Right Ventricular Dyssynchrony in Patients With Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are characterized by elevated pulmonary arterial pressure resulting in right heart failure. Right ventricular (RV) dyssynchrony may be associated with early-stage RV dysfunction; however, the differences in RV dyssynchrony between CTEPH and PAH and the factors contributing to RV dyssynchrony remain unclear.Methods and Results: Forty-four patients (CTEPH, 26; PAH, 18) were enrolled in this study. RV dyssynchrony was assessed by determining the standard deviation of the intervals from the peak QRS to peak systolic strain for 6 segments of the RV free and septal wall by using 2-dimensional speckle-tracking echocardiography (RV-6SD). The RV-6SD, pulmonary hemodynamics, echocardiographic findings, and patient demographics in CTEPH and PAH patients were compared and their correlations with RV-6SD were investigated. CTEPH patients were older and had significantly higher pulse pressure of the pulmonary artery (PP), tricuspid valve regurgitation pressure gradient, and RV-6SD, and lower pulmonary arterial compliance (PAC), despite showing comparable pulmonary arterial pressures. Age-adjusted multiple logistic analysis showed that RV-6SD and PAC were predictors of CTEPH rather than PAH. RV-SD6 was positively correlated with PP and RV dimension and negatively correlated with PAC. CONCLUSIONS: CTEPH patients showed more evident RV dyssynchrony than PAH patients. Low PAC and a widened PP may delay RV free wall motion and cause RV dyssynchrony.

Effectiveness and safety of oral direct factor Xa inhibitors for the treatment of venous thromboembolism in patients with cancer and/or older age.

Venous thromboembolism (VTE) is a multifactorial disease. Cancer and older age are risk factors for both recurrent VTE and bleeding under anticoagulant therapy. Oral direct factor Xa inhibitors (Xa inhibitors) have been widely used to treat VTE. However, their effectiveness and safety in cancer and elderly patients have not been fully elucidated. A total of 187 consecutive patients who started Xa inhibitors for VTE therapy between September 2014 and September 2016 were recruited. Patients' demographics, changes in VTE amount, VTE recurrence, clinically relevant bleeding, and death until February 2017 were compared between 92 cancer and 95 non-cancer patients, and 57 elderly (≥ 75 years) and 130 non-elderly patients. Compared with non-cancer patients, cancer patients had a significantly higher incidence of deep vein thrombosis (DVT) in the proximal legs, superior vena cava, and upper extremities (p = 0.034), although the patients' demographics and incidence of pulmonary thromboembolism (PE) were similar between the two groups. There were no significant differences in VTE recurrence (p = 0.328) and clinically relevant bleeding (p = 0.078) between the two groups. Death occurred in 29 cancer patients, 23 of whom died of cancer, while there were no deaths among the non-cancer patients. Elderly patients had a lower body weight and creatinine clearance than non-elderly patients. No significant differences between the two groups were found in relation to PE (p = 0.544), DVT site (p = 0.054), recurrent VTE (p = 0.194), clinically relevant bleeding (p = 0.130) and death (p = 0.241). In comparisons among the four groups (elderly and non-elderly patients with and without cancer), recurrent VTE and clinically relevant bleeding were comparable (p = 0.493 and 0.227, respectively), while death was more frequent in cancer patients regardless of age (p < 0.001). The efficacy and safety of Xa inhibitors as VTE treatment were comparable between cancer and non-cancer patients, and in elderly and non-elderly patients. This suggests that Xa inhibitors may be promising drugs for VTE treatment, irrespective of age and comorbid cancer.

Doppler ultrasound diagnosis of transient leg malperfusion caused by dynamic obstruction in a patient with chronic aortic dissection.

Leg malperfusion caused by dynamic obstruction is a serious complication of aortic dissection. A diagnosis of the malperfusion is difficult because it is made mainly on the basis of nonspecific symptoms such as intermittent claudication and numbness on walking. In the present study, we reported on a case of a 51-year-old man with leg malperfusion in chronic aortic dissection diagnosed by Doppler ultrasound. The combination of bisferious and dampened velocity waveform changes after walking may lead us to suspect a leg malperfusion caused by dynamic obstruction.

