Current treatment in cardiac amyloidosis

Opinion statement Involvement of the heart is a common finding in amyloidosis. The heart is usually infiltrated by amyloid fibrils in primary amyloidosis and age-related forms of amyloidosis, less commonly in transthyretin familial amyloidosis, and rarely in secondary amyloidosis. The most common clinical presentation is restrictive cardiomyopathy with right-sided heart failure. The second most frequent presentation is congestive heart failure due to systolic dysfunction, followed by arrhythmias and orthostatic hypotension. The diagnosis of amyloidosis requires tissue sample confirmation; at present, Congo red staining in polarized light is the diagnostic method of choice. The characterization of protein fibril type by immunohistochemistry or biochemistry is essential for patient prognosis and treatment. The therapeutic approach consists of specific treatment of amyloidosis and supportive treatment for cardiac-related symptoms. The treatment depends on the type of amyloidosis and the stage of disease. The mainstay of supportive treatment of cardiac failure is diuretic therapy. Primary amyloidosis treatment protocol includes melphalan and prednisone chemotherapy. Heart transplantation is only a palliative treatment. Stem cell transplantation is an emerging treatment alternative. Combination therapy of melphalan and stem cell transplantation has been shown to be a promising treatment strategy. Secondary amyloidosis requires aggressive treatment of the associated inflammatory and neoplastic process. Age-related (senile) amyloidosis benefits from supportive cardiac treatment when applicable. Transthyretin amyloidosis, the most common cardiac hereditary amyloidosis, is treated by liver or combined liver-heart transplantation. New therapies based on chemical and immunologic reaction with amyloid or its precursor are under intensive development.     

Phenotypic and genotypic heterogeneity in transthyretin-related cardiac amyloidosis: towards tailoring of therapeutic strategies?

Transthyretin-related hereditary amyloidosis (ATTR) is genotypically/phenotypically heterogeneous. We investigated myocardial involvement in ATTR in a cohort of patients with a wide range of mutations. Clinical/echocardiographic follow-up of 41 consecutive symptomatic ATTR patients from a single referral center was analyzed according to TTR mutation. Diagnosis was based on histology, immunohistochemistry and genotyping. Median follow up was 40 months (range 8-120). Among the 12 different mutations identified, Val30Met was found in 10 patients and Glu89Gln in seven. Compared with Val30Met, Glu89Gln was associated with higher LV mass index, lower left ventricular ejection fraction and shorter E-wave deceleration time. All Glu89Gln carriers had cardiomyopathy, which was more severe (for left ventricular thickness, left ventricular mass and restrictive pathophysiology) than in the six affected Val30Met patients. Glu89Gln was independently associated with higher risk of major cardiovascular events among cardiomyopathy patients. This follow-up study of ATTR patients carrying a wide range of mutations indicates that (1) cardiac involvement is a very important component of phenotypic expression; and (2) genotype is an important source of heterogeneity in myocardial involvement, with Glu89Gln being associated with a severe, heart-driven prognosis. We think that combined heart-liver transplantation could be considered for Glu89Gln carriers with established, morphologically severe cardiomyopathy.     

Recent advances in the noninvasive strategies of cardiac amyloidosis

The heart, like any organ in the body, is susceptible to amyloid deposition. Although more than 30 types of protein can cause amyloidosis, only two types commonly deposit in the ventricular myocardium: amyloid light chain and amyloid transthyretin. Amyloid cardiomyopathy is usually a major determinant of patient outcomes, and the diagnosis of heart involvement can be often relatively under-diagnosed, owing to nonspecific presenting symptoms and signs at a subclinical stage. The diagnosis of cardiac amyloidosis is usually performed by endomyocardial biopsy; however, the invasive nature and related high-risk complications restrict its wide use in clinical settings. Recently, with the advent of innovative techniques used for evaluating cardiac amyloidosis, noninvasive methods become increasingly important, especially in earlier diagnosis, distinguishing typing, risk prediction and response to treatment. Here, we will review recent developments in the noninvasive methods used in the assessment of cardiac amyloidosis, focused on the laboratory biomarkers and imaging modalities.     

Current therapeutic strategies in cardiorenal syndrome

Cardiorenal syndromes (CRS) are disorders of the heart and kidneys in which an acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. Primary disorders of one of these two organs often result in secondary dysfunction or injury of the other. The lack of specific trials in this field highlights the need for further studies aimed to assess titration and appropriate dosages of drugs, according to both the etiology of chronic heart failure (CHF) and also the severity of underlying renal dysfunction. Moreover, the most recent clinical trials evaluating clinical and renal outcome in acute heart failure syndromes (AHFS), failed to demonstrate an improvement in renal function and perfusion. Therefore, Current American and European Guidelines for AHFS does not provide specific recommendation for patients with renal impairment. In this scenario several questions regarding the drugs, their recommended dosage and potential adverse effects on cardiac and renal outcome need to be addressed. Subsequently, therapy inducing an improvement in the renal function, a reduction of neurohormonal activation and an improvement of renal blood flow, could lead to a reduction in mortality and hospitalization in patients with CRS.     

