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.

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.

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. .

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).

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.

Mitochondrial deformity confined to a single cardiomyocyte in human endomyocardial biopsy specimens: Report of 4 cases.

During electron microscopic examination of 156 consecutive human endomyocardial biopsy specimens, we found marked mitochondrial deformity within a single cardiomyocyte in each of 4 specimens. The deformed mitochondria were unevenly distributed, but the deformities were confined to the one cardiomyocyte. Those affected cardiomyocytes were accompanied by nonspecific degenerative changes such as nuclear hypertrophy and/or rarefaction of the myofibrils. Mitochondria in all other cells within the specimens appeared normal. Such an abnormality has never been reported to date. Each of the four cases was diagnosed with a different ailment: post-myocarditis, dilated cardiomyopathy, amyloidosis, and tachycardia-induced heart failure. However, all four cases were accompanied by left ventricular systolic dysfunction at biopsy. The very limited mitochondrial deformation may thus reflect a type of degenerative change that accompanies heart failure. .

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.

Refractory high output heart failure in a patient with primary mitochondrial respiratory chain disease.

A 40-year-old man who was referred to our hospital due to dyspnea was found to have high output cardiac failure on Swan-Ganz catheterization. An endomyocardial biopsy revealed cardiomyocyte hypertrophy with a vacuolar structure consistent with mitochondrial disease (MD). The patient was discharged, then readmitted for high output cardiac failure with hypotension and hyperlactacidemia. Treatment with cardiopulmonary support and hemodiafiltration gradually improved his general condition, although it resulted in ischemic necrosis of the right leg. The hyperlactacidemia completely resolved after amputation, and the high output cardiac failure has not recurred for two years. High output cardiac failure is rare in MD patients and is related to myocardial abnormalities and hyperlactacidemia.

A pediatric case of hypertrophic cardiomyopathy with mid-ventricular obstruction incidentally detected by electrocardiography.

A 13-year-old girl was admitted to our hospital because mitral P wave and ST depression in leads II, III, aVF, and V3-6 were incidentally detected on electrocardiography at a school health examination. Although she had noted no cardiac symptoms during club volley ball games, the treadmill exercise test induced chest discomfort in the absence of obvious electrocardiographic changes. B-type natriuretic peptide was elevated at 685 pg/ml. Echocardiography revealed left mid-ventricular hypertrophy and obstruction, sparing of the apical ventricle at end-systole, and severe left atrial dilatation. Continuous-wave Doppler echocardiography clarified a peak pressure gradient of about 40 mmHg between the apical and basal sites of the left ventricle. Swan-Ganz catheterization suggested elevated atrial pressure and left ventricular end-diastolic pressure. Left ventriculography showed an "hourglass" appearance. Endomyocardial biopsy revealed cardiac muscle cell disarray. We diagnosed a rare pediatric case of hypertrophic cardiomyopathy with mid-ventricular obstruction. This case reconfirms that electrocardiography during school health examinations is a very important screening tool for the detection of asymptomatic or mild symptomatic cardiac diseases.

Comparison of three current staging systems for hepatocellular carcinoma: Japan integrated staging score, new Barcelona Clinic Liver Cancer staging classification, and Tokyo score.

BACKGROUND AND AIM: Although various staging systems for hepatocellular carcinoma (HCC) have been developed in recent years, there is no worldwide consensus which staging system is best. The aim of the present study was to compare the performance of the currently developed three staging systems: the Japan integrated staging (JIS) score, new Barcelona Clinic Liver Cancer (BCLC) staging classification, and the Tokyo score. METHODS: A total of 290 consecutive patients with HCC before initial treatment at Kinki University between January 1999 and December 2001 were included. The patients were stratified according to the three staging systems, and the performance of the staging systems was compared using survival time as the only outcome measure. RESULTS: There were significant differences between all stages in the JIS score, while no significant difference was found between stages C and D in the BCLC staging classification and between all the scores, except between scores 0 and 1 and 2 and 3 in the Tokyo score. For all patients (n = 290), the radical treatment group (n = 208) and the non-radical treatment group (n = 82), the likelihood ratio chi(2)-test showed the highest value, and the Akaike information criterion value was lowest in the JIS score. CONCLUSION: The JIS score provided the best prognostic stratification in a Japanese cohort of HCC patients who were mainly diagnosed at early stages and treated with radical therapies.

