A multicenter, randomized, double-blind, controlled study to evaluate the efficacy and safety of dantrolene on ventricular arrhythmia as well as mortality and morbidity in patients with chronic heart failure (SHO-IN trial): rationale and design.

BACKGROUND: Leakage of Ca2+ from the sarcoplasmic reticulum (SR) is a critical contributing factor to heart failure pathophysiology. Therefore, reducing SR Ca2+ leaks may provide significant additive benefits when used in combination with conventional therapies. Dantrolene, a drug routinely used to treat malignant hyperthermia, also stabilizes the cardiac isoform of the release channel (RyR2), thus decreasing SR Ca2+ leaks. The purpose of this study is to evaluate the effect of chronic administration of dantrolene on heart failure and lethal arrhythmia in patients with chronic heart failure and reduced ejection fraction in a multicenter, randomized, double-blind, controlled study. METHODS: Patients with chronic heart failure who had functional status of New York Heart Association class II and III and a left ventricular ejection fraction <40% were treated according to the Japanese Circulation Society, the European Society of Cardiology, and the American Heart Association/the American College of Cardiology guidelines for diagnosis and treatment of acute and chronic heart failure. Patients were randomized and divided into two groups in a double-blind fashion: dantrolene group and placebo group (target sample size: 300 cases). These drugs were administered for 96 weeks. The primary endpoint is cardiovascular death, first hospitalization for exacerbation of heart failure, or lethal arrhythmia [ventricular tachycardia (VT) storm, sustained VT, ventricular fibrillation] for 2 years after starting administration of dantrolene 1 cap (25mg) three times daily (if not tolerable, two times daily) or matching placebo. RESULTS: This paper presents the rationale and trial design of the study. Recruitment for the study started on 8 December 2017. CONCLUSIONS: The results of this trial will clarify the efficacy and safety of dantrolene for ventricular arrhythmia, as well as mortality and morbidity in patients with chronic heart failure and reduced ejection fraction during guideline-directed medical treatment.

Open-Label Randomized Trial Comparing Oral Anticoagulation With and Without Single Antiplatelet Therapy in Patients With Atrial Fibrillation and Stable Coronary Artery Disease Beyond 1 Year After Coronary Stent Implantation.

BACKGROUND: Despite recommendations in the guidelines and consensus documents, there has been no randomized controlled trial evaluating oral anticoagulation (OAC) alone without antiplatelet therapy (APT) in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stenting. METHODS: This study was a prospective, multicenter, open-label, noninferiority trial comparing OAC alone to combined OAC and single APT among patients with atrial fibrillation beyond 1 year after stenting in a 1:1 randomization fashion. The primary end point was a composite of all-cause death, myocardial infarction, stroke, or systemic embolism. The major secondary end point was a composite of the primary end point or major bleeding according to the International Society on Thrombosis and Haemostasis classification. Although the trial was designed to enroll 2000 patients during 12 months, enrollment was prematurely terminated after enrolling 696 patients in 38 months. RESULTS: Mean age was 75.0±7.6 years, and 85.2% of patients were men. OAC was warfarin in 75.2% and direct oral anticoagulants in 24.8% of patients. The mean CHADS2 score was 2.5±1.2. During a median follow-up interval of 2.5 years, the primary end point occurred in 54 patients (15.7%) in the OAC-alone group and in 47 patients (13.6%) in the combined OAC and APT group (hazard ratio, 1.16; 95% CI, 0.79-1.72; P=0.20 for noninferiority, P=0.45 for superiority). The major secondary end point occurred in 67 patients (19.5%) in the OAC-alone group and in 67 patients (19.4%) in the combined OAC and APT group (hazard ratio, 0.99; 95% CI, 0.71-1.39; P=0.016 for noninferiority, P=0.96 for superiority). Myocardial infarction occurred in 8 (2.3%) and 4 (1.2%) patients, whereas stroke or systemic embolism occurred in 13 (3.8%) and 19 (5.5%) patients, respectively. Major bleeding occurred in 27 (7.8%) and 36 (10.4%) patients, respectively. CONCLUSIONS: This randomized trial did not establish noninferiority of OAC alone to combined OAC and APT in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after stenting. Because patient enrollment was prematurely terminated, the study was underpowered and inconclusive. Future larger studies are required to establish the optimal antithrombotic regimen in this population. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01962545.

Distal radial arterial hypertrophy after transradial intervention: A serial intravascular ultrasound study.

