Cardiac Sarcoidosis which Occurred four Years after Successful Treatment of Cutaneous Sarcoidosis with Minocycline.

A 67-year-old woman was admitted to our hospital because of a complete right bundle branch block. She had been treated with minocycline for skin sarcoidosis and her symptoms had ameliorated four years previously. Gallium scintigraphy revealed an abnormal uptake in the heart but not in the skin or lungs. She was diagnosed with cardiac sarcoidosis, although an endomyocardial biopsy could not detect any sarcoid lesions. Immunohistochemical staining for Cutibacterium acnes was positive for granulomas of the skin lesions which had been previously biopsied. One year after starting the administration of steroids, her condition improved.

Optimizing cardiac amyloidosis assessment: utility of 1-h and 3-h 99mTc-PYP imaging.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM), characterized by the extracellular deposition of an insoluble amyloid protein in the heart, is one of the main causes of heart failure in elderly patients. In this study, our primary objective was to explore the diverse applications and temporal significance of 1-h and 3-h imaging using 99mTc-PYP in the context of ATTR-CM. Additionally, we compared tracer kinetics in the heart and bone to comprehensively assess the diagnostic advantages and time-related considerations associated with these two incubation periods. METHODS: Twenty-seven patients at Nagasaki University Hospital who underwent 99mTc-PYP planar, and SPECT cardiac imaging were classified into two groups (ATTR-CM-positive and -negative groups) based on the American Heart Association statement. Cardiac retention was assessed with both a semiquantitative visual score and a quantitative analysis. To assess bone accumulation, a ROI with an equal volume was drawn on the sternum and calculated as the bone-to-contralateral ratio (B/CL). We also evaluated correlation between heart-to-contralateral lung (H/CL) ratio and left ventricular wall thickness. RESULTS: Among patients who underwent 99mTc-PYP imaging, the H/CL ratio was significantly higher at 1 h than at 3 h regardless of the group (from 2.20 ± 0.36 to 1.99 ± 0.35, p < 0.01 in the positive group and from 1.35 ± 0.12 to 1.19 ± 0.21, p = 0.01 in the negative group). The gap of H/CL between highest H/CL of negative case and lowest H/CL of positive case was narrower in 3 h. On the other hand, correlation between H/CL and left ventricular posterior wall thickness tends to be clearer in 3 h (p = 0.12, r = 0.30 for 1 h, p = 0.04, r = 0.39 at 3 h). CONCLUSION: Our study suggests that both 1-h and 3-h incubation times for 99mTc-PYP imaging have different benefits for ATTR cardiac amyloidosis. A one-hour incubation may be preferable for differential diagnostic purposes, while a three-hour incubation may provide greater utility in evaluating disease severity.

An Iron-chelating Agent Improved the Cardiac Function in a Patient with Severe Heart Failure Due to Hereditary Hemochromatosis.

A 24-year-old man was admitted to our hospital because of severe heart failure. Although he was treated with diuretics and positive inotropic agents, his heart failure progressed. An endomyocardial biopsy revealed iron deposition in his myocytes. Finally, he was diagnosed with hereditary hemochromatosis. After starting administration of an iron-chelating agent in addition to conventional treatment for heart failure, his condition improved. We should consider hemochromatosis in heart failure patients with severe right ventricular dysfunction in addition to left ventricular dysfunction.

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.

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.

Midterm Clinical Outcomes for Deferred Coronary Revascularization on the Basis of Resting Full-Cycle Ratio and Fractional Flow Reserve Measurements.

The midterm prognosis of patients with deferred revascularization based on resting full-cycle ratio (RFR) or fractional flow reserve (FFR) is not well established. We investigated the midterm clinical outcomes of 137 consecutive patients with deferred revascularization of 177 coronary arteries based on RFR and FFR. Patients were classified into 3 groups (concordant normal, concordant abnormal, discordant FFR and RFR), using known cutoffs for FFR (≤0.80) and RFR (≤0.89). All-cause mortality occurred in 9 (6.6%) and major adverse cardiac events (MACEs) in 16 patients (11.7%). Concordant abnormal, age, body mass index (BMI), and current or history of cancer were associated with increased risks of all-cause mortality. In a multivariable model, current or history of cancer was significantly associated with all-cause death (hazard ratio [HR] 6.8, p = 0.02). Concordant abnormal, current or history of cancer, BMI, and left ventricular ejection fraction were associated with increased risk of MACE, and all predictors correlated significantly with MACE (abnormal concordance: HR 4.2, p = 0.043; current or history of cancer: HR 4.0, p = 0.047; BMI: HR 0.8, p = 0.020; left ventricular ejection fraction: HR 0.9, p = 0.017). Although these results support performing percutaneous coronary intervention according to evidence-based RFR or FFR thresholds, deferred lesions with discordant FFR and RFR results were not associated with worse prognosis.

