Features and Outcomes of Histologically Proven Myocarditis With Fulminant Presentation.

BACKGROUND: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. METHODS: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. RESULTS: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion (<40%) on admission, and ventricular tachycardia or fibrillation on admission day were associated with worse 90-day survival. Severe histologic damage (damaged cardiomyocytes comprising ≥50% of the total cardiomyocytes) was associated with a worse 90-day prognosis in patients with lymphocytic myocarditis. CONCLUSIONS: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. REGISTRATION: URL: https://www.umin.ac.jp/ctr; Unique identifier: UMIN000039763.

Myocardial findings evaluated by echocardiography in cardiac sarcoidosis: A report of seven cases.

Sarcoidosis is a multisystem granulomatous disease of unknown cause. With cardiac sarcoidosis (CS), patients represent a wide range of cardiac manifestations from subtle to overt morphological and functional abnormalities. The advent of ultrasound technologies has enabled to identify not only typical findings to CS such as basal thinning of the ventricular septum, but also subclinical myocardial alterations. Based on our recent experiences, we currently introduce a variety of myocardial manifestations evaluated by echocardiography on seven CS patients being selected. Most of the patients exhibited typical cardiac involvement and the remaining fairly unusual.

Atrial Arrhythmias and Atrial Involvement in Cardiac Sarcoidosis.

Severe ventricular arrhythmias such as high-grade atrioventricular block and ventricular tachycardia may cause lethal conditions or sudden death in patients with cardiac sarcoidosis (CS). Physicians should examine patients carefully for these conditions and treat them appropriately. As arrhythmias are being better diagnosed and treated, physicians are increasingly aware of atrial arrhythmias, which have not been focused upon as CS-related conditions, in patients with CS. This article reports a case of atrial flutter in sarcoidosis, and discusses literature findings on atrial arrhythmias and atrial involvement of CS. It is highly likely that atrial arrhythmia and supraventricular conduction disorder associated with or caused by CS are more common than previously thought. Physicians should pay careful attention for these conditions in the diagnosis and treatment of CS.

Spontaneous Reduction in Abnormal Myocardial Uptake of Fluorine-18 Fluorodeoxygluose in a Patient with Cardiac Sarcoidosis.

Fluorine-18 fluorodeoxygluose (18F-FDG) positron emission tomography (PET) is a useful tool for evaluating disease activity in sarcoidosis including cardiac involvement. A 67-year-old patient who developed atrioventricular block requiring permanent pacemaker implantation was diagnosed with cardiac sarcoidosis. The patient did not undergo steroid or immunosuppressive therapy but underwent serial 18F-FDG PET examination, which showed spontaneous reduction in the myocardial FDG uptake, indicating the remission of immune-inflammatory activity. Although the global systolic function remained preserved, thinning of the septal wall emerged during the clinical course of follow-up, which is characteristic for cardiac sarcoidosis.

Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

A Case of Cardiomyopathy Associated with CD36 Deficiency: Role of 18F-Fluorodeoxyglucose Positron Emission Tomography in the Diagnosis.

We herein report a patient with type I CD36 deficiency. The patient was initially suspected of having isolated cardiac sarcoidosis based on the presence of non-sustained ventricular tachycardia, delayed myocardial enhancement on magnetic resonance imaging (MRI), and diffuse accumulation of 18F-fluorodeoxyglucose (18F-FDG) on cardiac positron emission tomography (PET). Our findings suggest that the diagnosis of cardiomyopathy associated with CD36 deficiency is often missed, highlighting the importance of a differential diagnosis of isolated cardiac sarcoidosis.

Atrial natriuretic peptide exerts protective action against angiotensin II-induced cardiac remodeling by attenuating inflammation via endothelin-1/endothelin receptor A cascade.

