Potential value of saline-induced Pd/Pa ratio in patients with coronary artery stenosis.

Background: Fractional flow reserve (FFR) is the current gold standard for identifying myocardial ischemia in individuals with coronary artery stenosis. However, FFR is not penetrated as much worldwide due to time consumption, costs associated with adenosine, FFR-related discomfort, and complications. Resting physiological indexes may be widely accepted alternatives to FFR, while the discrepancies with FFR were found in up to 20% of lesions. The saline-induced Pd/Pa ratio (SPR) is a new simplified option for evaluating coronary stenosis. However, the clinical implication of SPR remains unclear. Objectives: In the present study, we aimed to compare the accuracies of SPR and resting full-cycle ratio (RFR) and to investigate the incremental value of SPR in clinical practice. Methods: In this multicenter prospective study, 112 coronary lesions (105 patients) were evaluated by SPR, RFR, and FFR. Results: The overall median age was 71 years, and 84.8% were men. SPR was correlated more strongly with FFR than with RFR (r = 0.874 vs. 0.713, respectively; p < 0.001). Using FFR < 0.80 as the reference standard variable, the area under the receiver-operating characteristic (ROC) curve for SPR was superior to that of RFR (0.932 vs. 0.840, respectively; p = 0.009). Conclusion: Saline-induced Pd/Pa ratio predicted FFR more accurately than RFR. SPR could be an alternative method for evaluating coronary artery stenosis and further investigation including elucidation of the mechanism of SPR is needed (225 words).

Coronary Artery Aneurysm Caused by a Stent Fracture.

Coronary stent fracture (SF) is rare as a complication of percutaneous coronary intervention (PCI), and its adverse events are increasingly being recognized with the development in devices of PCI. The major adverse events caused by SFs are in-stent restenosis due to neointimal overgrowth caused by poor drug delivery.1,2) A coronary artery aneurysm (CAA) is a rare complication of SF, but may lead to lethal events such as acute coronary syndrome or rupture of the CAA further leading to cardiac tamponade.3-5) However, the management of CAAs is controversial with or without SF.6) Herein, we report a case of a CAA caused by an SF and discuss the management of CAA complicated with SF, along with a literature review. We suggest that surgical treatment should be considered the higher-priority strategy in the cases of CAA with SF as compared to CAA without SF.

Is it possible to perform gastric endoscopic submucosal dissection without discontinuation of a single antiplatelet of thienopyridine derivatives?

BACKGROUND AND STUDY AIMS: Combined use of thienopyridine derivatives and other antithrombotic agents is reported to be a risk factor for postoperative bleeding after gastric endoscopic submucosal dissection (ESD). However, risk associated with a single thienopyridine derivative has not been evaluated. In this study, we aimed to evaluate bleeding risks of gastric ESD without discontinuation of a single thienopyridine derivative agent. PATIENTS AND METHODS: This multicenter, prospective, observational cohort study included patients who had undergone implantation of a coronary artery stent and who were taking a combination of aspirin antiplatelet therapy and a thienopyridine derivative agent. Enrolled patients discontinued aspirin and underwent gastric ESD without the discontinuation of a single thienopyridine derivative agent. The primary endpoint was the major bleeding complication rate after gastric ESD. RESULTS: Eleven patients were enrolled in this study from April 2015 to November 2016 after written informed consent was obtained. Among them, 1 patient, who had undergone surgery for a primary cardiac tumor before ESD, was excluded from the study. Ten patients underwent gastric ESD for neoplasms. En-bloc resections were achieved in all cases without intraoperative bleeding complications. Two patients experienced postoperative bleeding although neither case required a blood transfusion (95 % CI 2.5 - 55.6 %). CONCLUSION: En-bloc resections were possible although the postoperative bleeding rate tended to be higher in gastric ESD without discontinuation of a single thienopyridine derivative agent. Additional preventive measures are mandatory to carry out safe gastric ESD in such settings.