Pathological features of biopsied myocardium in patients clinically diagnosed with peripartum cardiomyopathy.

The etiology of peripartum cardiomyopathy (PPCM) is unknown. Therefore, we evaluated the etiology of patients clinically diagnosed with PPCM using endomyocardial biopsy. We studied five patients diagnosed with PPCM following endomyocardial biopsy (age, 28-42 years; mean age, 35 years). Biopsied samples were evaluated using microscopy, including immunostaining and electron microscopy. The pathological findings were as follows: myocardial hypertrophy, myocardial fibrosis, and cell infiltration. Two patients were diagnosed with lymphocytic myocarditis, one with eosinophilic myocarditis, one with hypertensive heart disease, and one with a combination of hypertension and myocarditis. Endomyocardial biopsy suggested that the causes of PPCM were varied and related to myocarditis and myocardial overload due to hypertension.

Fulminant Myocarditis and Acute Appendicitis after COVID-19 Vaccination.

A 19-year-old Japanese man was hospitalized for cardiogenic shock 28 days after receiving a second dose of the coronavirus disease 2019 (COVID-19) mRNA-1273 vaccine. He had had a high fever for three days with vomiting and abdominal pain before arriving at our hospital. The patient visited a local hospital and was diagnosed with heart failure and acute appendicitis. An endomyocardial biopsy specimen showed myocarditis. Thereafter, Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were initiated immediately along with inotropic support and steroid pulse therapy. Given these findings, he was finally diagnosed with multiple inflammatory syndrome and fulminant myocarditis.

Association Between the Development of Thrombosis and Worsening of Disease Severity in Patients With Moderate COVID-19 on Admission　- From the CLOT-COVID Study.

BACKGROUND: The worsening of coronavirus disease 2019 (COVID-19) severity is a critical issue in current clinical settings and may be associated with the development of thrombosis.Methods and Results: This study used patient data obtained in the CLOT-COVID study, a retrospective multicenter cohort study. The demographics of patients with moderate COVID-19 on admission with and without worsened severity during hospitalization were compared and predictors were identified. Of 927 patients with moderate COVID-19 on admission, 182 (19.6%) had worsened severity during hospitalization. Patients with worsening of severity were older, more likely to have hypertension, diabetes, heart disease, and active cancer, and more likely to use pharmacological thromboprophylaxis. Patients with worsening of severity had higher D-dimer levels on admission and were more likely to develop thrombosis and major bleeding during hospitalization than those without worsening. Increased age (odds ratio [OR]: 1.02, 95% confidence interval [CI]: 1.01-1.03, P=0.005), diabetes (OR: 1.63, 95% CI: 1.11-2.33, P=0.012), D-dimer levels >1.0 µg/mL on admission (OR: 2.10, 95% CI: 1.45-3.03, P<0.001), and thrombosis (OR: 6.28, 95% CI: 2.72-14.53, P<0.001) were independently associated with worsening of COVID-19 severity. CONCLUSIONS: Approximately 20% of patients with moderate COVID-19 had worsened severity during hospitalization. Increased age, diabetes, D-dimer levels >1.0 µg/mL on admission, and the development of thrombosis during hospitalization were significantly associated with worsened COVID-19 severity.

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.

Nucleoside Triphosphate Hydrolases Assay in Toxoplasm gondii and Neospora caninum for High-Throughput Screening using a Robot Arm.

Protozoan parasites infect humans and many warm-blooded animals. Toxoplasma gondii, a major protozoan parasite, is commonly found in HIV-positive patients, organ transplant recipients and pregnant women, resulting in the severe health condition, Toxoplasmosis. Another major protozoan, Neospora caninum, which bears many similarities to Toxoplasma gondii, causes serious diseases in animals, as does Encephalomyelitis and Myositis-Polyradiculitis in dogs and cows, resulting in stillborn calves. All these exhibited similar nucleoside triphosphate hydrolases (NTPase). Neospora caninum has a NcNTPase, while Toxoplasma gondii has a TgNTPase-I. The enzymes are thought to play crucial roles in propagation and survival. In order to establish compounds and/or extracts preventing protozoan infection, we targeted these enzymes for drug discovery. The next step was to establish a novel, highly sensitive, and highly accurate assay by combining a conventional biochemical enzyme assay with a fluorescent assay to determine ADP content. We also validated that the novel assay fulfills the criteria to carry out high-throughput screening (HTS) in the two protozoan enzymes. We performed HTS, identified 19 compounds and six extracts from two synthetic compound libraries and an extract library derived from marine bacteria, respectively. In this study, a detailed explanation has been introduced on how to carry out HTS, including information about the preparation of reagents, devices, robot arm, etc.