BACKGROUND: Transradial intervention (TRI) may cause damage to the radial artery (RA). We have demonstrated intima-media thickening and luminal narrowing of the distal RA after TRI using intravascular ultrasound (IVUS). This study aimed to determine the predictors of intima-media thickening of RA after TRI in the same patients using serial IVUS. METHODS AND RESULTS: We enrolled 110 consecutive patients who underwent TRI. IVUS of RA was immediately performed after TRI and repeated 6 months later. Volumetric analyses were performed for the distal RA. The intima-media volume (IMV) increased from 53.56±10.85mm3 to 58.70±13.04mm3 (p=0.0022), whereas the lumen volume (LV) decreased from 146.87±40.53mm3 to 129.64±45.78mm3 (p=0.0018) and vessel volume (VV) decreased from 201.23±44.55mm3 to 188.34±52.25mm3 (p=0.0306). Multiple regression analysis revealed diabetes as the most powerful independent predictor of the percentage change in IMV of the distal RA after TRI. The percentage change in IMV significantly increased in the DM group compared with non-DM group (p<0.001). The percentage change in IMV was significantly positively correlated with HbA1c. CONCLUSIONS: Serial IVUS of the distal RA revealed a significant increase in IMV and decreases in LV and VV. Diabetes was the most powerful independent predictor of the percentage change in IMV of the distal RA after TRI. The percentage change in IMV was significantly positively correlated with HbA1c.

Retrospective survey of severe fever with thrombocytopenia syndrome in patients with suspected rickettsiosis in Japan.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne infectious disease caused by the SFTS virus (SFTSV). The aim of this study was to clarify whether SFTS is potentially mis-diagnosed as rickettsioses, including spotted fever, typhus fever, and scrub typhus, which are also tick-borne disease. A total of 464 serum samples collected from 222 patients with clinically suspected rickettsiosis between 1999 and 2012 were tested for antibodies against the SFTSV. Of the 464 serum samples, one was positive for antibodies against the virus in an enzyme-linked immunosorbent assay and indirect immunofluorescence assay. The patient of SFTSV antibody-positive sample (15 days after disease onset) was positive for SFTSV genome in the acute phase sample (3 days after disease onset) as determined via reverse transcription-quantitative polymerase chain reaction. This patient, who was a resident of the Yamaguchi prefecture in Western Japan, was in his 40s when he showed symptoms in 2011. As the result, 1 of 222 patients, who was clinically suspected of rickettsiosis, was retrospectively diagnosed with SFTS. In this case, both the C-reactive protein and white blood cell count levels were lower than the ranges of these parameters for patients diagnosed with rickettsiosis. Therefore, SFTS should be considered in the differential diagnosis for rickettsiosis in Japan.

Impact of milrinone on mitral annular velocity in patients with congestive heart failure.

PURPOSE: The purpose of this study is to assess the impact of milrinone on mitral annular velocity in patients with congestive heart failure. METHOD: We studied 27 patients with congestive heart failure. All patients underwent transthoracic echocardiography both before and after administration of milrinone. We measured the early transmitral velocity (E) and the mitral annular early diastolic velocity (Ea). The ratio of E to Ea (E/Ea) was calculated. After the baseline echocardiography, milrinone was administered as a continuous infusion at a rate of 0.25 µg/kg/min. Echocardiographic measurements were repeated 4 h after milrinone was begun. RESULTS: After administration of milrinone, Ea was significantly increased, while E/Ea was significantly decreased. The population of 27 patients was divided into 20 (74 %) with left ventricular ejection fraction (LVEF) <50 % and seven (26 %) with LVEF ≥50 %. Ea was significantly increased in both groups, while E/Ea was significantly decreased. CONCLUSION: Even low-dose milrinone produced an improvement in left ventricular (LV) diastolic function, as evidenced by an increase in Ea, and falls in LV filling pressures, as determined by a decrease in E/Ea, in patients with congestive heart failure throughout a wide range of LV systolic function.

Nonbacterial thrombotic endocarditis demonstrated by repeat echocardiography.

We report a case of nonbacterial thrombotic endocarditis (NBTE) in a patient with bladder cancer presenting with multiple cerebral infarctions. Initial transthoracic and transesophageal echocardiography did not show any abnormalities. However, repeat transthoracic and transesophageal echocardiography demonstrated a vegetation on the anterior leaflet of the mitral valve with mild mitral regurgitation and no evidence of leaflet destruction. Persistent high-grade fevers and leukocytosis were observed. The patient was suspected to have infective endocarditis. However, abdominal ultrasound and computed tomography scan revealed multiple metastatic masses, and serial blood cultures were negative. The patient was ultimately diagnosed with NBTE associated with multiple metastases of bladder cancer. This case suggests that even if echocardiography does not initially demonstrate any abnormalities in patients with embolism, it must be repeated at the recurrence of embolism, and that even if clinical signs of infection are documented, NBTE should be suspected in any cancer patient with thromboembolic events.

