This bibliometric analysis study analyzed the development of CA and echocardiography related research in the past 23years. Articles on CA and echocardiography showed a growing trend over the past decades, particularly since 2014. A similar trend was observed in a previous bibliometric study on CA alone, which found that the publication number has also grown substantially since 201214. The potential reason for the expansion of research might be due to the increasing recognition of the role of echocardiography in the development of CA and, therefore, increased research funding in this field. As of 2023, the year has seen 78 publications up to November 3rd, a number that does not signify a decline in research but rather corresponds to the cutoff date for data collection. Despite the data collection not covering the entire year of 2023, we can still infer that the research on echocardiography in the context of CA has reached a relatively mature phase, with a well-established body of knowledge and a slower rate of new discoveries.
With 633 publications and have established academic cooperation networks, the USA dominates the core of the field. Economic status has a significant influence on academic capability. As evidenced by its many outstanding scientific research institutions, influential researchers, and large number of influential scientific achievements. In addition, government expenditures on healthcare may be an important indicator of medical research outputs16. The USA also plays a prominent role in this research collaborations, which is in line with its prominent contribution to this academic field. In light of this, it is imperative to enhance collaborations between other countries/territories.
An analysis of the characteristics of international peer-reviewed journals is useful for understanding current trends in the field. Publishers from the USA and United Kingdom dominate the top 10 active journals in CA and echocardiography. Amyloid-Journal of Protein Folding Disorders was the most productive journal in the CA and echocardiography research field, not surprisingly., since the journal is a specialized scientific journal dedicated to the study of protein misfolding and amyloidosis. This journal encompasses a wide range of topics concerning the structure, biochemistry, molecular biology, genetics, clinical research, diagnosis, and treatment of amyloid proteins. Despite China and Japan contributing significantly to CA and echocardiography research, no publishers are based in East Asia, the importance of developing influential international journals in Asia is evident from this.
Publications are carried by high-impact journals, and outstanding articles contribute to the improvement of their impact. Among the top 10 journals, we can find 4 journals with IF>10 and 6 journals with an H index>10. CA and echocardiography research has been a strong focus of JACC- Cardiovascular Imaging publications in the last two years. An analysis of citations could provide insight into publications' academic influence. Circulation, being one of the journals with the highest citation counts, demonstrates its formidable academic influence. This high citation frequency not only reflects the journal's standing in the scientific community, but also indicates the relevance and importance of its published research in advancing the field of cardiovascular medicine.
In bibliometric analysis, hotspots refer to a certain topic in a particular research area during a particular period of time. An analysis of citations could provide insight into publications' academic influence. By analyzing highly cited literature, bibliometric analysis can uncover a field's cutting-edge scientific dynamics and capture the current scientific output. Among the 10 most cited articles identified in this study, the key focus was the diagnostic challenges and the differentiation between its types, notably AL and ATTR, utilizing various methods such as echocardiography, nuclear scintigraphy, and cardiac MRI. They collectively highlight the importance of assessing cardiac function and identifying prognostic factors, underscoring the disease's clinical complexity and variability17-26. A burst detection analysis reveals the evolution of academic interest hotspots through the analysis of bursts. An article with a high citation burst is actively discussed or used during a particular timeframe. In the field of CA and echocardiography research, there has been a significant evolution from initial descriptive and suggestive diagnostic approaches to more precise and comprehensive assessment methods. Initially, the research primarily focused on characterizing the general clinical features and echocardiographic manifestations of CA, such as ventricular wall thickening, diastolic function and changes in ventricular cavity size22,27.Contemporary research delves deeper into the application of various echocardiographic parameters for diagnosing CA, including strain imaging and measurements of ventricular wall thickness20. Recent advancements include the development of multi-parametric scoring systems or diagnostic algorithms that integrate morphological, functional, and strain parameters to reflect the comprehensive impact of cardiac amyloid infiltration more accurately28. Additionally, current studies are exploring the synergistic use of echocardiography with other diagnostic techniques, such as (99m) Tc-PYP cardiac scintigraphy, to enhance sensitivity and specificity in diagnosis29. This progression in research signifies a shift towards earlier, more accurate diagnosis and treatment of CA, underlining the critical role of echocardiography in the evolving landscape of CA management.
The keywords of the publication are meticulously selected by the authors, reflecting the direction of their research, academic theme, structure of the publication, and its core thesis, thereby delineating the precision and depth of their scholarly work. Statistical analysis of keyword frequency, along with co-occurrence and cluster analyses, serve as indicators of the central themes and emerging trends in CA and echocardiography research in the new century. These methods are crucial for researchers seeking to understand the evolving landscape and hotspots within the field. As revealed through the overlay visualization of author keywords. Moreover, the emergence of the new drug tafamidis has provided more precise and effective treatment for CA. Recently, the publication of guidelines by ASE (American Society of Echocardiography) and ESE (European Society of Echocardiography) on CA has led to more standardized diagnostic and treatment approaches, indicating that the field of CA research has reached a significantly mature phase. Recent research indicated that CA with the deep-learning algorithm showed that the LVH detection model could identify the etiologies of LVH with the AUC, sensitivity, and specificity of 0.98, 94%, and 91.6%, respectively30.
