Diphenyl-tetrazol-propanamide Derivatives Act as Dual-Specific Antagonists of Platelet CLEC-2 and Glycoprotein VI.

BACKGROUND: Platelet C-type lectin-like receptor 2 (CLEC-2) induces platelet activation and aggregation after clustering by its ligand podoplanin (PDPN). PDPN, which is not normally expressed in cells in contact with blood flow, is induced in inflammatory immune cells and some malignant tumor cells, thereby increasing the risk of venous thromboembolism (VTE) and tumor metastasis. Therefore, small-molecule compounds that can interfere with the PDPN-CLEC-2 axis have the potential to become selective antiplatelet agents. METHODS AND RESULTS: Using molecular docking analysis of CLEC-2 and a PDPN-CLEC-2 binding-inhibition assay, we identified a group of diphenyl-tetrazol-propanamide derivatives as novel CLEC-2 inhibitors. A total of 12 hit compounds also inhibited PDPN-induced platelet aggregation in humans and mice. Unexpectedly, these compounds also fit the collagen-binding pocket of the glycoprotein VI molecule, thereby inhibiting collagen interaction. These compounds also inhibited collagen-induced platelet aggregation, and one compound ameliorated collagen-induced thrombocytopenia in mice. For clinical use, these compounds will require a degree of chemical modification to decrease albumin binding. CONCLUSION: Nonetheless, as dual activation of platelets by collagen and PDPN-positive cells is expected to occur after the rupture of atherosclerotic plaques, these dual antagonists could represent a promising pharmacophore, particularly for arterial thrombosis, in addition to VTE and metastasis.

Prognostic significance of the Holter-derived T-wave variability in patients with ventricular tachyarrhythmias complicating acute coronary syndrome-TWIST study.

BACKGROUND: We aimed to investigate the association between ventricular repolarization instability and sustained ventricular tachycardia and ventricular fibrillation (VT/VF) occurring within 48 h (acute-phase VT/VF) after the onset of acute coronary syndrome (ACS) and the prognostic role of repolarization instability and heart rate variability (HRV) after discharge from the hospital. METHODS: We studied 572 ACS patients with a left ventricular ejection fraction >35%. The ventricular repolarization instability was assessed by the beat-to-beat T-wave amplitude variability (TAV) using high-resolution 24-h Holter ECGs recorded at a median of 11 days from the date of admission. We calculated the HRV parameters including the deceleration capacity (DC) and non-Gaussian index calculated on a 25 s timescale (λ25s). The DC and λ25s were dichotomized based on previous studies' thresholds. RESULTS: Acute-phase VT/VF developed in 43 (7.5%) patients. In-hospital mortality was significantly higher among VT/VF patients (4.7% vs. 0.9%, p = .03). An adjusted logistic model showed that the maximum TAV (odds ratio 1.02, 95% confidence interval [CI] 1.00-1.29, p = .04) was associated with acute-phase VT/VF. During a median follow-up period of 2.1 years, 19 (3.3%) patients had cardiac deaths or resuscitated cardiac arrest. Acute-phase VT/VF (p = .12) and TAV (p = .72) were not significant predictors of survival. An age and sex-adjusted Cox model showed that the DC (p < .01), λ25s (p < .01), and emergency coronary intervention (p < .01) were independent predictors. CONCLUSION: T-wave amplitude variability was associated with acute-phase VT/VF, but the TAV was not predictive of survival post-discharge. The DC, λ25s, and emergency coronary intervention were independent predictors of survival.

Utility of open-window mapping for catheter ablation of an accessory pathway in patients with Wolff-Parkinson-White syndrome.