Donepezil-induced torsades de pointes without QT prolongation.

We report a case of torsades de pointes (TdP) induced by donepezil without QT prolongation. An 86-year-old woman was admitted to our hospital because of a syncopal attack. She had been treated for Alzheimer's disease with donepezil. Initial 12-lead electrocardiogram showed atrial fibrillation and normal corrected QT interval. After admission, atrial fibrillation spontaneously recovered to normal sinus rhythm on electrocardiographic monitoring. On the second day, electrocardiographic monitoring documented TdP. We discontinued donepezil immediately. After washout of donepezil, TdP was not observed again. Corrected QT interval was normal throughout hospitalization. This case suggests that donepezil may cause life-threatening ventricular arrhythmias without QT prolongation. Even if corrected QT interval is normal in patients taking donepezil and experiencing symptoms associated with TdP, electrocardiographic monitoring is recommended. .

Effects of mineralocorticoid receptor antagonist spironolactone on atrial conduction and remodeling in patients with heart failure.

BACKGROUND: Spironolactone was shown to reduce mortality in patients with heart failure (HF). However, the effect of spironolactone on the incidence of atrial fibrillation remains unknown. Therefore, we examined the effects of spironolactone on atrial conduction and remodeling in patients with HF. METHODS AND RESULTS: A total of 21 patients with HF were divided into either spironolactone group (n=11) or control group (n=10). The patients were followed up for 12 months. Blood examination, echocardiogram, and signal-averaged electrocardiogram were performed at study enrollment and after 3 and 12 months of treatment. In the spironolactone group, atrial natriuretic peptide tended to reduce, left atrium dimension was significantly smaller, the ratio of E wave to A wave tended to improve, and P-duration was significantly shortened. CONCLUSIONS: Spironolactone improves atrial conduction and remodeling in patients with HF.

Defibrillation efficacy of a subcutaneous array lead: A case report.

We report a case of Brugada syndrome with a high defibrillation threshold (DFT) in whom a subcutaneous array lead was used to lower the DFT in combination with a transvenous right ventricular defibrillation lead. The patient had previously received pacemaker implantation due to sick sinus syndrome. An implantable cardioverter defibrillator (ICD) with a transvenous right ventricular defibrillation lead alone required a high DFT. A subcutaneous array lead improved defibrillation efficacy in combination with a right ventricular lead. These data suggest that a subcutaneous array lead facilitates implantation of an effective ICD lead system in patients requiring a high DFT.

Cardio-ankle vascular index is superior to brachial-ankle pulse wave velocity as an index of arterial stiffness.

Both cardio-ankle vascular index (CAVI) and brachial-ankle pulse wave velocity (baPWV) are noninvasive methods to estimate arterial stiffness. The purpose of this study is to determine whether CAVI or baPWV is superior as an index of arterial stiffness. One hundred and thirty patients with chest pain syndrome who underwent coronary angiography (CAG) were included in this study. We obtained intima-media-thickness (IMT) and the stiffness parameter beta of the carotid artery by carotid ultrasounds (CU). The peak early diastolic velocity (E), deceleration time of E (EDCT), peak atrial systolic velocity (A) of transmitral flow and left ventricular mass index (LVMI) were obtained by echocardiography. CAVI, baPWV, total cholesterol (T-C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglycerides (TG) were measured before CAG. There was a significant correlation between CAVI and baPWV (r = 0.64, p < 0.01). Both CAVI and baPWV were significantly correlated with age, IMT and beta (age: r = 0.64, p < 0.01 for CAVI, and r = 0.48, p < 0.01 for baPWV; IMT: r = 0.40, p < 0.01, and r = 0.31, p < 0.01; beta: r = 0.36, p < 0.01 and r = 0.25, p < 0.01). However, only CAVI was correlated with the parameters of left ventricular diastolic indices from echocardiography (E/A: r = 0.44, p < 0.01; EDCT: r = 0.36, p < 0.01). Additionally, LDL-C and T-C/HDL-C were also associated with only CAVI (LDL-C: r = 0.26, p < 0.02; T-C/HDL-C: r = 0.30, p < 0.01), not baPWV. Finally, only CAVI was significantly higher in the group with angina pectoris than in the normal group (9.708 +/- 1.423 vs. 9.102 +/- 1.412; p = 0.0178). All parameters associated with atherosclerosis suggested that CAVI was superior to baPWV as a parameter of arterial stiffness.

