Wild-type transthyretin cardiac amyloidosis (ATTRwt) is a cardiomyopathy causing myocardial hypoperfusion and impaired cardiac mitochondrial function. Trimetazidine is an antianginal agent used in patients with stable angina pectoris, which improves cardiac contractility and mitochondrial function. The aim of the study was to investigate the effect of trimetazidine on invasive haemodynamics and cardiac mitochondrial function in ATTRwt.

In a randomized, double-blind, placebo-controlled, crossover trial, 22 patients with ATTRwt received 4 weeks of trimetazidine and placebo in randomized order. After each treatment period followed examinations with endomyocardial biopsies taken for high-resolution respirometry and right heart catheterization at rest and during a cardiopulmonary exercise test. The primary endpoint was mean pulmonary artery wedge pressure (mPAWP) during peak exercise. The secondary endpoint was cardiac mitochondrial oxidative phosphorylation capacity. Exploratory endpoints were echocardiographic parameters, cardiac biomarker levels and quality of life.

Trimetazidine did not significantly reduce mPAWP during peak exercise (31 ± 12 vs. 31 ± 13 mmHg, P = 0.61) or improve the cardiac mitochondrial oxidative phosphorylation capacity (73.4 ± 7.7 vs. 75.3 ± 7.7 pmol O2/(mg*s), P = 0.81) compared with placebo, nor did treatment with trimetazidine improve ejection fraction (P = 0.93), global longitudinal strain (P = 0.23), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P = 0.92) or the patients' quality of life (P = 0.98).

In ATTRwt, treatment with trimetazidine did not improve mPAWP or cardiac mitochondrial oxidative phosphorylation capacity compared with placebo.

Amyloidosis, which is caused by misfolded proteins that form amyloid fibrils, is predominantly diagnosed in older adults. Although previously considered a rare disease, increased awareness and noninvasive diagnostic methods have resulted in a rise in diagnoses. As a multisystem disease that affects multiple organ systems (cardiac, gastrointestinal, renal, and neurological), there is significant overlap with both geriatric conditions and common conditions in heart failure. Frailty is recognized as a distinct biological syndrome of declines across multiple physiological systems, which prevents maintenance of homeostasis and limits the ability to respond to stressors. Frailty was initially characterized as physical frailty alone; however, it is increasingly recognized that it is multidimensional with components including nutrition, cognitive, psychological, and social. Frailty in cardiovascular disease has become an important risk factor, indicator for disease severity, and can help guide decisions around intervention. In certain patients, frailty may be reversible. Given the lack of consensus definitions, tools, and implementation of frailty in both clinical and research settings in the field of amyloidosis, we convened a group of experts from cardiology, geriatric cardiology, geriatrics, hematology, and allied health to form this state-of-the-art review. There are many points of intersectionality between amyloidosis, aging, and frailty which herald a need for multidisciplinary care. This review document aims to provide guidance in how to understand and address frailty in older patients with a specific focus on cardiac amyloidosis.

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by the deposition of insoluble amyloid fibrils in the myocardium, leading to abnormal cardiac function and heart failure. Diagnosis is often challenging due to its diverse symptoms and related comorbidities. Although endomyocardial biopsy is the gold standard for diagnosis, a complete diagnostic approach often includes non-invasive methods such as Cardiac Magnetic Resonance (CMR) and nuclear medicine techniques. Nuclear medicine bone-seeking agents are useful for diagnosing the transthyretin (ATTR) amyloidosis subtype. CMR is especially useful when echocardiography results are inconclusive or for differentiating cardiac amyloidosis from other conditions like hypertrophic cardiomyopathy. CMR provides a comprehensive evaluation of morphological and functional abnormalities, inversion time, late gadolinium enhancement, and can include advanced techniques such as T1 mapping and extracellular volume quantification for diagnostic and prognostic purposes. This review outlines how CMR and nuclear medicine are integral to the diagnostic process for cardiac amyloidosis, emphasizing their crucial roles and the synergy between various diagnostic techniques in assessing suspected cases. ESSENTIALS: REQUIRED SUMMARY STATEMENT: Nuclear medicine PYP scans and CMR play a pivotal role in the non-invasive diagnosis of cardiac amyloidosis, alongside other essential diagnostic modalities.