BACKGROUND: Open-window mapping (OWM) is a novel automated mapping method for catheter ablation of an accessory pathway (AP), in which the local signal is annotated with window-of-interest parameters to analyze both atrial and ventricular signals. This study aimed to determine the utility of OWM in visualizing the location and width of APs in patients with Wolff-Parkinson-White syndrome. METHODS: This two-center study enrolled 30 patients (20 males; mean age: 56 years, interquartile range [IQR]: 22-69 years) who underwent high-density OWM with the extended early-meets-late (EEML) algorithm using a 20-electrode, 5-spline catheter (PENTARAY, Biosense Webster). The lower threshold of the EEML was set to adjust the EEML gap to match the propagation mapping, and broad APs were defined as an EEML gap > 1 cm. RESULTS: The median mapping points, mapping time, and lower threshold of the EEML were 2482 (IQR: 1755-4000) points, 23 (IQR: 15-30) min, and 23 (IQR: 18-25), respectively. All 30 APs (24 in the mitral annulus and 6 in the tricuspid annulus) were successfully eliminated. Of these APs, 21 (70%) were eliminated by the first radio frequency (RF) application. OWM revealed broad APs in 11 patients (37%), in four of whom (36%) the first RF application achieved a loss of AP conduction (vs. 90% of patients without broad APs; p = .004). CONCLUSION: OWM facilitates the visualization of the location and width of APs, which may be particularly useful for predicting whether multiple RF applications are required for broad APs.

Interim Report of a Japanese Phase II Trial for Cardiac Stereotactic Body Radiotherapy in Refractory Ventricular Tachycardia　- Focus on Target Determination.

Background: Cardiac radiotherapy using stereotactic body radiation therapy (SBRT) has attracted attention as a minimally invasive treatment for refractory ventricular tachycardia. However, a standardized protocol and software program for determining the irradiation target have not been established. Here, we report the first preclinical stereotactic radioregulation antiarrhythmic therapy trial in Japan, focused on the target-setting process. Methods and Results: From 2019 onwards, 3 patients (age range 60-91 years) presenting with ischemic or non-ischemic cardiomyopathy were enrolled. Two patients were extremely serious and urgent, and were followed up for 6 and 30 months. To determine the irradiation targets, we aggregated electrophysiological, structural, and functional data and reflected them in an American Heart Association 17-segment model, as per the current recommendations. However, in all 3 patients, invasive electrophysiological study, phase-contrast computed tomography, and magnetic resonance imaging could not be performed; therefore, electrophysiological and structural information was limited. As alternatives, high-resolution ambulatory electrocardiography and nuclear medicine studies were useful in assessing arrhythmic substrates; however, concerns regarding test weighting and multiple scoring remain. Risks to surrounding organs were fully taken into account. Conclusions: In patients requiring cardiac SBRT, the information needed for target planning is sometimes limited to minimally invasive tests. Although there are issues to be resolved, this is a promising option for the life-saving treatment of patients in critical situations.

Utility and limitations of coherent mapping algorithm utilizing vectors and global propagation patterns in atrial tachycardia.

Background: A novel mapping algorithm utilizing vectors and global patterns of propagation (Coherent™, Biosense Webster) has been developed to help identify the mechanism of atrial tachycardia (AT). We aimed to determine the diagnostic accuracy of coherent mapping compared with that of ripple mapping. Methods and results: This study included 41 consecutive patients with 84 ATs (47 reentrant and 37 focal ATs). Two independent electrophysiologists confirmed the diagnoses using coherent mapping before the ripple map-guided ablation. AT termination was achieved in 75 of 84 ATs (89%) at first ablation lesion set. Four of the remaining nine ATs, which were terminated before an index radiofrequency (RF) application, were non-inducible after RF delivery at the first lesion set, whereas the other five ATs were terminated at the second lesion set. Diagnostic agreement between coherent and ripple maps was achieved in 51 of 84 ATs (61%): 28 of the 47 macroreentrant ATs (60%) and 23 of the 37 focal ATs (62%; P = 0.826). In typical macroreentrant ATs, including left atrial roof, perimitral, and cavotricuspid isthmus-dependent ATs, coherent maps achieved diagnostic agreement in 23 of 29 ATs (79%), which was higher than that in other ATs (51%, P = 0.018): 13 of 26 macroreentrant ATs (50%) and 15 of 29 focal ATs (52%, P = 1.000). Conclusion: Ripple map-guided AT ablation achieved a high termination rate in the first lesion set. Coherent mapping yielded a favorable diagnostic accuracy for typical macroreentrant ATs, though its value for diagnosing other ATs was limited.

