Amyloid cardiomyopathy

Cardiac amyloidosis is a heterogeneous group of diseases characterized by extracellular deposition of amyloid fibrils in many different organs finally resulting in organ failure. Cardiac involvement is common for immunoglobulin light chain amyloidosis (AL) or transthyretin amyloidosis (ATTR); the latter is caused by a transthyretin gene variant or wild-type protein. Precise diagnostic assessment including laboratory tests, electrocardiography, echocardiography, cardiac magnetic resonance imaging, biopsy, and/or bone scintigraphy is mandatory for definition of the amyloid type and finally for treatment initiation. Treatment of cardiac amyloidosis includes symptomatic therapy of heart failure as well as the underlying disease. Causative treatment of AL amyloidosis is according to regimens used for multiple myeloma. For many years, orthotopic liver transplantation was the only treatment available for hereditary ATTR amyloidosis, but important advances have been made after approval of a novel class of medication, namely, RNA silencers. However, currently no treatment is available to remove amyloid deposited in the tissue. Thus, early diagnosis is still critical to afford the best efficacy of available therapies.     

心脏淀粉样变性

淀粉样变性是以不可溶性的淀粉样物质沉积于器官或组织的细胞外区,导致相应的器官或组织功能障碍为特征的一组疾病。心脏是淀粉样变性常累及的器官。心脏淀粉样变性临床上通常按其病因分为原发性、家族性、老年性、继发性及透析相关性五种类型。其最常见的临床表现为限制性心肌病和顽固性心力衰竭,有时伴有传导阻滞。心肌活检可以确定诊断,近年来随着心外组织取样和显像技术的发展已大大减少了心内膜心肌活检的必要。尽管治疗上有所改进,但心脏淀粉样变性患者预后仍然较差,主要取决于原有疾病类型。     

Amyloid heart disease. New frontiers and insights in pathophysiology, diagnosis, and management

Amyloidosis comprises a unique group of diseases that share in common the extracellular deposition of insoluble fibrillar proteins in organs and tissues. Cardiovascular amyloidosis can be primary, a part of systemic amyloidosis, or a result of chronic systemic diseases elsewhere in the body. The most common presentations are congestive heart failure-mainly a restrictive infiltrative pattern--and conduction system disturbances. Recent developments in imaging techniques and extracardiac tissue sampling have minimized the need for invasive endomyocardial biopsy for amyloidosis. Despite advances in treatment, the prognosis for patients with amyloidosis is still poor and depends on the underlying disease type. Herein, we present new insights and recent advances in cardiovascular amyloidosis.     

Systemic amyloidosis: a clinical challenge

This study reports a case of an 82-year-old white woman with a history of congestive heart failure refractory to diuretic therapy who was found to have systemic amyloidosis, confirmed by a rectal biopsy. Cardiac involvement by amyloid should be considered in the differential diagnosis of any patient with heart failure with preserved ventricular systolic function, who does not have evidence of ischaemic heart disease or hypertension. However, the rarity of this disease and the various involvement of different organs and tissues are often responsible for missed or delayed diagnosis. Systemic amyloidosis is a life-threatening disease but an early diagnosis may modify its course; therefore it is important to maintain a high clinical suspicion and to increase the awareness of this overlooked condition among clinicians.     

Case Report: Isolated Cardiac Amyloidosis: An Enigma Unravelled

Amyloidosis is a rare, multisystem disease characterized by deposition of fibrils in extracellular tissue involving kidney, liver, heart, autonomic nervous system, and several other organs. This report discusses a 75-year-old male who presented with worsening dyspnea on exertion, orthopnea, and lower-extremity edema. On physical exam, he had elevated jugular venous pressure and lowerextremity edema. Electrocardiogram depicted low voltage in limb leads and a prolonged PR interval. Echocardiogram revealed left ventricular hypertrophy, severe biatrial dilatation, and restrictive filling physiology. Coronary angiography showed absence of significant epicardial coronary artery disease. On right heart catheterization, a “dip-and-plateau sign” was noted on right ventricular pressure tracings. A diagnosis of cardiac amyloidosis was considered, but a complete hematology work-up for systemic amyloidosis was negative. Cardiac magnetic resonance imaging was pursued, showing delayed gadolinium enhancement, and this ultimately led to the myocardial biopsy confirming the diagnosis of isolated cardiac amyloidosis. Further genetic analyses confirmed isolated cardiac amyloid caused by mutant transthyretin protein (Val-122-Ile). Isolated cardiac amyloidosis is an extremely rare entity, and diagnosis may be difficult despite the use of multimodality imaging. If the index of suspicion is high, then myocardial biopsy should be considered.     

