Clinical efficacy of tolvaptan in acute decompensated heart failure patients with severe aortic stenosis and atrial fibrillation: a sub-analysis from the LOHAS registry.

BACKGROUND: Severe aortic valve stenosis (AS) and atrial fibrillation (AF) are risk factors of hemodynamic instability in heart failure (HF) management due to low cardiac output, respectively. Therefore, the treatment of HF due to severe AS complicated with AF is anticipated to be difficult. Tolvaptan, a vasopressin V2 receptor inhibitor, is effective in controlling acute decompensated heart failure (ADHF) with hemodynamic stability. However, its clinical efficacy against ADHF caused by AS with AF remains to be determined. METHODS: Clinical information (from September 2014 to December 2017) of 59 patients diagnosed with ADHF due to severe AS (20 patients with AF; 39 patients with sinus rhythm [SR]) was obtained from the LOHAS registry. The registry collected data from seven hospitals and assessed the short-term effects of tolvaptan in patients hospitalized for ADHF with severe AS. We attempted to identify clinical differences from baseline up to 4 days, comparing patients with AF (AF group) versus those with SR (SR group). RESULTS: There were no significant differences between the groups in age (83.7 ± 4.5 vs. 85.8 ± 6.9 years, respectively; p = 0.11) and aortic valve area (0.60 [0.46-0.73] vs. 0.56 [0.37-0.70] cm2, respectively; p = 0.50). However, left atrial volume was larger (104 [85-126] vs. 87 [64-103] mL, respectively; p < 0.01), whereas stroke volume was lower (51.6 ± 14.8 vs. 59.0 ± 18.7 mL, respectively; p = 0.08) in the AF group versus the SR group. Body weight decreased daily from baseline up to day 4 in both groups (from 55.4 to 53.2 kg [p < 0.01] and from 53.5 to 51.0 kg [p < 0.01], respectively) without change in heart rate. Notably, the systolic blood pressure decreased slightly in the AF group after 2 days of treatment with tolvaptan. CONCLUSIONS: Short-term treatment with tolvaptan improved HF in patients hospitalized for severe AS, regardless of the presence of AF or SR. After achieving sufficient diuresis, a slight decrease in blood pressure was observed in the AF group, suggesting an appropriate timeframe for safe and effective use of tolvaptan.

Vericiguat and transcatheter edge-to-edge mitral valve repair for combined post- and pre-capillary pulmonary hypertension due to left ventricular low ejection fraction and functional mitral regurgitation.

A 66-year-old female was diagnosed with combined post- and pre-capillary pulmonary hypertension due to heart failure with reduced ejection fraction (47 %) and functional mitral regurgitation [mean pulmonary arterial wedge pressure: 27 mmHg; pulmonary arterial pressure: 91/30 (56) mmHg; pulmonary vascular resistance: 12.9 Wood units; and cardiac index: 1.77 L/min/m2]. Following treatment with vericiguat (a novel oral soluble guanylate cyclase stimulator), hemodynamics improved [mean pulmonary arterial wedge pressure: 27 mmHg; pulmonary arterial pressure: 54/26 (35) mmHg; pulmonary vascular resistance: 2.2 Wood units; and cardiac index: 2.80 L/min/m2]. Therefore, transcatheter edge-to-edge repair for functional mitral regurgitation was performed. One month later, further improvement in hemodynamics was confirmed. Learning objective: Vericiguat (a novel oral soluble guanylate cyclase stimulator) and transcatheter edge-to-edge mitral valve repair may improve combined post- and pre-capillary pulmonary hypertension due to low ejection fraction of the left ventricle and functional mitral regurgitation.

Development of Small-Molecule Anti-HIV-1 Agents Targeting HIV-1 Capsid Proteins.