Identification of the State of Maximal Hyperemia in the Assessment of Coronary Fractional Flow Reserve Using Non-Invasive Electrical Velocimetry.

Previous research revealed that, in patients with coronary pressure-derived fractional flow reserve (FFR) in the 'grey zone' (0.75-0.85), repeated FFR assessments sometimes yield conflicting results. One of the causes of the fluctuations in FFR values around the grey zone may be imprecise identification of the point where maximal hyperemia is achieved. Identification of the state of maximal hyperemia during assessment of FFR can be challenging. This study aimed to determine whether non-invasive electrical velocimetry (EV) can be used to identify the state of maximal hyperemia.Stroke volume (SV), SV variation (SVV), and systemic vascular resistance index (SVRI) were determined by EV in 15 patients who underwent FFR assessment. Time intervals from initiation of adenosine infusion to achieving maximal hyperemia (timemFRR), as well as to achieving maximal cardiac output (CO), SV, SVV, and SVRI (timemCO, timemSV, timemSVV, and timemSVRI, respectively), were determined. TimemCO and timemSVV were closer to timemFRR than other values (timemSVV/timemFRR versus timemSVRI/timemFRR = 1.03 ± 0.2 versus 1.36 ± 0.4, P < 0.05). The maximum of SV was difficult to determine owing to considerable variations, but the maximum of SVV was clearly recognized. TimemCO and timemSVV were significantly correlated with timemFFR, with timemSVV showing a stronger correlation than timemSV (timemSVV: r = 0.92, P < 0.01; timemCO: r = 0.80, P < 0.01).Maximal SVV is reached close to maximal hyperemia. Monitoring of SVV with non-invasive EV during FFR assessment can help identify the state of maximal hyperemia.

Feasibility of Extracorporeal Shock Wave Myocardial Revascularization Therapy for Post-Acute Myocardial Infarction Patients and Refractory Angina Pectoris Patients.

Extracorporeal shockwave myocardial revascularization (ESMR) is one of the new treatment options for refractory angina pectoris (RAP), and some studies have indicated its effectiveness. A single-arm prospective trial to assess the feasibility of ESMR using Cardiospec for patients with post-acute myocardial infarction (AMI) and RAP was designed and performed. The patients were treated with 9 sessions of ESMR to the ischemic areas for 9 weeks. The feasibility measures included echocardiography; cardiac magnetic resonance imaging; troponin T, creatine kinase-MB (CK-MB), and brain natriuretic peptide testing; and a Seattle Angina Questionnaire (SAQ) survey. Three post-AMI patients and 3 RAP patients were enrolled. The post-AMI patients had already undergone revascularization with percutaneous coronary intervention (PCI) in the acute phase. In two patients, adverse events requiring admission occurred: one a lumbar disc hernia in a post-AMI patient and the other congestive heart failure resulting in death in an RAP patient. No apparent elevations in CK-MB and troponin T levels during the trial were observed. Echocardiography revealed no remarkable changes of ejection fraction; however, septal E/E' tended to decrease after treatments (11.6 ± 4.8 versus 9.2 ± 2.8, P = 0.08). Concerning the available SAQ scores for two RAP patients, one patient reported improvements in angina frequency and treatment satisfaction and the other reported improvements in physical limitations and angina stability. In this feasibility study, ESMR seems to be a safe treatment for both post-AMI patients and RAP patients. The efficacy of ESMR for post-AMI patients remains to be evaluated with additional studies.

Serum neutrophil gelatinase-associated lipocalin concentration reflects severity of coronary artery disease in patients without heart failure and chronic kidney disease.

