Serial longitudinal changes of coronary calcified plaques with clear outer borders under intensive lipid management: insights from optical coherence tomography.

Percutaneous coronary intervention (PCI) for calcified lesions is one of the most challenging procedures related to worse clinical outcomes. To stabilize vulnerable plaques, intensive lipid management is recommended; however, the serial changes of calcified plaques under intensive lipid management are unknown. A total of 31 patients (mean age, 63 ± 10 years; men, 29 patients) who underwent PCI with intensive lipid management were retrospectively studied. We evaluated the serial longitudinal changes of calcified plaques with clear outer borders using optical coherence tomography (OCT) at two time points: at the time of PCI (baseline) and the chronic phase. The median interval from PCI to chronic phase was 287 (233-429) days. Twenty-eight patients (90.3%) had increased calcium volume at the chronic phase compared with those at baseline (2.6 [1.3-5.1] vs. 1.8 [0.7-4.3] mm2, p < 0.05), and the median increase rate of calcium volume was 27.4% at the chronic phase. According to the median increase rate of calcium volume (27.4%), patients were divided into the following two groups: rapid progression (≥ 27.4%, RP group) and non-rapid progression (< 27.4%, non-RP group). The RP group had more patients with diabetes, and diabetes was independently associated with rapid progression by multivariate analysis. Furthermore, patients with diabetes had significantly higher changes in calcium index and volume from the baseline to the chronic phase than those without diabetes. Coronary calcification progression during relatively short intervals was observed using OCT even under intensive lipid management. Diabetes was an independent predictor for rapid coronary calcification progression.

Incidence, Predictors, and Outcome Associated With Ventricular Tachycardia or Fibrillation in Patients Undergoing Primary Percutaneous Coronary Intervention for Acute Myocardial Infarction.

BACKGROUND: The characteristics and clinical outcomes associated with sustained ventricular tachycardia and fibrillation (VT/VF) in Japanese acute myocardial infarction (AMI) patients remain unknown.Methods and Results: Consecutive AMI patients (n=1,941) transferred to the Hirosaki University Hospital and treated with primary percutaneous coronary intervention (PCI) within 12 h of onset were retrospectively studied. The incidence of VT/VF during hospitalization was 8.3%, and 75% of cases occurred by the end of PCI. Independent predictors associated with VT/VF occurrence by the end of PCI and after PCI, respectively, were identified. Additionally, the differences between patients with VT and VF were examined, which revealed that the characteristics of patients and predictors for VT and VF were clearly different. Additionally, the QRS duration during VT was measured, which demonstrated the possible involvement of Purkinje fibers for VT in the acute phase of AMI. Of the patients with VT/VF, 12% required ECMO support due to refractory VT/VF despite intravenous antiarrhythmic agents such as ß-blockers, amiodarone, and nifekalant. Among the patients discharged alive, 1,690 were followed up for a mean of 3.7 years. VT/VF occurrence during hospitalization did not affect the mid-term clinical outcomes even in patients with VT. CONCLUSIONS: The results clearly indicated that VT/VF is still a serious complications of AMI. We need to identify patients at high risk of developing VT/VF for careful observation and appropriate intervention.

Reduced Left Ventricular Ejection Fraction Is a Risk for Sudden Cardiac Death in the Early Period After Hospital Discharge in Patients With Acute Myocardial Infarction.

BACKGROUND: The incidence of sudden cardiac death (SCD) after discharge in Japanese acute myocardial infarction (AMI) patients with reduced left ventricular ejection fraction (LVEF) treated with primary percutaneous coronary intervention (PCI) remains unknown.Methods and Results:The study population included 1,429 AMI patients (199 with LVEF ≤35% and 1,230 with LVEF >35%) admitted to the Hirosaki University Hospital, treated with primary PCI within 12 h after onset, and survived to discharge. LVEF was evaluated in all patients before discharge, and the patients were followed up for a mean of 2.6±0.8 years. The Kaplan-Meier survival curves revealed LVEF ≤35% was associated with all-cause death and SCD. The incidence of SCD was 2.6% at 1 year and 3.1% at 3 years in patients with LVEF ≤35%, whereas it was 0.1% at 1 year and 0.3% at 3 years in patients with LVEF >35%. Sixty-seven percent of SCDs in patients with LVEF ≤35% occurred within 4 months after discharge, and the events became less frequent after this period. A Cox proportional hazard model indicated LVEF ≤35% as an independent predictor for all-cause death and SCD. CONCLUSIONS: The incidence of SCD was relatively low in Japanese AMI patients treated with primary PCI, even in patients with LVEF ≤35% upon discharge. Careful management of patients with reduced LVEF is required to prevent SCD, especially in the early phase after discharge.