In cardiac amyloidosis (CA) cardiopulmonary exercise testing (CPET) is underexplored. This study evaluated exercise limitations in CA using CPET, focusing on the ventilation-to-carbon dioxide production (VE/VCO2) slope and peak oxygen uptake (VO2). Seventeen studies involving 1505 patients were analyzed and systematically reviewed according to PRISMA reporting guidelines. Subgroup analyses assessed differences by diagnosis (ATTR vs. AL), CPET modality, and age. The cohort included 12% with AL, 80% with ATTR (23% hereditary [ATTRv], 70% wild-type [ATTRwt], 7% unspecified), and 8% unidentified subtypes. VE/VCO2 slope was elevated across ATTR subgroups: 38.4 (95% CI: 36.9-40.0, I2 = 57%) in ATTRwt and 37.9 (95% CI: 35.1-40.7, I2 = 70%) in ATTRv. ATTR patients were older than AL patients by 9.0 years (95% CI: 0.4-17.6, I2 = 88%) and had a higher VE/VCO2 slope: 2.5 (95% CI: 0.2-4.8, I2 = 0%). CPET modality influenced peak VO2, which was lowest for treadmill exercise (13.7, 95% CI: 12.7-14.8, I2 = 0%, mL/min/kg) compared to upright cycle ergometry (14.7, 95% CI: 14.3-15.1, I2 = 33%) and semi-recumbent cycle ergometry (14.5, 95% CI: 14.1-14.9, I2 = 28%). A high VE/VCO2 slope characterizes both ATTRwt and ATTRv, while AL patients are younger with lower VE/VCO2 slope levels. Peak VO2 in ATTR patients may depend on exercise modality.

Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) could be common, but its diagnosis is often overlooked. If the imaging features of ATTR-CM can be identified using conventional computed tomography (CT), which is commonly employed in clinical practice, its diagnostic value would be great. This study aimed to assess the imaging features of the condition in conventional non-gated contrast-enhanced CT.

We retrospectively analyzed 43 consecutive patients diagnosed with wild-type ATTR-CM and performed a semi-quantitative evaluation of myocardial hypo-enhancement in the portal venous phase of conventional contrast-enhanced CT. A myocardial hypo-enhancement score (MHES) was calculated and compared between patients with ATTR-CM and 43 age-, sex-, height-, and weight-matched controls. Correlations between the score and clinical parameters such as the myocardial extracellular volume fraction (ECV) were also assessed.

The MHES was significantly higher in the ATTR-CM group than in the control group (p < 0.01). It was also significantly higher in the high-ECV ATTR-CM subgroup (> 55%) than in the low-ECV ATTR-CM (≤ 55%) subgroup and the control group. There was good agreement between myocardial hypo-enhancement and late enhancement (kappa = 0.43), with 90.4% of the hypo-enhanced segments showing late enhancement. The detection sensitivity of late enhancement segments was higher in gated coronary CT angiography than in non-gated portal venous phase CT (69.2% vs 87.1%, p < 0.01).

Wild-type ATTR-CM exhibited a tendency for myocardial hypo-enhancement, predominantly in the basal segments on conventional non-gated contrast-enhanced CT, suggesting an association with myocardial microcirculatory dysfunction.

Question Can myocardial hypo-enhancement in non-gated contrast-enhanced CT help diagnose wild-type ATTR-CM, particularly in settings where late iodine enhancement imaging is unavailable? Findings Hypo-enhancement, predominantly in basal segments, was higher in ATTR-CM patients and correlated with ECV and global longitudinal strain, suggesting microcirculatory dysfunction. Clinical relevance Identifying myocardial hypo-enhancement in basal segments on conventional non-gated contrast-enhanced CT may provide a valuable diagnostic clue for ATTR-CM, particularly in facilities lacking LIE imaging, allowing for earlier recognition and potential clinical intervention.