Long-term interferon maintenance therapy improves survival in patients with HCV-related hepatocellular carcinoma after curative radiofrequency ablation. A matched case-control study.

OBJECTIVE: To assess whether low-dose, long-term maintenance interferon (IFN) therapy inhibits recurrence after complete ablation of hepatocellular carcinoma (HCC) and improves patient survival. METHODS AND PATIENTS: From June 1999 through May 2006, a total of 127 HCC cases that met the requirements of both tumor diameter 3 cm or less, and number of tumors three or fewer, were curatively treated by radiofrequency ablation therapy (RFA). Among them, 43 patients received three million IU of IFN-alpha2b twice per week or pegylated IFN-alpha2a 90 microg once per week or once per 2 weeks without discontinuation (IFN maintenance group). The remaining 84 patients, whose sex, age, and platelet counts were randomly matched to those of the IFN maintenance group, did not receive IFN treatment (control group). RESULTS: Cumulative first, second, and third recurrence rates were significantly reduced in the IFN maintenance group compared with the control group by Kaplan-Meier estimate. The 5-year survival rate was 66% for the control group and 83% for the IFN maintenance group (p = 0.004). Multivariate analysis using the Cox proportional hazards model identified IFN maintenance therapy as an independent risk factor for survival, and the risk ratio was 0.21 (95% CI: 0.05-0.73). In conclusion, low-dose, long-term maintenance IFN therapy after curative RFA therapy of HCC significantly inhibits recurrence, and consequently improves patient survival.

Review of current staging systems for hepatocellular carcinoma.

Several staging systems have been developed to classify patients with hepatocellular carcinoma (HCC), however, there is no consensus on which of these is the most useful and reliable. In this review article, currently available integrated staging systems taking into account both liver function and tumor progression are presented, and their characteristics and applicability for current HCC patients, many of whom are diagnosed in the early stage of the disease and treated by curative therapy, are discussed. Based on the original andsubsequent validation studies of these staging systems, we recommend that further validation studies of staging systems for HCC should focus on the revised Barcelona Clinic Liver Cancer (BCLC) staging classification, Japan Integrated Staging (JIS) score and Tokyo score.

Clinical characteristics of NonBNonC- HCC: Comparison with HBV and HCV related HCC.

OBJECTIVE: To clarify the frequency and trends of both HBsAg and HCVAb negative hepatocellular carcinoma (NonBNonC-HCC) in all HCC, to clarify the etiology of NonBNonC-HCC, and to elucidate the clinical characteristics of NonBNonC-HCC compared with those of HBsAg-positive HCC (B-HCC) and HCVAb-positive HCC (C-HCC). METHODS: A total of 2,542 patients with HCC examined at three institutions between 1991 and 2004 were categorized based on their serum viral antigen/antibody positivities, and compared between groups for the etiology, annual trend of the incidence, and clinical characteristics. RESULTS: For the etiology, C-HCC was most prevalent, followed by B-HCC, NonBNonC-HCC, and both HBsAg and HCVAb-positive HCC (BC-HCC) in order. For survival, C-HCC had the most favorable prognosis, followed by NonBNonC-HCC, and B-HCC patients had the poorest prognosis in the three groups (C-HCC, B-HCC, and NonBNonC-HCC). In tumor-node metastasis (TNM) stages I+II, however, NonBNonC-HCC patients took the most favorable clinical course. The incidence of NonBNonC-HCC in all HCC was 5-8% from 1991 to 1998, and has increased to 10-12% since 1999. Additionally, the incidence of HBcAb-positive HCC in NonBNonC-HCC declined each year. Among NonBNonC-HCC patients, the morbidity of diabetic complications was significantly higher in HBcAb-negative patients than in HBcAb-positive patients. CONCLUSION: Although the incidence of NonBNonC-HCC among all HCC has an increasing trend recently, the incidence of HBcAb-positive HCC in NonBNonC-HCC has a tendency of decreasing. This fact suggest its etiology might be changing from occult HBV related HCC to unknown etiology such as nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) related HCC. The prognosis of NonBNonC-HCC was fairly good if the HCC was found in its early stage.