Characteristics of induced pluripotent stem cells from clinically divergent female monozygotic twins with Danon disease.

RATIONALE: Induced pluripotent stem cells (iPSCs) have been generated from patients with various forms of disease, including Danon disease (DD); however, few reports exist regarding disease-specific iPSCs derived from clinically divergent monozygotic twins. OBJECTIVE: We examined the characteristics of iPSCs and iPSC-derived cardiomyocytes (iPSC-CMs) generated from clinically divergent monozygotic female twins with DD. METHODS AND RESULTS: We generated iPSCs derived from T-cells isolated from clinically divergent, 18-year-old female twins with DD harboring a mutation in LAMP2 at the intron 6 splice site (IVS6+1_4delGTGA). Two divergent populations of iPSCs could prepare from each twin despite of their clinical divergence: one with wild-type LAMP2 expression (WT-iPSCs) and a second with mutant LAMP2 expression (MT-iPSCs). The iPSCs were differentiated into iPSC-CMs and then autophagy failure was observed only in MT-iPSC-CMs by electron microscopy, tandem fluorescent-tagged LC3 analysis, and LC3-II western blotting. Under these conditions, X-chromosome inactivation (XCI) was determined by PCR for the (CAG)n repeat in the androgen receptor gene, revealing an extremely skewed XCI pattern with the inactivated paternal wild-type and maternal mutant X-chromosomes in MT-iPSCs and WT-iPSCs, respectively, from each twin. CONCLUSION: Regardless of their clinical differences, we successfully established two sets of iPSC lines that expressed either wild-type or mutant LAMP2 allele from each monozygotic twin with DD, of which only the populations expressing mutant LAMP2 showed autophagic failure.

Clinical characteristics of spontaneous isolated visceral artery dissection.

OBJECTIVE: Spontaneous isolated visceral artery dissection (SIVAD) involving the celiac artery or superior mesenteric artery is rare, but it can be fatal. Given its rare incidence, the clinical characteristics of SIVAD are not fully understood. Therefore, the aim of this study was to investigate the clinical characteristics and prognosis of SIVAD. METHODS: We retrospectively reviewed 39 consecutive patients diagnosed with SIVAD from January 2007 to December 2016. Demographic characteristics, symptoms, vital signs, blood examination results, and computed tomography findings were retrieved through medical record review. RESULTS: The median age of the patients was 52 years; 94.9% were male, and 64.1% were symptomatic. Median follow-up duration was 11 months. Overall, hypertension (48.7%) and smoking (79.5%) were frequently observed. There were significant differences between symptomatic and asymptomatic patients in white blood cell count and creatine kinase level but not in fibrin degradation products or D-dimer level. There was a significant correlation between symptoms and length of dissection on computed tomography (P < .01). Conservative treatment was performed in 32 patients (82.1%), and only 7 patients required open surgery or intravascular intervention. Notably, the diameter of affected vessels decreased spontaneously with no rupture or symptom recurrence during follow-up, and mortality was 0% at both 30 days and 1 year. CONCLUSIONS: The utility of blood examination, especially for fibrin degradation products and D-dimer levels, for diagnosis of SIVAD is limited. A high index of suspicion is warranted in patients presenting with persistent severe abdominal pain. Conservative treatment should be considered first-line therapy in patients without any signs of bowel ischemia or rupture.

Application of an enhanced device to transluminal retrieval of malappositioned coronary stents: An experimental study.