We aimed to investigate whether atrial natriuretic peptide (ANP) attenuates angiotensin II (Ang II)-induced myocardial remodeling and to clarify the possible molecular mechanisms involved. Thirty-five 8-week-old male Wistar-Kyoto rats were divided into control, Ang II, Ang II + ANP, and ANP groups. The Ang II and Ang II + ANP rats received 1 µg/kg/min Ang II for 14 days. The Ang II + ANP and ANP rats also received 0.1 µg/kg/min ANP intravenously. The Ang II and Ang II + ANP rats showed comparable blood pressure. Left ventricular fractional shortening and ejection fraction were lower in the Ang II rats than in controls; these indices were higher (P < 0.001) in the Ang II + ANP rats than in the Ang II rats. In the Ang II rats, the peak velocity of mitral early inflow and its ratio to atrial contraction-related peak flow velocity were lower, and the deceleration time of mitral early inflow was significantly prolonged; these changes were decreased by ANP. Percent fibrosis was higher (P < 0.001) and average myocyte diameters greater (P < 0.01) in the Ang II rats than in controls. ANP decreased both myocardial fibrosis (P < 0.01) and myocyte hypertrophy (P < 0.01). Macrophage infiltration, expression of mRNA levels of collagen types I and III, monocyte chemotactic protein-1, and a profibrotic/proinflammatory molecule, tenascin-C (TN-C) were increased in the Ang II rats; ANP significantly decreased these changes. In vitro, Ang II increased expression of TN-C and endothelin-1 (ET-1) in cardiac fibroblasts, which were reduced by ANP. ET-1 upregulated TN-C expression via endothelin type A receptor. These results suggest that ANP may protect the heart from Ang II-induced remodeling by attenuating inflammation, at least partly through endothelin 1/endothelin receptor A cascade.

Survey on digital dependency, writing by hand, and group learning as learning styles among Japanese medical students: Assessing correlations between various accomplishments.

BACKGROUND: Although digital learning devices have become increasingly more common in medical education settings, it remains unclear how they influence medical student learning styles and various outcome measures. This study aimed to assess student learning styles, specifically as they relate to digital dependency, writing habits, and group learning practices among current medical students. MATERIALS AND METHODS: This questionnaire study was approved by the Research Ethics Committee of Osaka Medical and Pharmaceutical University. We conducted a questionnaire survey of 109 medical students who were 5th year students during the 2021 school year. Medical students were asked about their level of digital dependency, writing by hand, and group learning practices. We also analyzed the correlation between student learning styles and their respective outcomes on several summative evaluations. RESULTS: Of the 109 students targeted, we received responses from 62 (response rate, 56.8%). Among the respondents, digital dependency was 83.4 ± 18.6%, while hand writing ratio 39.8 ± 29.9% and group learning ratio 33.5 ± 30.5%. We also assessed correlations between these learning styles and scores on the CBT, OSCE, CC, and CC Integrative Test. Only writing by hand showed a small positive correlation with CC Integrative Test scores. CONCLUSION: Our questionnaire survey assessed the rates of digital dependency, writing by hand, and group learning practices, and analyzed the correlations between these learning styles and respective outcomes. Current medical students exhibited high digital dependency which was not correlated with performance outcomes.

Fatal Arrhythmic Risks in Cardiac Sarcoidosis With Mildly Impaired Cardiac Function.

Background: The prognosis and later fatal arrhythmia in cardiac sarcoidosis (CS) with relatively preserved cardiac function were unclear. Objectives: This study aimed to evaluate the prognosis and arrhythmic events in patients with CS and mildly impaired cardiac function. Methods: Data were collected from a nationwide Japanese cohort survey conducted in 57 hospitals (n = 420); 322 patients with CS with left ventricular ejection fraction (LVEF) >35% were investigated. Results: Ventricular tachycardia (VT) manifestation was present in 50 patients (16%) and absent in 272 (84%), of whom 36 (72%) and 46 (17%), respectively, had an implantable cardioverter-defibrillator (ICD). Over a median of 5 years, 23 all-cause deaths and 31 appropriate ICD discharges were observed. In Kaplan-Meier analysis, all-cause death did not differ between patients with and without VT manifestation (P = 0.660), although appropriate ICD therapy was significantly less used in patients without VT manifestation than in those with VT manifestation (P < 0.001). Of the 272 patients without VT manifestation, 18 had ventricular arrhythmic events (VAEs), including 3 sudden cardiac deaths and 15 appropriate ICD discharges. In multivariate analysis, concomitant nonsustained ventricular tachycardia (NSVT) with atrioventricular block (AVB), lower LVEF, abnormal gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography of the heart (Ga/PET), and concomitant NSVT with abnormal Ga/PET at CS diagnosis were independent predictors of VAEs (P = 0.008, P = 0.021, P = 0.049, and P = 0.024, respectively). Conclusions: If concomitant NSVT with AVB, concomitant NSVT with abnormal Ga/PET, or abnormal Ga/PET is observed in patients with CS and mildly impaired cardiac function (LVEF >35%), ICD should be considered as primary prevention.

