Cardiac amyloidosis: A survey of current awareness, diagnostic modalities, treatment practices, and clinical challenges among cardiologists in selected Middle Eastern countries

Abstract Background Cardiac amyloidosis (CA) is a chronic progressive disease caused by the deposition of amyloid fibrils in cardiac tissues. Diagnosis and management of CA are complicated and have developed over the years. Hypothesis Middle Eastern countries have significant knowledge disparities in diagnosing, managing, and treating different subtypes of CA. Methods An online survey was sent to cardiologists in four countries (Saudi Arabia, Lebanon, Egypt, and Iraq) interested in heart failure and practicing for more than a year. The survey questioned the characteristics of the participants and their institutions. It addressed their knowledge and practices in CA specifically diagnostic modalities, treatment options, and interest in education and knowledge exchange. Results A total of 85 physicians participated in the survey. There was a variation in the participating cardiologists' knowledge, experience level, and readiness of their institutes to manage patients with ATTR‐CM. Most participants believed that a high rate of ATTR‐CM misdiagnosis existed. Participants' knowledge of the diagnostic modalities and “red flags” raising suspicion about ATTR‐CM varied. Another challenge was the availability of essential diagnostic modalities among various cardiology centers. A knowledge gap was also observed regarding updates in ATTR‐CM management. However, there was a high endorsement of the need for more education, physician networking, and knowledge exchange. Conclusions This survey highlighted the need for increasing awareness levels among cardiologists in the four selected Middle Eastern countries. Cardiologists are most likely to benefit from additional training and knowledge exchange on the latest management advances of this disease. Thus, measures must be taken to focus on the physician's awareness of ATTR‐CM patient journey to achieve a better quality of care and outcome.


| INTRODUCTION
Cardiac amyloidosis (CA) is a progressive disease affecting the normal cardiac structure and function. 1 CA could be associated with organ involvement, including the kidneys, lungs, nervous systems, and bones. 2 As the disease progresses, more amyloid fibrils (AF) deposit leading to increased stiffness, diastolic dysfunction, and congestive heart failure (HF). 3 Cardiac involvement (CI) has a major impact on outcomes in amyloidosis patients. CA diagnosis remains challenging, and early diagnosis is critical for patient management. The most common subtypes are light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). 4 The prevalence of CA rates is not well known, and the current numbers underreport the actual statistics rendering the disease undiagnosed for years despite the recent advances in noninvasive testing modalities. [5][6][7] Cardiologists may lack specialization and expertise in diagnosing and managing ATTR, due to the low frequency of the disease and long time taken to make the diagnosis. A recent study have shown many patients spent 4 years before reaching a proper diagnosis. 8,9 Additionally, ATTR misdiagnosis is common because it may mimic many other cardiomyopathies and the misdiagnosis occurs in around 34%−57% of patients. 10 These factors are detrimental and lead to late diagnosis at advanced stage and thus worse disease outcomes. 11 Minimal data originated from Arab countries, Therefore, this study aims to investigate the cardiologists' awareness and knowledge in selected countries (Lebanon, Saudi Arabia [KSA], Egypt, and Iraq) about CA, and to gather insights on the diagnostic modalities, treatment options, willingness for education, and physicians' international collaborations for managing patients with cardiomyopathies associated with amyloid transthyretin.

| METHODS
A cross-sectional non-interventional study is conducted among 85 cardiologists in the selected countries. A Figure 1A).
The mean number of HF patients with reduced or preserved ejection fraction (EF) diagnosed by participating cardiologists in a month was 26, where 45% of HF patients (mean = 11.7) had HF with preserved EF. Overall, the mean number of CA patients over the last 3 years was 7.8 for transthyretin amyloid cardiomyopathy (ATTR-CM), 7.8 for AL-CM, and 6.3 for AA-CM.

| Beliefs and knowledge of CA
The participants were asked about their CA knowledge. Around 22% believed that the heart was affected in 100% of systemic amyloidosis cases, and 33% believed it affects the heart in 60%−75% and 30%−40% of the cases, respectively. Surprisingly, 12% believed that CA is rare in systemic amyloidosis. Regarding the perceived prevalence of each type of amyloidosis, 24% believed that the hereditary mutant TTR amyloidosis (ATTRm) prevalence is the same worldwide, and 13% believed that the wild-type TTR amyloidosis (ATTRwt) prevalence is not well known, 24% believed that neither prevalence statements accurately represented the ATTR-CM prevalence, and 40% believed both statements were accurate. Participants also believed that the main CA causes were as follows: Amyloid fibrils deposit due to mutant or wildtype transthyretin (51%), amyloid fibrils deposit due to abnormal monoclonal light-chains immunoglobulins (35%), there are 12 mutations worldwide for the ATTRm type CA (8%), and there are no other proteins precursors that could give amyloid fibrils (2%).
As per the physicians' beliefs about symptoms raising CA suspicion, physicians consider amyloidosis in case of HF symptoms with poor response or intolerance to standard therapy (78%), in concentric left ventricle hypertrophy (71%), in mildly reduced EF (69%), and in moderately or severely reduced EF (53%) ( Figure 1B).

