Association of computed tomography-derived myocardial mass with fractional flow reserve-verified ischemia or subsequent therapeutic strategy.

The aim of the present study was to examine the association of myocardial mass verified by computed tomography (CT) and invasive fractional flow reserve (FFR)-verified myocardial ischemia, or subsequent therapeutic strategy for the targeted vessels after FFR examination. We examined 333 vessels with intermediate stenoses in 297 patients (mean age 69.0 ± 9.5, 228 men) undergoing both coronary CT angiography and invasive FFR, and reviewed the therapeutic strategy after FFR. Of 333 vessels, FFR ≤ 0.80 was documented in 130 (39.0%). Myocardial volume supplied by the target vessel (MVT) was larger in those with FFR-verified ischemia than those without (53.4 ± 19.5 vs. 42.9 ± 22.2 cm3, P < 0.001). Addition of MVT to a model including patient characteristics (age, gender), visual assessment (≥ 70% stenosis, high-risk appearance), and quantitative CT vessel parameters [minimal lumen area (MLA), plaque burden at MLA, percent aggregate plaque volume] improved C-index (from 0.745 to 0.778, P = 0.020). Furthermore, of 130 vessels with FFR ≤ 0.80, myocardial volume exposed to ischemia (MVI) was larger in the vessels with early revascularization after FFR examination than those without (37.2 ± 20.0 vs. 26.8 ± 15.0 cm3, P = 0.003), and was independently associated with early revascularization [OR = 1.03, 95% confidence interval (1.02-1.11), P < 0.001]. Using an on-site CT workstation, MVT identified coronary arteries with FFR-verified ischemia easily and non-invasively, and MVI was associated with subsequent therapeutic strategy after FFR examinations.

Null mutation of the endothelin receptor type B gene causes embryonic death in the GK rat.

The Hirschsprung disease (HSCR) is an inherited disease that is controlled by multiple genes and has a complicated genetic mechanism. HSCR patients suffer from various extents of constipation due to dysplasia of the enteric nervous system (ENS), which can be so severe as to cause complete intestinal obstruction. Many genes have been identified as playing causative roles in ENS dysplasia and HSCR, among them the endothelin receptor type B gene (Ednrb) has been identified to play an important role. Mutation of Ednrb causes a series of symptoms that include deafness, pigmentary abnormalities, and aganglionosis. In our previous studies of three rat models carrying the same spotting lethal (sl) mutation on Ednrb, the haplotype of a region on chromosome (Chr) 2 was found to be responsible for the differing severities of the HSCR-like symptoms. To confirm that the haplotype of the responsible region on Chr 2 modifies the severity of aganglionosis caused by Ednrb mutation and to recreate a rat model with severe symptoms, we selected the GK inbred strain, whose haplotype in the responsible region on Chr 2 resembles that of the rat strain in which severe symptoms accompany the Ednrbsl mutation. An Ednrb mutation was introduced into the GK rat by crossing with F344-Ednrbsl and by genome editing. The null mutation of Ednrb was found to cause embryonic death in F2 progeny possessing the GK haplotype in the responsible region on Chr 2. The results of this study are unexpected, and they provide new clues and animal models that promise to contribute to studies on the genetic regulatory network in the development of ENS and on embryogenesis.

Pre-procedural glucose levels and the risk for contrast-induced acute kidney injury in patients undergoing emergency coronary intervention.

BACKGROUND: The incidence, risk factors, and outcome of contrast-induced acute kidney injury (CI-AKI) in 730 patients with acute coronary syndrome (ACS) undergoing emergency percutaneous coronary intervention (PCI), whose contrast volume was below maximum allowable contrast dose (MACD) was prospectively investigated. METHODS AND RESULTS: MACD was defined as (5ml×body weight [kg]/baseline creatinine [mg/dl]). CI-AKI was defined as a greater than 25% increase in creatinine from the baseline or an absolute increase of ≥0.5mg/dl within 48h after the procedure. CI-AKI occurred in 212 (29%) patients. Patients with CI-AKI had a higher risk for in-hospital mortality (9.4% vs. 1.5%, P<0.001) and a longer stay in the coronary care unit (median, 4.0 vs. 3.0 days, P<0.001) compared with those without CI-AKI. In a multivariate logistic analysis including 20 clinical variables, elevated glucose levels as variables categorized into quartiles were independently (P<0.001) associated with the development of CI-AKI. In addition, this relationship was seen in both the subgroup of patients with known diabetes and that of those without known diabetes. CONCLUSIONS: CI-AKI might occur commonly and could be be associated with a more complicated clinical course in ACS patients undergoing emergency PCI whose contrast volume does not exceed MACD. Elevated pre-procedural glucose might be a powerful and independent risk factor for the development of CI-AKI in this population.

