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.

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.