OBJECTIVES: This study investigated the application of a novel enhanced device to retrieval of deployed stents in a porcine coronary model. BACKGROUND: Recurrence of in-stent restenosis and stent thrombosis still remains to be resolved. Under these conditions, it is sometimes necessary to retrieve malfunctional stents responsible for thrombosis. However, few data exist regarding the feasibility and safety of retrieval device use in previously deployed coronary stents. METHODS: We have developed an enhanced device consisting of an asymmetric forceps, conducting shaft (1.6 mm diameter, 150 cm length), and control handle. Bare-metal stents (3 mm diameter) were implanted in four pigs to create a malapposition model. Coronary artery injury was evaluated by intravascular ultrasound (IVUS) and histological imaging on the first and 14th days. RESULTS: The device was delivered to the coronary artery using the existing catheter (7 Fr). After opening the forceps, the blade was forced into the space between the vessel wall and the stent, and the stent struts were then grasped with the forceps. This was then pulled back into the catheter, still grasping the stent struts with the forceps. All stents were successfully retrieved by this method (n = 4). On the first day, no apparent vessel wall injury was detectable by IVUS, although histological findings revealed damage to endothelial monolayer on retrieval of deployed stent. On the 14th day, mild intimal thickening was observed by IVUS and histology. CONCLUSIONS: These results demonstrate that the present device can be applied to transluminal retrieval of acquired malappositioned coronary stents.

Overview of the 81st Annual Scientific Meeting of the Japanese Circulation Society　- Cardiovascular Medicine for the Next Generation.

The 81stAnnual Scientific Meeting of the Japanese Circulation Society was held in Kanazawa, Japan, on March 17-19, 2017 under a miraculously clear sky. The frontlines of healthcare and medicine are dramatically changing. Thus, "Cardiovascular Medicine for Next Generation" was chosen as the main theme of this meeting. The program was constructed around major identified issues, including renewal of our understanding of basic cardiovascular medicine, translational research, and preventive molecular medicine, all of which are anticipated to transcend the medical field over the next generation. Despite the provincial location, 15,672 participants, including more than 400 from overseas countries, attended the 3-day meeting, and there were in-depth discussions in the various sessions. In particular, to our great pleasure, Her Imperial Highness Princess Takamado kindly attended the opening ceremony and extended congratulations to us. The meeting successfully completed and we sincerely appreciate the great cooperation and support from all affiliates.

Early endothelialization associated with a biolimus A9 bioresorbable polymer stent in a porcine coronary model.

Although Nobori®, with a bioresorbable polymer and biolimus A9 abluminal coating, has unique characteristics, few data exist regarding endothelialization early after implantation. Fifteen Nobori® and 14 control bare-metal stents (S-stent™) were implanted in 12 pigs. Histopathology of stented segments, inflammation, and intimal fibrin content was evaluated on the 2nd and 14th day after implantation. On the 2nd day, endothelial cells were morphologically and immunohistologically confirmed on the surface of both stents, although some inflammatory cells might be involved. Stent surface endothelialization evaluated with a scanning electron microscope showed partial cellular coverage in both stents. On the 14th day, neointimal thickness and percentage of the neointimal area were significantly lower in Nobori® than in S-stent™ (51.4 ± 4.5 vs. 76.4 ± 23.6 µm, p < 0.05 and 10.8 ± 2.6 vs. 14.1 ± 4.2%, p < 0.01). No significant differences were found in these parameters on the 2nd day (17.3 ± 14.9 vs. 26.7 ± 13.6 µm and 3.7 ± 3.0 vs. 6.7 ± 3.7%), in inflammatory and intimal fibrin content scores. These results demonstrate that endothelialization could occur early after Nobori® implantation with similar inflammatory reaction to bare-metal stents, probably contributing to low frequency of in-stent thrombosis and restenosis.

Impact of Enhanced Production of Endogenous Heme Oxygenase-1 by Pitavastatin on Survival and Functional Activities of Bone Marrow-derived Mesenchymal Stem Cells.