Low-dose, long-term, intermittent interferon-alpha-2b therapy after radical treatment by radiofrequency ablation delays clinical recurrence in patients with hepatitis C virus-related hepatocellular carcinoma.

OBJECTIVE: To assess whether or not interferon (IFN) therapy prevents recurrence, and eventually improves the prognosis of patients with hepatocellular carcinoma (HCC) after completion of radical radiofrequency ablation (RFA) therapy. METHODS: Included as the IFN group in this study were 24 patients in total, who received radical RFA therapy first, followed by medication with IFN-alpha2b at such a low dose of 3 MIU x 2/week for as long as possible. On the other hand, the control group comprised 33 patients in total, who received radical RFA therapy without subsequent treatment with IFN. The control group was matched to the IFN group in age, platelet counts and size of nodules. RESULTS: Of the 24 patients treated with IFN, only one patient showed sustained virologic response. The median tumor-free period until the first recurrence after radical RFA therapy was 3.4 years in the IFN group and 1.4 years in the control group (p = 0.02). During the first 3 years after commencement of IFN administration, the cumulative recurrence rate in the IFN group was found to be lower than in the control group (p = 0.01); however, with the lapse of time over 3 years, the recurrence rate in the IFN group increased. There was no difference in the cumulative survival rates between the IFN group and the control group (p = 0.25). CONCLUSION: Subsequently after radical RFA therapy, long-term, low-dose, intermittent IFN therapy successfully delayed clinical recurrence of HCC.

Multiple metastases from a meningeal hemangiopericytoma associated with severe hypoglycemia.

Hemangiopericytomas are rare vascular tumors that may be associated with profound hypoglycemia. We present correlative imaging findings for a 57-year-old woman who had multiple abdominal and muscular metastases with severe hypoglycemia 11 years after resection of meningeal hemangiopericytoma. The metastases were well-defined masses containing solid and cystic components, and they were extremely hypervascular in the solid component. Those characteristics on imaging associated with hypoglycemia and the past history of meningeal hemangiopericytoma may suggest the diagnosis and be helpful in differentiating the mass from other vascular tumors. Color and power Doppler ultrasound may play a valuable role in characterizing and diagnosing metastasis from hemangiopericytoma. A delay of several years between diagnosis of the primary hemangiopericytoma and the manifestation of metastasis appears to be a special feature of hemangiopericytoma.

Hepatic angiomyolipoma: identification of an efferent vessel as a hepatic vein by contrast-enhanced harmonic sonography.

Two cases of hepatic angiomyolipoma were studied by contrast-enhanced harmonic sonography. The special tumor hemodynamics, namely the efferent blood flow of the hepatic angiomyolipoma draining into the hepatic vein, were clearly shown on harmonic imaging, and they corresponded well with those seen on angiography and computed tomography during angiography. Benign hepatic tumors were diagnosed preoperatively in both cases according to the hemodynamic findings. Hepatic angiomyolipoma was finally identified histologically. The special tumor hemodynamics might be one of the important characteristics of hepatic angiomyolipoma. Contrast-enhanced harmonic sonography is useful for the detection of special tumor hemodynamics and may facilitate the differential diagnosis from other hepatic tumors, especially malignant liver tumors.