Diltiazem Inhibits Coronary Spasm via Inhibition of Cav1.2Phosphorylation and Protein Kinase C Activation in a Mouse Model of Coronary Spastic Angina.

Calcium antagonists are used for coronary spastic angina (CSA) treatment. We previously identified a phospholipase C (PLC) -δ1 gene variant that results in enhanced PLC activity in patients with CSA and developed a CSA animal model by generating vascular smooth muscle cell-specific human variant PLC-δ1 overexpression (PLC-TG) mice. In this study, we investigated the molecular mechanism of CSA using the PLC-TG mice and the inhibitory effect of a calcium antagonist, diltiazem hydrochloride (DL).We treated the PLC-TG and wild-type (WT) mice with oral DL or trichlormethiazide (TM) (control) for 2 weeks. Ergometrine injection-induced coronary spasm was observed on the electrocardiogram in all 5 PLC-TG mice treated with TM, but only in 1 of 5 PLC-TG mice treated with DL. Voltage-dependent calcium channel (Cav1.2) phosphorylation and protein kinase C (PKC) activity were enhanced in the aortas of PLC-TG mice treated with TM. DL treatment significantly inhibited Cav1.2 phosphorylation and PKC activity. Although total Cav1.2 expression was similar between WT and PLC-TG mice treated with TM, DL treatment significantly increased its expression in PLC-TG mice. Furthermore, its expression remained high after DL discontinuation. DL and PKC inhibitor suppressed intracellular calcium response to acetylcholine in cultured rat aortic smooth muscle cells transfected with variant PLC-δ1.These results indicate that enhanced PLC activity causes coronary spasm, presumably via enhanced Cav1.2 phosphorylation and PKC activity, both of which were inhibited by DL. Enhanced total Cav1.2 expression after DL discontinuation and high PKC activity may be an important mechanism underlying the calcium antagonist withdrawal syndrome.

Rivaroxaban attenuates cardiac hypertrophy by inhibiting protease-activated receptor-2 signaling in renin-overexpressing hypertensive mice.

Rivaroxaban (Riv), a direct factor Xa (FXa) inhibitor, exerts anti-inflammatory effects in addition to anticoagulation. However, its role in cardiovascular remodeling is largely unknown. We tested the hypothesis that Riv attenuates the progression of cardiac hypertrophy and fibrosis induced by continuous activation of the renin-angiotensin system (RAS) in renin-overexpressing hypertensive transgenic (Ren-Tg) mice. We treated 12-week-old male Ren-Tg and wild-type (WT) mice with a diet containing Riv (12 mg/kg/day) or a regular diet for 4 weeks. After this, FXa in plasma significantly increased in Ren-Tg mice compared with WT mice, and Riv inhibited this increase. Left ventricular wall thickness (LVWT) and the area of cardiac fibrosis evaluated by Masson's trichrome staining were greater in Ren-Tg mice than in WT mice, and Riv decreased them. Cardiac expression levels of the protease-activated receptor (PAR)-2, tumor necrosis factor-α, transforming growth factor (TGF)-ß1, and collagen type 3 α1 (COL3A1) genes were all greater in Ren-Tg mice than in WT mice, and Riv attenuated these increases. To investigate the possible involvement of PAR-2, we treated Ren-Tg mice with a continuous subcutaneous infusion of 10 µg/kg/day of the PAR-2 antagonist FSLLRY for 4 weeks. FSLLRY significantly decreased LVWT and cardiac expression of PAR-2, TGF-ß1, and COL3A1. In isolated cardiac fibroblasts (CFs), Riv or FSLLRY pretreatment inhibited the FXa-induced increase in the phosphorylation of extracellular signal-regulated kinases. In addition, Riv or FSLLRY inhibited FXa-stimulated wound closure in CFs. Riv exerts a protective effect against cardiac hypertrophy and fibrosis development induced by continuous activation of the RAS, partly by inhibiting PAR-2.