A histological and clinical comparison of new and conventional integrated backscatter intravascular ultrasound (IB-IVUS).

BACKGROUND: While the utilization of integrated backscatter intravascular ultrasound (IB-IVUS) for the quantitative in vivo assessment of coronary plaque continues to grow, the validity of IB-IVUS images obtained from newly developed and conventional systems remains uncertain. METHODS AND RESULTS: To assess the accuracy and reliability of a newly developed IB-IVUS system (VISIWAVE) as compared to the conventional system (Clearview), we compared quantitative IB-IVUS plaque characteristics in the 2 systems using 125 post-mortem specimens from 26 coronary arteries in 11 cadavers, as well as using 200 clinical plaques in 32 patients undergoing coronary intervention. The overall agreement between the histological and IB-IVUS diagnoses using VISIWAVE (Cohen's κ=0.82, 95%CI: 0.73-0.90) was similar to that using Clearview (Cohen's κ=0.80, 95%CI: 0.71-0.89). The 2 systems also demonstrated comparably high sensitivity and specificity. In the direct comparison, the overall agreement between IB-IVUS diagnoses using VISIWAVE and Clearview was also excellent (Cohen's κ=0.87, 95%CI: 0.78-0.95). In the clinical comparison, measured plaque dimensions were similar (VISIWAVE: 8.27±3.46 mm(2) vs. Clearview; 8.31±3.46 mm(2), P=0.44) and there was strong concordance between both greyscale and IB-IVUS parameters. CONCLUSIONS: There was close agreement of analyzed results in both systems when compared with the gold standard of histology. Both systems are able to reliably and accurately characterize coronary plaque and thereby make a valuable contribution to our understanding of atherosclerosis.

Circulating high-mobility group box 1 and cardiovascular mortality in unstable angina and non-ST-segment elevation myocardial infarction.

OBJECTIVE: High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern molecule, which suggests a potential role of this protein in the pathophysiology of acute coronary syndrome (ACS). Circulating HMGB1 has been shown to be independently associated with cardiac mortality in ST-segment elevation myocardial infarction. However, its prognostic value remains unclear in unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). METHODS: HMGB1, high-sensitivity C-reactive protein (hsCRP), cardiac troponin I and B-type natriuretic peptide concentrations were measured on admission in 258 consecutive patients (mean age of 67 years) hospitalized for UA/NSTEMI within 24h (mean, 7.4h) of the onset of chest symptoms. RESULTS: A total of 38 (14.7%) cardiovascular deaths, including 10 in-hospital deaths, occurred during a median follow-up period of 49 months after admission. In a stepwise Cox regression analysis including 19 well-known clinical predictors of ACS, HMGB1 [relative risk (RR) 3.24 per 10-fold increment; P = 0.0003], cardiac troponin I (RR 1.83 per 10-fold increment, P = 0.0007), Killip class>1 (RR 4.67, P = 0.0001) and age (RR 1.05 per 1-year increment, P = 0.03), but not hsCRP, were independently associated with cardiovascular mortality. In-hospital and cardiovascular mortality rates were higher in patients with increased HMGB1 (≥ 2.4 ng/mL of median value) than those without increased HMGB1 (6.3% vs. 1.5%, P = 0.04; and 23% vs. 6.9%, P = 0.0003). CONCLUSION: Circulating concentration of HMGB1 on admission may be a potential and independent predictor of cardiovascular mortality in patients hospitalized for UA/NSTEMI within 24h of onset.

Impact of statin therapy on plaque characteristics as assessed by serial OCT, grayscale and integrated backscatter-IVUS.

