Cardiac amyloidosis (CA) is a rare condition in which the myocardial interstation is expanded by an amorphous, β-sheet structured fibrillar proteinaceous material known as amyloid, resulting in progressive injury of cardiomyocytes and eventually leading to arrhythmia and heart failure [1, 2]. Although more than ten kinds of amyloid proteins can involve the heart, light chain CA (AL-CA) and transthyretin CA (TTR-CA) are the most two common types in clinical practice [3]. TTR-CA is classified by the sequence of the TTR gene, either wild-type transthyretin amyloid CA (ATTRwt-CA) (no mutation) or mutant transthyretin amyloid CA (ATTRm-CA) (a mutation is present). CA often manifests as diffuse myocardial hypertrophy and heart failure with preserved ejection fraction (HFpEF). It should be emphasized that it has a very poor prognosis compared with other types of cardiomyopathy [4]. Especially for AL-CA, the natural course of untreated AL-CA is about 6 months [5]. Developed countries such as the United States, some European countries and Japan have published some high-quality articles on the clinical characteristics and epidemiological investigation of AL-CA, which is of great significance to promote the diagnosis and treatment of CA [6, 7]. Enormous advances have been made over the last decade, both in the diagnosis and treatment of AL-CA, along with a recognition that the condition is more common than previously believed.

However, in developing countries such as China, due to the complex clinical manifestations and limited diagnostic and therapeutic methods, most cardiologists do not know enough about AL-CA, and many patients with AL-CA are misdiagnosed and missed. At the time of definite diagnosis, most of the patients were already in the late stage of the disease and lost the opportunity of early treatment [8, 9]. These result in a worse prognosis for AL-CA patients in China compared with developed countries. Meanwhile, a large number of case reports on the clinical characteristics and real-world prognosis of AL-CA are very few in China. Therefore, to strengthen the understanding and improve the level of diagnosis and treatment of AL-CA has become an urgent task in the field of cardiovascular medicine in China [10].

The purpose of the present study was to describe the main clinical characteristics, diagnostic approach and prognosis of a large cohort of patients with AL-CA in China.

This 8-year retrospective cohort study, conducted in a large tertiary referral teaching hospital in southern China, describes the current situation and provides insights on diagnosis, treatment and survival of AL-CA in China. To our knowledge, this is the largest number of cases report to evaluate the characteristics and the prognosis of patients with AL-CA in southern China.

AL-CA is a hematologic disorder of plasma cells closely related to, and more commonly diagnosed by Chinese cardiovascular physicians compared with TTR-CA. Several decades ago, some reports from Europe [6] and USA [14] systematically revealed the clinical characteristics and prognosis data of this condition. Compared with previous reports from developed countries, the demographic characteristics for AL-CA patients seem to be similar. Dubrey et al. [14] reported a nationwide survey on AL-CA from USA (n = 232), and revealed the majority of patients with AL-CA were male (n = 142, 61%) with a mean (± SD) age at diagnosis of 60 ± 11 years. In our AL-CA cases group, mean ages were 60.81 ± 10.46 and 70.59% (120/170) were male. Previous studies [6, 15] showed that the major manifestation leading to diagnosis was HF (80%), which was confirmed in 72.3% of this study subjects. (Table 4) The department of cardiovascular medicine was not the only department to diagnose AL-CA patients in the present study, 24 patients (14.12%) of AL-CA patients were diagnosed in nephrology, and 20 patients (11.76%) were diagnosed in hematology (Fig. 1).

In terms of assistant examination methods, extracardiac tissue biopsy was the most common assistant diagnostic procedure, with bone marrow biopsy performed in 134 (78.9%) AL-CA patients and subcutaneous fat biopsy performed in 89(52.4%) AL-CA patients, and CMR only performed in 88 (51.7%) patients. Endomyocardial biopsy was performed in only 21 (12.3%) patients. Since extracardiac biopsies are often associated with a high proportion of false negatives, some current studies [16‐19] have found CMR to have a high sensitivity and specificity for diagnosing AL-CA patients or even superior to extracardiac biopsies, but many patients cannot afford it due to the high price. Histological confirmation of endocardial biopsy is the gold standard for the diagnosis of suspected CA [7]. However, only a small number of patients rely on this method for diagnosis. This is different from previous published studies from developed countries, where the proportion of diagnosis based on endocardial biopsy is generally more than 50%. In addition to the lack of skilled technicians and the high price, a large proportion of patients had poor cardiac function, could not lie flat, and could not tolerate CMR and endomyocardial biopsy.