Cardiac organoids offer significant advantages for in vitro studies, as their 3D structure and cellular composition more closely replicate tissue complexity compared to 2D models. This is particularly relevant for studying complex diseases like heart failure (HF), which involve multiple cell types and cardiac structures. Thus, the primary aim of this study was to produce self-assembled, scaffold-free cardiac organoids from induced pluripotent stem cells (iPSCs), capable of simulating key aspects of HF in vitro. Gene expression analysis confirmed a transition from stemness markers (OCT4, NANOG) to cardiac markers (TNNT2, DES), validating their cardiac phenotype. To induce hallmark HF features, endothelin-1 (ET-1) treatment was applied. Key findings indicate that this experimental model successfully reproduced HF pathological markers, including the upregulation of genes encoding atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and the cytoskeletal protein α-skeletal actin (ACTA1), along with changes in microRNA (miR) expression profiles. Functionally, ET-1 treatment reduced organoid contractility, indicating a decline in contractile function-a hallmark of HF. Furthermore, histological analyses by Thioflavin T (ThT) staining, ThT fluorescence assay and filter trap assay on protein extracts demonstrated protein aggregation following ET-1 treatment. Co-administration of various nutraceuticals was shown to mitigate these effects. These findings underscore the value of this ET-1-stimulated cardiac organoid model as a powerful platform for studying HF mechanisms and evaluating novel therapeutic approaches.

Early cardiomyopathy diagnosis allows timely treatment and may help resolve problems that occur after cardiac implantable electronic device (CIED) implantation.

This study aims to describe a novel technique for endomyocardial biopsy (EMB) using a 3-dimensional (3D) delivery sheath during CIED implantation. In addition, we investigated 3D delivery-sheath characteristics using sheath deflection during bioptome insertion.

This study of 20 patients undergoing CIED implantation analyzed the EMB success rate and pathologic findings. Fluoroscopic images assessed 3D delivery sheath characteristics before and after bioptome insertion in 3 sheaths. CIEDs were implanted for sick sinus syndrome (n =3), atrioventricular conduction disorder (n = 16), and left ventricular dysfunction (n = 1). Fluoroscopic verification was performed using right anterior oblique (RAO) and left anterior oblique (LAO) views. EMB was performed with Selectra 3D (BIOTRONIK, Berlin, Germany), CSP Locator 3D (Abbott, Chicago, IL), and SSPC (Boston Scientific, Marlborough, MA) (12, 4, and 4 patients, respectively). The distance moved toward the right ventricular apex (RVA) in RAO was defined as Dis-RAO (mm) and that moved toward the RVA in LAO was defined as Dis-LAO (mm).

Among the 3 sheaths, only the CSP Locator 3D and Selectra 3D showed significant differences in Dis-RAO (13.2 ± 2.0 mm vs 19.8 ± 3.8 mm, P < .01) and Dis-LAO (8.1 ± 1.3 mm vs 15.3 ± 3.9 mm, P < .01). A total of 77 EMB samples from 20 patients were collected without any complication, and 4 patients (20%) were diagnosed with cardiac amyloidosis (CA) based on pathologic findings.

All 3D delivery sheaths were safe and effective for performing EMB from the RVS during CIED implantation, enabling early CA diagnosis in 20% of patients.

Hereditary transthyretin (TTR) amyloidosis (ATTRv amyloidosis) is a devastating disease characterized by broad range of clinical manifestations, including predominantly neurological, predominantly cardiac, and mixed phenotypes. This wide phenotypic variability hindered timely disease diagnosis and risk stratification in the past, especially in individuals with absent or uncharted family history. However, recent advances in noninvasive testing have led to greater awareness and earlier diagnosis. Further, medications have been discovered which proved effective in controlling the disease and improving outcomes including stabilizing TTR, silencing TTR variants, and removing TTR amyloid from affected tissues. Importantly, CRISPR gene editing, a groundbreaking technology, offers the unique potential to cure ATTRv amyloidosis, transforming lives and opening new doors in medical science. This review provides an update on ATTRv amyloidosis mechanisms, diagnosis, and management emphasizing the importance of early diagnosis as the steadfast underpinning for the capitalization of the advances in medical treatment to the benefit of the patients.