Gender differences in repeat-year experience, clinical clerkship performance, and related examinations in Japanese medical students.

While the number of female medical students is increasing in Japan, gender differences in medical school performance have not been studied extensively. This study aimed to compare gender differences in repeat-year experience, Clinical Clerkship (CC) performance, and related examinations in Japanese medical students. We retrospectively analyzed the number of repeat-year students and years to graduation for male and female medical students, and assessed gender differences in performance on computer-based testing (CBT) before CC, CC as evaluated by clinical teachers, the CC integrative test, and the graduation examination in 2018-2020 graduates from our medical school. Subgroup analyses excluding repeat-year students were also performed. From 2018 to 2020, 328 medical students graduated from our medical school. There were significantly fewer repeat-year female students compared to male students (P = .010), and the average number of years to graduate was significantly higher for male students than female students (P < .001). Female students showed higher scores and performance in all integrative tests and CC (P < .05, each). In analysis excluding repeat-year students, there were no significant gender difference in performance on the CBT, and CC integrative test, although female students significantly outperformed male students on the CC and graduation examination. Female medical students had a fewer number of repeat-years and performed better in the CC and graduation examination compared to their male counterparts.

Comparison of Younger and Older medical student performance outcomes: A retrospective analysis in Japan.

The present study examined the impact of age on medical student repeat-year experience and performance outcomes on the objective structured clinical examination (OSCE), Clinical Clerkship (CC), and other relevant examinations in the Japanese medical school system. This retrospective analysis examined the number of students with repeat-years and the years required to graduate, stratifying students by the age they entered medical school (Younger: within 4 years of high school graduation; Older: 5 or more years after high school graduation). Scores of the Pre-CC OSCE, Computer-based testing (CBT), CC performance, CC integrative test, and graduation exams were compared among those graduating from our medical school between 2018 and 2020, and examined correlations between student age and performance outcomes. From 2018 to 2020, 328 medical students graduated. Of these, 283 had entered within 4 years of high school graduation (Younger), while 45 did so 5 or more years after high school graduation (Older). The number of repeat-years did not differ significantly between groups. The average number of years required to graduate was slightly higher for the Older group and the Younger group scored significantly higher on the CC integrative test. No significant differences were found for the remaining tests. These results suggest that older medical students in general show no significant inferiority in their performance of most clinical skills and competencies relative to younger students in Japan.

The characteristics of Japanese guidelines on diagnosis and treatment of cardiac sarcoidosis compared with the previous guidelines.

Sarcoidosis in Japanese sarcoidosis is characterized by a high prevalence of cardiac involvement. In this regard, cardiac sarcoidosis (CS) continues to be an important focus of study among physicians caring for sarcoidosis in Japan. The Japanese Ministry of Health, Labor and Welfare (MHLW) and Japan Society of Sarcoidosis and other Granulomatous Disorders (JSSOG) have published clinical guidelines aiming to assist clinical practices. Recently, the Japanese Circulation Society (JCS) has published new clinical guidelines for the diagnosis and treatment of CS that contain several new insights compared to previously published guidelines in Japan and other countries.

Sex-related differences in the prognosis of patients with cardiac sarcoidosis treated with cardiac resynchronization therapy.

