Association between fingertip-measured advanced glycation end products and cardiovascular events in outpatients with cardiovascular disease.

BACKGROUND: The accumulation of advanced glycation end products (AGEs) is associated with cardiovascular events in patients with cardiovascular disease (CVD). However, the relationship between the AGEs measured by an AGEs sensor noninvasively at the fingertip and prognosis in patients with CVD remains unclear. Therefore, this study aimed to determine the relationship between AGEs score and prognosis among patients with CVD. METHODS: A total of 191 outpatients with CVD were included. AGEs score were measured using an AGEs sensor and the patients were classified into groups by the median value of AGEs score. The incidence of major adverse cardiovascular and cerebrovascular events (MACCE) at 30 months was compared between high- and low-AGEs score groups. In addition, receiver operating characteristic (ROC) curve analysis was used to calculate cutoff value for the AGEs score, which discriminates the occurrence of MACCE. Cox regression analysis was performed to identify the factors associated with the presence of MACCE. MACCE included cardiac death, myocardial infarction, percutaneous coronary intervention, heart failure, and stroke. RESULTS: AGEs score was normally distributed, with a median value of 0.51. No significant intergroup differences were found in laboratory findings, physical functions, or medications. The high-AGEs score group had a significantly higher incidence of MACCE than the low-AGEs score group (27.1 vs. 10.5%, P = 0.007). A high-AGEs score was a risk factor for MACCE (hazard ratio, 2.638; 95% confidence interval, 1.271-5.471; P = 0.009). After the adjustment for confounders other than 6-min walking distance, the AGEs score remained a factor associated with the occurrence of MACCE. The best cutoff AGEs score for the detection of MACCE was 0.51 (area under the curve, 0.642; P = 0.008; sensitivity, 72.2%; specificity, 54.8%). CONCLUSIONS: AGEs score measured at the fingertip in patients with CVD is associated with MACCE. AGEs score, which can be measured noninvasively and easily, may be useful as an assessment for the secondary prevention of CVD in patients with CVD.

Clinical outcomes and plaque characteristics in patients with coronary artery disease and concomitant sleep-disordered breathing treated by continuous positive airway pressure.

BACKGROUND: Sleep-disordered breathing (SDB) is a risk factor for recurrent adverse events in patients with coronary artery disease (CAD). However, the prognosis of continuous positive alveolar pressure (CPAP) treatment for SDB with CAD remains unknown. METHODS: A total of 281 consecutive patients with stable CAD requiring percutaneous coronary intervention (PCI) were included and classified into three groups according to the concomitance of SDB and CPAP treatment (untreated SDB group, n = 61; CPAP-SDB group, n = 24; and non-SDB group, n = 138). The incidence of major adverse cardiac and cerebrovascular events (MACCEs) within a year after PCI was compared between the three groups. The characteristics of the culprit plaques, including macrophage accumulation, were further assessed using optical coherence tomography. RESULTS: The incidence of MACCEs was significantly different among the three groups (p = 0.037), with the highest incidence in the untreated-SDB group (22.9%) and 8.3% and 10.1% in the CPAP-SDB and non-SDB groups, respectively. The incidence of MACCEs at 1 year was significantly lower in patients with appropriate CPAP use than that in inadequately treated patients with SDB (0.0 vs. 22.5%, p = 0.048). Macrophage accumulation differed significantly among the three groups, with the highest accumulation in the untreated SDB group. CONCLUSIONS: CPAP treatment for SDB may be associated with a lower incidence of MACCEs following PCI and a lower prevalence of macrophages in the culprit plaques.

Crystal structure of the AlbEF complex involved in subtilosin A biosynthesis.