Powerful single-molecule approaches have been developed for the accurate measurement of protein oligomers, but they are often low throughput and limited to the measurement of specific systems. To overcome this problem, nanopore-based detection holds the promise of providing the high throughput, broad applicability, and accuracy necessary to characterize protein oligomers in a variety of contexts. Nanopores provide accuracy comparable with that of state-of-the-art single-molecule detection methods, but with the added potential for fast and accurate measurements that may be amenable to industrial-scale manufacture. Key to enabling this expansion is combination with other emerging technologies such as DNA nanostructure tagging, machine learning-enabled signal analysis, and innovative detection device manufacture. Together, these technologies could enable widespread adoption of nanopore-based sensing in oligomer detection, revolutionizing diagnostics and biomarker detection in protein misfolding diseases.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is a progressive and infiltrative cardiac disorder that may cause fatal consequences if left untreated. The estimated survival time from diagnosis is approximately 3-6 years. Because of the non-specificity of initial symptom manifestation and insufficient awareness among treating physicians, approximately one-third of patients with ATTRwt-CM are initially misdiagnosed with other cardiac diseases. Although heart failure (HF) is the most common initial manifestation of ATTRwt-CM, observed in nearly 70% of affected patients, patients may also present with other cardiologic symptoms, such as atrial fibrillation (AF) and aortic stenosis (AS). This non-specific and diverse nature of the initial ATTRwt-CM presentation indicates that various cardiology subspecialties are involved in patient diagnosis and management. Standard guideline-directed pharmacological treatment for HF is not recommended for patients with ATTRwt-CM because of its limited effectiveness. However, no established algorithms are available regarding HF management in this patient population. This literature review provides an overview of the red flags for ATTRwt-CM and research findings regarding HF management in this patient population. In addition to commonly recognized red flags for ATTRwt-CM (e.g., HF, AF and severe AS), published literature identified potential red flags such as coronary microvascular dysfunction. For HF management in patients with ATTRwt-CM, the use of mineralocorticoid receptor antagonists (MRAs) was reported as a well-tolerated option associated with a low discontinuation rate and reduced mortality. Although there is no concrete evidence for recommendations against sodium-glucose cotransporter 2 inhibitor (SGLT2i) administration, research supporting its use is limited to small-scale studies. Robust evidence is lacking for AF ablation, implantable cardioverter-defibrillators and cardiac resynchronization therapy. Based on the published findings and our clinical experience as Japanese ATTRwt-CM experts, red-flag symptom clusters for each cardiology specialty (HF, arrhythmia and ischaemia/structural heart disease) and a treatment scheme for HF management are presented. As this research area remains at an exploratory stage, our observations would require further discussion among experts worldwide.

In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE.

Participants who previously received acoramidis through month 30 in ATTRibute-CM continued to receive it (continuous acoramidis), and those who received placebo through month 30 were switched to acoramidis (placebo to acoramidis). Participants who received concomitant tafamidis in ATTRibute-CM were required to discontinue it to be eligible to enroll in the OLE. Clinical efficacy outcomes analyzed through month 42 included time to event for all-cause mortality (ACM) or first cardiovascular-related hospitalization (CVH), ACM alone, first CVH alone, ACM or recurrent CVH, change from baseline in NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, serum transthyretin, and Kansas City Cardiomyopathy Questionnaire Overall Summary score. Safety outcomes were analyzed through month 42.

Overall, 438 of 632 participants in ATTRibute-CM completed treatment, and 389 enrolled in the ongoing OLE (263 continuous acoramidis and 126 placebo to acoramidis). The hazard ratio for ACM or first CVH was 0.57 (95% CI, 0.46-0.72) at month 42 based on a stratified Cox proportional hazards model (P<0.0001) favoring continuous acoramidis. Similar analyses were performed on ACM alone and first CVH alone, with hazard ratios of 0.64 (95% CI, 0.47-0.88) and 0.53 (95% CI, 0.41-0.69), respectively, at month 42. Treatment effects for NT-proBNP and 6-minute walk distance also favored continuous acoramidis. On initiation of open-label acoramidis in the placebo-to-acoramidis arm, there was a prompt increase in serum transthyretin. Quality of life assessed by Kansas City Cardiomyopathy Questionnaire Overall Summary score was well preserved in continuous-acoramidis participants compared with the placebo-to-acoramidis participants. No new clinically important safety issues were identified in this long-term evaluation.