Heavy Ion Irradiation Reduces Vulnerability to Atrial Tachyarrhythmias　- Gap Junction and Sympathetic Neural Remodeling.

BACKGROUND: Low-invasive stereotactic body radiation therapy is a novel anti-arrhythmic strategy. The mechanisms underlying its effects against ventricular tachycardia/fibrillation (VT/VF) are gradually becoming clear, whereas those underlying atrial tachycardia/fibrillation (AT/AF) remain unknown. This study investigated the effects of carbon ion beam on gap junction expression and sympathetic innervation.Methods and Results: Atrial and ventricular tachyarrhythmia models was established in 26 hypercholesterolemic (HC) 3-year-old New Zealand white rabbits; 12 rabbits were irradiated with a single 15-Gy carbon ion beam (targeted heavy ion irradiation [THIR]) and 14 were not (HC group). Eight 3-month-old rabbits (Young) were used as a reference group. In vivo induction frequencies in the Young, HC, and HC+THIR groups were 0%, 9.9%, and 1.2%, respectively, for AT/AF and 0%, 7.8%, and 1.2%, respectively, for VT/VF (P<0.01). The conduction velocity of the atria and ventricles on optical mapping was significantly reduced in the HC group; this was reversed in the HC+THIR group. Connexin-40 immunolabelling in the atria was 66.1-78.7% lower in the HC than Young group; this downregulation was less pronounced in the HC+THIR group (by 23.1-44.4%; P<0.01). Similar results were obtained for ventricular connexin-43. Sympathetic nerve densities in the atria and ventricles increased by 41.9-65.3% in the HC vs. Young group; this increase was reversed in the HC+THIR group. CONCLUSIONS: Heavy ion radiation reduced vulnerability to AT/AF and VT/VF in HC elderly rabbits and improved cardiac conductivity. The results suggest involvement of connexin-40/43 upregulation and suppression of sympathetic nerve sprouting.

Ablation index-guided cavotricuspid isthmus ablation with contiguous lesions using fluoroscopy integrated 3D mapping in atrial flutter.

PURPOSE: The feasibility and safety of cavotricuspid isthmus (CTI) ablation with contiguous lesions using ablation index (AI) under the guidance of fluoroscopy integrated 3D mapping (CARTO UNIVU/CU) in typical atrial flutter (AFL) remains uncertain. This study aimed to determine the efficacy of AI-guided CTI ablation with contiguous lesions in patients with AFL. METHODS: In this single-center, prospective, non-randomized, single-arm, observational study, procedural outcomes were determined in 151 patients undergoing AI-guided CTI ablation (AI group) with a target AI value of 450 and an interlesion distance of ≤ 4 mm under CU guidance. These outcomes were compared with those of 30 patients undergoing non-AI-guided ablation (non-AI group). RESULTS: Among 151 patients, first-pass conduction block was achieved in 120 (80%) patients in the AI group (67% in the non-AI group, P = 0.152) with a shorter fluoroscopy time of 0.2 ± 0.4 min (1.7 ± 2.0 min in the non-AI group, P < 0.001). Conduction gaps were located at the atrial aspects near the inferior vena cava in 24 of 31 (78%) patients without first-pass conduction block. The AI group received 11 ± 5 (12 ± 4 in the non-AI group, P = 0.098) radiofrequency (RF) applications, and the RF time was 4.2 ± 2.4 (5.1 ± 2.5 min in the non-AI group, P = 0.011). Despite the occurrence of steam pop in 3 (2%) patients, none of them developed cardiac tamponade. No patients had recurrence within 6 months of follow-up. CONCLUSIONS: AI-guided CTI ablation in combination with CU was feasible and effective in reducing radiation exposure in patients with AFL.

Ambulatory electrocardiographic markers predict serious cardiac events in patients with chronic kidney disease: The Japanese Noninvasive Electrocardiographic Risk Stratification of Sudden Cardiac Death in Chronic Kidney Disease (JANIES-CKD) study.