Subtilosin A is a sactipeptide bacteriocin produced by Bacillus subtilis strain 168, containing intramolecular thioether bonds and a head-to-tail macrocyclic peptide bond. Macrocyclization is presumably catalyzed by AlbE and AlbF proteins encoded by the subtilosin A biosynthesis gene cluster. However, the underlying mechanism of macrocyclization remains uncertain as the tertiary structures of the proteins are undetermined. Here, we report the crystal structures of AlbE and AlbF homologs in Quasibacillus thermotolerans, wherein the subtilosin biosynthesis gene cluster is highly conserved. Structural analysis and pull-down assays revealed that AlbE and AlbF form heterodimeric complexes. Although the AlbEF complex shows structural similarity to M16B family metalloproteases, the substrate-binding chamber is shallower and more open than the other M16B family proteins. The chamber surface showed electrostatic complementarity to the precursor of subtilosin. Our findings provide insights into the role of AlbEF in metalloprotease catalysis and macrocyclic peptide bond formation.

Development of a novel peptide inhibitor of subtilisin BPN'.

Proteinaceous protease inhibitors can strongly and specifically inhibit cognate proteases, but their use as pharmaceuticals is limited by their size. As such, the development of effective protease peptide inhibitors would be beneficial for biochemical studies and drug discovery. In this study, we applied a phage display system to select subtilisin BPN'-binding peptides and evaluated their inhibitory activities against subtilisin BPN'. A 12mer peptide with an intramolecular disulfide bond inhibited subtilisin BPN' (Ki value of 13.0 nm). Further mutational analyses of the peptide resulted in the development of a short peptide inhibitor against subtilisin BPN' that showed high inhibitory activity and binding affinity (Ki value of 0.30 nm). This activity was found to be derived from the conformational rigidity caused by the intramolecular disulfide bond and the small residue at the P1' site and from the interaction of the P4 and P6' residues with subtilisin BPN'.

Advanced Glycation End Products Are Associated with Diabetes Status and Physical Functions in Patients with Cardiovascular Disease.

Advanced glycated end products (AGEs) accumulate systemically and cause diabetes complications. However, whether noninvasive measurable AGEs are associated with diabetes status and physical functions remains unclear. One hundred and ten patients with cardiovascular disease (CVD) who underwent outpatient cardiac rehabilitation were included. AGEs scores, using AGEs sensors, were evaluated concomitantly with a physical evaluation, including testing the isometric knee extension strength (IKES) and 6 min walking distance (6MWD). Thirty-three (30%) patients had a history of diabetes mellitus (DM). The AGEs score was not different in the presence of DM history (0.52 ± 0.09 vs. 0.51 ± 0.09, p = 0.768) and was not correlated with blood glucose (r = 0.001, p = 0.995). The AGEs score was positively correlated with hemoglobin A1c (HbA1c, r = 0.288, p = 0.004) and negatively correlated with physical functions (IKES, r = −0.243, p = 0.011; 6MWD, r = −0.298, p = 0.002). The multivariate analysis demonstrated that 6MWD was independently associated with a high AGEs score (>0.52). The AGEs score was associated with HbA1c, IKES, and 6MWD in patients with CVD. The AGEs score might be a useful indicator for evaluating not only glycemic control but also physical functions.

A case with recovery from high degree atrioventricular-block with steroid therapy in cardiac sarcoidosis with AH block: a possible new sign of responder?

BACKGROUND: Although some reports have documented cases who exhibited recovery from atrioventricular block (AVB) by steroid therapy in cases with cardiac sarcoidosis (CS), they could not determine predictors for such good response to steroid therapy. In this case, a 54-year-old female was referred to our hospital due to intermittent 2:1 AVB. Echocardiography revealed normal ventricular function. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) exhibited enhanced uptake in basal anterior-septal area of the left ventricle. The electrophysiologic study exhibited marked AH prolongation (324 ms) but no HV prolongation. Sarcoidosis was diagnosed basing on non-caseating granulomas detected in skin biopsy. Because the 2:1 AVB was temporal, oral prednisolone (PSL) was started without planning implantation of permanent pacemaker. In 10 days from start of PSL, PR interval was gradually normalized from 0.34 to 0.14 sec and temporal 2:1 AVB disappeared. 18F-FDG PET also exhibited disappearance of enhanced uptake. During the following 2 years, the patient continued to exhibit normal PR interval. This case exhibited AH prolongation in EPS, although the degree of AVB was serious. Additionally, 18F-FDG PET exhibited enhanced uptake in the area around AV-node. AH block and FDG enhancement around AV-node area might be novel predictors for good response to PSL in cases with CS. .