BACKGROUND: Past studies have shown the sex-related difference in the efficacy of cardiac resynchronization therapy (CRT). However, the data for cardiac sarcoidosis (CS) are limited. OBJECTIVE: The purpose of this study was to assess the sex-related prognostic differences in CS patients with CRT. METHODS: This multicenter CS survey included 430 patients (295 females) who met the diagnostic criteria for CS. Patients were divided into those treated with primary CRT or upgraded CRT from the pacemaker (CRT group; n = 73) and others (control group; n = 357). Sex differences in the incidence of all-cause death, heart failure (HF) death including heart transplantation, ventricular arrhythmia events (VAEs) (sudden death, appropriate device therapy), cardiac adverse events (CAEs) (HF death, VAEs), changes in serum brain natriuretic peptide (BNP) levels, and left ventricular ejection fraction (LVEF) over the follow-up period were analyzed. RESULTS: During median follow-up of 5.2 years, males, but not females, in the CRT group had significantly worse all-cause mortality than patients in the control group (P <.001). In the CRT group, there was no significant sex-related difference in the incidence of HF death; however, females had significantly better VAE- and CAE-free survival than males (P = .033 and P = .008, respectively). Multivariate analysis of the CRT group showed that female sex (hazard ratio 0.37; 95% confidence interval 0.15-0.89; P = .02 and P = .6) independently predicted freedom from CAEs. During follow-up, BNP levels were significantly improved in all groups. LVEF was maintained in females with CRT. CONCLUSIONS: In CS patients with CRT, HF death-free survival was similar between sexes. However, females exhibited better VAE- and CAE-free survival than males.

Ca2+/calmodulin-dependent kinase IIdelta causes heart failure by accumulation of p53 in dilated cardiomyopathy.

BACKGROUND: Dilated cardiomyopathy (DCM), characterized by dilatation and dysfunction of the left ventricle, is an important cause of heart failure. Many mutations in various genes, including cytoskeletal protein genes and contractile protein genes, have been identified in DCM patients, but the mechanisms of how such mutations lead to DCM remain unknown. METHODS AND RESULTS: We established the mouse model of DCM by expressing a mutated cardiac alpha-actin gene, which has been reported in patients with DCM, in the heart (mActin-Tg). mActin-Tg mice showed gradual dilatation and dysfunction of the left ventricle, resulting in death by heart failure. The number of apoptotic cardiomyocytes and protein levels of p53 were increased in the hearts of mActin-Tg mice. Overexpression of Bcl-2 or downregulation of p53 decreased the number of apoptotic cardiomyocytes and improved cardiac function. This mouse model showed a decrease in myofilament calcium sensitivity and activation of calcium/calmodulin-dependent kinase IIdelta (CaMKIIdelta). The inhibition of CaMKIIdelta prevented the increase in p53 and apoptotic cardiomyocytes and ameliorated cardiac function. CONCLUSIONS: CaMKIIdelta plays a critical role in the development of heart failure in part by accumulation of p53 and induction of cardiomyocyte apoptosis in the DCM mouse model.

A display of combined left ventricular function and dyssynchrony using Doppler tissue imaging: its application in acute response to cardiac resynchronization therapy.

BACKGROUND: We have recently proposed a novel method for displaying left ventricular (LV) function and mechanical dyssynchrony, which is based on the "vector analysis" using Doppler tissue imaging (DTI). The aim of this study was to examine acute-phase impact of cardiac resynchronization therapy (CRT) on the parameters assessed by this method. METHODS: We studied a total of 25 patients with systolic heart failure, 14 undergoing simultaneous acute pacing-hemodynamic study and DTI; and 11 patients DTI within a few days before and one week after CRT. Parameters derived from the displaying method were followings: (1) percentage area of the hexagon, the area divided by the overall graph area, reflecting global LV systolic function; (2) net-delay magnitude, the length of the composite vector for the six vectors, a dyssynchrony index; and (3) delayed contraction site, graphical position of the composite vector. RESULTS: CRT significantly increased cardiac output (3.1 ± 1.0 to 3.4 ± 0.7 L/min, P = 0.02) and +dp/dt (782 ± 149 to 1,089 ± 270 mm Hg/s, P < 0.01), and decreased mitral regurgitaion jet area (7.9 ± 3.0 to 4.8 ± 2.4 cm(2) , P < 0.01). As with the new method, there were significant decreases in the percentage area of the hexagon (20.7 ± 6.6 to 18.6 ± 6.5%, P < 0.01) and the net-delay magnitude (122 ± 59 to 72 ± 48 ms, P < 0.01). The reduction of net-delay magnitude accompanied alteration of delayed contraction site; 16 patients had the most delayed site between the lateral and inferior segments before CRT, and seven patients after CRT (P = 0.02). CONCLUSIONS: The new method would be a useful tool to assess efficacy of CRT in patients with systolic heart failure.

Correlation of student performance on clerkship with quality of medical chart documentation in a simulation setting.