Successful percutaneous transluminal renal angioplasty with multimodality imaging guidance for a juvenile patient with renovascular hypertension due to fibromuscular dysplasia.

Percutaneous transluminal renal angioplasty (PTRA) is an effective treatment for renovascular hypertension due to fibromuscular dysplasia (FMD). PTRA for renovascular FMD is performed with only balloons based on the consensus that stent kinking and fracture have been reported in cases of PTRA using stents for FMD. Therefore, it is important to avoid procedural complications, such as flow-limiting dissection or arterial rupture, in PTRA for renovascular FMD.We present a case of a juvenile patient who presented with renovascular hypertension due to FMD. Angiography revealed focal stenosis of the right renal artery, and the pressure wire showed a resting distal coronary to aortic pressure ratio (Pd/Pa) of 0.83. Intravascular ultrasound (IVUS) showed an intima-media complex that could not be qualitatively assessed. Optical coherence tomography (OCT) showed intimal fibroplasia and medial hyperplasia with areas of low intensity. Based on the OCT images, balloon angioplasty was performed using a semi-compliant balloon. After balloon angioplasty, IVUS and OCT revealed luminal expansion with mild residual stenosis, and the Pd/Pa ratio was 0.99. We decided not to increase the balloon size to avoid vascular injuries. In conclusion, PTRA with only balloon can be safely performed for FMD under the guidance of multimodal imaging, using IVUS, OCT, and a pressure wire. Learning objectives: This report describes successful percutaneous transluminal renal angioplasty (PTRA) for a juvenile patient with renovascular hypertension due to fibromuscular dysplasia (FMD) under the guidance of multimodal imaging, using intravascular ultrasound (IVUS), optical coherence tomography (OCT), and a pressure wire. When IVUS for FMD cannot assess the culprit lesion qualitatively, OCT could be effective in performing angioplasty with only balloon, without significant vascular injuries. A pressure wire can show the endpoint of PTRA and help avoid increasing the balloon size to prevent significant vascular injuries.

Fulminant Myocarditis 24 Days after Coronavirus Disease Messenger Ribonucleic Acid Vaccination.

A 60-year-old Japanese woman was hospitalized for cardiogenic shock 24 days after receiving the second dose of the coronavirus disease 2019 BNT162b2 vaccine. Impella CP left ventricular assist device implantation and venoarterial peripheral extracorporeal membranous oxygenation were immediately initiated along with inotropic support and steroid pulse therapy, as an endomyocardial biopsy specimen showed myocarditis. Three weeks later, her cardiac function had recovered, and she was discharged. An immune response associated with the presence of spike protein in cardiac myocytes may be related to myocarditis in the present case because of positive immunostaining for severe acute respiratory syndrome coronavirus 2 spike protein and C4d in the myocardium.

Comparison of Dasatinib- and Imatinib-Related Cardiotoxic Adverse Events in Japanese Patients With Chronic Myeloid Leukemia and Gastrointestinal Stromal Tumor.

Background: Despite the beneficial effects of BCR-ABL1 tyrosine kinase inhibitors (TKIs) in the treatment of chronic myeloid leukemia (CML), they may also cause adverse events (AEs), especially cardiovascular toxicity. The incidence of TKI-induced AEs may vary among ethnic groups, and there is little specific information for Japanese patients. Methods and Results: Sixty-nine consecutive patients who were started on treatment with dasatinib (n=25) or imatinib (n=44) for CML or gastrointestinal stromal tumor (GIST) between December 2008 and December 2019 were retrospectively recruited to the study. We determined the prevalence of AEs through October 2020 and compared the incidence of AEs between the 2 drugs. Baseline characteristics were comparable between the 2 groups. However, compared with the imatinib-treated group, the dasatinib-treated group had a higher incidence of congestive heart failure (CHF; 20.0% vs. 2.3%; P=0.04), pleural effusion (48% vs. 20.5%; P=0.03), pericardial effusion (24% vs. 4.6%; P=0.02), QT prolongation (4 vs. 0 patients; P=0.02), and pulmonary hypertension (3 vs. 0 patients; P=0.04). In the dasatinib-treated group, CHF tended to be associated with tricuspid valve regurgitation pressure gradient, and pleural effusion was observed in all patients. All-cause mortality and other cardiovascular events did not differ significantly between the 2 groups. Conclusions: Cardiotoxic AEs occurred more frequently in Japanese patients with CML and GIST treated with dasatinib than imatinib.

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.