The capsid of human immunodeficiency virus type 1 (HIV-1) forms a conical structure by assembling oligomers of capsid (CA) proteins and is a virion shell that encapsulates viral RNA. The inhibition of the CA function could be an appropriate target for suppression of HIV-1 replication because the CA proteins are highly conserved among many strains of HIV-1, and the drug targeting CA, lenacapavir, has been clinically developed by Gilead Sciences, Inc. Interface hydrophobic interactions between two CA molecules via the Trp184 and Met185 residues in the CA sequence are indispensable for conformational stabilization of the CA multimer. Our continuous studies found two types of small molecules with different scaffolds, MKN-1 and MKN-3, designed by in silico screening as a dipeptide mimic of Trp184 and Met185 have significant anti-HIV-1 activity. In the present study, MKN-1 derivatives have been designed and synthesized. Their structure-activity relationship studies found some compounds having potent anti-HIV activity. The present results should be useful in the design of novel CA-targeting molecules with anti-HIV activity.

Feasibility and Outcome of Transjugular Intracardiac Echocardiography-Guided Transcatheter Aortic Valve Replacement.

Background: There are limited data on the impact of intracardiac echocardiography (ICE)-guided transcatheter aortic valve replacement (TAVR) on the new permanent pacemaker implantation (PPMI) rate. Objectives: This study investigated the feasibility and outcome of transjugular ICE (TJ-ICE) -guided TAVR, by visualizing the relationship between the membranous septum (MS) and the transcatheter aortic valve (TAV). Methods: Among patients with severe aortic stenosis who underwent TAVR between February 2017 and June 2020, this study enrolled a total of 163 patients with TJ-ICE-guided TAVR. MS length was measured by ICE. The primary endpoint of this study was the incidence of new PPMI at 30 days. Results: The mean age of the patients in this study was 84.9 ± 4.6 years, and 71.2% of the patients were female. Device success was 96.3% with TJ-ICE guidance. A TJ-ICE-related complication occurred in 1 case (0.6%). The median length of the MS was 5.8 mm (IQR: 5.0-6.9 mm). Excellent intraobserver (intraclass correlation coefficient [ICC]: 0.94; 95% CI:0.79-0.98; P < 0.001) and interobserver (ICC: 0.93; 95% CI: -0.05 to 0.98; P < 0.001) agreements were shown. The new PPMI rate was 6.7% at 30 days without a significant difference between balloon-expandable valves and self-expandable valves (3.4% vs 8.7%; P = 0.226). Patients with a TAV implantation depth less than MS length had a significantly lower incidence of new PPMI compared with patients with a TAV implantation depth greater than MS length (2.1% vs 13.4%; P = 0.005), regardless of baseline right bundle branch block presence (6.7% vs 66.7%; P = 0.004) or absence (1.2% vs 8.2%; P = 0.041). Conclusions: TJ-ICE-guided TAVR demonstrated remarkable feasibility and safety. The TJ-ICE-guided final TAV position had a significant impact on the new PPMI rate. (Tokai Valve Registry; UMIN000036671).

Incremental Value of Global Longitudinal Strain for Confirming Heart Failure-Related Symptoms in Severe Aortic Stenosis.

The indications or timing of aortic valve replacement for symptomatic aortic stenosis (AS) are based on a patient's life expectancy and symptoms. However, clinical decision-making may be difficult because symptoms are subjective and cannot be quantitatively assessed and confirmed. This study aimed to evaluate the association between heart failure (HF)-related symptoms and cardiac hemodynamic left ventricular deformations in patients with severe AS using transthoracic echocardiographic assessments of left ventricular global longitudinal strain (LV-GLS). The medical records of patients hospitalized for AS between February 2017 and September 2019 were retrospectively screened. Independent cardiologists analyzed the transthoracic echocardiographic images of a digital echocardiography database. The cohort comprised 177 hospitalized patients with severe AS and no history of HF. The subgroup with HF-related symptoms included 87 patients, whereas that without HF-related symptoms included 90 patients. In 145 patients without atrial fibrillation, the left atrial volume index (LAVI) and LV-GLS were significantly associated with HF-related symptoms (odds ratio 1.033, 95% confidence interval 1.008 to 1.059, p = 0.011 and odds ratio 1.224, 95% confidence interval 1.118 to 1.340, p <0.0001, respectively). Moreover, the combination of brain natriuretic peptide level, LAVI, and LV-GLS showed better diagnostic accuracy than the combination of brain natriuretic peptide level and LAVI (p = 0.005). However, there were no such tendencies in 32 patients with atrial fibrillation. The HF-related symptoms in patients with severe AS were strongly linked to LV-GLS. LV-GLS showed incremental value for confirming HF-related symptoms.