Current therapeutic strategies in Hodgkin lymphoma

Zum Thema In den letzten Jahren haben sich die Behandlungsstrategien der Hodgkin-Lymphome gewandelt. Für die frühen und mittleren Stadien der Hodgkin-Lymphome hat sich der risikoadaptierte kombinierte Einsatz von Chemotherapie und Strahlentherapie durchsetzen k?nnen.In frühen und intermedi?ren Stadien liegt das Gesamtüberleben nach 5 Jahren bei über 90%.Mit Einsatz neuer Chemotherapieprotokolle in den fortgeschrittenen Stadien überleben langfristig etwa 80% aller Patienten nach intensiver Chemotherapie mit additiver Strahlentherapie auf Resttumoren und Bulk.Nachfolgend werden die gegenw?rtigen Studienkonzepte der Deutschen Hodgkin-Lymphom-Studiengruppe (DHSG) detailliert dargestellt. Prof.Dr.V. Diehl Klinik I für Innere Medizin, Universit?t zu K?ln, 50924 K?ln, E-Mail: V.Diehl@uni-koeln.de     

Current therapeutic strategies for HCV-associated cryoglobulinemia

Cryoglobulinemia refers to the presence in serum of immunoglobulins, that reversibly precipitate at low temperatures. Cryoglobulins are classified according to their immunochemical properties as type I, composed of a single monoclonal immunoglobulin, and types II and III, referred as mixed cryoglobulinemia (MC), composed by a mixture of monoclonal (type II) and polyclonal (type III) IgM that have rheumatoid factor activity and bind to polyclonal IgGs. MC is a systemic vasculitis with cutaneous and multiple organ involvement including chronic hepatitis, membrano-proliferative glomerulonephritis, and peripheral neuropathy. In more than 90% of patients, MC is associated with chronic hepatitis C virus (HCV) infection, which is considered the triggering factor of the disease. Patients with HCV-related MC may be managed by means of etiological, pathogenetic or symptomatic therapeutic modalities. The choice of the more appropriate treatment is strictly related to the assessment of disease activity, and to the extent and severity of organ involvement. This paper reviews the currently available therapeutic strategies for MC syndrome, emphasizing the importance of HCV eradication, and the safety/efficacy of new biologic therapies for selective control of cryoglobulin-producing B-cells.     

Current therapeutic strategies in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease ranging from simple steatosis through steatohepatitis (NASH) to increasing fibrosis and eventual cirrhosis. NAFLD is the hepatic manifestation of the metabolic syndrome and has now become the most common cause of liver disease in Western countries, with the more advanced stages of disease being associated with an increased risk of liver-related morbidity and mortality. The optimal management of patients with NAFLD remains a clinical challenge. The aim of this study is to describe established and emerging strategies for the treatment of NAFLD. Relevant research and review articles were identified by searching PubMed. Selected articles referenced in these publications were also examined. Good quality randomized controlled studies have demonstrated the need for multifaceted lifestyle interventions in patients with NAFLD including the need for diet, exercise and behavioural counselling. Despite several trials of pharmacological agents, no highly effective treatment yet exists, with surgery representing the mainstay for advanced disease. A multidisciplinary approach, with a major focus on lifestyle change, represents best treatment pending the development of new therapeutic options.     

Current therapeutic strategies for acute myeloid leukaemia

Improvements in survival in adult acute myeloid leukaemia (AML) have yet to be gleaned from either refinements in the understanding of the pathophysiology of the disease or from the expanding pool of targeted therapies. Outcomes have remained particularly dismal in older patients. Ongoing and planned trials will assess the effects of drugs targeting biological pathways whose clinical importance may vary as a function of the unique genotype and phenotype of each case of AML. The success of these ventures will ultimately require well-designed clinical trials in subsets of patients with risk being dependent not only on age and cytogenetics, but on additional, increasingly quantifiable biological variables. Inhibitors of fms-like tyrosine kinase-3, farnesyl transferase, apoptotic and angiogenic pathways are being studied alone and in combination with chemotherapy. Biological therapies, including monoclonal antibodies, peptide vaccines and interleukin-2, are undergoing evaluation. The role of autologous as well as allogeneic myeloablative and reduced-intensity transplantation continues to be defined. Several potentially useful new cytotoxic agents are being introduced. Critically important to advancing the field in light of such an increasing number of choices is a reassessment of traditional phase II trial designs so that more efficient evaluation of new therapies may take place, even as well-designed phase III trials continue to be performed.     