Serum neutrophil gelatinase-associated lipocalin (NGAL) is recognized as a useful biomarker for acute kidney injury. Recently, elevated NGAL levels were reported in patients with heart failure and cardiac events, but the association between serum NGAL and severity of coronary artery disease (CAD) has not been investigated adequately. This study aimed to evaluate the association between serum NGAL concentration and CAD severity in patients without heart failure and chronic kidney disease. Two-hundred thirteen patients [mean age: 66.2 ± 9.2 (SD)] without heart failure and chronic kidney disease (estimated glomerular filtration rate >60 mL/min/1.73 m(2)) who underwent coronary angiography were retrospectively analyzed using the SYNTAX score. The mean concentration of serum NGAL was 134.3 ± 111.3 ng/mL. A statistically significant correlation was observed between serum NGAL levels and the SYNTAX score (R = 0.18, P = 0.0091). Multivariable analysis also showed elevated serum NGAL as an independent risk factor for a high SYNTAX score (P < 0.01). Moreover, we evaluated the association of serum NGAL and brain natriuretic peptide (BNP) with the SYNTAX score. Patients with high levels of serum NGAL (>100 ng/mL) and high levels of BNP (>25 pg/mL) had a higher SYNTAX score (low-low vs. high-high: 13.8 ± 13.4 vs. 20.8 ± 18.9, P < 0.05). Serum NGAL levels were positively and significantly associated with CAD severity, and the evaluation of both serum NGAL and BNP was useful for predicting CAD in patients without renal dysfunction and heart failure. Serum NGAL might be a biomarker for CAD severity.

Plasma neutrophil gelatinase-associated lipocalin predicts major adverse cardiovascular events after cardiac care unit discharge.

BACKGROUND: Emerging acute kidney injury biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), have a high potential for predicting worsening renal function. Acute exacerbation of renal dysfunction has a great impact on the outcomes of cardiovascular patients in critical conditions. This study aimed to evaluate whether plasma NGAL can predict the mortality and major adverse cardiovascular events (MACEs) after discharge from the cardiac care unit (CCU). METHODS: Patients who were admitted to the CCU of the Tokyo University Hospital were prospectively enrolled (101 patients). Blood and urinary markers, including the blood NGAL, brain natriuretic peptide, creatinine, cystatin C, urinary albumin, N-acetyl-ß-d-glucosaminidase, and L-type fatty acid-binding protein, were measured at CCU discharge. The primary outcome was MACEs until at least 6 months after CCU discharge. RESULTS: Thirty-five patients experienced MACEs (35%). Multivariate logistic analysis revealed that the plasma NGAL, length of CCU stay, and existence of diabetes and heart failure were independent predicting factors for MACEs. Patients with the highest NGAL at discharge (>75th percentile) showed a significantly higher risk of MACEs than those with the lowest NGAL (<25th percentile) (log-rank test; hazard ratio, 5.15; 95% confidence interval 1.84-18.20; p<0.01). CONCLUSION: Plasma NGAL at CCU discharge is a significant prognostic indicator of outcomes at 6 months in critically ill cardiac patients treated in a CCU.

Impact of the distance from the stent edge to the residual plaque on edge restenosis following everolimus-eluting stent implantation.

OBJECTIVES: This study aimed to assess the relation between stent edge restenosis (SER) and the distance from the stent edge to the residual plaque using quantitative intravascular ultrasound. BACKGROUND: Although percutaneous coronary intervention with drug-eluting stents has improved SER rates, determining an appropriate stent edge landing zone can be challenging in cases of diffuse plaque lesions. It is known that edge vascular response can occur within 2 mm from the edge of a bare metal stent, but the distance to the adjacent plaque has not been evaluated for drug-eluting stents. METHODS: A total of 97 proximal residual plaque lesions (plaque burden [PB] >40%) treated with everolimus-eluting stents were retrospectively evaluated to determine the distance from the stent edge to the residual plaque. RESULTS: The SER group had significantly higher PB (59.1 ± 6.1% vs. 51.9 ± 9.1% for non-SER; P = 0.04). Higher PB was associated with SER, with the cutoff value of 54.74% determined using receiver operating characteristic (ROC) curve analysis. At this cutoff value of PB, the distance from the stent edge to the lesion was significantly associated with SER (odds ratio = 2.05, P = 0.035). The corresponding area under the ROC curve was 0.725, and the cutoff distance value for predicting SER was 1.0 mm. CONCLUSION: An interval less than 1 mm from the proximal stent edge to the nearest point with the determined PB cutoff value of 54.74% was significantly associated with SER in patients with residual plaque lesions.