Mechanisms and implications of mitral regurgitation in patients with severe aortic stenosis who received transcatheter aortic valve replacement.

INTRODUCTION: This study aimed to investigate the mechanisms and clinical implications of mitral regurgitation (MR) in patients with severe aortic stenosis (AS) who received transcatheter aortic valve replacement (TAVR). METHODS: We conducted retrospective echocardiographic analyses at baseline and 6 months after TAVR in 140 patients with symptomatic AS (85 ± 5 years) who underwent TAVR. We defined significant MR as ≥ moderate based on evaluation of transthoracic echocardiography (TTE). RESULTS: There were 48 patients (34%) with preexisting MR at the baseline. Among measured TTE parameters, end-systolic wall stress (ESWS), mitral annulus area, and mitral valve thickening index were independent factors associated with preexisting MR (odds ratio [OR]: 1.013, 95% confidence interval [CI]: 1.005-1.021; OR: 1.740, 95% CI: 1.314-2.376; OR: 2.306, 95% CI: 1.426-3.848; respectively). Six months after TAVR, there were 34 patients with post-existing MR, A history of atrial fibrillation and ESWS after TAVR were independent factors (OR: 3.013, 95% CI: 1.208-7.556; OR: 1.013, 95% CI: 1.000-1.023; respectively). The Kaplan-Meier plot indicated that preexisting MR was a risk factor for heart failure-related events within 1 year of discharge after TAVR (p = .012). CONCLUSIONS: In patients who underwent TAVR for severe AS, preexisting MR was associated with having a thickened mitral valve and large mitral annulus size induced by high ESWS. These patients may have worse prognosis after TAVR and should be closely monitored in the long term.

Short-term recurrence of takotsubo syndrome with phenotypic variation: a case report.

Background: Takotsubo syndrome (TTS) is an acute and usually reversible heart failure syndrome characterized as an uncommon left ventricular (LV) cardiomyopathy. Recurrence of TTS is rare, estimated to be 1-6%. We report a rare case of TTS that occurred three times in 2 months but manifested various phenotypes. Case summary: A 68-year-old woman was admitted to our hospital with acute-onset chest pain and hypertension. The coronary angiography findings were normal, although left ventriculography revealed inferior wall hypokinesis, leading to a mid-ventricular TTS diagnosis. She was discharged on Day 3 after her symptoms improved and vitals stabilized. The patient's condition remained uneventful until 2-week post-discharge, when acute chest pain and hypertension recurred. She was admitted again with the same diagnosis. However, LV morphology revealed an apical ballooning pattern, with inferior LV wall hypokinesis. She was discharged on Day 7 after her symptoms and electrocardiography findings improved but was readmitted again 2 weeks later after acute chest pain and hypertension recurred. Left ventriculography performed a third time demonstrated mid-ventricular TTS. The patient was prescribed additional medications and discharged on Day 12. Her electrocardiography findings normalized, and the patient remained asymptomatic without recurrence 4 months after the initial presentation. Discussion: Recurrence and phenotypic change of TTS are rare. Some cases have been reported but occurring months to years after initial diagnosis. Combined treatment with ß-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists may be more effective to prevent the recurrence than monotherapies.