Clinical impact of complete atrioventricular block in patients with ST-segment elevation myocardial infarction.

Complete atrioventricular block (CAVB) is a common complication of ST-segment elevation myocardial infarction (STEMI). Although STEMI patients complicated with CAVB had a higher mortality in the thrombolytic era, little is known about the impact of CAVB on STEMI patients who underwent primary percutaneous coronary intervention (PCI). The study aimed at evaluating the clinical impact of CAVB on STEMI patients in the primary PCI era. We consecutively enrolled 1295 STEMI patients undergoing primary PCI within 24 hours from onset. Patients were divided into two groups according to the infarct location: anterior STEMI (n = 640) and nonanterior STEMI (n = 655). The outcomes were all-cause death and major adverse cardiocerebrovascular events (MACCE) with a median follow-up period of 3.8 (1.7-6.6) years. Eighty-one patients (6.3%) developed CAVB. The incidence of CAVB was lower in anterior STEMI patients than in nonanterior STEMI (1.7% vs 10.7%, p < .05). Anterior STEMI patients with CAVB had a higher incidence of all-cause deaths (82% vs 20%, p < .05) and MACCE (82% vs 25%, p < .05) than those without CAVB. Although higher incidence of all-cause deaths was found more in nonanterior STEMI patients with CAVB compared with those without CAVB (30% vs 18%, p < .05), there was no significant difference in the incidence of MACCE (24% vs 19%). Multivariate analysis showed that CAVB was an independent predictor for all-cause mortality and MACCE in anterior STEMI patients, but not in nonanterior STEMI. CAVB is rare in anterior STEMI patients, but remains a poor prognostic complication even in the primary PCI era.

Clinical Outcomes of Acute Myocardial Infarction Patients With a History of Malignant Tumor.

BACKGROUND: Little is known about the clinical outcomes of acute myocardial infarction (AMI) in patients with a history of malignant tumor (MT). PATIENTS AND METHODS: We retrospectively studied 1,295 consecutive patients with AMI who underwent primary percutaneous coronary intervention within 24 hours of onset. The patients were divided into two groups: those with a history of MT (MT group, n=50) and those without (non-MT group, n=1,245). RESULTS: The MT group was older, and had lower hemoglobin, total protein, and albumin levels. All-cause mortality and re-admission rates due to acute decompensated heart failure (ADHF) were significantly higher in the MT group. Multivariate analysis showed that a history of MT was an independent predictor for all-cause mortality and re-admission due to ADHF. CONCLUSION: The clinical outcomes of patients with AMI with a history of MT are poor, and a history of MT is an independent predictor for all-cause mortality and re-admission due to ADHF. These patients may need careful risk management for heart failure to avoid re-admissions due to ADHF.

Blockade of PAR-1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin-Overexpressing Hypertensive Mice.

Background Although PAR-1 (protease-activated receptor-1) exerts important functions in the pathophysiology of the cardiovascular system, the role of PAR-1 signaling in heart failure development remains largely unknown. We tested the hypothesis that PAR-1 signaling inhibition has protective effects on the progression of cardiac remodeling induced by chronic renin-angiotensin system activation using renin-overexpressing hypertensive (Ren-Tg) mice. Methods and Results We treated 12- to 16-week-old male wild-type (WT) mice and Ren-Tg mice with continuous subcutaneous infusion of the PAR-1 antagonist SCH79797 or vehicle for 4 weeks. The thicknesses of interventricular septum and the left ventricular posterior wall were greater in Ren-Tg mice than in WT mice, and SCH79797 treatment significantly decreased these thicknesses in Ren-Tg mice. The cardiac fibrosis area and monocyte/macrophage deposition were greater in Ren-Tg mice than in WT mice, and both conditions were attenuated by SCH79797 treatment. Cardiac mRNA expression levels of PAR-1, TNF-α (tumor necrosis factor-α), TGF-ß1 (transforming growth factor-ß1), and COL3A1 (collagen type 3 α1 chain) and the ratio of ß-myosin heavy chain (ß-MHC) to α-MHC were all greater in Ren-Tg mice than in WT mice; SCH79797 treatment attenuated these increases in Ren-Tg mice. Prothrombin fragment 1+2 concentration and factor Xa in plasma were greater in Ren-Tg mice than in WT mice, and both conditions were unaffected by SCH79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation, and SCH79797 pretreatment abolished this enhancement. Furthermore, gene expression of PAR-1, TGF-ß1, and COL3A1 were enhanced by factor Xa, and all were inhibited by SCH79797. Conclusions The results indicate that PAR-1 signaling is involved in cardiac remodeling induced by renin-angiotensin system activation, which may provide a novel therapeutic target for heart failure.