Although mesenchymal stem cells (MSCs) have a therapeutic potential for the repair of tissue injuries, their poor viability in damaged tissue limits their effectiveness. Statins can induce an increased production of heme oxygenase-1 (HO-1), which may prevent this detrimental effect in MSCs. We investigated the protective effect of statin-induced overexpression of HO-1 by examining changes in gene expression and function in MSCs after pitavastatin treatment. The relative expression of the HO-1 and endothelial nitric oxide synthase genes in MSCs was significantly increased after treatment with pitavastatin (MSCs). Immunocytological analysis showed that MSCs also stained with phospho-Akt. After exposure to oxidative stress, MSCs showed increased resistance to induced cell death compared with control MSCs. Under serum starvation conditions, MSCs treated with 1 µM pitavastatin showed enhanced cell proliferation and a marked increase in vascular endothelial growth factor production compared with control MSCs. Interestingly, MSCs showed enhanced tube formation under both normoxia and hypoxia. These results demonstrate that pitavastatin can enhance endogenous HO-1 expression in MSCs, which may protect the cells into the environment of oxidative stress with partial activation of endothelial nitric oxide synthase and Akt phosphorylation.

Impact of Elevated D-Dimer on Diagnosis of Acute Aortic Dissection With Isolated Neurological Symptoms in Ischemic Stroke.

BACKGROUND: Plasma D-dimer is known to be a useful clinical marker of thrombogenic status, and D-dimer is used as a diagnostic marker for acute aortic dissection (AAD). Little is known, however, regarding the clinical value of D-dimer for diagnosis of asymptomatic AAD in patients with ischemic stroke. We investigated whether D-dimer could be used for early diagnosis of AAD with isolated neurological symptoms in ischemic stroke patients. METHODS AND RESULTS: We evaluated a total of 1,236 consecutive patients with symptomatic ischemic stroke without chest or back pain who underwent either head computed tomography or magnetic resonance imaging. D-dimer was measured within 24 h after onset. There were 9 patients with Stanford type A AAD and they had significantly higher D-dimer than the patients without AAD (mean, 46.47±54.48 µg/ml; range, 6.9-167.1 µg/ml vs. 2.33±3.58 µg/ml, 0.3-57.9 µg/ml, P<0.001). When a cut-off of 6.9 µg/ml was adopted for d-dimer on the basis of receiver operating characteristics analysis, the sensitivity and specificity for AAD were 100% and 94.8%, respectively, while the positive and negative predictive values were 14.7% and 100%, respectively. CONCLUSIONS: D-dimer might be a useful marker for the early diagnosis of AAD with isolated neurological symptoms in ischemic stroke patients. Whole-body contrast-enhanced computed tomography should be performed in ischemic stroke patients who have high D-dimer.

Effects of tafamidis on the left ventricular and left atrial strain in patients with wild-type transthyretin cardiac amyloidosis.

AIMS: Although tafamidis is used in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), its specific effect on cardiac function is unclear. Thus, this study aimed to investigate the effect of tafamidis on left atrial (LA) and left ventricular function using speckle-tracking echocardiography for 1 year of treatment in patients with ATTRwt-CA. METHODS AND RESULTS: We included 23 patients (mean age, 76 years) with ATTRwt-CA confirmed via biopsy. We analysed the left ventricular and LA strain using 2D speckle-tracking echocardiography and compared these parameters before and 1 year after starting treatment with tafamidis between 16 patients with sinus rhythm (SR) and 7 patients with atrial fibrillation (AF). In ATTRwt-CA patients with SR, LA reservoir strain significantly improved by 1-year tafamidis treatment (10.5 ± 5.0% to 11.9 ± 5.3%, P = 0.0307) although global longitudinal strain (GLS) did not (-10.6 ± 3.1% to -11.3 ± 3.0%, P = 0.0608). In contrast, LA reservoir strain was not significantly changed (5.4 ± 2.9% to 4.9 ± 1.7%, P = 0.4571), and GLS deteriorated (-8.4 ± 2.3% to -6.8 ± 1.4%, P = 0.0267) in ATTRwt-CA patients with AF. CONCLUSION: LA function improved with tafamidis treatment in ATTRwt-CA patients with SR but not left ventricular function. However, these cardiac functions did not improve with tafamidis treatment in ATTRwt-CA patients with AF.

Amyloid Deposition Mainly Localized in the Basal Area of the Left Ventricle in a Patient with Amyloid Transthyretin Cardiac Amyloidosis.