Amyloidosis and the heart: a comprehensive review

Infiltration of the heart from insoluble protein deposits in amyloidosis often results in restrictive cardiomyopathy that manifests late in its course with heart failure and conduction abnormalities. While the rare primary amyloidosis-related heart disease has been well characterized, senile amyloidosis occurring in the seventh decade of life most frequently affects the heart. Early diagnosis of cardiac amyloidosis may improve outcomes but requires heightened suspicion and a systematic clinical approach to evaluation. Demonstration of tissue infiltration of biopsy specimens using special stains, followed by immunohistochemical studies and genetic testing, is essential in defining the specific protein involved. The therapeutic strategy depends on the characterization of the type of amyloid protein and extent of disease and may include chemotherapy, stem cell transplantation, and liver transplantation. Heart transplantation is controversial and is generally performed only at isolated centers.     

Subcutaneous fat biopsy in the diagnosis of amyloidosis secondary to chronic arthritis

Subcutaneous fat biopsy was investigated for its sensitivity in giving a diagnosis in 44 consecutive patients with rheumatoid arthritis or ankylosing spondylitis suspected of systemic amyloidosis. In 26 of these patients amyloidosis could be demonstrated by fat or rectal biopsy or biopsies from organs suspected of amyloid deposition. Fourteen of the 26 (54%) fat biopsy specimens of the patients with amyloidosis were positive after staining with Congo red and 22 (85%) of the rectal biopsy specimens were positive. All 12 kidney biopsy specimens and 4 biopsy specimens from other organs of these 26 patients were positive for amyloidosis. In 2 patients with a negative rectal biopsy specimen, fat biopsy would have obviated the need for a more invasive biopsy. All patients experienced fat biopsy as less demanding compared to other biopsy procedures. These results imply that in patients with chronic arthritis subcutaneous fat biopsy is a useful screening procedure. In this patient group fat biopsy is less sensitive for the diagnosis of amyloidosis compared to rectal biopsy.     

Diagnosis of cardiac amyloidosis using magnetic resonance imaging: a new reliable, non-invasive technique to be validated

Introduction

Amyloidosis is characterised by extracellular tissue deposition of insoluble fibrillar protein in various organs. Cardiac involvement is associated with the worse prognosis and the main cause of death. It needs a prompt diagnosis, which could be sometimes difficult to obtain. Endomyocardial biopsy remains the gold standard diagnostic technique, but recent studies on cardiac magnetic resonance imaging (MRI) indicate that this imaging procedure may be useful to the diagnosis of amyloidosis.

Case reports

We report three patients with systemic amyloidosis who underwent cardiac MRI for the diagnosis or the follow-up of their disease. In addition to poorly specific signs of restrictive cardiomyopathy, cardiac MRI showed, after gadolinium enhancement that was considered characteristic of amyloidosis.

Conclusion

Cardiac MRI is a useful diagnostic tool in cardiac amyloidosis, as it was shown in recent studies. Compared to endomyocardial biopsy it is a non-invasive technique that is now more readily accessible and that seems to have an acceptable specificity.     