Extraction of J-V, G/ω-V-f and C-V-f Characteristics for p-Type Silicon/Intrinsic Ultrananocrystalline Diamond/n-Type Nanocrystalline Iron Disilicide Heterojunction Photodiodes.

The production of p-type silicon/intrinsic ultrananocrystalline diamond/n-type nanocrystalline iron disilicide heterojunction devices was conducted via coaxial arc plasma deposition and pulsed laser deposition. The results of current density-voltage (J-V) curves justified a large leakage current along with minimal response under illumination. A recombination process controls the mechanism for carrier portage in the zone of V ≤ 0.16 V, while a space-charge-limited current process governs the carrier portage mechanism in the circumstance of V value beyond 0.16 V. Frequency (f) dependent conductance (G/ω)-V and capacitance (C)-V curves were measured to extract the series resistance (Rs) and density of the interface state (nss). On the basis of extraction in the manner of Nicollian-Brews, the value of Rs rose with f abatement. With zero bias voltage applied, the value of Rs was 189.84 Ω at 2 MHz and rose to 715.10 Ω at 20 kHz. The acquired Rs may be attributable to the occurrence of Rs in the neutral zones as well as Ohmic contact. The values for nss, which were extracted in the manner of Hill-Coleman, were 1.23×1011 eV-1 cm-2 at 2 MHz and 6.51×1012 eV-1 cm-2 at 20 kHz. This result was an indicator of the occurrence of interface states at the zone of the junction interface performing as a source of leakage current and a trap center for the carriers originated by light.

Early intravenous beta-blockers in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: A patient-pooled meta-analysis of randomized clinical trials.

BACKGROUND: Conflicting evidence is available on the efficacy and safety of early intravenous beta-blockers before primary percutaneous coronary intervention for ST-segment elevation myocardial infarction. We performed a patient-pooled meta-analysis of trials comparing early intravenous beta-blockers with placebo or routine care in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. AIM: The aim of this study was to evaluate the clinical and safety outcomes of intravenous beta-blockers in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention. METHODS: Four randomized trials with a total of 1150 patients were included. The main outcome was one-year death or myocardial infarction. Secondary outcomes included biomarker-based infarct size, left ventricular ejection fraction during follow-up, ventricular tachycardia, and a composite safety outcome (cardiogenic shock, symptomatic bradycardia, or hypotension) during hospitalization. RESULTS: One-year death or myocardial infarction was similar among beta-blocker (4.2%) and control patients (4.4%) (hazard ratio: 0.96 (95% confidence interval: 0.53-1.75, p=0.90, I2=0%). No difference was observed in biomarker-based infarct size. One-month left ventricular ejection fraction was similar, but left ventricular ejection fraction at six months was significantly higher in patients treated with early intravenous beta-blockade (52.8% versus 50.0% in the control group, p=0.03). No difference was observed in the composite safety outcome or ventricular tachycardia during hospitalization. CONCLUSION: In ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention, the administration of early intravenous beta-blockers was safe. However, there was no difference in the main outcome of one-year death or myocardial infarction with early intravenous beta-blockers. A larger clinical trial is warranted to confirm the definitive efficacy of early intravenous beta-blockers.

Prognostic impact of body mass index and culprit lesion calcification in patients with acute myocardial infarction.

