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.

[Research of Cognitive Impairment in Lung Cancer Patients Undergoing Chemotherapy].

Nineteen non-small cell lung cancer patients admitted for chemotherapy were investigated for cognitive dysfunction and factors affecting cognitive function. The results showed that the patients experienced some decline in cognitive function, and fatigue affected cognitive function and quality of life. Cognitive function in cancer patients affects their treatment choices, employment, and social life. We need to be aware of the cognitive dysfunction of cancer patients, and at the same time, we need to intervene with consideration for cognitive function, as fatigue can easily lead to a sense of cognitive decline.

Value of Placental Growth Factor as a Predictor of Adverse Events During the Acute Phase of Acute Decompensated Heart Failure.

BACKGROUND: Few biomarkers, even B-type natriuretic peptide (BNP), can predict the long-term outcome in patients with acute decompensated heart failure (ADHF) on the first day of admission. Placental growth factor (PlGF), a member of the vascular endothelial growth factor family of cytokines, is a key molecule in cardiorenal syndrome and a predictor of adverse events in chronic kidney disease patients. However, its significance in ADHF patients remains poorly understood. Methods and Results: We studied 408 ADHF patients admitted between April 2011 and December 2016 by measuring their PlGF levels on the first day of admission. Primary endpoints were all-cause and cardiovascular (CV) death. Patients were divided into 2 groups according to PlGF quartiles. Kaplan-Meier analysis revealed that the high PlGF group (quartile 4: ≥12.6 pg/mL) had a worse prognosis than the low PlGF group (quartiles 1-3; <12.6 pg/mL) in terms of all-cause (hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.13-2.14; P<0.01) and CV death (HR, 1.68; 95% CI, 1.04-2.66; P<0.05). After adjustment for covariates, PlGF remained an independent predictor of all-cause and CV death. CONCLUSIONS: PlGF on the first day of admission was significantly associated with both all-cause and CV death, suggesting that it provides novel prognostic information in the acute phase of ADHF.

Sex differences in clinical characteristics and long-term outcome in acute decompensated heart failure patients with preserved and reduced ejection fraction.

In patients with acute decompensated heart failure (ADHF), sex differences considering clinical and pathophysiologic features are not fully understood. We investigated sex differences in left ventricular (LV) ejection fraction (LVEF), plasma B-type natriuretic peptide (BNP) levels, and prognostic factors in patients with ADHF in Japan. We studied 748 consecutive ADHF patients of 821 patients registered in the ADHF registry between January 2007 and December 2014. Patients were divided into four groups based on sex and LVEF [reduced (ejection fraction, or EF, <50%, heart failure with reduced EF, or HFrEF) or preserved (EF ≥50%, heart failure with preserved LVEF, or HFpEF)]. The primary endpoint was the combination of cardiovascular death and heart failure (HF) admission. The present study consisted of 311 female patients (50% HFrEF, 50% HFpEF) and 437 male patients (63% HFrEF, 37% HFpEF). There was significant difference between sexes in the LVEF distribution profile. The ratio of HFpEF patients was significantly higher in female patients than in male patients (P= 0.0004). Although there were no significant sex differences in median plasma BNP levels, the prognostic value of BNP levels was different between sexes. Kaplan-Meier analysis revealed that the high BNP group had worse prognosis than the low BNP group in male but not in female patients. In multivariate analysis, log transformed BNP at discharge predicted cardiovascular events in male but not in female HF patients (female, hazard ratio: 1.169; 95% confidence interval: 0.981-1.399;P= 0.0806; male, hazard ratio: 1.289; 95% confidence interval: 1.120-1.481;P= 0.0004). In patients with ADHF, the distribution of LV function and the prognostic significance of plasma BNP levels for long-term outcome were different between the sexes.

Early onset of cardiomyopathy and intellectual disability in a girl with Danon disease associated with a de novo novel mutation of the LAMP2 gene.