Short-term Outcomes of Urgent Transcatheter Aortic Valve Replacement in Symptomatic Aortic Stenosis That Requires Emergency Hospital Admission.

Objective This study retrospectively compared the outcomes of emergently admitted patients with aortic stenosis (AS) with or without urgent transcatheter aortic valve replacement (TAVR). Methods Patients hospitalized between February 2015 and December 2019 for symptomatic AS were retrospectively analyzed by comparing the received conservative management [continued medical therapy with or without elective surgical transcatheter replacement (SAVR) or TAVR scheduled after the index hospitalization] and urgent TAVR (TAVR during the index hospitalization). Results The cohort comprised 114 patients with symptomatic AS who required emergency admission. Urgent TAVR was performed for 37 patients, while conservative management was provided for 77 patients, including 1 who received urgent SAVR. Urgent TAVR was more likely to be performed in patients with a history of hospitalization for heart failure, high New York Heart Association class scores, a lower clinical frailty scale at admission, and a high aortic valve peak velocity (p=0.01, p<0.001, p<0.01 and p=0.02, respectively). Kaplan-Meier analyses with log-rank test revealed favorable outcomes of urgent TAVR in all-cause mortality and cardiovascular events within 60 days of admission (p<0.01, p<0.01, respectively). Conclusion Urgent TAVR had better short-term outcomes in patients with symptomatic AS who required emergency hospital admission than conservative management. When considering urgent TAVR, patients with typical heart failure symptoms due to AS with a history of heart failure hospitalization and relatively little frailty can be selected.

Sustained Myocarditis following Messenger RNA Vaccination against Coronavirus Disease 2019: Relation to Neutralizing Antibody and Amelioration by Low-Dose Booster Vaccination.

We recently reported that sub-acute myocarditis occurred following the initial two doses of messenger RNA-based vaccination against coronavirus disease 2019 (0.3 mL Comirnaty®) in elderly Japanese patients with cardiac dysfunction. The present retrospective study of 76 patients revealed that myocarditis following the initial doses persisted for 12 months, was associated with low levels of neutralizing antibodies, and was ameliorated by reducing the third vaccine dose. Low neutralizing antibody levels (<220 U/mL) after the initial doses were an independent predictor of persistent clinical events, defined as death or marked changes in brain natriuretic peptide levels. When the third dose was reduced (0.1 mL), changes in brain natriuretic peptide levels were significantly smaller (p = 0.02, n = 25), no deaths occurred due to heart failure, and neutralizing antibody levels increased 41-fold (p < 0.001) compared with the initial doses. Reduced booster doses could facilitate the worldwide distribution of messenger RNA vaccines.

Low-molecular-weight anti-HIV-1 agents targeting HIV-1 capsid proteins.

The HIV-1 capsid is a shell that encapsulates viral RNA, and forms a conical structure by assembling oligomers of capsid (CA) proteins. Since the CA proteins are highly conserved among many strains of HIV-1, the inhibition of the CA function could be an appropriate goal for suppression of HIV-1 replication, but to date, no drug targeting CA has been developed. Hydrophobic interactions between two CA molecules through Trp184 and Met185 in the protein are known to be indispensable for conformational stabilization of the CA multimer. In our previous study, a small molecule designed by in silico screening as a dipeptide mimic of Trp184 and Met185 in the interaction site was synthesized and found to have significant anti-HIV-1 activity. In the present study, molecules with different scaffolds based on a dipeptide mimic of Trp184 and Met185 have been designed and synthesized. Their significant anti-HIV activity and their advantages compared to the previous compounds were examined. The present results should be useful in the design of novel CA-targeting anti-HIV agents.

