How to Identify Transthyretin Cardiac Amyloidosis at an Early Stage

Cardiac involvement of systemic amyloidosis is preferentially observed in patients with amyloid light chain amyloidosis or transthyretin amyloidosis (ATTR). Owing to the development of diagnostic modalities and changes in recognition by physicians, transthyretin cardiac amyloidosis (ATTR-CA) is now understood to be a more common cause of heart failure than previously thought. Recent progress in disease-modifying therapeutic interventions, such as transthyretin stabilizers, has resulted in ATTR-CA changing from an incurable disease to a curable disease. These interventions are particularly effective in patients with mild symptoms of heart failure, thus indicating that early detection and a precise diagnosis are important for improving the prognosis. In this review article, we summarize the recent reports of early screening of ATTR-CA and describe some important points regarding the making of a precise diagnosis, especially focusing on histological evaluations.     

Cardiac Amyloidosis Treatment

Cardiac amyloidosis (CA) is a restrictive cardiomyopathy with a traditionally poor prognosis. Until recently, CA treatment options were limited and consisted predominantly of managing symptoms and disease-related complications. However, the last decade has seen significant advances in disease-modifying therapies, increased awareness of CA, and improved diagnostic methods resulting in earlier diagnoses. In this review, we provide an overview of current and experimental treatments for the predominant types of CA: transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain (AL)-mediated CA (AL-CA).The mainstay of AL-CA treatment is proteasome inhibitor-based chemotherapy with daratumumab and, when feasible, autologous stem cell transplantation. For ATTR-CA, the stabilizer tafamidis is the only US Food and Drug Administration (FDA)-approved treatment. However, promising novel therapies on the horizon target various points in the ATTR-CA amyloidogenic cascade. These include transthyretin gene (TTR) silencing agents to prevent TTR formation, TTR tetramer stabilization and inhibition of oligomer aggregation to prevent fibril formation, anti-TTR fiber antibodies, and amyloid degradation. For end-stage CA, advanced interventions may need to be considered, including heart, heart-kidney, and, for hereditary ATTR-CA, heart-liver transplantation. Despite the evolution of treatment options, CA management remains complex due to patient frailty and therapeutic side effects or intolerance with advanced cardiac disease. This is particularly relevant for those with AL-CA, when active teamwork between the hematologist-oncologist and the cardiologist is critical for treatment success. Often, referral to an expert center is necessary for timely diagnosis, initiation of treatment, and participation in clinical trials.     

心肌淀粉样变性患者的临床特征及预后分析

目的:分析心肌淀粉样变性患者的临床特征并分析影响患者生存率的因素.方法:针对重庆市部分医院经病理检查确诊的34例心肌淀粉样变性患者进行临床特征统计分析.应用多因素Logistic回归分析寻找可能影响患者生存的因素.结果:34例确诊患者中,从出现症状到明确诊断的时间为(15.2±2.9)个月(1～72个月).初诊时,有1...     

An Unusual Case of Cardiac Amyloidosis

Cardiac amyloidosis can result from any of the systemic amyloidoses. The disease is often characterized by a restrictive cardiomyopathy although the particular signs and symptoms depend in part on the underlying cause. In addition to managing the symptoms of heart failure, treatment options vary depending on the etiology of amyloid deposition. It is therefore critical to identify the cause of cardiac amyloidosis before initiating definitive therapy. We present a patient with presumed immunoglobulin (AL) amyloidosis who had a circulating lambda monoclonal protein, but a bone marrow biopsy with kappa predominant plasma cells. This unusual finding called into question the diagnosis of AL amyloidosis and highlights the importance and difficulty of determining the cause of cardiac amyloid deposition before initiating treatment. We review the different forms of cardiac amyloidosis and propose a diagnostic algorithm to help identify the etiology of cardiac amyloid deposition before beginning therapy.     

以体循环淤血为主要表现的淀粉样变性心肌病临床特点分析

目的分析探讨淀粉样变性心肌病的临床特点。方法对7例淀粉样变性心肌病患者行超声心动图、X线胸片、电子计算机断层摄影术(CT)及常规血生化检查,分析归纳其临床特点、超声表现及辅助检查结果。结果7例患者,2例猝死,其中1例患者曾用免疫抑制剂及激素治疗,一度好转,后猝死。结论对55岁以上男性患者,出现体循环淤血的限制型心肌病表现时,超声心动图表现为左心室对称性或非对称性心肌肥厚伴收缩功能障碍,而心电图呈低电压,应高度怀疑淀粉样变性心肌病。     

Opportunities for Earlier Diagnosis and Treatment of Cardiac Amyloidosis

Despite the rapid expansion of noninvasive (nonbiopsy) diagnosis, contemporary patients with cardiac amyloidosis too often present with advanced features of disease, such as diminished quality of life, elevated natriuretic peptides, and advanced heart failure. Therapeutics for transthyretin cardiomyopathy (ATTR-CM) are most effective when administered before significant symptoms of cardiac dysfunction manifest, making early identification of affected individuals of paramount importance. Community engagement and ensuring that a broad range of clinicians have working knowledge of how to screen for ATTR-CM in everyday practice will be an important step in moving disease identification further upstream. However, reliance on the appropriate and timely diagnosis by individual clinicians may continue to underperform. This review highlights how targeted screening of special populations may facilitate earlier diagnosis. Systems of care that operationalize screening of high-risk subpopulations and prospective validation of novel approaches to ATTR-CM identification are needed.     