Danon disease, primary lysosome-associated membrane protein-2 (LAMP-2) deficiency, is characterized clinically by cardiomyopathy, myopathy and intellectual disability in boys. Because Danon disease is inherited in an X-linked dominant fashion, males are more severely affected than females, who usually have only cardiomyopathy without myopathy or intellectual disability; moreover, the onset of symptoms in females is usually in adulthood. We describe a girl with Danon disease who presented with hypertrophic cardiomyopathy and Wolff-Parkinson-White (WPW) syndrome at 12 years of age. Subsequently, she showed signs of mild learning disability and intellectual disability on psychological examinations. She had a de novo novel mutation in the LAMP-2 gene and harbored an identical c.749C > A (p.Ser250X) variant, resulting in a stop codon in exon 6. She showed decreased, but not completely absent LAMP-2 expression on immunohistochemical and Western blot analyses of a skeletal muscle biopsy specimen, which has been suggested to be caused by a 50% reduction in LAMP-2 expression (LAMP-2 haploinsufficiency) in female patients with Danon disease caused by a heterozygous null mutation. To our knowledge, our patient is one of the youngest female patients to have been given a diagnosis of Danon disease. In addition, this is the first documented case in a girl that was clearly associated with intellectual disability, which is very rare in females with Danon disease. Our findings suggest that studies of female patients with Danon disease can extend our understanding of the clinical features of this rare disease.

Echocardiographic characteristics of patients with acute heart failure requiring tolvaptan: a retrospective study.

BACKGROUND: No study has investigated the admission echocardiographic characteristics of acute heart failure (AHF) patients who are resistant to conventional diuretics and require tolvaptan. METHODS: We retrospectively analyzed the echocardiographic characteristics of AHF patients who were resistant to conventional diuretics and took tolvaptan (tolvaptan group: 26 patients), and compared them to those who were sensitive to conventional diuretics (conventional group: 180 patients). RESULTS: The tolvaptan group had a higher left atrial volume index (96.0 ± 85.0 mL/m2 vs. 45.8 ± 25.9 mL/m2, p < 0.0001), maximum inferior vena cava diameter (20.7 ± 6.9 mm vs. 18.1 ± 4.2 mm, p < 0.01), and higher tricuspid regurgitation grade (1.1 ± 0.8 vs. 0.8 ± 0.6, p < 0.05) than the conventional group. However, the left ventricular ejection fraction and end diastolic diameter were similar between the groups. Responders of tolvaptan had no significant echocardiographic differences compared to the non-responders. CONCLUSIONS: The admission echocardiographic characteristics of AHF patients requiring tolvaptan included a larger left atrium, inferior vena cava, and more severe tricuspid regurgitation. Echocardiography may provide useful information for the early and appropriate initiation of tolvaptan.

Evaluation of left ventricular diastolic function by fractional area change using cine cardiovascular magnetic resonance: a feasibility study.

BACKGROUND: Evaluation of left ventricular (LV) diastolic function is essential for the management of heart failure. We verified whether LV diastolic function could be evaluated by measuring the fractional area change (FAC) using cine cardiovascular magnetic resonance (CMR). METHODS: We collected clinical data from 59 patients who underwent echocardiography and cine CMR. Normal, impaired relaxation, pseudonormal, and restrictive LV filling were observed in 15, 28, 11, and 5 patients, respectively. We calculated FAC during the first 30% of diastole (diastolic-index%) in the short-axis view, by tracing the contours on only three MR cine images. RESULTS: The diastolic index was significantly lower (p < 0.0001) in patients with impaired relaxation (32.4 ± 7.5), pseudonormal filling (25.4 ± 5.6), and restrictive filling (9.5 ± 1.5) compared to those with normal diastolic function (67.7 ± 10.8), and the index decreased significantly with worsening of diastolic dysfunction. The diastolic index correlated positively with early diastolic mitral annular velocity measured by tissue Doppler imaging (r = 0.75, p < 0.0001), respectively. CONCLUSIONS: Measurement of FAC can be useful for the evaluation of LV diastolic function using cine CMR.

[A case of crescentic glomerulonephritis developed under oral anastrozole treatment].

A 69-year-old postmenopausal woman who was prescribed anastrozole for 10 months after surgical removal of her breast cancer, was referred to our hospital for acute renal failure. Because it was possible that her renal failure was related to her treatment with anastrozole, the treatment was immediately discontinued. After renal biopsy was performed to examine her renal failure, she was diagnosed as crescentic glomerulonephritis, probably related with the treatment of anastrozole. Twenty mg of oral prednisolone was administered daily after methylprednisolone pulse therapy(500 mg/day intravenous administration for three days). Her renal dysfunction was gradually improved. Renal dysfunction was considered to be a rare complication of anastrozole. Patients who are prescribed anastrozole should be watched carefully for the development of renal dysfunction.

[The protocol of dose reduction in liver perfusion computed tomography].