Midterm follow-up after retrievable inferior vena cava filter placement in venous thromboembolism patients with or without malignancy.

BACKGROUND: A clear indication and strategy for placement of retrievable inferior vena cava filters (IVCFs) have not been established. This study was designed to evaluate the efficacy and disadvantages of the retrievable IVCF use particularly in venous thromboembolism (VTE) patients with malignancy. HYPOTHESIS: Retrievable IVCFs might be safe and useful in VTE patients with malignancy. METHODS: The study population consisted of 56 consecutive patients undergoing IVCF placement at our institution from January 1, 2008 to December 31, 2011. Prognostic data were retrospectively reviewed in April 2013. RESULTS: Mean follow-up period was 584.6 (range, 1-1857) days. Twenty-six of the 56 patients had a malignancy. In 16 of the 30 patients without malignancy, the filter was retrieved, whereas the other 14 patients eventually received permanent implantation. There was no significant difference in the survival rate between the retrieval group and the nonretrieval group in the nonmalignancy patients (1-year survival rates, 94% vs 85%). In patients with malignancy, the nonretrieval group showed a significantly lower survival rate (P < 0.01). The 1-year and 2-year survival rates were 100% vs 46% and 100% vs 18%, respectively. There was no medical record of pulmonary thromboembolism occurrence or recurrence. All deaths in the patients with malignancy were malignancy related. In 4 of 5 malignancy patients who could undergo tumor resection surgery, adequate thrombus regression enabled us to retrieve the IVCF after surgery. CONCLUSIONS: Permanent use of a retrievable IVCF is relatively safe in short- or midterm follow-up regardless of malignancy status. Retrievable filter use might be reasonable in malignancy patients.

Involvement of P2Y12 receptor in vascular smooth muscle inflammatory changes via MCP-1 upregulation and monocyte adhesion.

Antiplatelet drugs, frequently used for cardiovascular events with thrombotic involvement, are also regarded as possible promising agents for cardiovascular primary prevention. The roles of P2Y12, an ADP receptor and the target of thienopyridine antiplatelet drugs, are not satisfactorily known in the vascular wall. We investigated the hypothesis that vascular smooth muscle cell (VSMC) P2Y12 is involved in vascular wall inflammatory changes by upregulating monocyte chemoattractant protein-1 (MCP-1) and promoting monocyte adhesion. ADP at 10(-5) M induced a 3.6 ± 0.3-fold upregulation of MCP-1 mRNA in cultured rat VSMCs, which was significantly inhibited by R-138727, the active metabolite of P2Y12 inhibitor prasugrel and siRNAs against P2Y12. ADP also induced MCP-1 protein upregulation, which was diminished by R-138727 and P2Y12 siRNAs. JNK (c-Jun NH2-terminal kinase) inhibition attenuated ADP-induced MCP-1 mRNA and protein upregulation. R-138727 and P2Y12 siRNAs inhibited ADP-induced JNK activation. The reactive oxygen species (ROS) inhibitors N-acetylcysteine (NAC), diphenyleneiodonium (DPI), and Tempol also diminished MCP-1 upregulation and JNK activation induced by ADP. ADP induced MCP-1 promoter activation, which was inhibited by R-138727 and P2Y12 siRNAs. Nuclear factor-κB (NF-κB) consensus sites in the MCP-1 promoter region were involved in this activation. ADP-induced NF-κB pathway activation, examined by a plasmid containing multiple NF-κB sites, was diminished by P2Y12 inhibition. For cellular function analysis, stimulation of VSMC with ADP increased subsequent THP-1 monocyte adhesion. P2Y12 siRNAs and CCR2 antagonism diminished this ADP-induced monocyte adhesion. These data suggested that ADP, via the VSMC P2Y12 receptor, induces vascular inflammatory changes by upregulating MCP-1 and promoting monocyte adhesion.