Prognosis of Patients With Reduced Left Ventricular Ejection Fraction and Chronic Total Occlusion According to Treatment Applied.

BACKGROUND: Chronic total occlusion (CTO) is common among patients with coronary artery disease. Very few studies have focused on outcomes of patients with CTO and reduced left ventricular ejection fraction (LVEF), according to treatment applied. The aim of our study was to determine the potential influence of the selected treatment on the prognosis in patients with CTO associated with reduced LVEF. METHODS: Between June 2010 and October 2013, all consecutive patients with at least one CTO and reduced LVEF (<40%) were enrolled. Major adverse cardiac events (MACE), defined as the composite of cardiac mortality or myocardial infarction (MI) and its individual components, were compared between three treatment groups: medical therapy (MT), percutaneous coronary intervention (PCI), and coronary bypass graft (CABG). RESULTS: In 256 included patients, the follow-up was 1129 ± 556 days. The incidence of MACE was 40% in the MT group, compared with PCI (20.3%) and CABG (16.7%); p < 0.001. All-cause and cardiac mortality were also higher in the MT group (40.7% and 33.3%, respectively) versus the PCI (21.9% and 15.6%) and CABG (11.9% and 9.5%) groups (p < 0.001 for both endpoints); MI rate did not differ among groups. In the adjusted multivariate analysis, CABG had lower MACE risk, compared with MT (HR = 0.39, 0.17-0.91; p = 0.029); successful PCI also trended toward lower risk of MACE, compared with MT. CONCLUSIONS: Patients with CTO and reduced LVEF treated with MT had a worse prognosis than those treated with revascularization (either CABG or PCI). Patients with an indication for CABG appeared to perform best during long-term follow-up.

Achilles tendon thickening is associated with higher incidence of adverse cardiovascular event in patients with coronary artery disease.

Achilles tendon thickening (ATT) is a marker of high risk for coronary artery disease (CAD). However, the association between the presence of ATT and the incidence of cardiovascular events in patients with CAD is unclear. A total of 406 consecutive patients who underwent percutaneous coronary intervention (PCI) and ATT assessment were analyzed. ATT was defined as the Achilles tendon thickness of 9 mm or more on radiography. The incidence of major adverse cardiovascular events (MACE) at 1-year was compared between patients with ATT and those without ATT. MACE included cardiac death, non-fatal myocardial infarction, stroke, target vessel revascularization (TVR), and non-TVR. ATT was found in 67 patients (16.5%). The incidence of cardiac death (3.2 vs. 0.0%, p = 0.001), TVR (12.7 vs. 4.0%, p = 0.005) and MACE (20.6 vs. 9.6%, p = 0.011) was significantly higher in the ATT group than the no ATT group. Patients with ATT had significantly higher incidence of cardiac death (5.6 vs. 0%, p < 0.001) than those without ATT even if they did not meet the diagnostic criteria of familial hypercholesterolemia. A multivariate model demonstrated that ATT was independently associated with the MACE at 1-year (Hazard ratio, 2.09; 95% Confidence Interval, 1.09-4.00, p = 0.026). The presence of ATT was independently associated with 1-year recurrence of cardiovascular events in patients with CAD undergoing PCI. Assessment of ATT might be useful for risk stratification of secondary cardiovascular events.

Moderate Hypothermia Modifies Coronary Hemodynamics and Endothelium-Dependent Vasodilation in a Porcine Model of Temperature Management.