Utility of Combined Indexes of Electrocardiography and Echocardiography in the Diagnosis of Biopsy Proven Primary Cardiac Amyloidosis

Objective: Primary cardiac amyloidosis (CA) is associated with poor prognosis. However, the noninvasive diagnostic tools are limited. The aim of the study is to assess the utility of combined indexes of electrocardiography (ECG) and echocardiography (ECHO) in the diagnosis of primary CA. Methods: A total of 20 consecutive patients (7 men, mean age 50 ± 12 years) referred for endomyocardial biopsy (EMB) were included. Eleven of these patients (55%) confirmed primary CA, the rest of 9 patients were EMB negative and used for the control. Results: The voltage of S_V1+ R_V6 < 1.2 mV has a sensitivity of 91% and specificity of 89% for the identification of primary CA, yields the positive and negative predictive values of 91% and 89%, respectively. Among ECHO parameters, there were no significant differences between the 2 groups, except for left ventricular ejection fraction (47 ± 12% in primary CA vs 67 ± 11% in the control, P < 0.001). However, the combined indexes of ECG and ECHO parameters, including the ratio of R_I/LVPW as well as R_V5/LVPW and R_V6/LVPW, were significantly lower in the patients with primary CA than the control. The ratio of R_I/LVPW < 0.4 has the sensitivity of 91% and specificity of 100%, yields the positive and negative predictive values of 100% and 91%, respectively. The ratios of R_V5(6)/LVPW < 0.7 have the sensitivity of 91% and specificity of 89%, yield the positive and negative predictive values of 91% and 89%, respectively. Conclusion: Patients with clinically suspected primary CA, combined indexes of ECGs and ECHOs could be used as the noninvasive diagnostic tools. Ann Noninvasive Electrocardiol 2011;16(1):25–29     

Heart Transplantation and End-Stage Cardiac Amyloidosis: A Review and Approach to Evaluation and Management

Cardiac amyloidosis is one of the most common of the infiltrative cardiomyopathies and is associated with a poor prognosis. The extent of cardiac involvement with amyloid deposition is an important determinant of treatment options and is the major determinant of outcome in patients with amyloidosis. Several small case series with sequential orthotopic heart transplantation and autologous stem cell transplant have demonstrated an improvement in post-transplant outcome and have revived enthusiasm about heart transplantation for patients with end-stage heart failure due to AL amyloidosis. The purpose of this review is to summarize the evaluation and management of cardiac amyloidosis and to provide our single-center experience with end-stage heart failure due to AL amyloidosis treated with heart transplantation followed by an autologous stem cell transplant.     

Direct Current Cardioversion of Atrial Arrhythmias in Adults With Cardiac Amyloidosis

Background

Arrhythmias, conduction abnormalities, and intracardiac thrombus are common in patients with cardiac amyloidosis (CA). Outcomes of direct-current cardioversion (DCCV) for atrial arrhythmias in patients with CA are unknown.

Low Prevalence of Clinically Apparent Cardiac Amyloidosis Among Carriers of Transthyretin V122I Variant in a Large Electronic Medical Record

BackgroundTransthyretin (TTR) gene mutations are the most common cause of hereditary amyloidosis. Valine replaced by isoleucine in position 122 (V122I) variant is common, particularly in the black population. Carriers of V122I have increased risk for developing cardiac amyloidosis. Despite a relatively high prevalence, the penetrance of V122I is not firmly established. This study sought to determine the prevalence of clinically apparent cardiac amyloidosis among carriers of the TTR V122I variant.MethodsBioVU, a Vanderbilt University resource linking DNA samples and pre-existing genetic data to de-identified electronic medical records was used to identify TTR V122I mutation carriers. Automated billing code queries (International Classification of Diseases, 9th revision codes), problem list searches, and manual chart reviews were used to identify subjects with clinically diagnosed cardiac amyloidosis.ResultsAmong 28,429 subjects with available genotype data, 129 were V122I carriers. Carriers had a median age of 42 years (interquartile range 16-64). Noncarriers had a median age of 62 years, (interquartile range 41-77). The carrier rate was 3.7% in blacks and 0.02% in whites. Overall, the prevalence of clinically apparent cardiac amyloidosis was 0.8% in carriers and 0.04% in noncarriers (P = .05). Above age 60, the prevalence of cardiac amyloidosis was 2.6% in carriers and 0.06% in noncarriers (P = .03).ConclusionCarriers of the TTR V122I variant are at a higher risk for development of cardiac amyloidosis, particularly at age>60 years. However, clinically apparent cardiac amyloidosis in this population was uncommon. These results support that the penetrance of TTR V122I is age dependent and suggest it may be significantly lower than previously reported.