OBJECTIVES: The purpose of this study was to evaluate the effect of statin treatment on coronary plaque composition and morphology by optical coherence tomography (OCT), grayscale and integrated backscatter (IB) intravascular ultrasound (IVUS) imaging. BACKGROUND: Although previous studies have demonstrated that statins substantially improve cardiac mortality, their precise effect on the lipid content and fibrous cap thickness of atherosclerotic coronary lesions is less clear. While IVUS lacks the spatial resolution to accurately assess fibrous cap thickness, OCT lacks the penetration of IVUS. We used a combination of OCT, grayscale and IB-IVUS to comprehensively assess the impact of pitavastatin on plaque characteristics. METHODS: Prospective serial OCT, grayscale and IB-IVUS of nontarget lesions was performed in 42 stable angina patients undergoing elective coronary intervention. Of these, 26 received 4 mg pitavastatin after the baseline study; 16 subjects who refused statin treatment were followed with dietary modification alone. Follow-up imaging was performed after a median interval of 9 months. RESULTS: Grayscale IVUS revealed that in the statin-treated patients, percent plaque volume index was significantly reduced over time (48.5 ± 10.4%, 42.0 ± 11.1%; p = 0.033), whereas no change was observed in the diet-only patients (48.7 ± 10.4%, 50.4 ± 11.8%; p = NS). IB-IVUS identified significant reductions in the percentage lipid volume index over time (34.9 ± 12.2%, 28.2 ± 7.5%; p = 0.020); no change was observed in the diet-treated group (31.0 ± 10.7%, 33.8 ± 12.4%; p = NS). While OCT demonstrated a significant increase in fibrous cap thickness (140 ± 42 µm, 189 ± 46 µm; p = 0.001), such changes were not observed in the diet-only group (140 ± 35 µm, 142 ± 36 µm; p = NS). Differences in the changes in the percentage lipid volume index (-6.8 ± 8.0% vs. 2.8 ± 9.9%, p = 0.031) and fibrous cap thickness (52 ± 32 µm vs. 2 ± 22 µm, p < 0.001) over time between the pitavastatin and diet groups were highly significant. CONCLUSIONS: Statin treatment induces favorable plaque morphologic changes with an increase in fibrous cap thickness, and decreases in both percentage plaque and lipid volume indexes.

Coronary CT angiographic characteristics of culprit lesions in acute coronary syndromes not related to plaque rupture as defined by optical coherence tomography and angioscopy.

AIMS: Pathological and clinical optical coherence tomography (OCT) studies have indicated that acute coronary syndrome (ACS) lesions have either ruptured fibrous caps (RFC-ACS) or intact fibrous caps (IFC-ACS). Although computed tomographic (CT) angiographic characteristics of RFC-ACS include low-attenuation plaques and positive plaque remodelling, features associated with IFC-ACS have not been previously described. The aim of this study was to assess the CT characteristics of IFC-ACS lesions. METHODS AND RESULTS: Seventy-four patients with ACS/stable angina consented to multimodality imaging, of which 66 underwent CT angiography. Of these, 57 culprit lesions in 57 patients were evaluated with sufficient image quality from all four of OCT, angioscopy, intravascular ultrasound, and CT angiography. Intraluminal thrombus was assessed by OCT/angioscopy, and culprit lesions further classified by OCT-based demonstration of fibrous cap integrity. Of 35 culprit lesions with ACS, OCT revealed IFC with thrombus in 10 (29%) and RFC in the remaining 25 (71%); all 22 lesions with stable angina had intact fibrous caps. Fibrous caps were significantly thinner in RFC-ACS than IFC-ACS and stable angina (45 ± 12, 131 ± 57, and 321 ± 146 µm, respectively; P = 0.001). CT angiography revealed that low-attenuation plaques were more frequently observed in RFC-ACS than IFC-ACS and stable angina (88, 40, and 18%; P = 0.001) lesions. Similarly, positive remodelling was more predominantly seen in RFC-ACS than IFC-ACS and stable angina (96, 20, and 14%; P = 0.001). However, none of the specific CT angiography features clearly distinguished IFC-ACS from stable lesions. CONCLUSION: In contrast to the situation with RFC-ACS, distinct culprit lesion characteristics associated with non-rupture-related mechanisms are not identified by CT angiography. It will therefore not be possible to differentiate plaques likely to develop IFC-ACS from stable plaques.

Do drug elution components increase the risk of fracture of sirolimus-eluting stents?

OBJECTIVES: Stent fracture (SF) of sirolimus-eluting stents (SES) has emerged recently in the literature and shown to be associated with an increased risk of restenosis; however, little is known regarding SF after bare-metal stent implantation. We sought to assess whether the use of SES was associated with an increased risk of SF compared with its bare-metal platform, the Bx-velocity stent (BX-BMS). METHODS: A total of 478 lesions in 416 patients undergoing SES implantation and subsequent angiography 6-9 months after the index procedure were compared with 152 lesions in 142 consecutive patients treated with BX-BMS. Stented lesions with total stent-length greater than 40 mm were excluded. RESULTS: There were no significant differences in overall baseline clinical and anatomic features between the SES and BX-BMS groups, or in SF frequencies at 6-9 month follow-up (4.4% for SES and 1.3% for BX-BMS, P= 0.078). In-stent restenosis was observed more often in SF lesions versus non-SF lesions (34.8 vs. 7.7%, P< 0.001) in association with a higher 3-year adverse events rate (27.3 vs. 13.6%, P = 0.076). The risk of SF at 6-9 months was independently associated with total stent length [odds ratio (OR), 2.13; 95% confidence interval (CI), 1.18-3.83; P = 0.012], angulated lesions (OR, 4.25; 95% CI, 1.80-10.00; P = 0.001), and right coronary artery lesions (OR, 3.55; 95% CI, 1.46-8.62; P = 0.005) but not with SES use. CONCLUSION: Stent implantation in right coronary artery lesions, tortuous lesions, and/or longer lesions covered with longer stents, and not SES versus BX-BMS use, may be associated with increased likelihood of SF.