Patients with acute myocardial infarction (AMI) with low body mass index (BMI) have worse outcomes than obese patients, and this phenomenon is recognized as "obesity paradox." Coronary calcification is associated with cardiac events. However, the association between BMI and calcification and their involvement in the mortality of AMI patients remain unknown. This study consecutively enrolled 517 patients with AMI who underwent emergent coronary intervention within 24 h after onset. Patients were divided into four groups according to the baseline BMI interquartile ranges: Q1 (BMI < 21.9 kg/m2), Q2 (21.9 ≤ BMI < 24.0 kg/m2), Q3 (24.0 ≤ BMI < 26.0 kg/m2), and Q4 (BMI ≥ 26.0 kg/m2). Calcification in the culprit lesion was also evaluated. The Q1 group was older and had a lower frequency of coronary risk factors. Moderate/severe calcification was most frequently observed in Q1, followed by Q2, Q3, and Q4. The Q1 group had the highest all-cause mortality, and patients with moderate/severe calcification had a higher all-cause mortality than that in patients without calcification. The highest all-cause mortality was observed in Q1with calcification, and the lowest was in Q4 without calcification. Q1 and the presence of moderate/severe calcification were independently associated with all-cause mortality. Although low-BMI patients with AMI had a lower frequency of coronary risk factors, they had a worse all-cause mortality than that in high-BMI patients. Our findings suggest that lesion calcification and its possible association with low BMI are involved in the higher mortality rate in these patients.

IQGAP1 activates PLC-δ1 by direct binding and moving along microtubule with DLC-1 to cell surface.

Phospholipase C (PLC)-δ1, activated by p122RhoGTPase-activating protein (GAP)/deleted in liver cancer-1 (p122RhoGAP/DLC-1), contributes to the coronary spastic angina (CSA) pathogenesis. The present study aims to further investigate the p122RhoGAP/DLC-1 protein. We examined molecules assisting this protein and identified a scaffold protein-IQ motif-containing GTPase-activating protein 1 (IQGAP1). IQGAP1-C binds to the steroidogenic acute regulatory-related lipid transfer (START) domain of p122RhoGAP/DLC-1, and PLC-δ1 binds to IQGAP1-N, forming a complex. In fluorescence microscopy, small dots of PLC-δ1 created fine linear arrays like microtubules, and IQGAP1 and p122RhoGAP/DLC-1 were colocated in the cytoplasm with PLC-δ1. Ionomycin induced the raft recruitment of the PLC-δ1, IQGAP1, and p122RhoGAP/DLC-1 complex by translocation to the plasma membrane (PM), indicating the movement of this complex is along microtubules with the motor protein kinesin. Moreover, the IQGAP1 protein was elevated in skin fibroblasts obtained from patients with CSA, and it enhanced the PLC activity and peak intracellular calcium concentration in response to acetylcholine. IQGAP1, a novel stimulating protein, forms a complex with p122RhoGAP/DLC-1 and PLC-δ1 that moves along microtubules and enhances the PLC activity.

Prasugrel versus clopidogrel for residual thrombus burden in patients with ST-segment elevation myocardial infarction: an optical coherence tomography study.

BACKGROUND: Prasugrel was shown to inhibit platelet activity more rapidly and consistently than clopidogrel. We compared the effects of prasugrel and clopidogrel on residual thrombus burden assessed by optical coherence tomography after stent implantation in patients with ST-segment elevation myocardial infarction (STEMI). PATIENTS AND METHODS: A total of 76 patients with STEMI undergoing percutaneous coronary intervention (PCI) within 12 h after the onset were retrospectively enrolled. Of them, 34 patients were treated with prasugrel (loading dose, 20 mg) and the remaining 42 with clopidogrel (loading dose, 300 mg). Stent volume and in-stent thrombus volume were assessed by post-PCI optical coherence tomography. RESULTS: Baseline clinical characteristics, angiographic findings, and PCI procedure did not differ between the two groups. There was no difference in in-stent volume between patients with prasugrel and clopidogrel [169 (134-214) versus 166 (128-210) mm, P=0.83]. Patients with prasugrel had a significantly reduced in-stent thrombus volume compared with those with clopidogrel [0.59 (0.16-1.09) vs. 1.08 (0.32-2.30) mm, P=0.03]. The mean area and maximum area of in-stent thrombus were also significantly smaller in prasugrel than in clopidogrel group [0.03 (0.01-0.05) vs. 0.05 (0.01-0.10) mm, P=0.04, and 0.45 (0.27-0.75) vs. 0.77 (0.34-1.23) mm, P=0.03, respectively]. CONCLUSION: Prasugrel more effectively reduced residual thrombus burden after stent implantation in patients with STEMI, indicating a faster and more potent platelet inhibitory effect of prasugrel compared with clopidogrel.

Immediate effects of leg-press exercises with tibial internal rotation on individuals with medial knee osteoarthritis.