Practices in diagnosis and treatment
Regarding the perceived CA misdiagnosis rate, 24% believed that over 75% of patients were misdiagnosed, 33% believed that many patients are misdiagnosed (51%−75%), and 29% believed that a moderate number of patients (26%−50%) were misdiagnosed. Only 14% believed that below 25% of patients were misdiagnosed (Table 3a).
T A B L E 1 Description of the participants' subspecialties and self-reported knowledge of cardiac amyloidosis (CA), experience with HF, and CA across the four countries.  Perception of misdiagnosis of cardiac amyloidosis  13 The study has highlighted CA awareness and mastery among physicians in the selected countries.
In general, participants have encountered few CA cases.
Electronic medical records treatment in cardiology centers in the region could be an encouraging research potential. 14 a common ECG finding, especially in ATTR-CM and studies have recently focused more on relative low voltage as it is more frequent in ATTR-CM compared to absolute low ECG voltage. 19,20 Although participants had a fair knowledge of CA symptoms and signs, there is room for more ATTR-CM red flags awareness.
Hypertrophic cardiomyopathy is a common misdiagnosis that needs to be ruled out by signs such as asymmetrically increased septal wall thickness and other diagnostic findings using bone scintigraphy, cardiac MRI, and genetic testing. 17,21 The perceptions of participants widely varied the CA misdiagnosis rate; however, more than half of participants believed there was a high misdiagnosis rate. This could be due to low disease suspicion index, fragmented information about the disease, clinical presentation of CA that could be variable from 1 patient to another, and lack of experience in CA. A previous study observed that the diagnosis of 42% of ATTRwt was delayed for more than 4 years. 8 An Egyptian study discovered that 1 out of 11 patients with undiagnosed cardiomyopathy had CA when undergoing cardiac biopsy. 22 Hence, early and accurate CA diagnosis is critical.
Accordingly, noninvasive diagnostic modalities should be recommended in cardiomyopathy and HF of unknown origin.
Surprisingly, a considerable number of participants were unaware of the role of heart bone scintigraphy in diagnosing CA.
This awareness level was similar to the Swiss survey results (44%). 13 According to ESC recommendations, the heart bone-scintigraphy was proven highly specific and sensitive for ATTR-CM as a noninvasive technique and is considered an essential confirmatory ATTR-CA test in AL absence in patients with clinical, echocardiographic, and electrocardiographic CA "red flags." 18,23 The low awareness level of this diagnostic tool explains the low diagnosis ATTR-CM rate. National and regional efforts should be exerted to make this modality widely known and available in cardiology centers and raise awareness about it. Additionally, nuclear medicine specialists should be trained on the correct protocol to use it and how to interpret the results to avoid false diagnoses.
Conversely, echocardiography and cardiac biopsy were among the highest "go-to" diagnostic modalities. Also, cardiac and tissue biopsies were believed to confirm ATTR-CM and light-chain amyloidosis, respectively. However, a cardiac biopsy is not common in our region and is considered an invasive intervention with a significant risk of bleeding, arrhythmia, and perforation. Although cardiac biopsy may have the gold standard for diagnosing ATTR-CM, previous evidence demonstrated that grade 2−3 uptake on bone scintigraphy of the heart has a 100% positive predictive value for ATTR-CM after AL exclusion using monoclonal-protein biomarkers. 24 The latest ESC guidelines highlighted the importance of serum and urine protein electrophoresis in detecting monoclonal proteins; this will support ATTR-CM screening in family members in case of identified mutant type. 18 NT-ProBNP and troponin were among the lowest biological tests cited in our survey to rule out CI, suggesting a lack of deep CA knowledge. Previous studies supported that these two biomarkers could be elevated with cardiac impairment in both AL and ATTR. 25 Most participants believed that genetic testing should be individualized among ATTR-CM patients. However, the ESC guidelines specifically recommended assessing ATTR mutation status in patients with grade 2/3 cardiac uptake on scintigraphy and negative monoclonal proteins. 18 Accordingly, genetic testing is essential in all ATTR-CM patients, irrespective of age. Also, screening family members in case of hereditary type is recommended, which will support an early diagnosis of the disease once symptoms appear.
In addition, this diagnostic modality is limited to main cardiology centers in the selected countries.

| CONCLUSION
Surveying cardiologists in four selected Middle Eastern countries has highlighted significant knowledge disparities in the diagnosis, management, and treatment of ATTR-CM. Physicians from these countries will likely benefit from additional training and exposure to the latest advances in managing this disease. These measures would be beneficial to ensure better patient care and lower rates of late referrals or misdiagnosis.

AUTHOR CONTRIBUTIONS
All authors contributed to the conception and design, literature search, data collection, analysis and interpretation of results, manuscript preparation, manuscript editing, and manuscript review.
This manuscript has been read and approved by all the authors.

ACKNOWLEDGMENTS
We'd like to thank CTI MEA for their support in medical writing and editing support. This study was sponsored by Pfizer.

CONFLICTS OF INTEREST STATEMENT
I. A. and M. G. are Pfizer employees and were involved in study conception and manuscript approval. The remaining authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
Data are available upon request. The data generated and analyzed in this study is available with the corresponding author upon request.