DAPagliflozin for the attenuation of albuminuria in Patients with hEaRt failure and type 2 diabetes (DAPPER study): a multicentre, randomised, open-label, parallel-group, standard treatment-controlled trial.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the urinary albumin-to-creatinine ratio (UACR) in patients with elevated levels of albuminuria in the presence or absence of heart failure (HF) or type 2 diabetes mellitus (T2D). However, these effects have not yet been reported in the presence of both HF and T2D. This lack of evidence prompted us to conduct a clinical trial on the effects of dapagliflozin on UACR in patients with HF and T2D. Methods: DAPPER is a multicentre, randomised, open-labeled, parallel-group, standard treatment-controlled trial that enrolled patients at 18 medical facilities in Japan. Eligible participants with both HF and T2D and aged between 20 and 85 years were randomly assigned to a dapagliflozin or control (anti-diabetic drugs other than SGLT 2 inhibitors) group with a 1:1 allocation. The primary outcome was changes in UACR from baseline after a two-year observation, and secondary endpoints were cardiovascular (CV) events and parameters related to HF. This trial was registered with the UMIN-CTR registry, UMIN000025102 and the Japan Registry of Clinical Trials, jRCTs051180135. Findings: Between 12 May 2017 and 31 March 2020, 294 patients were randomly assigned to the dapagliflozin group (n = 146) or control group (n = 148). The mean age of patients was 72.1 years and 29% were female. The mean glycated hemoglobin value was 6.9%, mean NT-proBNP was 429.1 pg/mL, mean estimated GFR was 65.7 mL/min/1.73 m2, and median UACR was 25.0 (8.8-74.6) mg/g Cr in the dapagliflozin group and 25.6 (8.2-95.0) mg/g Cr in the control group. Of the 146 patients in the dapagliflozin group, 122 completed the study, and 107 (87.7%) were taking 5 mg of dapagliflozin daily at the end of the observation period. The primary outcome did not significantly differ between the dapagliflozin and control groups. Among the secondary endpoints, the mean decrease in left ventricular end-diastolic dimensions as one of the echocardiographic parameters was larger in the dapagliflozin group than in the control group. The composite endpoint, defined as CV death or hospitalisation for CV events, hospitalisation for HF events, hospitalisation for all causes, and an additional change in prescriptions for heart failure in a two-year observation, was less frequent in the dapagliflozin group than in the control group. Interpretation: Although dapagliflozin at a dose of 5 mg daily did not reduce urinary albumin excretion in patients with HF and T2D from that in the controls, our findings suggest that dapagliflozin decreased CV events and suppressed left ventricular remodeling. Funding: AstraZeneca KK, Ono Pharmaceutical Co., Ltd.

Case of atrial septal defect closure relieving refractory migraine.

The effectiveness of patent foramen ovale closure for migraine has been previously discussed. By contrast, very few studies have reported the association between migraine and atrial septal defect closure. Here, we report a case in which atrial septal defect closure effectively relieved migraine headaches.

Gender Differences in Takotsubo Syndrome.

Most patients with Takotsubo Syndrome (TTS) are postmenopausal females. TTS in males is rare and gender differences have not been sufficiently investigated. Therefore, we investigated gender differences in TTS. TTS in males and females is often triggered by physical and emotional stress, respectively. Heart failure, a severe in-hospital complication, requires greater mechanical respiratory support in males. Fatal arrhythmias such as ventricular tachycardia and ventricular fibrillation and in-hospital mortality rates are higher in males. The white blood cell (WBC) count has been shown to be higher in males than in females with cardiovascular death compared with non-cardiovascular death. Therefore, the WBC count, a simple marker, may reflect severe TTS. Decreased estrogen levels, common in postmenopausal females, are a pathogenic mechanism of TTS. Females have a more significant increase in the extracellular matrix-receptor interaction than males. Moreover, the pathological findings after hematoxylin-eosin staining were different in males and females. Males had more severe complications than females in the acute phase of TTS; thus, more careful observations and interventions are likely required. From these results, it can be considered that the mechanism of the onset of TTS may be different between males and females. Therefore, it is necessary to fully understand the gender differences in order to more effectively manage TTS.