Response of urinary liver-type fatty acid-binding protein to contrast media administration has a potential to predict one-year renal outcome in patients with ischemic heart disease.

Urinary liver-type fatty acid-binding proteins (uL-FABP) have recently been recognized as a useful biomarker for predicting contrast-induced nephropathy. Although accumulating studies have evaluated short-term outcomes, its prognostic value for long-term renal prognosis in patients undergoing coronary angiography (CAG) has not been fully examined. This study aimed to evaluate the predictive value of uL-FABP for long-term renal outcome in patients with ischemic heart disease (IHD). Consecutive 24 patients with impaired renal function (serum creatinine >1.2 mg/dL) who underwent CAG were enrolled. uL-FABP was measured before CAG, 24 and 48 h after CAG. The changes in estimated glomerular filtration rate (eGFR) throughout CAG and at 1 year later were compared with the uL-FABP levels. The patients with a greater decrease in eGFR 1 year later had higher uL-FABP levels at all points, but only the value at 48 h after CAG reached statistical significance (lower vs. higher decreased eGFR group, 4.61 ± 3.87 vs. 17.71 ± 12.96; P < 0.01). Measurement of uL-FABP at 48 h after CAG (48h-uL-FABP) showed better correlation with the change in eGFR (pre-CAG uL-FABP vs. 48h-uL-FABP: R = 0.27, P = 0.20 vs. R = 0.65, P < 0.01). Moreover, the high-pre and high-48h-uL-FABP group showed a significantly larger decrease in eGFR compared with the high-pre and low-48h-uL-FABP group (change in eGFR; 8.12 ± 4.06 vs. 1.25 ± 2.23 mL/min/1.73 m2, P < 0.01), although the baseline eGFR levels were similar between these two groups. In this pilot study, measurement of uL-FABP levels at 48 h after CAG may be useful in detecting renal damage, and in predicting 1-year renal outcome in IHD patients undergoing CAG.

Effect of purified eicosapentaenoic acid on red cell distribution width in patients with ischemic heart disease.

A recent study showed eicosapentaenoic acid (EPA) is a promising treatment for prevention of coronary events in hypercholesterolemic patients. Meanwhile, a high red blood cell distribution width (RDW) is a known risk factor for cardiovascular events. However, few studies have addressed the association between EPA levels and RDW. We examined whether EPA administration reduced the levels of RDW in patients with ischemic heart disease (IHD). We retrospectively analyzed the data of 66 EPA-treated IHD patients, and these EPA-treated patients were compared with control IHD patients. The median follow-up period was 189 days in EPA-treated patients. All patients were not associated with anemia. In the follow-up period, the ratio of EPA levels to arachidonic acid levels (EPA/AA) was significantly increased. A significant decrease was observed in RDW at follow-up [ΔRDW (%); EPA vs. control = -0.34 ± 0.84 (SD) vs. 0.08 ± 0.86, P < 0.01]. These RDW changes were more marked in diabetic patients with high serum levels of high-sensitive C-reactive protein (hs-CRP) [ΔRDW (%); EPA vs. control = -0.53 ± 0.69 vs. 0.56 ± 0.85, P < 0.01]. There was no correlation between the amount of change in EPA/AA and RDW (R = 0.037, P = 0.32), but a significant negative correlation was observed in diabetic patients with high hs-CRP levels (N = 14, R = -0.506, P = 0.046). In conclusion, EPA has the potential to reduce RDW in IHD patients. This effect was intensified especially among diabetic patients with high hs-CRP levels. IHD patients with high RDW levels may be suitable for treatment with purified EPA.