BACKGROUND: Noninvasive electrocardiographic markers (NIEMs) are promising arrhythmic risk stratification tools for assessing the risk of sudden cardiac death. However, little is known about their utility in patients with chronic kidney disease (CKD) and organic heart disease. This study aimed to determine whether NIEMs can predict cardiac events in patients with CKD and structural heart disease (CKD-SHD). METHODS: We prospectively analyzed 183 CKD-SHD patients (median age, 69 years [interquartile range, 61-77 years]) who underwent 24-h ambulatory electrocardiographic monitoring and assessed the worst values for ambulatory-based late potentials (w-LPs), heart rate turbulence, and nonsustained ventricular tachycardia (NSVT). The primary endpoint was the occurrence of documented lethal ventricular tachyarrhythmias (ventricular fibrillation or sustained ventricular tachycardia) or cardiac death. The secondary endpoint was admission for cardiovascular causes. RESULTS: Thirteen patients reached the primary endpoint during a follow-up period of 24 ± 11 months. Cox univariate regression analysis showed that existence of w-LPs (hazard ratio [HR] = 6.04, 95% confidence interval [CI]: 1.4-22.3, p = .007) and NSVT [HR = 8.72, 95% CI: 2.8-26.5: p < .001] was significantly associated with the primary endpoint. Kaplan-Meier analysis demonstrated that the combination of w-LPs and NSVT resulted in a lower event-free survival rate than did other NIEMs (p < .0001). No NIEM was useful in predicting the secondary endpoint, although the left ventricular mass index was correlated with the secondary endpoint. CONCLUSION: The combination of w-LPs and NSVT was a significant risk factor for lethal ventricular tachyarrhythmias and cardiac death in CKD-SHD patients.

Impact of exercise capacity on the long-term incidence of atrial arrhythmias in heart failure.

We sought to demonstrate the impact of improved peak exercise oxygen consumption (V̇O2) during maximal exercise testing after cardiac rehabilitation (CR) on the incidence of arrhythmias in patients with heart failure (HF). The present study comprised of 220 patients with HF, and peak V̇O2 was examined at 2 and 5 months after CR. Of the 220 patients, 110 (50%) had a low peak V̇O2 of < 14 mL/min/kg at 2 months. The peak V̇O2 improved in 86 of these 110 (78%) patients at 5 months after CR. During a median follow-up of 6 years, the patients with improvement in peak V̇O2, compared to those without peak V̇O2 improvement, had a lower rate of mortality (4% vs. 29%, log-rank, P < 0.001) and HF hospitalization (6 vs. 17%, log-rank, P = 0.044) and a lower incidence of new-onset atrial arrhythmias (9 vs. 27%, log-rank, P = 0.013), with no difference in the incidence of ventricular arrhythmias between groups (1 vs. 4%, log-rank, P = 0.309). The majority of deaths in the patients without an improved peak V̇O2 were because of cardiovascular events (73%), particularly progressive HF (55%). Early detection and management of atrial arrhythmias may improve outcomes in patients without peak V̇O2 improvement after CR.

Clinical Significance of the Head-Up Tilt Test in Improving Prognosis in Patients with Possible Neurally Mediated Syncope.

Syncope is commonly encountered in daily clinical practice. Depending on its etiology (benign or life-threatening conditions or environmental triggers), syncope can be neurally mediated (reflex), cardiac, or orthostatic. Furthermore, neurologic disease can cause symptoms that mimic syncope. However, there is limited research on neurally mediated syncope (NMS), which is considered a benign disorder, and close follow-ups are rarely performed. NMS can cause serious clinical events, including severe trauma and car accidents. The head-up tilt test (HUTT) is the gold standard for diagnosing NMS; however, its clinical significance remains unknown, and its relevance to NMS prognosis requires further research. This retrospective study aimed to assess the clinical significance of the HUTT for NMS. We reviewed the charts of 101 patients who underwent HUTT at Tokai University Hospital in Japan between January 2016 and March 2019. During the HUTT, 72 patients (69.2%) experienced syncope. Patients were followed up for 886.1 ± 457.7 days (interquartile range: 518-1293 days). The syncope recurrence rate was 16.9%; however, no significant difference was observed between the two groups (HUTT positive vs. negative) (13.8% vs. 18.1%, p = 0.772). Four of 29 (13.9%) and two of 72 (2.8%) patients in the negative and positive HUTT groups, respectively, experienced cardiac events (p = 0.019). Negative HUTT results may assist in anticipating unexpected clinical events within a few years. A negative HUTT result may allow us to reconsider the NMS diagnosis based on clinical information. Close outpatient follow-up of patients with negative HUTT results is warranted.