Broad Spectrum Cardiovascular Pathologies
CA may be present in ≤15% of patients with AS31. It was found that 16% of the ATTRwt patients 32 and 9% of AL-CA patients33 also suffered from AS. In AS patients, CA increases the risk of heart failure, mortality, and treatment futility with aortic valve replacement17. Most patients with CA present with diastolic HF with preserved left ventricular ejection fraction (LVEF), but nearly one-third have reduced LVEF34. ATTR-CA associated with a severe AS phenotype of low-flow low-gradient with mildly reduced ejection fraction17. Deposition of amyloid substance in the walls of the atria often leads to common supraventricular arrhythmias and causes a separation between the electrical and mechanical activities of the atrioventricular region. This condition is linked to a higher risk of blood clots and worsening heart failure35 36. The occurrence of conduction disorders, resulting from the infiltration of amyloid in the conduction tissue, is frequently observed during the early stages of the disease37.
Conventional echocardiographic features of CA
In CA patients, amyloid deposits in the ventricles, vessels, and valves can cause thickening of the walls, left ventricle (LV) volume reduction, biatrial enlargement, and thickening of the valves 38,39. In addition, progressing from diastolic dysfunction to restrictive cardiomyopathy leads to pericardial effusion, pleural effusion, and vena cava dilation. LV hypertrophy (LVH) is CA patients’ most common echocardiographic feature. Nearly 5% of patients initially diagnosed with hypertrophic cardiomyopathies were ultimately diagnosed as ATTRm after gene detection40. A common complication of amyloid deposition is non-dilated ventricular hypertrophy, which leads to decreased ventricular volume. Biatrial enlargement is another characteristic lesion of CA, secondary to the impaired diastolic function and increased pressure in the left ventricle. An enlarged left atria (LA) may serve as an imaging marker of the early subclinical ATTR-CA changes due to diastolic cardiac dysfunction41. Enlargement of the left atrium (LA) in CA patients not only increases the risk of thrombosis, linked to factors like endocardial disturbances and diastolic dysfunction, but also elevates right atrium (RA) pressure, as evidenced by changes in the inferior vena cava42,43. Valve thickening in CA patients often overlaps with aortic stenosis (AS), with common factors leading to both conditions; approximately 15% of AS patients also have CA. Amyloid deposits in CA can accelerate valve leaflet hypertrophy and calcification, resulting in left ventricular hypertrophy and heart failure. In addition to the aortic valve, CA can also cause thickening of the mitral and tricuspid valves, leading to varying levels of regurgitation33,44. However, these ultrasound features are difficult to diagnose CA due to lack of specificity 45-47.
Speckle‑tracking echocardiography of CA: Global Longitudinal Strain (LS)
With the advancement of speckle tracking echocardiography, it has provided increasingly substantial evidence in the diagnosis and prognosis of CA playing a more significant role. Amyloids affecting multiple cardiac chambers can be assessed using GLS from the four-chamber view48. Recent study found that CA-LVH patients have lower four-chamber LS compared to the average, linking it to major adverse cardiovascular events. Additionally, LV GLS is more effective than traditional echocardiographic measures for detecting early changes in left heart function and predicting heart disease prognosis leading to LVH49. Apical sparing may be observed in CA patients, characterized by lower LV-GLS, lower LS in the basal and mid segments, and non-significantly lower LS in the apical segment50,51. Apical sparing suggests that amyloid might accumulate more at the heart's base. Even so, apical sparing has a high sensitivity (93%) and specificity (82%), but it is not specific to CA, as it can occur in patients with other infiltrative heart diseases as well, such as Fabry disease52, Danon disease53 and end-stage kidney diseases54. Patients with and without ATTR-CA need prospective assessments of their outcomes after transcatheter aortic valve replacement (TAVR). Speckle tracking imaging (STI) shows that GLS≥-14.81, FLC-diff, NT-proBNP, and age were independent predictors of survival in AL-CA with preserved LVEF50. Global area strain (GAS), along with GLS and global circumferential strain (GCS), is a key indicator of myocardial motion in CA, obtained from 3D speckle-tracking echocardiography. Some researchers found that GLS≤16.10% and GAS≤32.95% are markers of cardiac involvement in systemic amyloidosis, with GLS showing higher sensitivity and specificity55. Furthermore, GAS<−19%56and basal longitudinal strain (LS)≤13.07%57 are identified as prognostic factors in CA. Right ventricular (RV) involvement, often early in CA, is characterized by changes in RV longitudinal strain (RV-LS), indicated that distinctive RV strain patterns in AL-CA compared to ATTR-CA58.Differences are also noted in left atrium (LA) and right atrium (RA) involvement in CA. While impaired LA is associated with diminished pump and reservoir functions59, RA involvement leads to reduced pump, reservoir, and conduit functions, with RA functions correlated with prognosis60