Background Hypothermia has been associated with therapeutic benefits including reduced mortality and better neurologic outcomes in survivors of cardiac arrest. However, undesirable side effects have been reported in patients undergoing coronary interventions. Using a large animal model of temperature management, we aimed to describe how temperature interferes with the coronary vasculature. Methods and Results Coronary hemodynamics and endothelial function were studied in 12 pigs at various core temperatures. Left circumflex coronary artery was challenged with intracoronary nitroglycerin, bradykinin, and adenosine at normothermia (38°C) and mild hypothermia (34°C), followed by either rewarming (38°C; n=6) or moderate hypothermia (MoHT; 32°C, n=6). Invasive coronary hemodynamics by Doppler wire revealed a slower coronary blood velocity at 32°C in the MoHT protocol (normothermia 20.2±11.2 cm/s versus mild hypothermia 18.7±4.3 cm/s versus MoHT 11.3±5.3 cm/s, P=0.007). MoHT time point was also associated with high values of hyperemic microvascular resistance (>3 mm Hg/cm per second) (normothermia 2.0±0.6 mm Hg/cm per second versus mild hypothermia 2.0±0.8 mm Hg/cm per second versus MoHT 3.4±1.6 mm Hg/cm per second, P=0.273). Assessment of coronary vasodilation by quantitative coronary analysis showed increased endothelium-dependent (bradykinin) vasodilation at 32°C when compared with normothermia (normothermia 6.96% change versus mild hypothermia 9.01% change versus MoHT 25.42% change, P=0.044). Results from coronary reactivity in vitro were in agreement with angiography data and established that endothelium-dependent relaxation in MoHT completely relies on NO production. Conclusions In this porcine model of temperature management, 34°C hypothermia and rewarming (38°C) did not affect coronary hemodynamics or endothelial function. However, 32°C hypothermia altered coronary vasculature physiology by slowing coronary blood flow, increasing microvascular resistance, and exacerbating endothelium-dependent vasodilatory response.

Methylene Blue Inhibits Formation of Tau Fibrils but not of Granular Tau Oligomers: A Plausible Key to Understanding Failure of a Clinical Trial for Alzheimer's Disease.

Alzheimer's disease pathology is characterized by extracellular deposits of amyloid-ß (Aß) and intracellular inclusions of hyperphosphorylated tau. Although genetic studies of familial Alzheimer's disease suggest a causal link between Aß and disease symptoms, the failure of various Aß-targeted strategies to slow or halt disease progression has led to consideration of the idea that inhibition of tau aggregation might be a more promising therapeutic approach. Methylene blue (MB), which inhibits tau aggregation and rescue memory deficits in a mouse model of tauopathy, however, lacked efficacy in a recent Phase III clinical trial. In order to gain insight into this failure, the present study was designed to examine the mechanism through which MB inhibits tau aggregation. We found that MB inhibits heparin-induced tau aggregation in vitro, as measured by thioflavin T fluorescence. Further, MB reduced the amount of tau in precipitants recovered after ultracentrifugation of the aggregation mixture. Atomic force microscopy revealed that MB reduces the number of tau fibrils but increases the number of granular tau oligomers. The latter result was confirmed by sucrose gradient centrifugation: MB treatment was associated with higher levels of granular tau oligomers (fraction 3) and lower levels of tau fibrils (fractions 5 and 6). We previously demonstrated that the formation of granular tau oligomers, rather than tau fibrils, is essential for neuronal death. Thus, the fact that MB actions are limited to inhibition of tau fibril formation provides a mechanistic explanation for the poor performance of MB in the recent Phase III clinical trial.

Incidence, factors, and clinical significance of cholesterol crystals in coronary plaque: An optical coherence tomography study.

BACKGROUND AND AIMS: Intraplaque cholesterol crystal (CC) is recognized as a component of vulnerable plaques. However, the clinical characteristics of patients with CC and the impact of CC on clinical events remain unknown. METHODS: A total of 340 consecutive patients who underwent optical coherence tomography (OCT) imaging of culprit lesions were included in the study. CC was defined as a thin linear structure with high reflectivity and low signal attenuation on OCT images. The incidence of major adverse cardiovascular events (MACE) at 1-year was compared between patients with CC (CC group) and those without CC (non-CC group). MACE included cardiac death, non-fatal myocardial infarction, target vessel revascularization (TVR), and non-TVR (NTVR). RESULTS: CC was observed in 29% (n = 98) of the patients. There was no significant difference in baseline clinical characteristics between the CC and non-CC groups, other than in eicosapentaenoic acid (EPA)/arachidonic acid (AA) ratio (0.39 ±â€¯0.29 vs. 0.47 ±â€¯0.33, p = 0.047) and hemoglobin A1c (HbA1c) levels (6.51 ±â€¯0.97 vs. 6.25 ±â€¯0.87%, p = 0.016). The incidence of MACE and NTVR at 1-year was significantly higher in the CC group than in the non-CC group (15.3 vs. 7.9%, P = 0.038; 8.1 vs. 2.5%, p = 0.017). The presence of CC was significantly associated with a higher rate of 1-year MACE (odds ratio 4.78, confidential interval 2.02-10.10, p < 0.001). CONCLUSIONS: Patients with CC in the culprit lesion had higher HbA1c and lower EPA/AA than patients without CC. The 1-year clinical outcomes in patients with CC in the culprit lesion were worse than in those without CC.