OBJECTIVE: Although patients with knee osteoarthritis (OA) demonstrate abnormal kinematics involving greater tibial external rotation during squatting, there have not been any previous studies investigating an exercise focused on correcting knee rotational kinematics. This study aimed to determine the immediate effects of exercise with tibial internal rotation (IR) on symptoms and functions in patients with knee osteoarthritis (KOA). METHODS: This study provides Level II evidence using a small randomized controlled trial. Sixty patients were allocated to either the tibial IR or neutral rotation (NR) group in this randomized controlled trial. The IR group performed a leg press activity with the tibia in maximal IR, whereas the NR group performed leg press activity with the tibia in NR. Outcome measures were (a) 10-m walk test; (b) Timed Up and Go test, (c) knee flexion angle while squatting, (d) knee pain during walking and squatting, and (e) difficulty during walking and squatting. RESULTS: Significant interaction was observed in all outcomes. The IR group exhibited significant improvement on all outcome measures, whereas the NR group exhibited significant improvements only in the 10-m walk. CONCLUSION: The IR group exhibited greater improvements than the NR group on all outcome measures. After a single session, leg press activity with the tibia in maximal IR improved the symptoms and functions measured in this study more effectively than leg press activity with the tibia in a neutral position. This suggests that correcting rotational malalignment is more important than strengthening the quadriceps for maintaining or even improving function of OA knees. (Clinical trials registration number: UMIN000021751).

Relationship Between Serum Eicosapentaenoic Acid Levels and J-Waves in a General Population in Japan.

We previously showed that J-waves were found more frequently in patients with low levels of serum eicosapentaenoic acid (EPA) in the acute phase of myocardial infarction, and were associated with the incidence of ischemia-related ventricular arrhythmias. However, the relationship between J-waves and serum EPA levels in a general population remains to be elucidated.The Iwaki Health Promotion Project is an ongoing community-based health promotion study in Iwaki, Hirosaki, which is in northern Japan. A total of 1,052 residents (mean age, 53.9 ± 15.4 years; 390 men) who participated in this project in 2014 were studied. A standard 12-lead electrocardiogram (ECG) was recorded and serum EPA levels were measured to evaluate the relationship between J-waves and serum EPA levels. J-waves were found in 52 (5%) subjects and were observed more frequently in male than female subjects (44 [11%] versus 8 [1%], P < 0.0001). More than half of the J-waves were the notched type (60%), and J-waves were detected most frequently in inferior leads on ECG (52%). The RR interval was longer and QTc duration shorter in subjects with J-waves than those without. No significant difference was found in serum EPA levels between subjects with and without J-waves (70 [49-116] versus 65 [41-106] µg/mL, P = 0.40). In multivariate analysis, male gender and RR interval were independent factors associated with the presence of J-waves.There was no significant relationship between J-waves and serum EPA levels in this general population in Japan. Various mechanisms for manifestation of the J-waves are suggested.

Safety and Efficacy of Subcutaneous Cardioverter Defibrillator in Patients at High Risk of Sudden Cardiac Death　- Primary Japanese Experience.

BACKGROUND: The entirely subcutaneous implantable cardioverter defibrillator (S-ICD) was introduced as a new alternative to conventional transvenous ICD (TV-ICD) in Japan in February 2016, but its safety and efficacy are unclear.Methods and Results:A total of 60 patients (48 men, median age, 60 years; IQR, 44-67 years; primary prevention, n=24) underwent S-ICD implantation between February 2016 and August 2017. The device pocket was formed in the intermuscular space between the serratus anterior muscle and the latissimus dorsi muscle, and the parasternal S-ICD lead was placed according to pre-implant screening. Defibrillation test was performed in 56 patients (93%). Ventricular fibrillation (VF) was induced in 55 patients and terminated by a single 65-J shock in all patients. The median time to shock therapy was 13.4 s (IQR, 12.1-14.9 s) and the median post-shock impedance of the S-ICD lead was 64 Ω (IQR, 58-77 Ω). There were no operation-related complications or subsequent infectious complications. During follow-up (median, 275 days; IQR, 107-421 days), 1 patient (1.7%) had appropriate shock for VF with successful termination, whereas 5 patients (8.3%) had inappropriate shock due to oversensing of myopotential (n=3) or T-wave (n=1), and detection of supraventricular tachycardia (n=1). CONCLUSIONS: S-ICD is a safe and effective alternative to conventional TV-ICD. The long-term safety and efficacy of the S-ICD need further investigation.