Myocardial work
Myocardial work, which is based on myocardial strain, considers the effects of LV deformation and afterload during the assessment of LV pressure, providing references for evaluating cardiac function. This is standardized through the LV pressure-strain loop, which integrates myocardial strain and LV pressure measurements. This method more effectively reflects early LV systolic function changes in ejection fraction reserved for heart failure (HFpEF) patients than GLS. Previous study demonstrated that CA patients have a significantly lower LV myocardial work index (LVMWI) than the general population, which can improve with exercise61. However, the continuous decline in LV myocardial work efficiency (LVMWE) indicates poor myocardial energy utilization in CA patients. Recent study assessed cardiac load in CA and HFpEF patients using LVMWE, finding that global work efficiency (GWE) was lower in AL-CA than ATTR-CA patients, suggesting more severe myocardial dysfunction in AL-CA. They also found that a GWE<86.5% effectively differentiates between AL-CA and ATTR-CA, with a sensitivity of 80.0% and a specificity of 66.7% 62.
Models for multiparametric echocardiography
Based on conventional echocardiography parameters, CA with LVEF and mild LVH was detected with favorable sensitivity (89.7%) and specificity (91.7%) using LVEF/GLS63. Scoring systems like AL and IWT, based on multiple echocardiographic parameters, were established. These systems could effectively confirm or exclude CA diagnosis, with the scores correlating positively with myocardial amyloid protein content28. Additionally, the ATTR-CM scoring system was designed to screen high-risk ATTR-CA patients within the HFpEF group64. The AMYLI scoring system, utilizing relative wall thickness and E/e’, was also developed to assess suspected AL-CA and unexplained ventricular hypertrophy65.
In the realm of artificial intelligence (AI) in echocardiography, AI models have been shown to surpass human limitations in image analysis, identifying minute changes with high accuracy. AI was used for echocardiographic texture analysis to identify the etiologies of LVH66. Semi-automatic diagnostic network was created to comparing echocardiograms of different heart diseases, showing that AI-enhanced models significantly improved the detection of LVH etiologies with high sensitivity and specificity30
Disease typing and Treatment
CA treatment modalities are closely associated with amyloid's pathological nature. In AL therapy, anti-plasmapheresis (steroids, high-dose melphalan, proteasome inhibitors, and immunomodulators) is used as well as autologous stem cell transplantation. Current treatments for ATTR-CA target different stages of the TTR amyloid cascade: TTR production silencing, stabilization, and amyloid clearance. Liver transplantation, used for hereditary ATTR, replaces mutant TTR with wild type, but has limitations like organ scarcity and incomplete arrest of cardiac dysfunction. New approaches include RNA interference and antisense oligonucleotides to reduce TTR production, TTR stabilizers like diflunisal and tafamidis, and doxycycline combined with tauroursodeoxycholic acid to disrupt fibril formation9
Advanced Cardiac Imaging and Function Analysis
With advancements in imaging techniques, endomyocardial biopsy is no longer the sole method of diagnosing CA. Cardiac magnetic resonance imaging (CMRI), with tissue characterization, is a sensitive tool for detecting myocardial amyloid deposits. As the disease progresses, late gadolinium enhancement (LGE) shows a continuum of cardiac infiltration, from subendocardial LGE to increasing transmurality. The distribution of LGE was similar to that of interstitial amyloid deposition. Nuclear scintigraphy is a valuable tool for ongoing monitoring of disease progression and noninvasive diagnosis. AL can be distinguished from ATTR CA, and 99mTc-PYP cardiac imaging may be used to identify those with ATTR CA. The heart-to-contralateral ratio >1.5, indicating diffuse myocardial tracer retention, provided an accuracy of 97% and a specificity of 100%, with an area under the curve of 0.992 (P < 0.0001)⁶⁸.These advancements, integrated with traditional methods like echocardiography, enable a more comprehensive understanding of cardiac ailments, highlighting the synergy of multimodal imaging.
Our study has several limitations. First, the data were retrieved from WOSCC alone. However, some articles might have been missed in WOSCC, despite its reputation as one of the most reliable databases for bibliometric analysis. Secondly, most articles were published in English, which may lead to selection biases in terms of publishing languages.