In our study, the median survival time from diagnosis to death was 8 months in the AL-CA group. This is the same as 0.75 years (9 months) reported by Dubrey et al. [14] in the USA 20 years ago. Recently (published in 2019), Sidana et al. [20] reported a median survival of 16 months in patients with AL-CA in the current USA. The prognosis of AL-CA patients in China have a worse prognosis compared with those living in the USA or Europe. This may be attributed to the following reasons after comparing the previous studies. Firstly, when AL-CA was diagnosed, most of the patients were in severe condition. In our study, 76.5% (130/170) of the patients were NYHA III-IV. In the study of Quarta et al. [15], only 29% of the patients were NYHA III-IV. Secondly, the proportion of patients receiving chemotherapy is small. In the cohort of Sidana et al. [20], among 348 patients, 60 (17%) patients receiving autologous stem cell transplantation (ASCT), 83 (24%) patients receiving bortezomib, 144 (41%) patients receiving alkylator and/or immunomodulatory drugs and only 54 (16%) patients receiving palliative care. However, 106 (62.4%) patients in our study were receiving palliative care, and in chemotherapy group, only 39 (22.9%) patients receiving bortezomib. According to previous studies. [21, 22] and data from the present study, patients receiving chemotherapy live significantly longer. Besides, in the real world, most of the patients in the chemotherapy group in our study had a cardiac function grade of NYHA I-III, which may lead to a bias of the data. So, we did subgroup analysis and found that, in patients with NYHA I-III, receiving chemotherapy equally improved outcome significantly (15.00 vs 10.00, p = 0.031) (Fig. 2b). This illustrates that the proportion of chemotherapy received is also an important reason affecting the prognosis of AL-CA patients. There is also a phenomenon to point out that some patients who choose palliative treatment use thalidomide or lenalidomide monotherapy in our study. Whether these people actually benefit from it is not clear.

In this study, we also reveal some urgent clinical problems in the diagnosis and treatment of AL-CA in China. First of all, the misdiagnosis and missed diagnosis rate of AL-CA was high, 56 (32.9%) patients with AL-CA were misdiagnosed in the past. This shows that cardiovascular physicians in primary hospitals in China have insufficient knowledge of this kind of disease. According to previous studies [23, 24] in European and American countries, approximately 10% of patients with AL-CA will have evidence of overt multiple myeloma(MM), and a similar proportion of MM patients will have AL-CA. However, 58 (34.12%) were multiple myeloma in our study, a proportion much higher than that in the countries mentioned above. We therefore speculate that there are a significant number of patients with MM in whom cardiac involvement has been overlooked. Of course, we also cannot rule out an ethnic distinction in AL-CA, therefore, it is necessary to strengthen the understanding and diagnosis of AL-CA in China and more studies are needed to report the clinical features of AL-CA in Chinese, especially the clinical features and natural history. Secondly, the prevalence of non-invasive diagnosis of CA is low. In recent years, some studies [18, 19] have revealed that CMR has strong specificity in the diagnosis of AL-CA. These are powerful noninvasive diagnostic methods to assist in the diagnosis of AL-CA and can make up for the false negative situation of tissue biopsy. However, the utilization rate of CMR in China is at a low level. Thirdly, AL-CA patients did not receive timely chemotherapy, most physicians abandoned to prescribe chemotherapy based on uncertainty about the clinical diagnosis and many patients needed to be diagnosed with MM before they could be administered chemotherapy, which resulted in patients losing the opportunity for early treatment in the early course of their disease. Of course, increasing the rate of treatment also requires to improve clinical diagnostic accuracy, which may need to benefit from clinically experienced physicians and noninvasive diagnostic methods such as CMR.

Although our study tries to truly reflect the diagnosis and treatment status of AL-CA in China, it is just a single center retrospective cohort study. In this study, only a small number of AL-CA patients were confirmed by endocardial biopsy, and most of them were confirmed by non-myocardial biopsy histological confirmation and CMR. For follow-up, about 30% of our data were censored. We took all-cause death as the end point of the study and did not exclude non cardiovascular death.

Clinical characteristics, diagnosis and prognosis of AL-CA patients in southern China were examined. Although clinicians have improved their understanding of Al-CA in recent years, the prognosis of Al-CA is still poor, and the misdiagnosis rate and missed diagnosis rate are still very high in China. It is imperative to improve the recognition and early diagnosis of this condition, which may require multidisciplinary collaboration among cardiologists, hematologists and nephrologists.