improved prediction of cardiovascular events (log-rank p=0.001). CONCLUSIONS baPWV has an incremental prognostic value to traditional risk factors and MPI. Therefore, baPWV can be used to identify subjects at higher risk of cardiovascular events in patients undergoing SPECT.

Comparison of outcomes after treatment of in-stent restenosis using newer generation drug-eluting stents versus drug-eluting balloon: Patient-level pooled analysis of Korean Multicenter in-Stent Restenosis Registry

BACKGROUND Studies comparing the drug-eluting balloon (DEB) with contemporary drug-eluting stent (DES) in the treatment of in-stent restenosis (ISR) have been scarce. We compared that the efficacy and safety of contemporary DES versus DEB in unselected, real world patients of ISR occurred in bare-metal stent or DES. METHODS Patient-level pooled analysis from nationwide multicenter registries was performed with 628 consecutive patients who underwent ISR treatment using 2nd or 3rd generation DES or DEB. Target lesion failure (TLF) and patient-oriented composite outcomes (POCO, composite of all-cause mortality, all-cause myocardial infarction, or any revascularization) at 1-year follow-up were compared between the DES and DEB groups. RESULTS A total of 628 patients with 697 ISR lesions were treated using newer generation DES (n=409) or DEB (n=219). About 55.1% presented with acute coronary syndrome, and 15.1% showed left ventricular dysfunction. The risks of TLF and POCO were significantly lower in the DES group, even after being adjusted by an inverse probability weighted model (TLF, 9.2% vs. 17.9%, HRadjust 0.22, 95% CI 0.11-0.47; POCO, 12.4% vs. 24.1%, HRadjust 0.25, 95% CI 0.13-0.48, all p-values<0.001), mainly driven by the significantly lower risk of target lesion revascularization (TLR) (7.6% vs. 13.0%, HRadjust 0.21, 95% CI 0.09-0.49, p<0.001). Treatment of ISR with DEB independently predicted TLF (HR 1.87, 95% CI 1.05-3.02, p=0.034) along with multi-vessel disease, chronic kidney disease, type B2 or C lesion, and number of treated lesion>1. CONCLUSIONS In unselected patients of ISR, clinical outcome at one year was mainly dependent on difference in TLR and found to be better with contemporary DES than DEB.

Clinical Relevance of 18F-Sodium Fluoride Positron-Emission Tomography in Noninvasive Identification of High-Risk Plaque in Patients With Coronary Artery DiseaseCLINICAL PERSPECTIVE

Background— 18F-sodium fluoride (18F-NaF) positron-emission tomography has been introduced as a potential noninvasive imaging tool to identify plaques with high-risk characteristics in patients with coronary artery disease. We sought to evaluate the clinical relevance of 18F-NaF uptake using optical coherence tomography (OCT), intravascular ultrasound (IVUS), and coronary computed tomography angiography in patients with coronary artery disease. Methods and Results— The target population consisted of 51 prospectively enrolled patients (93 stenoses) who underwent 18F-NaF positron-emission tomography before invasive coronary angiography. 18F-NaF uptake was compared with IVUS- and OCT-derived plaque characteristics. In the coronary computed tomography angiography subgroup (46 lesions), qualitative lesion characteristics were compared between 18F-NaF–positive and 18F-NaF–negative plaques using adverse plaque characteristics. The plaques with 18F-NaF uptake showed significantly higher plaque burden, more frequent posterior attenuation and positive remodeling in IVUS, and significantly higher maximum lipid arc and more frequent microvessels in OCT (all P<0.05). There were no differences in minimum lumen area and area of calcium between 18F-NaF–positive and 18F-NaF–negative lesions. Among 51 lesions with 18F-NaF–positive uptake, 48 lesions (94.1%) had at least one of high-risk characteristics. The 18F-NaF tissue-to-background ratio in plaques with high-risk characteristics was significantly higher than in those without (1.09 [95% confidence interval, 0.85–1.34] versus 0.62 [95% confidence interval, 0.42–0.82], P<0.001 for IVUS definition; 0.76 [95% confidence interval, 0.54–0.98] versus 0.42 [95% confidence interval, 0.21–0.62], P=0.014 for OCT definition). Among the 15 lesions that met both IVUS- and OCT-defined criteria for high-risk plaque, 14 (93.3%) showed 18F-NaF–positive uptake. There was no difference in the prevalence of plaques with any adverse plaque characteristics between 18F-NaF–positive and 18F-NaF–negative plaques in the coronary computed tomography angiography subgroup (85.2% versus 78.9%; P=0.583). Conclusions— This study’s results suggest that 18F-NaF positron-emission tomography can be a useful noninvasive diagnostic tool to identify and localize plaque with high-risk characteristics. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02388412.

Percutaneous Coronary Intervention at Centers With and Without On-Site Surgical Backup: An Updated Meta-Analysis of 23 Studies.

Background— Emergency coronary artery bypass grafting for unsuccessful percutaneous coronary intervention (PCI) is now rare. We aimed to evaluate the current safety and outcomes of primary PCI and nonprimary PCI at centers with and without on-site surgical backup. Methods and Results— We performed an updated systematic review and meta-analysis by using mixed-effects models. We included 23 high-quality studies that compared clinical outcomes and complication rates of 1 101 123 patients after PCI at centers with or without on-site surgery. For primary PCI for ST-segment–elevation myocardial infarction (133 574 patients), all-cause mortality (without on-site surgery versus with on-site surgery: observed rates, 4.8% versus 7.2%; pooled odds ratio [OR], 0.99; 95% confidence interval, 0.91–1.07; P=0.729; I2=3.4%) or emergency coronary artery bypass grafting rates (observed rates, 1.5% versus 2.4%; pooled OR, 0.76; 95% confidence interval, 0.56–1.01; P=0.062; I2=42.5%) did not differ by presence of on-site surgery. For nonprimary PCI (967 549 patients), all-cause mortality (observed rates, 1.6% versus 2.1%; pooled OR, 1.15; 95% confidence interval, 0.94–1.41; P=0.172; I2=67.5%) and emergency coronary artery bypass grafting rates (observed rates, 0.5% versus 0.8%; pooled OR, 1.14; 95% confidence interval, 0.62–2.13; P=0.669; I2=81.7%) were not significantly different. PCI complication rates (cardiogenic shock, stroke, aortic dissection, tamponade, recurrent infarction) also did not differ by on-site surgical capability. Cumulative meta-analysis of nonprimary PCI showed a temporal decrease of the effect size (OR) for all-cause mortality after 2007. Conclusions— Clinical outcomes and complication rates of PCI at centers without on-site surgery did not differ from those with on-site surgery, for both primary and nonprimary PCI. Temporal trends indicated improving clinical outcomes in nonprimary PCI at centers without on-site surgery.

TCT-68 Clinical Outcomes According to Fractional Flow Reserve or Instantaneous Wave-Free Ratio in Deferred Lesions

Invasive physiologic index such as fractional flow reserve (FFR) or instantaneous wave-free ratio (iFR) are used in clinical practice to select ischemia-causing stenosis and to guide the treatment strategy for patients with coronary artery disease. We investigated 2-year clinical outcomes according