Early initiation and continuous use of acoramidis in the ATTRibute-CM study through month 42 of the ongoing OLE study were associated with sustained clinical benefits in a contemporary transthyretin amyloid cardiomyopathy cohort, with no clinically important safety issues newly identified.

URL: https://www.clinicaltrials.gov; Unique identifier: NCT04988386.

Cardiac amyloidosis (CA) is an increasingly recognized cardiomyopathy with an associated risk of arrhythmias and conduction disorders; however, managing arrhythmias and conductive disorders remains largely undefined.

This study aims to gather French expert experience on current practices and treatment strategies for managing arrhythmias and conduction disorders in CA. The main areas of interest included atrial fibrillation (AF) management, anticoagulation therapy, and criteria for implanting cardiac rhythm devices.

A modified Delphi method was employed, involving a panel of 56 cardiologists and electrophysiologists specializing in CA. The panel evaluated 248 statements over 2 rounds. Consensus was defined as agreement from at least 66.7% of the panel, with strong consensus requiring more than 50% complete agreement.

Consensus was achieved on 177 out of 248 statements across 2 rounds (71%). Key agreements included 1) the necessity for regular Holter monitoring and anticoagulation therapy in high-risk scenarios; 2) a rhythm control management strategy, including the use of amiodarone and AF ablation, particularly in the early stages of the disease; and 3) the use of cardiac devices for advanced conduction disorders, with decisions influenced by disease staging and left ventricular ejection fraction.

Approximately 70% of the proposed statements achieved agreement among the experts, reflecting reasonable alignment on anticoagulation therapy, AF management, and implantable cardiac devices. However, the study also highlights the need for personalized, multidisciplinary management of arrhythmias and conduction disorders in CA and emphasizes the need for future research to develop evidence-based guidelines.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and frequently underdiagnosed cause of heart failure characterized by the pathological deposition of misfolded transthyretin (TTR) proteins in the cardiac tissue, leading to a poor prognosis and a significant reduction in quality of life. Despite its severity, therapeutic options remain limited, and knowledge gaps persist. This study aims to construct a knowledge map and identify research hotspots within the field of ATTR-CM. Methods: Data were extracted from the Web of Science Core Collection (WoSCC), covering the period from January 1, 2000 to June 1, 2024. Bibliometric analyses were supplemented by qualitative assessments. VOSviewer, CiteSpace, and Bibliometrix were used to visualize academic community clusters, collaboration and citation networks to identify trends and hotspots in ATTR-CM research. Results: A total of 1855 publications were analyzed. Contributions from multiple disciplines fueled a consistent upward trend in publications and citations. Europe and the United States dominated ATTR-CM research, with Mathew S. Maurer as the most prolific author, and the University of London as the leading research institution. The journals publishing these documents and references demonstrated credibility and broad disciplinary coverage. Reference analysis identified 10 main research fields. Keyword analysis unveiled five promising themes for research: early diagnosis and prognosis algorithm, specific medication development, management of comorbidities and complications, epidemiology and genotype-phenotype correlation, and molecular biology and mechanisms. Conclusion: This study is the first comprehensive bibliometric analysis of the ATTR-CM field, supplemented by qualitative assessments. It systematically examines development trends, academic networks, and research themes, while identifying research hotspots and proposing future directions and approaches. These findings provide valuable insights to deepen the understanding of ATTR-CM and may foster advancements in scientific research and clinical applications.