Cerebral perfusion computed tomography (CT) has been widespread, but abdominal perfusion CT has not been very popular because there has been a problem with regard to the limit of irradiation range and respiratory effects. Recently, it became easy to perform perfusion of abdominal organs because the use of multi detector row CT (MDCT) has been extensive. Along with it, the number of hospitals that perform liver perfusion CT has increased. However, patient dose of the liver perfusion CT is very high, making it very important to reduce patient dose. We created the virtual data that reduced the number of irradiation by partly reducing the data obtained on the liver perfusion CT. We compared the analysis results of all data with that of the partly reduced. It is possible to reduce the patient dose by reducing the number of irradiation because there was no significant difference in the analysis results.

Histopathological and epigenetic changes in myocardium associated with cancer therapy-related cardiac dysfunction.

AIMS: Cancer therapy-related cardiac dysfunction (CTRCD) is commonly reported, but its histopathology, mechanisms, and risk factors are not known. We aimed to clarify the histopathology and mechanisms of CTRCD to identify risk factors. METHODS AND RESULTS: We performed myocardial histopathological studies on 13 endomyocardial biopsies from CTRCD patients, 35 autopsied cancer cases with or without cardiac dysfunction, and controls without cancer (10 biopsies and 9 autopsies). Cardiotoxicity risk scores were calculated based on medication; and patient-related risk factors, fibrosis, and cardiomyocyte changes were scored; and p53 and H3K27ac histone modification were evaluated by histological score (H-score). In the biopsy cases, all histopathological changes and the p53 evaluation were significantly higher in the CTRCD group than in the controls [p53 H-score; 63 (9.109) vs. 33 (5.099), P < 0.05]. In patients with a short time between drug and disease onset (<4.2 years), fibrosis and p53 positively correlated (r = 0.76, P < 0.05), and in those with late onset disease (>4.2 years), cellular abnormalities and p53 trended to a positive correlation and cardiotoxicity risk scores and p53 positively correlated (r = 0.95, P < 0.05). A year after biopsy, the short-term group had significant recovery of ejection fraction compared with the long-term group (P < 0.05). The CTRCD group had a significantly worse overall survival prognosis than the control group [hazard ratio 7.61 (95% confidence interval 1.30-44.6), P < 0.05]. Autopsy cases with cancer treatment also had a high grade of histopathological changes, with even more severe changes in patients with cardiac dysfunction, and had increased p53 and H3K27ac expression levels, compared with controls. H-scores of p53 and H3K27ac showed a positive correlation in the CTRCD group in biopsy cases (r = 0.62, P < 0.05) and a positive correlation in autopsy cases. CONCLUSIONS: Our results indicate distinct morphological characteristics in myocardial histopathology associated with CTRCD. p53 and H3K27ac histone modification could be sensitive markers of CTRCD and suggest a mechanistic involvement of epigenetic changes.

Transthyretin Amyloid Cardiomyopathy: Impact of Transthyretin Amyloid Deposition in Myocardium on Cardiac Morphology and Function.

BACKGROUND: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is increasingly being recognized as a cause of left ventricular (LV) hypertrophy (LVH) and progressive heart failure in elderly patients. However, little is known about the cardiac morphology of ATTR-CM and the association between the degree of TTR amyloid deposition and cardiac dysfunction in these patients. METHODS: We studied 28 consecutive patients with ATTR-CM and analyzed the relationship between echocardiographic parameters and pathological features using endomyocardial biopsy samples. RESULTS: The cardiac geometries of patients with ATTR-CM were mainly classified as concentric LVH (96.4%). The relative wall thickness, a marker of LVH, tended to be positively correlated with the degree of non-cardiomyocyte area. The extent of TTR deposition was positively correlated with enlargement of the non-cardiomyocyte area, and these were positively correlated with LV diastolic dysfunction. Additionally, the extent of the area containing TTR was positively correlated with the percentage of cardiomyocyte nuclei stained for 8-hydroxy-2'deoxyguanosine, a marker of reactive oxygen species (ROS). ROS accumulation in cardiomyocytes was positively correlated with LV systolic dysfunction. CONCLUSION: Patients with ATTR-CM mainly displayed concentric LVH geometry. TTR amyloid deposition was associated with cardiac dysfunction via increased non-cardiomyocyte area and ROS accumulation in cardiomyocytes.

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling.

[Figure: see text].

Involvement of chronic inflammation via monocyte chemoattractant protein-1 in uraemic cardiomyopathy: a human biopsy study.