Diagnosis and prevention of the vasodepressor type of neurally mediated syncope in Japanese patients.

We investigated circulatory dynamics in patients with vasodepressor type neurally mediated syncope (VT-NMS) by performing high-resolution Holter electrocardiography and a correlation analysis of changes in adenylate cyclase activity, blood pressure, and pulse during the head-up tilt test. Holter electrocardiography was performed for 30 patients. Adenylate cyclase activity was evaluated in lymphocytes from blood samples taken at rest and during the head-up tilt test. There was no change in autonomic nerve fluctuation during electrocardiography in VT-NMS patients, but our results showed a significant difference in blood pressure and adenylate cyclase activity between VT-NMS patients and healthy volunteers; the systolic blood pressure of VT-NMS patients decreased after 5 min, while at 10 min, the adenylate cyclase activity was the highest (0.53%) and the systolic blood pressure was the lowest (111.8 mm Hg). Pulse rates increased after 10 min. VT-NMS patients showed higher blood pressure, pulse rate, and adenylate cyclase activity during the tilt test than did healthy volunteers. In patients with syncope, standing for longer than 10 minutes may increase the risk of VT-NMS. From our results, we consider it likely that high systolic blood pressure and adenylate cyclase activity at rest cause fainting in VT-NMS patients. Our findings may be helpful for identifying individuals with a high risk of developing NMS in the healthy population.

Should beta-blockers be continued as a treatment for myocardial infarction in the case of Kounis syndrome?

A 71-year-old male patient reported to our hospital with anaphylactic shock, and the following two issues were focused in this case. First, he was resistant to adrenaline because of taking beta-blocker, and shock was repeated until glucagon administration was initiated. Second, he developed acute coronary syndrome. Two mechanisms contributing to Kounis syndrome were differentiated: 1) adrenaline induced coronary spasm and platelet activation or 2) a mismatch between oxygen supply and demand due to an allergic reaction. Beta-blocker therapy was discontinued because his cardiac function was preserved. Secondary preventive beta-blockers in recovering myocardial infarction with severe anaphylaxis history should be carefully considered.

Late-onset atrioventricular block after transcatheter aortic valve replacement.

BACKGROUND: Conduction disturbances leading to permanent pacemaker implantation (PPI) rarely occur late after transcatheter aortic valve replacement (TAVR). The clinical features of this phenomenon and its association with periprocedural conduction disturbances remain uncertain. OBJECTIVES: We aimed to determine the incidence and characteristics of late-onset atrioventricular block (AVB) after TAVR. METHODS: This single-center study included 246 patients undergoing TAVR. Late-onset AVB was defined as AVB ≥1 month after the TAVR. RESULTS: Periprocedural AVB (periAVB) occurred in 43 patients (17%). Patients with periAVB had a higher rate of right bundle branch block (47% vs 7%, P < .0001). Of the 43 patients with periAVB, 15 underwent PPI (35%) at a median duration of 6 days, whereas 1 of the remaining 203 patients without periAVB underwent PPI within 1 month (0.5%). During a median follow-up duration of 365 days, late-onset AVB occurred in 10 of 230 patients without PPI within 1 month (4%) at a median duration of 76 days. All 10 patients presented transient periprocedural atrioventricular conduction disturbances, including 8 patients with periAVB (80%), all of whom recovered within 1 month, and 9 patients underwent self-expanding valve implantation (90%). The mortality rate in patients with PPI within 1 month was higher than in those without, although the difference was not statistically significant (hazard ratio 2.68, 95% confidence interval 0.97-9.05, log-rank P = .09). CONCLUSION: Late-onset AVB occurred in a minority of patients undergoing TAVR. Greater vigilance is warranted, particularly in patients with transient conduction disturbances during the periprocedural period following self-expanding valve implantation.