Impact of Absorb bioresorbable scaffold implantation technique on post-procedural quantitative coronary angiographic endpoints in ST-elevation myocardial infarction: a sub-analysis of the BVS STEMI STRATEGY-IT study.

AIMS: The aim of the study was to evaluate the impact of bioresorbable vascular scaffold (BRS) implantation technique on post-procedural quantitative coronary angiography (QCA) parameters in ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We assessed 442 STEMI patients who underwent BRS implantation in the BVS STEMI STRATEGY-IT study. Optimal BRS implantation was assessed using the PSP score, developed and validated in the GHOST-EU registry. We analysed post-implantation QCA parameters, including minimum lumen diameter (MLD) and maximum footprint, in patients with and without optimal BRS implantation, coded as maximum PSP score. Patients with optimal BRS implantation had higher post-procedural MLD and lower maximum footprint than those without. Multivariate analysis demonstrated that optimal BRS implantation was an independent predictor of high post-procedural MLD, defined as ≥2.4 mm for 2.5 or 3.0 mm BRS and ≥2.8 mm for 3.5 mm BRS. Thrombectomy before optimal BRS implantation showed a trend towards higher post-procedural MLD and lower maximum footprint. There was no relationship between optimal BRS implantation and device-oriented composite events at one year. CONCLUSIONS: Optimal BRS implantation, as assessed by PSP score, was associated with better post-procedural QCA parameters in STEMI. Thrombectomy before optimal BRS implantation might improve angiographic results in STEMI. Long-term follow-up is needed to analyse the relationship between QCA parameters and clinical outcomes after BRS implantation in STEMI patients.

A Prospective Evaluation of a Pre-Specified Absorb BVS Implantation Strategy in ST-Segment Elevation Myocardial Infarction: The BVS STEMI STRATEGY-IT Study.

OBJECTIVES: The aim of this study was to assess the feasibility and clinical results following a pre-specified bioresorbable scaffold (Absorb BVS) implantation strategy in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Concerns were raised about the safety of Absorb because a non-negligible rate of thrombosis was reported within 30 days and at midterm follow-up after primary percutaneous coronary intervention. METHODS: This was a prospective, multicenter study of patients with STEMI (<75 years of age with symptom onset <12 h) undergoing primary percutaneous coronary intervention with Absorb following a dedicated implantation protocol. The primary endpoint was a device-oriented composite endpoint of cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization within 30 days. RESULTS: During the study period, 505 patients with STEMI (16.9% of the overall STEMI population) were treated with the Absorb BVS. The mean age was 56.6 ± 9.4 years, and 487 patients (96.4%) were in Killip class I or II at admission. According to the study protocol, direct Absorb implantation was feasible in 47 patients (9.3%), whereas post-dilatation was performed in 468 cases (92.7%). Procedural success was attained in 94.8% of the cases. Dual antiplatelet therapy with ticagrelor or prasugrel was administered at discharge in 481 patients (95.1%). At 30-day follow-up, the hierarchical device-oriented composite endpoint rate was 0.6% (0.4% cardiac death, 0.2% target vessel myocardial infarction and ischemia-driven target lesion revascularization). One episode (0.2%) of probable scaffold thrombosis was reported. CONCLUSIONS: A pre-specified Absorb implantation strategy in real-world patients with STEMI undergoing primary percutaneous coronary intervention was feasible and associated with a low 30-day device-oriented composite endpoint rate. Mid- and long-term follow-up is strongly needed to eventually confirm these early results. (Use of BVS in ST-Segment Elevation Myocardial Infarction [STEMI]: The BVS STEMI STRATEGY-IT Prospective Registry [STRATEGY-IT]; NCT02601781).