The fate of incomplete stent apposition with drug-eluting stents: an optical coherence tomography-based natural history study.

AIMS: To assess the fate of incomplete stent apposition (ISA) after deployment of sirolimus-eluting stents (SESs). METHODS AND RESULTS: Thirty-two patients having intravascular ultrasound (IVUS)-guided PCI with SESs underwent assessment of stent deployment with quantitative coronary angiography, IVUS, and optical coherence tomography (OCT) pre-procedure, post-procedure, and at 10 months follow-up. Incomplete stent apposition was defined as separation of a stent strut from the inner vessel wall by >160 microm. At follow-up, 4.67% of struts with ISA at deployment failed to heal and 7.59% which were well apposed did not develop neointimal hyperplasia even after 10 months. Lesion remodelling was responsible for the development of late ISA in only 0.37% of struts. Failure of adequate neointimal hyperplasia was quantitatively the most important mechanism responsible for persistent acute ISA, classified in previous studies, which relied only on follow-up OCT, as late ISA. Thrombus was visualized in 20.6% of struts with ISA at follow-up and in 2.0% of struts with a good apposition (P < 0.001). CONCLUSION: In patients with SESs, ISA can fail to heal and even complete apposition can be associated with no neointimal hyperplasia. Incomplete stent apposition without neointimal hyperplasia was significantly associated with the presence of OCT-detected thrombus at follow-up, and may constitute a potent substrate for late stent thrombosis.

Pentraxin 3 in unstable angina and non-ST-segment elevation myocardial infarction.

PURPOSE: We prospectively investigated the prognostic value of pentraxin 3 (PTX3) in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). BACKGROUND: PTX3 may be a useful marker for localized vascular inflammation and damage to the cardiovascular system. Recent studies have shown that plasma PTX3 is elevated in patients with UA/NSTEMI; however, its prognostic value in UA/NSTEMI remains unclear. METHODS: PTX3, high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and cardiac troponin I were measured on admission in 204 consecutive patients (mean age of 69 years; 144 males) hospitalized for UA/NSTEMI within 24h (mean of 7.5h) after the onset of chest symptoms. A cardiac event, which was defined as cardiac death, rehospitalization for acute coronary syndrome (ACS), or rehospitalization for worsening heart failure, was monitored for 6 months after admission. RESULTS: A total of 26 (13%) cardiac events occurred during the 6-month follow-up period. In a stepwise Cox regression analysis including 18 well-known clinical and biochemical predictors of ACS outcome, both PTX3 (relative risk 3.86 per 10-fold increment, P=0.01) and NT-proBNP (relative risk 2.16 per 10-fold increment, P=0.02), but not hsCRP, were independently associated with the 6-month cardiac event. The cardiac event rate was higher in patients with increased PTX3 (> or = 3.1ng/mL of median value) than those without (20% vs. 5.8%, P=0.003). A Kaplan-Meier analysis revealed that patients with increased PTX3 had a higher risk for cardiac events than those without (P=0.002). CONCLUSION: PTX3 and NT-proBNP may be potent and independent predictors for 6-month cardiac events in patients hospitalized for UA/NSTEMI within 24h after the onset. Measurement of plasma PTX3 may substantially improve the early risk stratification of patients with UA/NSTEMI.

Cystatin C in acute heart failure without advanced renal impairment.

BACKGROUND: The prognostic value of cystatin C relative to glomerular filtration rate (GFR) estimated by the Modification of Diet in Renal Disease Study (MDRD) equation modified for Japan has not been investigated in acute heart failure patients with normal to moderately impaired renal function. More accurate detection of mild renal impairment might improve the risk stratification of heart failure patients, especially patients with normal to moderately impaired renal function. METHODS: Cystatin C and creatinine levels were measured on admission in 328 consecutive patients hospitalized for worsening chronic heart failure with a GFR estimated by MDRD equation modified for Japan >or=30 mL/min/1.73 m(2). RESULTS: During a median follow-up period of 915 days, there were 52 (16%) cardiac deaths. In stepwise Cox regression analyses including cystatin C and GFR estimated by MDRD equation modified for Japan (either as continuous variables or as variables categorized into quartiles), cystatin C (P <.0001), but not GFR estimated by MDRD equation modified for Japan, was independently associated with cardiac mortality. Adjusted relative risk according to the quartiles of these markers and Kaplan-Meier analyses revealed that the cystatin C was a better marker to separate low-risk from high-risk patients. Furthermore, receiver-operating characteristic curve analyses of these markers revealed that cystatin C showed a higher precision in predicting cardiac mortality. CONCLUSION: Measurements of cystatin C might improve early risk stratification compared with GFR estimated by MDRD equation modified for Japan in acute heart failure patients with normal to moderately impaired renal function.

