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.

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.

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.

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.

Plasma soluble lectin-like oxidized low-density lipoprotein receptor-1 as a novel prognostic biomarker in patients with ST-segment elevation acute myocardial infarction.

BACKGROUND: Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) level is a reliable prognostic biomarker in acute coronary syndrome. However, it is unclear whether its plasma level at acute phase is related to the long-term prognosis in patients with ST-segment elevation acute myocardial infarction (STEMI). METHODS AND RESULTS: We prospectively examined the relation between plasma sLOX-1 level on admission and prognosis in 153 consecutive STEMI patients admitted within 24 h of onset. Primary percutaneous coronary intervention was performed in 144 patients. The patients were divided into 2 groups by the median value (71 pg/ml) of plasma sLOX-1 level on admission [sLOX-1 level ≤71 pg/ml (n=77) and >71 pg/ml (n=76)], and were followed for median of 1,156 days. All-cause mortality and the combined endpoints of major adverse cardiovascular events (MACE) defined as cardiovascular mortality and recurrent MI were both significantly higher in patients with sLOX-1 values above median than in those below median (25.0% vs. 3.9%, P<0.001, and 19.4% vs. 6.5%, P=0.019 by log-rank test, respectively). Even after adjustment for confounders, a level of sLOX-1 above median was an independent predictor for all-cause mortality (hazard ratio (HR): 5.893; 95% confidence interval (CI): 1.665-20.854, P=0.006) and MACE (HR: 3.457; 95% CI: 1.164-10.270, P=0.030). CONCLUSIONS: Elevated plasma sLOX-1 level on admission independently predicts long-term all-cause mortality and MACE after STEMI.

Low serum eicosapentaenoic acid level is a risk for ventricular arrhythmia in patients with acute myocardial infarction: a possible link to J-waves.

Eicosapentaenoic acid (EPA) has antiarrhythmic effects. The J-wave on an electrocardiogram is associated with a high incidence of ventricular tachycardia/fibrillation (VT/VF). We evaluated relationships between EPA and J-waves, and their involvement in the occurrence of VT/VF in acute myocardial infarction (AMI). Two hundred consecutive patients undergoing successful percutaneous coronary intervention within 12 h after AMI onset were enrolled. Serum EPA level and J-waves at admission were evaluated. The patients were divided into two groups according to the optimal cutoff value (2.94) of serum EPA level (% of total fatty acids): LOW (<2.94, 61 ± 11 years, n = 103) and HIGH groups (≥2.94, 70 ± 13 years, n = 81). J-waves were observed more frequently in the LOW (36/103, 35 %) than in HIGH group (16/81, 20 %) (P = 0.020). The 30-day incidence of VT/VF including those occurring before admission was higher in the LOW (19.5 %) than in HIGH group (6.2 %) (P = 0.009). The patients with J-waves showed a higher incidence of VT/VF (23.1 %) than those without J-waves (9.9 %) (P = 0.019). Kaplan-Meier analysis showed that the highest incidence of VT/VF was observed in the LOW with J-wave group (27.8 %), followed by the LOW without J-wave (15.0 %), HIGH with J-wave (12.5 %), and HIGH without J-wave (4.6 %) (P = 0.013). Cox proportional hazard analysis revealed that Killip grade and low serum EPA level or presence of J-waves were significantly associated with the incidence of VT/VF. Low serum EPA level is a risk for incidence of VT/VF in the acute phase of myocardial infarction. Involvement of the J-wave and its possible link with EPA in the pathogenesis of ischemia-induced VT/VF are suggested.

Re-elevation of T-wave from day 2 to day 4 after successful percutaneous coronary intervention predicts chronic cardiac systolic dysfunction in patients with first anterior acute myocardial infarction.

This study evaluates the clinical significance of re-elevation of T-wave in patients with ST segment elevation acute myocardial infarction (STEMI) undergoing successful percutaneous coronary intervention (PCI). Resolution of ST elevation within 24 h after reperfusion is associated with better outcome. However, little is known about the serial electrocardiography (ECG) changes and their significance. Seventy-five patients (52 men; 66 ± 1 years) with the first anterior STEMI in whom 12-lead ECG was recorded every day from day 0 to day 8 after PCI were studied. JT interval was quartered (points 1-5), and the deviations from isoelectric line at each point were analyzed in leads V2, V3, and V4. Serial ECG showed ST resolution and T-wave inversion within 2 days after PCI in all patients at the middle of JT interval (point 3), and subsequent re-elevation of T-wave on day 4 in 73 patients (97.3 %). The patients were divided into two groups: Group A (n = 37) with less JT deviation changes (<0.25 mV) from day 2 to day 4 at point 3; and Group B (n = 38) with greater JT deviation changes (≥0.25 mV). Group B had less retrograde collateral flow and longer JT interval in the acute phase, and lower left ventricular ejection fraction (LVEF), worse regional contractility, and higher plasma brain natriuretic peptide levels at 6 months after the onset than Group A (all P < 0.05). The JT deviation change was negatively correlated with and an independent predictor for LVEF in the chronic phase. Re-elevation ≥0.25 mV of T-wave at the middle of JT interval after successful PCI predicts chronic cardiac systolic dysfunction in patients with first anterior STEMI.

"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.

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.

Enhanced transient receptor potential channel-mediated Ca2+ influx in the cells with phospholipase C-δ1 overexpression: its possible role in coronary artery spasm.

We reported that coronary spasm was induced in the transgenic mice with the increased phospholipase C (PLC)-δ1 activity. We investigated the effect of enhanced PLC-δ1 on Ca2+ influx and its underlying mechanisms. We used human embryonic kidney (HEK)-293 and coronary arteries smooth muscle cells (CASMC). Intracellular free Ca2+ concentration ([Ca2+ ]i ; nm) was measured by fura-2, and Ca2+ influx was evaluated by the increase in [Ca2+ ]i after addition of extracellular Ca2+ . Acetylcholine (ACh) was used to induce Ca2+ influx. ACh-induced peak Ca2+ influx was 19 ± 3 in control HEK-293 cells and 71 ± 8 in the cells with PLC-δ1 overexpression (P < 0.05 between two groups). Nifedipine partially suppressed this Ca2+ influx, whereas either 2-APB or knockdown of classical transient receptor potential channel 6 (TRPC6) blocked this Ca2+ influx. In the human CASMC, ACh-induced peak Ca2+ influx was 29 ± 6 in the control and was increased to 45 ± 16 by PLC-δ1 overexpression (P < 0.05). Like HEK-293 cells, pretreatment with nifedipine partially suppressed Ca2+ influx, whereas either 2-APB or knockdown of TRPC6 blocked it. ACh-induced Ca2+ influx was enhanced by PLC-δ1 overexpression, and was blocked partially by nifedipine and completely by 2-APB. TRPC-mediated Ca2+ influx may be related to the enhanced Ca2+ influx in PLC-δ1 overexpression.