A 74-year-old Japanese man was admitted to our hospital for catheter ablation of paroxysmal atrial fibrillation. Transthoracic echocardiography revealed basal interventricular septal hypertrophy without apical sparing. Cardiac magnetic resonance imaging revealed late gadolinium enhancement in the hypertrophic lesions. The Kumamoto criteria was one point, and the patient had no carpal tunnel syndrome. However, technetium-99m pyrophosphate scintigraphy revealed an accumulation in the basal region of the left ventricle. A skin biopsy revealed transthyretin (TTR) amyloid deposition. A TTR gene examination revealed no variants. This case suggests that amyloid deposition in TTR may occur in the basal area of the interventricular septum.

Prevalence of Left Ventricular Myocardial Crypts in Japanese Patients.

Background Myocardial crypts are congenital abnormalities associated with hypertrophic cardiomyopathy (HCM) and other conditions. This study assessed the prevalence of myocardial crypts in Japanese patients. Methods and Results Myocardial crypts were evaluated in a consecutive series of 300 patients (13-92 years old) who underwent computed tomography angiography (CTA) because of clinical suspicion of ischemic heart disease. We found a myocardial crypt incidence of 9.7% (29 patients) in our study population, with multiple crypts observed in 2.3% (7 patients). Among these, myocardial crypts were found in 2 out of 8 (25%) patients with hypertrophic cardiomyopathy (HCM), 1 of which was apical-type HCM. In patients with a single crypt (22 patients), the most common location of the crypt was at the left ventricular apex (16/22 patients, 72.7%), followed by the inferior wall (5/22 patients, 22.7%) and the interventricular septum (1/22 patients, 4.6%). Conclusion The incidence of myocardial crypts observed in our study aligns with that reported in previous studies, although the most common location among the Japanese population was the left ventricular apex.

Real-world Safety and Effectiveness of Edoxaban in Patients with Venous Thromboembolism with or without Preceding Parenteral Anticoagulants: A Single-center Retrospective Study.

Objective Edoxaban is an anticoagulant used for venous thromboembolism (VTE) treatment and requires pretreatment with parenteral anticoagulants. However, pretreatment is not always performed in the clinical setting. In this study, we investigated the safety and effectiveness of edoxaban treatment in patients with VTE with or without pretreatment. Methods We retrospectively enrolled 364 patients who received edoxaban for VTE treatment between September 2014 and March 2020 and investigated patient demographics, VTE recurrence, and major bleeding as clinical outcomes in patients with or without pretreatment. Furthermore, the factors contributing to pretreatment decisions were assessed. Results Patients without pretreatment (n=208) had more active cancer cases and fewer pulmonary embolism complications than those with pretreatment (n=156). Lower levels of hemoglobin and higher levels of white blood cell counts, C-reactive protein, and D-dimer at the diagnosis were found in patients who received pretreatment than in those without pretreatment. No symptomatic VTE recurrence was observed. After propensity score matching, the cumulative incidence of major bleeding was not significantly higher in patients with pretreatment than in those without it (log-rank test, p=0.136). The incidence of deteriorated VTE on imaging did not significantly differ between patients with and without pretreatment, even after propensity matching (log-rank test, p=0.414). Conclusion In a real-world clinical setting, where physicians determined the use of parenteral anticoagulant lead-in according to their experience, patient demographics, and VTE characteristics, no significant differences were found regarding safety and effectiveness in edoxaban-treated VTE patients with or without pretreatment with parenteral anticoagulants.

Ubiquitin, p62, and Microtubule-Associated Protein 1 Light Chain 3 in Cardiomyopathy.