BACKGROUND: Medical chart documentation is an essential skill acquired in a clinical clerkship (CC). However, the utility of medical chart writing simulations as a component of the objective structured clinical examination (OSCE) has not been sufficiently evaluated. In this study, medical chart documentation in several clinical simulation settings was performed as part of the OSCE, and its correlation with CC performance was evaluated. METHODS: We created a clinical situation video and images involving the acquisition of informed consent, cardiopulmonary resuscitation, and diagnostic imaging in the emergency department, and assessed medical chart documentation performance by medical students as part of the OSCE. Evaluations were conducted utilizing original checklist (0-10 point). We also analyzed the correlation between medical chart documentation OSCE scores and CC performance of 120 medical students who performed their CC in 2019 as 5th year students and took the Post-CC OSCE in 2020 as 6th year students. RESULTS: Of the OSCE components, scores for the acquisition of informed consent and resuscitation showed significant correlations with CC performance (P<0.001 for each). In contrast, scores for diagnostic imaging showed a slightly positive, but non-significant, correlation with CC performance (P = 0.107). Overall scores for OSCE showed a significant correlation with CC performance (P<0.001). CONCLUSION: We conducted a correlation analysis of CC performance and the quality of medical chart documentation in a simulation setting. Our results suggest that medical chart documentation can be one possible alternative component in the OSCE.

Prognosis and Outcomes of Clinically Diagnosed Cardiac Sarcoidosis Without Positive Endomyocardial Biopsy Findings.

Background: Diagnosis of cardiac sarcoidosis (CS) is sometimes difficult due to a low positive rate of epithelioid granulomas by endomyocardial biopsy (EMB). Accordingly, Japanese guidelines can allow the CS diagnosis using clinical data alone without EMB results (clinical CS) since 2006. However, little is known about prognosis and outcome of clinical CS. Objectives: Purpose of this study was to analyze the prognosis, outcomes, and response to corticosteroid of clinical CS using large-scale cohort survey. Methods: Overall, 422 CS patients (mean age 60 ± 13 years, 68% female, median follow-up period of 5 years), including 345 clinical CS and 77 EMB-positive patients, histologically diagnosed CS (histological CS) by Japanese guidelines, were enrolled and examined. Results: Clinical profile (age, sex, initial cardiac arrhythmias, and abnormal uptake of gallium-67 scintigraphy or 18F-fluorodeoxyglucose positron emission tomography in heart) was similar in both groups. Although clinical CS had better prognosis (P = 0.018) and outcome (all-cause death, appropriate defibrillator therapy, and heart transplantation; P = 0.008), multivariate Cox hazard analysis revealed that left ventricular ejection fraction (LVEF) and sustained ventricular tachycardia history were independently associated with outcome (P < 0.001 and P = 0.002, respectively), but not with the diagnosed CS category. Moreover, similar LVEF recovery after corticosteroid was observed in both groups with low LVEF (≤35%) at the 1-year follow-up period (P < 0.001). Conclusions: In clinical CS according to the Japanese guideline, prophylactic implantable-cardioverter-defibrillator and immunosuppressive therapy are important in patients with low LVEF or ventricular tachycardia history, similar to histological CS.

ATF6 is important under both pathological and physiological states in the heart.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) evokes the ER stress response, including activating transcription factor 6 (ATF6), a key transcriptional activator to maintain cellular homeostasis. The ER stress has recently been reported to cause various diseases, but the role of ATF6 in the heart remains unknown. We clarified the role of ATF6 in the heart. The ATF6 activity was increased in the murine heart after myocardial infarction (MI). Treatment of mice with 4-(2-aminoethyl) benzenesulfonyl fluoride, an inhibitor of ATF6, further reduced cardiac function and increased the mortality rate at 14days after MI. Pharmacological inhibition of ATF6 induced dilatation of left ventricle and depression of cardiac function even in sham-operated murine hearts. The transgenic mice that expressed dominant negative mutant of ATF6 showed larger left ventricular dimension and reduced fractional shortening compared with wild-type littermates, resulting in death of heart failure at approximately 8weeks of age. In contrast, cardiac function after MI was better in transgenic mice that expressed constitutively active mutant of ATF6, compared with wild-type littermates. These results suggest that activation of the ER stress response factor ATF6 plays a critical role in not only protecting hearts under the pathological state but also maintaining cardiac function under the physiological state.