Cardio-ankle vascular index is a new noninvasive parameter of arterial stiffness.

BACKGROUND: Beta is an index of arterial stiffness independent of blood pressure. Beta of the thoracic descending aorta (TDA) has been obtained by transesophageal echocardiography (TEE) and the cardio-ankle vascular index (CAVI) is a new noninvasive estimation of beta. METHODS AND RESULTS: The purpose of this study was to evaluate the accuracy and usefulness of CAVI and to compare it with other parameters of arteriosclerosis by carotid ultrasound (CU). The instantaneous dimensional change of the TDA on TEE was measured simultaneously with systemic pressure of the brachial artery in 70 patients in sinus rhythm. There were significant correlations between CAVI and age (r=0.65, p<0.01), and CAVI and the beta from TEE (Aobeta) (r=0.67, p<0.01). Next, 110 patients with chest pain syndrome underwent CU and measurement of CAVI, intima - media thickness (IMT), plaque score and beta. There were significant relationships between CAVI and IMT (r=0.42, p<0.01), and between CAVI and beta (r=0.39, p<0.01). CAVI of the group diagnosed with plaque was significant higher than that of the normal group (9.872+/-1.464 vs 9.038+/-1.377, p=0.0039). CONCLUSIONS: CAVI is measured easily and noninvasively and is a new index of arterial stiffness that is independent of blood pressure.

Tricuspid pouch can cause systemic embolization in adulthood.

A 63-year-old-man with significant left hemiplegia was admitted to hospital. He had experienced a transient cerebral ischemic attack 10 years ago. Computed tomography revealed hypodensity along the right lateral ventricle, which corresponded to the left paralysis. Echocardiography and left ventricular angiography revealed an aneurysm of the membranous septum (AMS) without a ventricular septal defect (VSD). Therefore, the embolism was thought to be of cardiac origin, but surgery revealed that it was not caused by AMS. The aneurysm was created when the septal leaflet of tricupid valve formed a giant capsule during the process of natural closure of the VSD. It was a large pouch, 2.0 cm in diameter, adjacent to the septal leaflet. Anomalies of the tricuspid valve, including pouches, can resemble AMS.

[Cardioversion of amiodarone-insensitive atrial fibrillation by bepridil in heart failure: two case reports].

Two patients presented with atrial fibrillation which was refractory to amiodarone but successfully treated with bepridil. A 76-year-old man with ischemic cardiomyopathy, non-sustained ventricular tachycardia (NSVT) and atrial fibrillation received amiodarone for NSVT, which disappeared but atrial fibrillation was sustained. A month after receiving amiodarone, interstitial pneumonia occurred. Interstitial pneumonia was improved after amiodarone was discontinued, but NSVT occurred again. He received bepridil, when NSVT and atrial fibrillation disappeared. An 83-year-old man with dilated cardiomyopathy, NSVT, and atrial fibrillation received amiodarone for NSVT, which disappeared but atrial fibrillation was sustained. Five months after receiving amiodarone, interstitial pneumonia occurred. Interstitial pneumonia was improved after amiodarone was discontinued, but NSVT occurred again. He received bepridil, when NSVT and atrial fibrillation disappeared.

Complete proximal occlusion of all three main coronary arteries complicated with a left main coronary aneurysm: a case report.

A 68-year-old woman with recurrent chest pain was referred to our institution. Coronary angiography showed 100% obstruction of the left main trunk, the proximal right coronary artery with good collaterals to the left anterior descending artery and left circumflex artery along the conus artery. Emergency surgical revascularization was undertaken with two saphenous vein grafts. The saphenous vein grafts were placed in the left anterior descending artery, obtuse marginal branch and the posterolateral and posterior descending coronary arteries with excellent flow. The postoperative course was uneventful and follow-up angiography was obtained 20 days after the surgery. Coronary angiography demonstrated a saccular aneurysm (10 x 9 mm) originating at the distal segment of the left main coronary artery with 90% stenosis, and excellent patency of both saphenous vein grafts. Follow-up angiography was performed 1 and 3 years after the surgery. The size of the left main coronary aneurysm remained unchanged at both examinations. The patient did well with no further cardiac symptoms after 5 years.

[Hypertrophic obstructive cardiomyopathy with ruptured mitral chordae tendineae: a case report].