Mechanoactivation of the angiotensin II type 1 receptor induces ß-arrestin-biased signaling through Gαi coupling.

Ligand activation of the angiotensin II type 1 receptor (AT1R), a member of the G protein-coupled receptor (GPCR) family, stimulates intracellular signaling to mediate a variety of physiological responses. The AT1R is also known to be a mechanical sensor. When activated by mechanical stretch, the AT1R can signal via the multifunctional adaptor protein ß-arrestin, rather than through classical heterotrimeric G protein pathways. To date, the AT1R conformation induced by membrane stretch in the absence of ligand was thought to be the same as that induced by ß-arrestin-biased agonists, which selectively engage ß-arrestin thereby preventing G protein coupling. Here, we show that in contrast to the ß-arrestin-biased agonists TRV120023 and TRV120026, membrane stretch uniquely promotes the coupling of the inhibitory G protein (Gαi ) to the AT1R to transduce signaling. Stretch-triggered AT1R-Gαi coupling is required for the recruitment of ß-arrestin2 and activation of downstream signaling pathways, such as EGFR transactivation and ERK phosphorylation. Our findings demonstrate additional complexity in the mechanism of receptor bias in which the recruitment of Gαi is required for allosteric mechanoactivation of the AT1R-induced ß-arrestin-biased signaling.

"30-minute-delta" of high-sensitivity troponin I improves diagnostic performance in acute myocardial infarction.

BACKGROUND: Rapid and accurate diagnosis of acute myocardial infarction (AMI) are critical for the initiation of effective medical treatment. Recently, a high-sensitivity cardiac troponin I (hs-cTnI) assay was developed as a biochemical marker for the early diagnosis of AMI. Current guidelines recommend that serial measurements of cardiac troponin should be performed in patients who present symptoms suggestive of acute coronary syndrome. The aim of this study was to evaluate the diagnostic performance of 30-minute serial measurements of hs-cTnI for the detection of AMI. METHODS: We prospectively enrolled patients presenting with suspected AMI within 12h from symptom onset. We measured hs-cTnI levels at presentation and 30min later to calculate the "30-minute-delta". The diagnostic performance was determined by the area under the receiver operating characteristic curve (AUC). RESULTS: Among the 71 patients enrolled in this study, 55 (77%) were diagnosed with AMI. The hs-cTnI level at presentation was significantly greater in the patients with AMI than in those without AMI [306.2 (77.3-1809.9)pg/mL versus 22.5 (7.2-115.5)pg/mL, p<0.01]. The "30-minute-delta" was also significantly greater in patients with AMI [54.6 (13.5-288.0)pg/mL versus 1.9 (0.6-6.3)pg/mL, p<0.01]. The AUC of the "30-minute-delta" was significantly greater than that of a single measurement at presentation (0.911 versus 0.829, p<0.05). CONCLUSIONS: The "30-minute-delta" of hs-cTnI presents improved diagnostic performance for AMI compared with a single measurement.

Gαi is required for carvedilol-induced ß1 adrenergic receptor ß-arrestin biased signaling.

The ß1 adrenergic receptor (ß1AR) is recognized as a classical Gαs-coupled receptor. Agonist binding not only initiates G protein-mediated signaling but also signaling through the multifunctional adapter protein ß-arrestin. Some ßAR ligands, such as carvedilol, stimulate ßAR signaling preferentially through ß-arrestin, a concept known as ß-arrestin-biased agonism. Here, we identify a signaling mechanism, unlike that previously known for any Gαs-coupled receptor, whereby carvedilol induces the transition of the ß1AR from a classical Gαs-coupled receptor to a Gαi-coupled receptor stabilizing a distinct receptor conformation to initiate ß-arrestin-mediated signaling. Recruitment of Gαi is not induced by any other ßAR ligand screened, nor is it required for ß-arrestin-bias activated by the ß2AR subtype of the ßAR family. Our findings demonstrate a previously unrecognized role for Gαi in ß1AR signaling and suggest that the concept of ß-arrestin-bias may need to be refined to incorporate the selective bias of receptors towards distinct G protein subtypes.