Methods to assess bioresorbable vascular scaffold devices behaviour after implantation.

Bioresorbable vascular scaffolds (BRS) represent a novel approach for coronary revascularization offering several advantages as compared to current generation DES, potentially reducing rate of late adverse events and avoiding permanent vessel caging. Nevertheless, safety concerns have been raised for an increased risk of scaffold thrombosis (ScT) in both early and late phases, probably related to a suboptimal scaffold implantation. In this context, the use of different imaging methodologies has been strongly suggested in order to guarantee an optimal implantation. We herein analyze the different imaging methodologies available to assess BRS after implantation and at follow-up.

Impact of stent overlapping on long-term clinical outcomes in patients with ST-segment elevation myocardial infarction: insights from the five-year follow-up of the EXAMINATION trial.

AIMS: The aim of this study was to compare the long-term outcomes of STEMI patients treated with overlap vs. no-overlap stents. METHODS AND RESULTS: We analysed the one- and five-year clinical outcomes of 1,498 STEMI patients according to overlapping stent implantation. The primary endpoint was a patient-oriented composite endpoint (PoCE) of all-cause death, myocardial infarction, and repeat revascularisation. Stent thrombosis data were also analysed. Four hundred and four (27.0%) patients were treated with overlapping stents, whereas the remaining 1,094 (73.0%) were not. At one and five years, there was no difference in PoCE between the overlap vs. no-overlap group, even after adjustment (14.9% vs. 12.4%; HR 1.20, 95% CI: 0.76-1.90; p=0.44, and 26.3% vs. 22.3%; HR 1.14, 95% CI: 0.80-1.62; p=0.47, respectively). At five years, within the overlap group, patients who received BMS had a trend towards a higher rate of PoCE and DoCE as compared to those who received EES. At one year, there was a trend towards a higher rate of definite/probable stent thrombosis in the overlap compared to the no-overlap group (2.2% vs. 1.6%; HR 2.35, 95% CI: 0.95-5.90; p=0.06). This difference was driven by a higher rate for BMS compared to EES (4.4% vs. 0%, p for interaction=0.03) in the overlap group. At five years, the absolute risk difference for overlap (3.5% vs. 2.2%, p=0.99) and interaction for BMS (p=0.03) were similar. CONCLUSIONS: In patients presenting with STEMI, the long-term PoCE was similar for the overlap and no-overlap groups. Overlap among patients receiving BMS appears to be associated with a higher risk for adverse cardiovascular outcomes and stent thrombosis.

Serial optical coherence tomography assessment of malapposed struts after everolimus-eluting stent implantation. A subanalysis from the HEAL-EES study.

BACKGROUND: Incomplete stent apposition (ISA) is related to stent thrombosis, which is a serious adverse event. We aim to assess the time-course of ISA after 2nd generation everolimus-eluting stent (EES) implantation. METHODS: In HEAL-EES study, we enrolled 36 patients who underwent percutaneous coronary intervention (PCI) with EES. OCT imaging was performed at baseline and follow-up. Patients were randomized 1:1:1 into 3 groups according to the time in which follow-up was performed: group A (6-month), group B (9-month), and group C (12-month). In this subanalysis, patients who had ISA segments at baseline and/or follow-up OCT were analyzed. RESULT: At baseline, among 41 lesions in 36 patients, 20 lesions in 18 patients had ISA segments and were analyzed. At baseline, there were 3.0% ISA struts in group A (n=8), 2.8% in group B (n=4), and 4.5% in group C (n=8). At follow-up, ISA struts were present in 0.09%, 0.16% and 0.64%; respectively in groups A, B, and C. At follow-up, there was a significant decrease in the frequency of ISA: group A 3.0% vs. 0.09% (p<0.001), group B 2.8% vs. 0.16% (p<0.001), and group C 4.5% vs. 0.64% (p<0.001). In group A, there was one late acquired ISA at follow-up. CONCLUSIONS: In patients undergoing 2nd generation EES implantation, area of acute ISA assessed by OCT, was almost resolved at 6-month follow-up.