Primary cardiac amyloidosis -- condition which can be diagnosed by a cardiologist

Primary amyloidosis is a systemic disorder caused by the clonal production and tissue deposition of immunoglobulin light chain proteins. The disease symptoms are typical of multisystem failure. Common presenting features include nephrotic syndrome, hepatomegaly, sensomotor peripheral neuropathy and, in the case of cardiac involvement, congestive heart failure. This last sign appears very seldom as alone, without any others. Cardiac involvement generally denotes a poor prognosis, regardless of the method of treatment. The median survival rate from onset of congestive heart failure is 6 months. Only the patients with earliest diagnosis made and advanced treatment (chemotherapy, autologous stem-cell transplantation, heart transplantation) introduced have the chance of the lengthening of life. The authors present a case of 52-year-old man with a primary amyloidosis, who suffered from severe, not responding to treatment, congestive heart failure. Because of lack of the other organ involvement symptoms, the correct diagnosis was made very late. The authors place emphasis on a simple diagnostic tool such as the correlation between the low voltage in the limb ECG leads and the echocardiographic sings of left ventricular hypertrophy. The combination of specific ECG, echocardiographic findings and positive extracardiac tissue biopsy may be sufficient to reach correct diagnosis. These examinations are easy accessible in non-specialist hospitals.     

Management of Cardiac Amyloidosis: Do’s and Don’ts

Cardiac amyloidosis is a potentially deadly disease characterized by progressive infiltration of amyloid fibrils, and it is increasingly recognized as an underdiagnosed but important cause of heart failure. Given its unique pathogenesis, there are key differences in the management of cardiac amyloidosis compared with other forms of heart failure. Moreover, the 2 common forms of cardiac amyloidosis, transthyretin and light-chain amyloidosis, are distinct entities with varying clinical manifestations and prognoses, leading to the need for tailored approaches to management. In the past decade, there have been many significant advances in the diagnosis and treatment of both forms of cardiac amyloidosis. For example, in selected cases, transthyretin cardiac amyloidosis can be diagnosed noninvasively with the use of bone scintigraphy imaging, avoiding the need for a biopsy. Effective, more targeted therapies have been developed for both transthyretin and light-chain amyloidosis. However, these treatments are much more effective in early stages of disease before significant end-organ amyloid deposition has occurred. Consequently, it is increasingly imperative that clinicians aggressively screen at-risk groups, identify early signs of disease, and initiate treatment. Finally, once thought to be ill advised, heart transplantation should be considered in carefully selected patients with end-stage cardiac amyloidosis, because transplant outcomes in these patients is now similar to other those for other cardiomyopathies. Given these and other recent changes in clinical practice, this article discusses several key considerations for the clinical care of patients with cardiac amyloidosis.     

Myocardial Amyloidosis: The Exemplar Interstitial Disease

Cardiac involvement drives prognosis and treatment choices in cardiac amyloidosis. Echocardiography is the first-line examination for patients presenting with heart failure, and it is the imaging modality that most often raises the suspicion of cardiac amyloidosis. Echocardiography can provide an assessment of the likelihood of cardiac amyloid infiltration versus other hypertrophic phenocopies and can assess the severity of cardiac involvement. Visualizing myocardial amyloid infiltration is challenging and, until recently, was restricted to the domain of the pathologist. Two tests are transforming this: cardiac magnetic resonance (CMR) imaging and bone scintigraphy. After the administration of contrast, CMR is highly sensitive and specific for the 2 main types of ventricular myocardial amyloidosis, light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). CMR structural and functional assessment combined with tissue characterization can redefine cardiac involvement by tracking different disease processes, ranging from amyloid infiltration, to the myocardial response associated with amyloid deposition, through the visualization and quantification of myocardial edema and myocyte response. Bone scintigraphy (paired with exclusion of serum free light chains) is emerging as the technique of choice for distinguishing ATTR from light chain cardiac amyloidosis and other cardiomyopathies; it has transformed the diagnostic pathway for ATTR, allowing noninvasive diagnosis of ATTR without the need for a tissue biopsy in the majority of patients. CMR with tissue characterization and bone scintigraphy are rewriting disease understanding, classification, and definition, and leading to a change in patient care.     