Iatrogenic Atrial Septal Defect Requiring Transcatheter Closure Following Transcatheter Mitral Valve Repair.

BACKGROUND: Transcatheter mitral valve repair with the MitraClip system has been established in selected high-risk patients. The MitraClip procedure results in a relatively large iatrogenic atrial septal defect (iASD). This study aimed to investigate the prevalence and clinical course of iASD requiring transcatheter closure following the MitraClip procedure.Methods and Results: This study was conducted at all 59 institutions that perform transcatheter mitral valve repair with the MitraClip system in Japan. The data of patients on whom transcatheter iASD closure was performed were collected. Of the 2,722 patients who underwent the MitraClip procedure, 30 (1%) required transcatheter iASD closure. The maximum iASD size was 9±4 mm (range, 3-18 mm). The common clinical course of transcatheter iASD closure was hypoxemia with right-to-left shunt or right-sided heart failure with left-to-right shunt. Of the 30 patients, 22 (73%) required transcatheter closure within 24 h following the MitraClip procedure, including 12 with hypoxemia and 5 with right-sided heart failure complicated with cardiogenic shock. Of the 5 patients, 2 required mechanical circulatory support devices. Twenty-one patients immediately underwent transcatheter iASD closure, and hemodynamic deteriorations were resolved; however, 1 patient died without having undergone transcatheter closure. CONCLUSIONS: Transcatheter iASD closure was required in 1% of patients who underwent the MitraClip procedure. Many of these patients immediately underwent transcatheter iASD closure because of hypoxemia with right-to-left shunt or right-sided heart failure with left-to-right shunt.

Impact of tolvaptan on improvement of tricuspid regurgitation and right ventricular dimension in patients with right-sided heart failure.

Managing right-sided chronic heart failure (CHF) due to tricuspid regurgitation (TR) remains a clinical challenge. Tolvaptan (TLV), a vasopressin V2 receptor inhibitor, is effective in controlling decompensated HF. However, its effects on right-sided CHF caused by TR are unclear. We sought to clarify the effects of TLV in CHF patients complicated with TR. The cohort consisted of 33 CHF patients with moderate or severe TR and permanent atrial fibrillation, who required hospitalization for HF. We observed 19 patients treated with TLV plus conventional therapies (TLV group) and 14 patients with conventional therapies alone (conventional group). Clinical characteristics, echocardiographic parameters, and laboratory data were investigated. Baseline characteristics were similar between groups. In the TLV group, the severity of TR at admission was 73.7% moderate and 26.3% severe. In the conventional group, these percentages were 85.7% and 14.3%, respectively. During the follow-up, the severity of TR improved in the TLV group (trivial-mild: 52.6%; moderate: 36.8%; severe: 10.5%) (p < 0.01). However, it did not improve in the conventional group (trivial-mild: 21.4%; moderate: 50.0%; severe: 28.6%) (p = 0.08). The diameter of the tricuspid annulus (p < 0.01), basal (p = 0.02), and mid right ventricle (p = 0.04) was reduced at follow-up in the TLV group. Nevertheless, these parameters did not change in the conventional group. Serum creatinine levels were maintained (p = 0.74) in the TLV group, but deteriorated in the conventional group (p = 0.03). TLV reduced right ventricular dimensions and improved TR without deterioration of renal function. Thus, TLV may be a new drug for the treatment of CHF patients with TR.

Efficacy of treat-and-repair strategy for atrial septal defect with pulmonary arterial hypertension.