AIMS: Patients undergoing dialysis, even those without coronary artery disease or valvular abnormalities, sometimes present with reduced heart function, which resembles dilated cardiomyopathy (DCM). This condition is known as uraemic cardiomyopathy (UCM). The mechanisms of UCM development are not fully understood. Previous studies demonstrated that the balance between placental growth factor (PlGF) and fms-like tyrosine kinase-1 (Flt-1) is correlated with renal function, and PlGF/Flt-1 signalling is involved in the development of cardiovascular diseases in patients with chronic kidney disease. This study was conducted to evaluate the pathogenesis of UCM and clarify the differences in the mechanisms of UCM and DCM by using human endomyocardial biopsy and blood samples. METHODS AND RESULTS: The clinical and pathological features of 30 patients on dialysis with reduced cardiac function [left ventricular ejection fraction (LVEF) ≤50%] (UCM group; mean age: 58.5 ± 9.4 years and LVEF: 39.1 ± 7.2%), 196 DCM patients (DCM group; mean age: 62.7 ± 14.0 years and LVEF: 33.5 ± 8.8%) as controls with reduced cardiac function (LVEF ≤ 45%), and 21 patients as controls with normal cardiac function (control group; mean age: 56.2 ± 19.3 years and LVEF: 67.5 ± 6.7%) were analysed. The percentage of the interstitial fibrosis area in the UCM group was greater than that in the DCM group (P = 0.045). In UCM patients, the percentage of the interstitial fibrosis area was positively correlated with the duration of renal replacement therapy (P < 0.001). The number of infiltrated CD68-positive macrophages in the myocardium and expression of monocyte chemoattractant protein-1 (MCP-1) in cardiomyocytes were significantly greater in the UCM group than in the other groups (P < 0.001, respectively). Furthermore, while the serum level of soluble form of Flt-1, an endogenous inhibitor of PlGF, in the UCM group was lower compared with that in the DCM group (P < 0.001), the serum levels of PlGF and PlGF/soluble form of Flt-1 ratio and plasma level of MCP-1 in the UCM group were higher than those in the DCM group (P < 0.001, respectively). CONCLUSIONS: These results suggest that activated PlGF/Flt-1 signalling and subsequent macrophage-mediated chronic non-infectious inflammation via MCP-1 in the myocardium are involved in the pathogenesis of UCM.

Serum iron: a new predictor of adverse outcomes independently from serum hemoglobin levels in patients with acute decompensated heart failure.

Iron is an essential trace element in the body. However, in heart failure (HF), iron is only recognized as the cause of anemia. Actually, iron itself affects myocardial exercise tolerance and cardiac function via mitochondrial function. Therefore, it is necessary to clarify the pathological significance of iron in acute HF, irrespective of concomitant anemia. We investigated the impact of serum iron level at discharge on the prognosis of 615 patients emergently admitted with acute decompensated HF (ADHF). Patients were divided into two groups according to the median level of serum iron (62 µg/dL). The endpoint was the composite outcome, which included all-cause mortality and readmission for HF. During the mean follow-up period of 32.1 months, there were 333 events. Kaplan-Meier analysis showed that the incidence of the composite outcome was significantly higher in the Low iron group (P < 0.0001). In the multivariate analysis adjusted with factors including hemoglobin and ferritin levels, low serum iron was an independent predictor for the composite outcome (hazard ratio, 1.500; 95% confidence interval, 1.128-1.976; P = 0.0044). Low serum iron was an independent predictor of poor prognosis in ADHF, irrespective of hemoglobin or ferritin level, providing a new concept that iron may play a role in the pathophysiology of ADHF via non-hematopoietic roles.

Effect of the Sodium-Glucose Cotransporter 2 Inhibitor Canagliflozin for Heart Failure With Preserved Ejection Fraction in Patients With Type 2 Diabetes.

Background: The efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in elderly patients with heart failure with preserved ejection fraction (HFpEF) remains unclear. Methods and Results: In a multicenter, controlled trial, the CANONICAL study, we enrolled 82 HFpEF (left ventricular ejection fraction [LVEF] ≥50%) patients with type 2 diabetes (T2D) aged ≥65 years, with plasma B-type natriuretic peptide (BNP) ≥100 pg/mL or plasma N-terminal pro BNP (NT-proBNP) ≥400 pg/mL or history of HF. Patients were randomly assigned to 2 groups and were administered either the SGLT2 inhibitor canagliflozin (100 mg/day) for 24 weeks or standard therapy. The primary endpoints were changes in body weight (BW) and BNP concentrations. Mean (±SD) patient age, body mass index, and LVEF were 75.7±6.5 years, 25.0±3.6 kg/m2 and 61.5±7.6%, respectively. At 24 weeks, BW was significantly lower in the canagliflozin than standard therapy group. The extent of BNP reductions at 4 weeks was significantly greater in the canagliflozin than standard therapy group (P<0.05), but at 24 weeks there was no significant difference between the 2 groups. Conclusions: In this study, canagliflozin treatment reduced BW, but did not significantly reduce plasma BNP concentrations compared with standard therapy after 24 weeks treatment in T2D patients with HFpEF. Further large-scale randomized studies are needed to conclude the beneficial effects of canagliflozin in T2D patients with HFpEF.