非小细胞肺癌的非手术综合治疗进展

非小细胞肺癌 (ｎｏｎ ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒ,ＮＳＣＬＣ)占原发性肺癌的 75 %～ 80 %。就诊时已有 70 %～ 80 %属中、晚期 ,失去手术机会。这部分患者总的 5年生存率低于 5 % [1] 。约1/ 3的ＮＳＣＬＣ属于Ⅲ期 ,即所谓局部晚期。过去 ,高剂量放疗是局部或局部晚期ＮＳＣＬＣ的常规疗法。单纯胸部放疗的中位生存期 <1年 ,5年生存率仅 5 %～ 7%。尽管新的放疗方法不断推出 ,如超分割放疗、加速超分割放疗 ,以及连续超分割加速放疗等。胸部放疗能控制局部病灶 ,并有效缓解肿瘤引起的症状 ,但对于提高晚期肿瘤患者的生存率…     

肝细胞癌防治热点与策略

对肝细胞癌（HCC）的防治已成为人类一大挑战。近年来,在HCC的临床和基础肿瘤细胞生物学研究方面均有较大进展,出现了一批可提供高级别循证医学证据的临床试验结果,也为HCC的防治带来新的关注热点。临床实践中仍然存在不规范治疗和费效比低等严重问题。本文论及HCC防治的热点,旨在指导医生遵守循证医学证据,采用个体化、优化治疗策略,使HCC患者临床治疗最大获益。     

Senile cardiac amyloidosis

A case of senile cardiac amyloidosis with recurrent episodes of congestive heart failure is reported here. An 83-year-old woman with a history of hypertension was admitted for the treatment of worsening dyspnea. The echocardiography revealed diffuse mild hypokinesis of the left ventricle with an ejection fraction of 46%. An elevated E wave and shortened deceleration time in the left ventricular inflow waveform was demonstrated with Doppler echocardiography, which suggested that the nature of the heart failure was restrictive. The patient required hospitalization for the treatment of congestive heart failure four times in 2 years. An autopsy revealed deposition of prealbumin-positive amyloid substance in the atrial myocardium and the intramyocardial arterioles of the left ventricle. Recurrent congestive heart failure was presumed to be a result of diastolic dysfunction due to senile cardiac amyloidosis.     

Current complications of diagnostic and therapeutic cardiac catheterization

Data from 2,883 cardiac catheterizations performed during an 18 month period (from July 1986 through December 1987) were analyzed to assess the current complication profile of diagnostic and therapeutic procedures. Procedures performed during the study period included 1,609 diagnostic catheterizations, 933 percutaneous transluminal coronary angioplasties and 199 percutaneous balloon valvuloplasties. Overall, the mortality rate was 0.28% but ranged from 0.12% for diagnostic catheterizations to 0.3% for coronary angioplasty and 1.5% for balloon valvuloplasty. Emergency cardiac surgery was required in 12 angioplasty patients (1.2%). Cardiac perforation occurred in seven patients (0.2%), of whom six were undergoing valvuloplasty, and five (2.5% of valvuloplasty attempts) required emergency surgery for correction. Local vascular complications requiring operative repair occurred in 1.9% of patients overall, ranging from 1.6% for diagnostic catheterization to 1.5% for angioplasty and 7.5% for valvuloplasty. Although the complication rates for diagnostic catheterization compare favorably with those of previous multicenter registries, current overall complication rates are significantly higher because of the performance of therapeutic procedures with greater intrinsic risk and the inclusion of increasingly aged and acutely ill or unstable patients.     

QT interval in cardiac amyloidosis

The aim of the study was to investigate whether cardiac amyloidosis is associated with QT interval abnormalities and ventricular arrhythmias. A controlled study of 30 patients was undertaken at a university cardiology department in a large referral hospital. Thirty patients (18 men, 12 women, mean age 56 ± 12 years) with systemic amyloidosis verified by biopsy and strong indications of cardiac amyloidosis comprised the study group, with 30 healthy age- and sex-matched individuals serving as controls. Complete M-mode and two-dimensional echocardiographic study was undertaken and QT interval and QT_c were calculated. All patients and controls underwent 24-h Holter monitoring for arrhythmias. Left ventricular (LV) wall thickening was found in all patients with cardiac amyloidosis. The LV mass in the patients with cardiac amyloidosis was significantly greater than that of the control group, as was the ratio LVmass/body surface area (p < 0.001). There was no significant difference in the max QT interval or in QT_c dispersion between the two groups, although the max QT_c was greater in the patients with cardiac amyloidosis. Patients with cardiac amyloidosis did not have a higher incidence of arrhythmias than the controls. Although patients with thickened cardiac walls due to cardiac amyloidosis have a prolonged QT_c in comparison with controls, they do not show an increase in interlead QT_c dispersion which might suggest the possibility of regional disturbances of the uniformity of repolarization. Patients with cardiac amyloidosis do not have a higher incidence of arrhythmias than controls.     

Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies

The concept and clinical implication of left ventricular remodeling have been gradually extended. Cardiac remodeling plays important roles in the progression of cardiovascular diseases including myocardial infarction, valvular heart diseases, myocarditis, and dilated cardiomyopathy. In addition to cardiac myocytes, fibroblasts, extracellular matrix proteins and coronary vasculature are also involved in the remodeling process. Cardiac remodeling is associated with alterations of many mediators such as neurohumoral factors, cytokines, enzymes, ion channels, oxidative stress and mechanical stress. Although remodeling is initially an adaptive response to maintain normal cardiac function, it gradually becomes maladaptive and leads to progressive decompensation. Recent research has attempted to elucidate underlying molecular mechanisms of cardiac remodeling and to develop novel therapeutic strategies for heart failure. The modulation of remodeling process is effective for preventing the progression of heart failure.