OBJECTIVE: Therapeutic strategies for atrial septal defect (ASD) with severe pulmonary arterial hypertension (PAH) are controversial. This study aimed to evaluate the efficacy of PAH-specific medications and subsequent transcatheter closure (ie, treat-and-repair strategy) on clinical outcomes. METHODS: We enrolled 42 patients who were referred to 13 institutions for consideration of ASD closure with concomitant PAH and underwent the treat-and-repair strategy. The endpoint was cardiovascular death or hospitalisation due to heart failure or exacerbated PAH. RESULTS: At baseline prior to PAH-specific medications, pulmonary to systemic blood flow ratio (Qp:Qs), pulmonary vascular resistance (PVR), and mean pulmonary artery pressure (PAP) were 1.9±0.8, 6.9±3.2 Wood units and 45±15 mm Hg. Qp:Qs was increased to 2.4±1.2, and PVR and mean PAP were decreased to 4.0±1.5 Wood units and 35±9 mm Hg at the time of transcatheter ASD closure after PAH-specific medications. Transcatheter ASD closure was performed without any complications. During a median follow-up period of 33 months (1-126 months) after transcatheter ASD closure, one older patient died and one patient was hospitalised due to heart failure, but the other patients survived with an improvement in WHO functional class. PAP was further decreased after transcatheter ASD closure. CONCLUSIONS: The treat-and-repair strategy results in low complication and mortality rates with a reduction in PAP in selected patients with ASD complicated with PAH who have a favourable response of medical therapy.

Examination of gender differences in patients with takotsubo syndrome according to left ventricular biopsy: two case reports.

BACKGROUND: Takotsubo syndrome is a stress-induced disease that makes up 2-3% of acute coronary syndrome cases. However, its onset mechanism remains unclear. Although females are overwhelmingly affected, males end up having more cardiac complications. CASE PRESENTATION: We examined the differences in stress responses in the myocardium between sexes in patients with takotsubo syndrome. We biopsied samples from an over 70-year-old Japanese male and an over 80-year-old Japanese female. Tissues from the left ventricle apex in the acute phase and the apical ballooning-type were examined using histopathology and deoxyribonucleic acid (DNA) microarray analysis. Our data showed that left ventricular ejection fractions were 38% and 56%, and peak creatinine kinase concentrations during hospitalization were 629 U/L and 361 U/L, for the male and female patient, respectively. The pulmonary capillary wedge pressure was 26 mmHg and 11 mmHg for the male and female patient, respectively. Negative T did not return to normal in the male subject after 6 months. Histopathology results indicated that contraction band necrosis and lymphocyte infiltration were more common in the male subject. CONCLUSIONS: We noticed that possible differences may exist between male and female patients using pathological examination and some DNA analyses. In particular, it may help treat acute severity in males. We will elucidate the mechanism of takotsubo syndrome development by increasing the number of samples to support the reliability of the data in the future.

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.

Gender Differences in the Circadian and Seasonal Variations in Patients with Takotsubo Syndrome: A Multicenter Registry at Eight University Hospitals in East Japan.

Objective The aim of this study was to clarify the circadian and seasonal variations in addition to identify sex-based differences in Japanese patients with Takotsubo syndrome (TTS). Methods The authors conducted a retrospective observational study to analyse the differences between the groups based on sex. Patients The patients were registered out of each institute registry of the acute coronary syndrome (ACS) which contains a total of 10,622 cases in eight academic hospitals in east Japan. Results Data for 344 consecutive TTS (73 male and 271 female) were extracted from each hospital registry. In-hospital mortality was higher in the male group than in the female group (18% vs. 7%; p=0.005). With regard to the circadian variations in all study patients, TTS events occurred most often in the afternoon and least often during the night. Moreover, the patterns of circadian variations in the female and male groups were the same as that of all study patients. TTS events occurred most frequently in the autumn and least often in the spring in the whole study cohort. Moreover, the seasonal variation in the female group showed the same pattern as that of the whole cohort. However, there were no significant seasonal differences in the incidence of TTS in the male group. Conclusion In a multicenter study in Japan, seasonal variation was observed in the female group but not in the male group. Circadian variation was observed in both groups. These results suggested that the pathogenesis and clinical features of TTS might therefore differ according to sex.