Improvement in Left Cardiac Function Following Mitral Valve Repair: Analyses Based on Cardiac Magnetic Resonance Imaging.

AIM: This study aimed to evaluate the structural and functional changes of left-sided cardiac chambers by cardiac magnetic resonance imaging (CMRI) in patients with chronic mitral regurgitation after mitral valve repair (MVR). PATIENTS AND METHODS: Among 103 patients who underwent MVR, 21 showed normal left ventricular (LV) function; their pre- and postoperative left atrial (LA) and LV functions were examined by CMRI. RESULTS: LV end-diastolic volume, LV end-systolic volume, and LV mass significantly were reduced postoperatively (p<0.01) and postoperative LV ejection fraction tended to decrease. LA volume parameters also significantly decreased postoperatively (p<0.01). The conduit function positively affected the LV filling volume postoperatively (p<0.01); however, no effect on the booster pump function was noted (p=0.01). CONCLUSION: Restoration of LA and LV functions after a successful MVR was not associated with structural improvement in LA and LV.

Role of climatic factors in the incidence of Takotsubo syndrome: A nationwide study from 2012 to 2016.

AIMS: This study aimed to investigate the influence of climatic factors on the onset of Takotsubo syndrome (TTS). METHODS AND RESULTS: We performed a retrospective nationwide study among patients registered in the Japanese Registry of All Cardiac and Vascular Diseases and Diagnosis Procedure Combination (JROAD-DPC) discharge database, between 2012 and 2016. Before the analysis, a multicentre validation study was conducted for assessing the accuracy of the JROAD-DPC classification for TTS. First, we investigated the seasonal variation of incidences of TTS. Second, we analysed the associations between the incidence of TTS and climatic factors using the hierarchical Poisson regression modelling, and we also investigated the associations between typhoon landfalls and hospitalization for TTS, using the fixed-effects conditional Poisson regression model. The sensitivity and specificity for diagnosis were 83% and 100%, respectively. Then we analysed 5643 patients with TTS. The mean patient age was 74 (standard deviation ± 11) years; 79% were female. TTS was diagnosed significantly more frequently in the summer and early autumn. The incidence of TTS was related to higher temperatures; adjusted incidence rate ratios were 1.46 [95% confidence interval (CI): 1.33-1.60, P < 0.01] and 1.47 (95% CI: 1.34-1.62, P < 0.01) for temperatures of 20-25°C and >25°C, respectively. The incidence rate ratio for the first 2 days after a typhoon landfall was 1.85 (95% CI: 1.07-3.19; P = 0.03). CONCLUSIONS: This study demonstrates distinct patterns of seasonal variation in the incidence of TTS, as well as a significant association between its onset and climatic factors, including typhoon landfalls.

Vacuolated cardiomyocytes in human endomyocardial biopsy specimens.

We encountered an unfamiliar finding during electron microscopic examination of an endomyocardial biopsy obtained from a 55-year-old woman suffering from heart failure due to dilated phase hypertrophic cardiomyopathy. Many cardiomyocytes contained large vacuoles that were mainly empty except for small amounts of amorphous substrate. These were not autophagic vacuoles, as they lacked limiting membranes. Six years later, we encountered similar histological findings in three successive biopsies sourced from another hospital. They were obtained from a 77-year-old man with hypertrophic cardiomyopathy, a 28-year-old woman with endocardial fibrosis, and a 33-year-old man with dilated cardiomyopathy. This biopsy was the second for the endocardial fibrosis patient, and her first biopsy showed no vacuoles within cardiomyocytes. Close inspection of the procedures revealed that in all of these cases the fixed biopsy specimens were carried to the hospital from other institutes using a refrigerated courier service. We then fixed rat heart tissues, froze them once, and processed them for electron microscopy. In that experiment, we were able to reproduce the vacuolar cardiomyocytes, thereby demonstrating it to be a laboratory artifact. We therefore want to emphasize to physicians not to freeze biopsy specimens and not to use a refrigerated courier service for their transport. .