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.

Trends in Prevalence of Non-Valvular Atrial Fibrillation and Anticoagulation Therapy in a Japanese Region　- Analysis Using the National Health Insurance Database.

BACKGROUND: Direct oral anticoagulants (DOACs) are effective in reducing thromboembolism events in patients with non-valvular atrial fibrillation (NVAF). However, little is known about trends in NVAF prevalence and DOAC prescriptions in daily clinical practice. This study investigated the current status and trends in NVAF prevalence and DOAC prescriptions in a region of Japan.Methods and Results:Annual data for the 4 years from May 2014 to May 2017 in the Tsugaru region of Aomori Prefecture, Japan, were obtained for analysis from the Japanese National Health Insurance database ("Kokuho" database [KDB]). The prevalence of NVAF in subjects aged 40-74 years increased gradually over the 4-year study period (1,094/57,452 [1.90%] in 2014, 1,055/56,018 [1.88%] in 2015, 1,072/54,256 [1.98%] in 2016, and 1,154/52,341 [2.20%] in 2017). The proportion of NVAF patients prescribed warfarin decreased (42%, 33%, 24%, and 21% in 2014, 2015, 2016, and 2017, respectively), the proportion of those prescribed DOACs increased (30%, 42%, 50%, and 57%, respectively), and the proportion not prescribed an oral anticoagulant (OAC) decreased (28%, 25%, 26%, and 22%, respectively). However, 17% of patients with a CHADS2score ≥2 were not prescribed an OAC in 2017. CONCLUSIONS: By using the KDB we found that the prevalence of NVAF has increased gradually from 2014 to 2017. In the Tsugaru region in Japan, DOACs prescriptions increased and warfarin prescriptions decreased over the 4-year period.

Safety and efficacy of contemporary catheter ablation for atrial fibrillation patients with a history of cardioembolic stroke in the era of direct oral anticoagulants.

BACKGROUND: The safety and efficacy of the contemporary atrial fibrillation (AF) ablation in patients with a recent or previous history of cardioembolic stroke (CS) or transient ischemic attack (TIA) remain to be established. METHODS: A total of 447 patients who underwent first-ever contact force (CF)-guided AF ablation with circumferential pulmonary vein isolation were included. Of these, 17 had CS or TIA within 6 months before ablation (Group 1), 30 more than 6 months before ablation (Group 2), and the other 400 without CS or TIA (Group 3). Procedural complications and recurrence of AF and atrial tachyarrhythmias were compared among the 3 groups. RESULTS: The mean age was 71±7, 66±9, and 61±11 years in Groups 1, 2, and 3, respectively (p<0.05, Group 1 versus Group 3). The oral anticoagulants were warfarin (n=108, 24.1%), dabigatran (n=101, 22.6%), rivaroxaban (n=147, 32.9%), apixaban (n=87, 19.5%), and edoxaban (n=4, 0.9%), and did not differ among the 3 groups. Median follow-up period was 14 [IQR 12-22], 13 [12-14], and 12 [10-16] months, respectively. One episode of cardiac tamponade, 2 episodes of arteriovenous fistula, and some minor complications occurred in Group 3, but no complications occurred in Groups 1 and 2 in the periprocedural period. Although one episode of CS occurred 11 days after the procedure in Group 3, there were no periprocedural CS, TIA, or major bleedings in Groups 1 and 2. AF recurrence-free rate after the procedure was 76.5%, 86.7%, and 79.1% in Groups 1, 2, and 3, respectively, and there was no difference in Kaplan-Meier curves among the 3 groups. CONCLUSION: The safety and efficacy of CF-guided AF ablation in the era of direct oral anticoagulants in patients with a recent or previous history of CS or TIA are similar to those in patients without it.

Long Postpacing Interval After Entrainment of Tachycardia Including a Slow Conduction Zone Within the Circuit.

BACKGROUNDS: Postpacing interval (PPI) measured after entrainment pacing describes the distance between pacing site and reentrant circuit. However, the influential features to PPI remain to be elucidated. METHODS AND RESULTS: This study included 22 cases with slow/fast atrioventricular (AV) nodal reentrant tachycardia (AVNRT), 14 orthodromic AV reciprocating tachycardia (AVRT) using an accessary pathway, 22 typical atrial flutter (AFL), and 18 other macroreentrant atrial tachycardia (atypical AFL). Rapid pacing at a pacing cycle length (PCL) 5% shorter than tachycardia cycle length (TCL) was done from a site on or close to the reentry circuit. Pacing sites included the coronary sinus ostium in AVNRT, earliest atrial activation site in AVRT, and cavotricuspid isthmus in typical AFL. In atypical AFL, tachycardia circuit was determined on the basis of CARTO mapping, and then the pacing site was. TCL was significantly longer in AVNRT and AVRT than in typical AFL and atypical AFL (both P < 0.05). PCL minus TCL value was similar among the 4 groups. PPI minus TCL value (milliseconds) was significantly longer in AVNRT (median, 40 [IQR, 29-60.8]) and AVRT (34 [20-47]) than in typical AFL (0 [0-4]) and atypical AFL (3.5 [0-8]) (both P < 0.05). Furthermore, PPI minus TCL was prolonged with shortening of PCL in AVNRT and AVRT (both P < 0.05), whereas it was unchanged in typical AFL (P = 0.50). CONCLUSION: PPI after concealed entrainment is prolonged compared with TCL when the reentry circuit involves a slow conduction zone with a decremental conduction property such as the AV node.