伴心肌肌钙蛋白I持续升高和心绞痛症状的系统性淀粉样变性

系统性淀粉样变性相对少见,累及心脏时,可出现多种临床表现,极易造成误诊和漏诊。本例报道了一位66岁女性,表现为持续性肌钙蛋白I升高和反复发作的胸痛,根据心脏影像学检查,结合单克隆免疫球蛋白试验及骨髓细胞学和骨髓活检,最终诊断为“系统性淀粉样变性（心脏受累）”。因此,对于射血分数保留的不能解释原因的心衰、肌钙蛋白升高、心脏影像学异常或存在系统性疾病,均应警惕有无淀粉样变可能。     

Utility of technetium Tc 99m pyrophosphate bone scanning in cardiac amyloidosis

Thirty-four patients with amyloidosis proved by biopsy specimen were studied using technetium Tc 99m pyrophosphate scintigraphy to assess its utility in the diagnosis of amyloid heart involvement. Of 14 patients studied retrospectively, only three had intense uptake judged to be diagnostic of cardiac amyloidosis. In a prospective analysis of 20 patients with amyloidosis, all of whom had evidence of cardiac involvement by two-dimensional echocardiography, 17 had abnormal scans. Fourteen of the 17 scans had only 1+ or 2+ uptake, a finding that also was present in 15 of the 20 control patients (without amyloid heart disease). Only three of the 20 patients with cardiac amyloidosis had intense uptake that was considered unequivocal and diagnostic of amyloidosis. Of the five patients with biopsy specimen proof of endomyocardial amyloidosis, only one had intense uptake and one had no uptake. When intense uptake of technetium Tc 99m pyrophosphate is found in the heart of a patient, amyloidosis is highly likely. The technique, however, is not sufficiently sensitive to warrant routine screening of patients with amyloidosis or cardiomyopathies. Cross-sectional echocardiography is superior to pyrophosphate scintigraphy for recognition of cardiac amyloidosis.     

A case report of localized gastric amyloidosis

AIM: To elucidate the clinical and laboratory features of localized gastric amyloidosis via a rare report along with a review of related literatures. METHODS: The clinical manifestations, laboratory results and surgical treatment of a female patient with localized gastric amyloidosis in our hospital were summarized. The relevant literatures were reviewed on the etiology, clinical features, diagnosis, treatment and prognosis of this disease. RESULTS: The patient was lack of specific clinical manifestations and positive laboratory results. Prior to the treatment, she was suspected to be of malignization from gastric ulcer by both gastroscopy and endoscopic ultrasonography, which was denied by the gastric biopsy. The patient was treated with subtotal gastrectomy and clearance of perigastric lymph nodes. The postoperative pathological diagnosis determined the lesion to be the deposition of amyloid materials in the gastric mucosa, submucosa and blood vessel walls with intestinal metaplasia and atrophy of the gastric glands, in which no malignant tumor was found. Congo red staining with prior potassium permanganate incubation confirmed the AA type of amyloid in this case. Multiple biopsies from esophagus, remnant stomach, duodenum, colon and bone marrow in the follow-up survey showed no amyloidal deposition in these tissues and organs. Up to the present, no signs of recurrence have been found in this patient. CONCLUSION: Localized gastric amyloidosis, being rare in incidence, should be considered in the differentiation of gastric tumors, in which biopsy is the only means to confirm the diagnosis. Currently, surgical resection of pathological tissue and circumambient lymph nodes may be a preferable therapeutic strategy for the localized amyloidosis to prevent possible complications. Although with a benign prognosis, gastric amyloidosis possesses a recurrent tendency as suggested by the literatures.     

Primary systemic amyloidosis presenting with advanced heart failure

Primary systemic amyloidosis (AL) is a rare, sporadic disease caused by deposition of immunoglobulin light chains in various tissues; symptoms vary based on which organs are infiltrated by the amyloid fibrils. Cardiac involvement occurs in up to 50% of patients with primary amyloidosis and is associated with a very poor prognosis. We report a case of a 57-year-old black man who presented with symptoms consistent with congestive heart failure. He was later found to have primary systemic amyloidosis, confirmed by abdominal fat pad biopsy.     