Telmisartan activates endothelial nitric oxide synthase via Ser1177 phosphorylation in vascular endothelial cells.

Because endothelial nitric oxide synthase (eNOS) has anti-inflammatory and anti-arteriosclerotic functions, it has been recognized as one of the key molecules essential for the homeostatic control of blood vessels other than relaxation of vascular tone. Here, we examined whether telmisartan modulates eNOS function through its pleiotropic effect. Administration of telmisartan to mice significantly increased the phosphorylation level of eNOS (Ser1177) in the aortic endothelium, but administration of valsartan had no effect. Similarly, telmisartan treatment of human umbilical vein endothelial cells significantly increased the phosphorylation levels of AMP-activated protein kinase (Thr172) and eNOS and the concentration of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). Furthermore, pretreatment with a p38 mitogen-activated protein kinase (p38 MAPK) inhibitor suppressed the increased phosphorylation level of eNOS and intracellular cGMP concentration. These data show that telmisartan increases eNOS activity through Ser1177 phosphorylation in vascular endothelial cells mainly via p38 MAPK signaling.

Prognostic implication of macrocytosis on adverse outcomes after coronary intervention.

BACKGROUND: Macrocytosis, as a qualitative abnormality of erythrocytes, has not drawn attention as a prognostic indicator after PCI, while anemia, as a quantitative abnormality of erythrocytes, has been recognized as a predictor of adverse outcomes. The aim of this study was to perform prognostic risk stratification of patients after PCI based on the presence or absence of macrocytosis. METHODS: The clinical records of 941 consecutive patients who underwent PCI at a single institution were retrospectively reviewed. The prognostic implication of macrocytosis was evaluated by univariate and multivariate Cox's proportional hazard regression analysis. RESULTS: There were 130 (13.8%) patients with macrocytosis. A significantly higher all-cause and cardiac mortality, as well as incidence of composite adverse events were observed in the Macrocytic group. Kaplan-Meier analysis also showed a significantly poorer overall survival in patients with macrocytosis. Even after exclusion of anemic patients, this tendency was still observed. Furthermore, macrocytosis was significantly and independently associated with adverse outcomes after PCI (aHR of cardiac death: 3.45, 95%CI: 1.22-9.80, P=0.019). Interestingly, fewer patients with macrocytosis were prescribed statins compared with those without it (33.8% vs. 47.1%, P=0.005). CONCLUSIONS: The results of the study indicate that measuring mean corpuscular volume (MCV) as a qualitative index of erythrocytes might be helpful for a prognostic risk stratification of patients subjected to PCI.

Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element.

Osteopontin (OPN) is known to be one of the cytokines that is involved in the vascular inflammation caused by aldosterone (Aldo). Previous reports have shown that Aldo increases OPN transcripts, and the mechanisms for this remain to be clarified. In this study, we investigated how Aldo increases OPN transcripts in the vascular smooth muscle cells of rats. Aldosterone increased OPN transcripts time-dependently as well as dose-dependently. This increase was diminished by eplerenone, a mineralocorticoid receptor (MR) antagonist. Luciferase promoter assays showed that the OPN promoter deleted to the -1599 site retained the same promoting ability as the full-length OPN promoter when stimulated by 10(-7) M Aldo, but the promoter deleted to the -1300 site lost the promoting ability. A glucocorticoid response element (GRE) is located in that deleted region. Luciferase assays of a mutated promoter without the GRE lost the luciferase upregulation, although mutated promoters with the deletion of other consensus sites maintained the promoter activity. The binding of the Aldo-MR complex to the GRE fragment was confirmed by an electrophoretic-mobility shift assay. This is the first report showing that Aldo regulates the transcriptional levels of OPN and inflammatory responses in the vasculature through a specific GRE site in the OPN promoter region.