[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.

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.

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.

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.

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.

Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling.

[Figure: see text].

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.

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. .

AST-120, an Oral Carbon Absorbent, Protects against the Progression of Atherosclerosis in a Mouse Chronic Renal Failure Model by Preserving sFlt-1 Expression Levels.

Soluble Flt-1 (sFlt-1), an endogenous antagonist of the proatherogenic cytokine placental growth factor, is decreased in chronic kidney disease (CKD), leading to atherosclerotic progression. In this study, we investigated the effect of AST-120, an oral carbon adsorbent which can remove uremic toxins, on sFlt-1 expression levels and atherosclerosis progression. Atherosclerotic apolipoprotein E-deficient mice underwent a 5/6 nephrectomy (5/6 NR) or a sham operation (sham) at 8 weeks of age and were then treated or not with oral AST-120 for 12 weeks. sFlt-1 expression levels and the degree of atherosclerosis were assessed at 22 weeks of age in each of the four groups (sham; n = 7, 5/6 NR; n = 10, sham + AST-120: n = 8, 5/6 NR + AST-120; n = 8). The expression levels of sFlt-1 mRNA in the kidney were significantly lower in the 5/6 NR group than in the sham group, but AST-120 treatment prevented this decrease in sFlt-1 levels. Similarly, the atherosclerotic plaque area of the thoracoabdominal aorta was significantly larger in the 5/6 NR group than in the sham group, and AST-120 treatment prevented this increase in atherosclerosis. AST-120 could, therefore, be used as a therapeutic to treat atherosclerosis in patients with CKD.

Differences in blood pressure riser pattern in patients with acute heart failure with reduced mid-range and preserved ejection fraction.

AIMS: Heart failure (HF) is classified into three types according to left ventricular ejection fraction (EF). The effect of blood pressure (BP) on the pathogenesis of each type is assumed to be different. However, the association between the prognosis of each type of HF and abnormal BP variations assessed by ambulatory BP monitoring (ABPM), such as nocturnal hypertension and the riser pattern, remains unclear. METHODS AND RESULTS: We studied 325 consecutive patients with decompensated HF who were acutely admitted to our hospital and underwent ABPM at discharge. During a mean follow-up of 30.0 months, 52 cardiovascular and 112 all-cause deaths occurred. The Cox proportional hazards model showed that the mean values of 24 h, awake, and sleep-time systolic BP (SBP), and abnormal 24 h ABPM patterns, such as nocturnal hypertension and non-dipper pattern, were not associated with either all-cause or cardiovascular mortality in patients with HF with reduced EF (HFrEF), HF with mid-range EF (HFmrEF), or HF with preserved EF (HFpEF), except for sleep-time SBP in HFrEF. However, the riser pattern was a significant and independent predictor of all-cause and cardiovascular deaths in patients with HFpEF (hazard ratio, 2.01; 95% confidence interval, 1.12-3.62; 0.0200; and hazard ratio, 2.48; 95% confidence interval, 1.08-5.90; 0.0332, respectively). Sleep-time pulse rate was similarly decreased in both the riser and non-riser groups. CONCLUSIONS: The riser pattern of SBP was associated with an increased risk of adverse outcomes among patients with HFpEF but not HFrEF or HFmrEF.

Possible mechanism for disposal of degenerative cardiomyocytes in human failing hearts: phagocytosis by a neighbour.

The index case was a 51-year-old woman suffering from doxorubicin cardiomyopathy. In her endomyocardial biopsy specimen, we observed under electron microscopy six scenes in which degenerative cardiomyocytes were engulfed by neighbouring cardiomyocytes. The enclosed cardiomyocytes appeared more degenerative than the enclosing ones in every pair: the myofibrils were more severely damaged. At more degenerative stages, some desmosomes of the intercalated discs on the enclosed cardiomyocyte had disappeared. The membranes between the cardiomyocytes were occasionally disrupted, and there appeared to be sharing of cellular contents between the cells. One pair of such a phagocytosis-like figure was observed in one case with 5-fluorouracil cardiomyopathy (a 68-year-old man) among eight other chemotherapy-induced cardiomyopathies but none among 30 non-drug-induced dilated cardiomyopathies. The findings suggest a mechanism for disposal of degenerative cardiomyocytes in human failing hearts: phagocytosis by a neighbour, although alternative interpretations remain (e.g. giant autophagic vacuoles or two cardiomyocytes with degenerative intercalated discs).

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.

Alteration of ß-Adrenoceptor Signaling in Left Ventricle of Acute Phase Takotsubo Syndrome: a Human Study.

Accumulating evidence indicates alteration of the ß-adrenoceptor (AR), such as desensitization and subtype switching of its coupling G protein, plays a role in the protection against catecholamine toxicity in heart failure. However, in human takotsubo syndrome (TTS), which is associated with a surge of circulating catecholamine in the acute phase, there is no histologic evidence of ß-AR alteration. The purpose of this study was to investigate the involvement of alteration of ß-AR signaling in the mechanism of TTS development. Left ventricular (LV) biopsied samples from 26 patients with TTS, 19 with normal LV function, and 26 with dilated cardiomyopathy (DCM) were studied. G protein-coupled receptor kinase 2 (GRK2) and ß-arrestin2, which initiate the alteration of ß-AR signaling, were more abundantly expressed in the myocardium in acute-phase TTS than in those of DCM and normal control as indicated by immunohistochemistry. The percentage of cardiomyocytes that showed positive membrane staining for GRK2 and ß-arrestin2 was also significantly higher in acute-phase TTS. Sequential biopsies in the recovery-phase for two patients with TTS revealed that membrane expression of GRK2 and ß-arrestin2 faded over time. This study provided the first histologic evidence of the involvement of alteration of ß-ARs in the development of TTS.

Prognostic Value of Urinary Neutrophil Gelatinase-Associated Lipocalin on the First Day of Admission for Adverse Events in Patients With Acute Decompensated Heart Failure.

BACKGROUND: Urinary neutrophil gelatinase-associated lipocalin (U-NGAL) is an early predictor of acute kidney injury and adverse events in various diseases; however, in acute decompensated heart failure patients, its significance remains poorly understood. This study aimed to investigate the prognostic value of U-NGAL on the first day of admission for the occurrence of acute kidney injury and long-term outcomes in acute decompensated heart failure patients. METHODS AND RESULTS: We studied 260 acute decompensated heart failure patients admitted to our department between 2011 and 2014 by measuring U-NGAL in 24-hour urine samples collected on the first day of admission. Primary end points were all-cause death, cardiovascular death, and heart failure admission. Patients were divided into 2 groups according to their median U-NGAL levels (32.5 µg/gCr). The high-U-NGAL group had a significantly higher occurrence of acute kidney injury during hospitalization than the low-U-NGAL group (P=0.0012). Kaplan-Meier analysis revealed that the high-U-NGAL group exhibited a worse prognosis than the low-U-NGAL group in all-cause death (hazard ratio 2.07; 95%CI 1.38-3.12, P=0.0004), cardiovascular death (hazard ratio 2.29; 95%CI 1.28-4.24, P=0.0052), and heart failure admission (hazard ratio 1.77; 95%CI 1.13-2.77, P=0.0119). The addition of U-NGAL to the estimated glomerular filtration rate significantly improved the predictive accuracy of all-cause mortality (P=0.0083). CONCLUSIONS: In acute decompensated heart failure patients, an elevated U-NGAL level on the first day of admission was related to the development of clinical acute kidney injury and independently associated with poor prognosis.