Background: The accumulation of ubiquitinated proteins has been detected in diseased hearts and has been associated with the expression of p62 and microtubule-associated protein 1 light chain 3 (LC3), which are related to autophagy. We evaluated differences in ubiquitin accumulation and p62 and LC3 expression in cardiomyopathy using endomyocardial biopsies. Methods and Results: We studied 24 patients (aged 24-70 years; mean age 55 years) diagnosed with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), or non-cardiomyopathy (NCM) who underwent endomyocardial biopsy. Biopsied samples were evaluated by microscopy for ubiquitin accumulation and expression of p62 and LC3. Ubiquitin accumulation and p62 and LC3 expression were observed in all patients. Ubiquitin accumulation was higher in DCM than in HCM or NCM; p62 expression was higher in DCM than in HCM. There were no significant differences in LC3 expression among the groups. Ubiquitin accumulation was significantly related to serum N-terminal pro B-type natriuretic peptide concentration and the expression of p62, but not LC3. Conclusions: Ubiquitin accumulation was more prominent in DCM than in HCM and NCM, which may be due to a relative shortage of clearance, including autophagy, compared with production.

Intramural hematoma with intramural blood pool associated with vertebral compression fracture.

Although intramural blood pools due to intercostal arteries in intramural hematoma have been reported as a traumatic aortic injury, the precise mechanism is unclear. We present the case of an elderly patient who presented with an intramural blood pool due to an intercostal artery prolapse in an intramural hematoma associated with a compression fracture of the thoracic vertebra after a fall. .

Delayed Acute Perimyocarditis and Bilateral Facial Nerve Palsy in a Patient with COVID-19.

A 41-year-old Japanese man was admitted to our hospital with acute perimyocarditis 4 weeks after coronavirus disease 2019 (COVID-19) infection. Ten days after admission, the patient showed bilateral facial nerve palsy in the course of improvement of perimyocarditis under treatment with aspirin and colchicine. After prednisolone therapy, perimyocarditis completely improved, and the facial nerve palsy gradually improved. Acute perimyocarditis and facial nerve palsy can occur even 4 weeks after contracting COVID-19.

Comparison of Effectiveness and Safety Among 3 Direct Oral Anticoagulants in Patients With Venous Thromboembolism　- A Single-Center Retrospective Study.

Background: Direct oral anticoagulants (DOACs), including edoxaban, rivaroxaban, and apixaban, are administered for the treatment of venous thromboembolism (VTE) in Japan. However, only a few reports have compared the effectiveness and safety of these DOACs. Methods and Results: We retrospectively enrolled 702 patients who received DOACs for VTE treatment between September 2014 and March 2020. We investigated patient demographics, VTE recurrence, major bleeding, and mortality until March 2021, and compared them among the 3 DOACs. Most patients (~70%; n=496) were prescribed edoxaban, followed by apixaban (n=107) and rivaroxaban (n=99). Age, body mass index, renal function, and the proportion of cancer patients did not differ significantly among the DOACs. Edoxaban was administered relatively more in women with low body weight and anemia. The rate of pulmonary embolism was significantly lower among patients receiving edoxaban than apixaban or rivaroxaban (24.4% vs. 41.1% and 53.5%, respectively). VTE reoccurred in 2 patients administered apixaban and 1 patient administered edoxaban. The cumulative incidence of major bleeding at 1 year was 11.7%, 18.5%, and 9.0% in the edoxaban, apixaban, and rivaroxaban groups, respectively. There were no significant differences in the cumulative incidence of major bleeding and all-cause death, estimated by Kaplan-Meier analysis, among the DOACs (log-rank P=0.316 and 0.722, respectively). Conclusions: The safety of the 3 DOACs did not differ significantly in clinical settings, despite differences in patient demographics.

Acute Coronary Syndrome Developed in a 17-year-old Boy with Sitosterolemia Comorbid with Takayasu Arteritis: A Rare Case Report and Review of the Literature.

A 17-year-old boy with acute coronary syndrome was admitted to our hospital. He had xanthomas over his elbow and Achilles tendon and a high level of low-density lipoprotein cholesterol; therefore, his initial diagnosis was familial hypercholesterolemia. However, a genetic analysis revealed a compound heterozygous mutation in the ABCG5 gene with a high serum level of sitosterol, leading to the diagnosis of sitosterolemia. After lipid-lowering treatment, percutaneous coronary intervention was performed. Furthermore, a persistently high C-reactive protein level and images of large arteries led to a diagnosis of Takayasu arteritis. To our knowledge, this is the first case of sitosterolemia complicated by Takayasu arteritis.