Primary systemic amyloidosis presenting as angina pectoris due to intramyocardial coronary artery involvement: a case report

We describe a 76-year-old Japanese woman with primary systemic amyloidosis who presented with angina pectoris associated with ST-segment and T-wave abnormalities resulting from intramyocardial coronary artery amyloidosis. The patient was admitted to our hospital because of dyspnea and pretibial edema 7 years after the diagnosis of variant angina. A diagnosis of primary systemic amyloidosis (AL amyloid protein) was made after examination of gastric and endomyocardial biopsy specimens. The patient died of progressive, uncontrolled heart failure 3 months later. An autopsy study demonstrated only mild-to-moderate atherosclerosis in the epicardial coronary arteries. However, histological examination of the heart revealed diffuse stenoses and obstructions in the intramural coronary arteries by amyloid deposits. This patient had small-vessel coronary disease with ST-segment changes and angina caused by cardiac amyloidosis. A correct diagnosis of ischemic heart disease due to primary amyloidosis is important for estimation of the prognosis and for appropriate management. Received: November 5, 2001 / Accepted: February 5, 2002     

Gastrointestinal amyloidosis: A focused review

Amyloidosis, a heterogenous group of disorders, is characterized by the extracellular deposition of autologous, insoluble, fibrillar misfolded proteins. These extracellular proteins deposit in tissues aggregated in ß-pleated sheets arranged in an antiparallel fashion and cause distortion to the tissue architecture and function. In the current literature, about 60 heterogeneous amyloidogenic proteins have been identified, out of which 27 have been associated with human disease. Classified as a rare disease, amyloidosis is known to have a wide range of possible etiologies and clinical manifestations. The exact incidence and prevalence of the disease is currently unknown. In both systemic and localized amyloidosis, there is infiltration of the abnormal proteins in the layers of the gastrointestinal (GI) tract or the liver parenchyma. The gold standard test for establishing a diagnosis is tissue biopsy followed by Congo Red staining and apple-green birefringence of the Congo Red-stained deposits under polarized light. However, not all patients may have a positive tissue confirmation of the disease. In these cases additional workup and referral to a gastroenterologist may be warranted. Along with symptomatic management, the treatment for GI amyloidosis consists of observation or localized surgical excision in patients with localized disease, and treatment of the underlying pathology in cases of systemic amyloidosis. In this review of the literature, we describe the subtypes of amyloidosis, with a primary focus on the epidemiology, pathogenesis, clinical features, diagnosis and treatment strategies available for GI amyloidosis.     

淀粉样变性71例临床分析

目的 提高临床对淀粉祥变性(AD)的认识。方法 回顾性分析了1982年2月至2002年2月经组织活检和临床证实符合AD诊断的患者71例。结果 系统性AD57例,57例中原发性AD33例,继发性AD22例,家族性AD多神经病2例l局限性ADl4例。82％的系统性AD表现为心脏彩超异常,腹壁脂肪及齿龈活检刚果红染色阳性率分别为80．0％和87．5％。系统性AD多用马法兰和泼尼松(MP)或MP 秋水仙碱治疗,局限性患者采用观察或局部手术切除。15例系统性AD住院期间死亡,其中5例死于心力衰竭。结论 系统性AD累及多系统器官,临床表现多样,预后较差,而局限性预后较好。因此区分AD为系统性抑或局限性非常重要。齿龈或腹壁脂肪活检是安全而有效的活检部位,心脏彩超对诊断也很有帮助。     

Hepatic amyloidosis with light chain deposition disease. A rare association

Monoclonal immunoglobulin deposition diseases are due to pathological protein deposition in various tissues and organs. Protein deposits may be found in a single tissue or systemically and the organs most frequently involved are kidney, heart, peripheral nerves and the liver. Depending on the pattern of the deposits and the type of immunoglobulin, these diseases are distinguished as primary amyloidosis, light chain deposition disease. Differential diagnosis is made in tissue specimens: microscopically by the identification of positive Congo red staining of the deposits, by immunohistochemical demonstration of proteins reacting with light chain (λ or k) antisera or by recognition of fibrillar structures on electron microscopy. We report an unusual case of light chain deposition disease associated with amyloidosis, where hepatomegaly was the presenting manifestation and liver failure the cause of death, without any kidney involvement.     

Primary cardiac amyloidosis with pathologic hip fracture secondary to bone amyloid

A rare combination of primary cardiac amyloidosis and bone amyloidosis is described in a 39-year-old female. The presenting features were restrictive heart disease and a destructive bone lesion. The diagnosis was confirmed with the help of endomyocardial and bone biopsy.