Restenosis and stent fracture following sirolimus-eluting stent (SES) implantation.

BACKGROUND: Restenosis still occurs, even with the sirolimus-eluting stent (SES), and the precise mechanisms and the impact of stent fracture on restensosis have not yet been elucidated. METHODS AND RESULTS: Intravascular ultrasound (IVUS)-guided SES implantation was performed in 184 lesions in 151 patients with stable and unstable angina. Serial (pre-, post- and follow-up) quantitative coronary angiography analysis was obtained in 169 lesions in 138 patients (angiographic follow-up rate: 91%) and 12-month clinical follow-up was done in all patients. Restenosis occurred in 13 (7.7%) of 169 lesions. Stent fracture occurred in 4 (2.4%) of 169 lesions at follow-up. Of the 13 restenotic lesions, 8 had intimal hyperplasia, 4 had stent fracture, and 1 had late stent thrombosis at 7 months. Although multivariate logistic regression analysis revealed that minimal lumen area (min-LA) post (p=0.027), total stent length (p=0.003) and diabetes (p=0.032) were significant independent predictors of restenosis, univariate analysis showed that stent fracture was more common in the restenosis than in the non-restenosis groups (p=0.001). CONCLUSIONS: Although min-LA post by IVUS, total stent length by QCA and diabetes are independent predictors for angiographic restenosis, stent fracture occurred in 4 lesions (2.4%) and all of them resulted in restenosis (31% of the restenosis). The impact of stent fracture and its potential role in the development of restenosis deserves further study.

Comparing the accuracy of video-oculography and the scleral search coil system in human eye movement analysis.

The measurement of eye movements in three dimensions is an important tool to investigate the human vestibular and oculomotor system. The primary methods for three dimensional eye movement measurement are the scleral search coil system (SSCS) and video-oculography (VOG). In the present study, we compare the accuracy of VOG with that of SSCS using an artificial eye. We then analyzed the Y (pitch) and Z (yaw) component of human eye movements during saccades, smooth pursuit and optokinetic nystagmus, and the X (roll) component of human eye movement during the torsional vestibulo-ocular reflex induced by rotation in normal subjects, using simultaneous VOG and SSCS measures. The coefficients of the linear relationship between the angle of a simulated eyeball and the angle measured by both VOG and SSCS was almost unity with y-intercepts close to zero for torsional (X), vertical (Y) and horizontal (Z) movements, indicating that the in vitro accuracy of VOG was similar to that of SSCS. The average difference between VOG and SSCS was 0.56 degrees , 0.78 degrees and 0.18 degrees for the X, Y and Z components of human eye movements, respectively. Both the in vitro and in vivo comparisons demonstrate that VOG has accuracy comparable to SSCS, and is a reliable method for measurement of three dimensions (3D) human eye movements.

Horizontal eye response to an abrupt lateral head drop in normal subjects and patients with Meniere's disease.

OBJECTIVE: To detect the endolymphatic hydrops by using the otolithic nature in patients with Meniere's disease and delayed hydrops. METHODS: We developed a new technique for measuring horizontal eye movements, corresponding to lateral head drop in total darkness, approximately 1g environment. Normal subjects (n=16, mean age: 27.3 years old) and patients (seven for pre-operative state, four for furosemide test at pre-operative state; two for post-operative state) were employed in the test. The principle of the test is to drop the head in a lateral position separately from the body with a rapid release exposing the head. Bitemporal EOG, accelometric and trigger signals for the releaser were recorded for processing at 1 KHz sampling time. RESULTS: The drop was performed five times in succession. The latency of horizontal eye response was of 40 ms order in normal subjects on both sides and were never beyond 60 ms. Eye response of the patients was in different patterns from normal subjects and the latencies delayed either to normal side or to the affected side. Following furosemide intravenous injection, more certain information was obtained. Three of four patients were recovered to normal range as to the latency. CONCLUSIONS: We emphasize that this test may provide a new measure sensitive to the hydrops and can underline this test to detect the hydrops in Meniere's disease.