A 61-year-old man was treated medically under a diagnosis of hypertrophic obstructive cardiomyopathy 7 years previously. He was transferred to our hospital because of sudden onset of dyspnea. Chest radiography showed marked pulmonary congestion. Echocardiography revealed hypertrophic obstructive cardiomyopathy, with a left ventricular pressure gradient of 120 mmHg, accompanied by severe mitral regurgitation due to ruptured chordae tendineae. Mitral valve replacement and the Morrow operation were performed. After the operation, no left ventricular outflow pressure gradient was detected by echocardiography and cardiac catheterization. The patient did well and no further cardiac symptoms were detected for 3 years.

[Ampulla cardiomyopathy with left ventricular apical mural thrombi resolved by anticoagulant therapy without systemic complication: a case report].

A 79-year-old woman was admitted for treatment of bronchial asthma. ST-segment elevation in the precordial leads (V4-V6) and T-wave inversion in leads II, III, and aVF was recognized. Transthoracic echocardiography and emergent cardiac catheterization demonstrated two large mobile thrombi (1.2 x 1.3 cm, 0.7 x 1.0 cm) attached to the left ventricular wall. There was no organic stenosis. Left ventriculography revealed anterolateral, apical and inferior dyskinesis, and basal hyperkinesis. The clinical diagnosis was ampulla cardiomyopathy. Anticoagulant therapy was started. Prothrombin time-international normalized ratio was remained at 2.5-3 and partial thromboplastin time was controlled at 1.5-2 times compared with the normal value. Repeated echocardiography showed the mass reduced gradually and had disappeared about 2 weeks later.

Coronary arterial remodeling in differing clinical presentations of unstable angina pectoris--an intravascular ultrasound study.

BACKGROUND: Coronary arterial remodeling influences the clinical presentation of ischemic heart disease; however, there is little information on the relationship between coronary arterial remodeling and the type of angina pectoris that patients manifest. HYPOTHESIS: The study was undertaken to determine the difference of coronary arterial remodeling in patients with different types of angina pectoris. METHODS: We analyzed 100 patients with ischemic heart disease using intravascular ultrasound (IVUS). Intracoronary IVUS images of proximal reference (PR), distal reference (DR), and target lesion were recorded, and intraluminal area (LA) and external elastic membrane (EEM) were measured. We defined a remodeling index as 100 x (lesion EEM - [PR-EEM + DR-EEM]/2) / ([PR-EEM + DR-EEM]/2). Cases were classified into three groups according to the clinical history (Group 1a: de novo unstable angina pectoris, Group 1b: accelerating unstable angina pectoris, and Group 2; stable angina pectoris). RESULTS: The remodeling index in Group 1a was significantly larger than that in Groups 1b and 2 (18.6 +/- 28.5 vs. 5.3 +/- 27.1 and 18.6 +/- 28.5 vs. -2.7 +/- 17.6, p = 0.0347 and p = 0.0005, respectively), but there was no statistical difference in remodeling index between Groups 1b and 2. CONCLUSIONS: Our results indicate that positive coronary arterial remodeling is more prevalent in patients with new onset of angina pectoris. The specific type of coronary arterial remodeling may affect the clinical presentation of patients with coronary artery disease.

Effects of candesartan and probucol on restenosis after coronary stenting: results of insight of stent intimal hyperplasia inhibition by new angiotensin II receptor antagonist (ISHIN) trial.

The purpose of this study was to determine whether candesartan and its combination with probucol reduce restenosis after coronary stenting. A total of 132 patients who successfully underwent stenting were randomly assigned to a control group (n=45), a candesartan group (8 mg daily, n=43), or a candesartan plus probucol group (+ probucol 500 mg daily, n=44). No differences in late loss were observed between the control and candesartan groups. In the candesartan plus probucol group, late loss was significantly smaller than in the control and candesartan groups (p=0.003, 0.015). The restenosis rate was 27% in the control group, 26% in the candesartan group (p>0.99), and 11% in the candesartan plus probucol group (p=0.104 vs the control group and p=0.103 vs the candesartan group). Intravascular ultrasound revealed no differences in stent area among the 3 groups, and no differences in lumen area or in intimal hyperplasia area between the control and candesartan groups. However, the intimal hyperplasia area in the candesartan plus probucol group was significantly less than that in the control and candesartan groups (p<0.001, p<0.001). This study demonstrated that candesartan failed to inhibit the neointimal hyperplasia and although the combination treatment did reduce neointimal hyperplasia, it did not statistically reduce the restenosis rate.