Background: ATTRv and ATTRwt cardiac amyloidosis (CA) are underrecognized causes of heart failure with preserved left ventricular ejection fraction. The diagnosis of CA remains challenging due to low diagnostic suspicion and clinical overlap with more common diseases. The aim of this study was to use [99mTc]-PYP SPECT-CT to perform a volumetric evaluation of bone scintigraphy to overcome the limitations of current practices. Methods: A monocentric prospective study was conducted to evaluate a lot of 22 patients with a mean age of 52.86 ± 13.80 years, diagnosed with hereditary cardiac transthyretin amyloidosis (ATTR). Results: Correlations between the quantitative SPECT-CT, clinical data, and morphological parameters were performed, demonstrating moderate to strong correlation of SUVmaxMyocardium/SUVmaxBone to both ECG low voltage and EchoGLS, SUVmaxMyocardium/SUVmaxLiver to myocardial gadolinium kinetics with T1 mapping MRI, diastolic disfunction, sensory-motor polyneuropathy, and EchoGLS, SUVmaxMyocardium/SUVmeanBone with diastolic disfunction and sensory-motor polyneuropathy, as well as SUVmaxMyocardium/SUVmaxSoft tissue to S II, respectively. Conclusions: The moderate to strong correlations among advanced quantitative SPECT-CT metrics and clinical and paraclinical data create the premises to use these parameters for early diagnosis of cardiac ATTR. Further multicentric studies in a larger patient population are needed to validate the newly identified quantitative SPECT-CT parameters.

Transthyretin amyloidosis (ATTR amyloidosis) is characterized by the buildup of amyloid protein in organs like the gut and the heart. As a result, hypoperfusion, edema, and dysautonomia cause an imbalance in the gut microbiome. We aimed to identify the gut microbiome composition in ATTR amyloidosis patients with and without heart involvement, as well in controls. Sixty participants were divided into three groups: 20 with ATTR amyloidosis and heart involvement (G1), 19 with ATTR amyloidosis but no heart disease (G2), and 21 controls (G3). The microbiome profiles were obtained through 16S rRNA gene sequencing. Additional evaluations included a clinical questionnaire, echocardiogram, six-minute walk tests, troponin, BNP, and genotype analysis. Compared to G3, G1, and G2 groups had different levels of Streptococcus, Lachnospiraceae, and Sellimonas, while the controls showed a higher relative abundance of Methanosphaera. Streptococcus was linked to higher troponin levels. Lachnospiraceae was associated with lower BNP levels and smaller left atrium volumes. Sellimonas was associated with a higher intestinal symptom score, while Methanosphaera with a lower symptom score. ATTR amyloidosis patients have a different intestinal microbiome profile compared to the control group. There were correlations with genotype, gastrointestinal symptoms, heart failure biomarkers, echocardiographic parameters, and the six-minute walk test.

A recent analysis compared the proteome of (i) blood clots seen in two diseases-sepsis and long COVID-when blood was known to have clotted into an amyloid microclot form (as judged by staining with the fluorogenic amyloid stain thioflavin T) with (ii) that of those non-amyloid clots considered to have formed normally. Such fibrinaloid microclots are also relatively resistant to fibrinolysis. The proteins that the amyloid microclots contained differed markedly both from the soluble proteome of typical plasma and that of normal clots, and also between the diseases studied (an acute syndrome in the form of sepsis in an ITU and a chronic disease represented by Long COVID). Many proteins in the amyloid microclots were low in concentration in plasma and were effectively accumulated into the fibres, whereas many other abundant plasma proteins were excluded. The proteins found in the microclots associated with the diseases also tended to be themselves amyloidogenic. We here ask effectively the inverse question. This is: can the clot proteome tell us whether the clots associated with a particular disease contained proteins that are observed uniquely (or are highly over-represented) in known amyloid clots relative to normal clots, and thus were in fact amyloid in nature? The answer is in the affirmative in a variety of major coagulopathies, viz., venous thromboembolism, pulmonary embolism, deep vein thrombosis, various cardiac issues, and ischaemic stroke. Galectin-3-binding protein and thrombospondin-1 seem to be especially widely associated with amyloid-type clots, and the latter has indeed been shown to be incorporated into growing fibrin fibres. These may consequently provide useful biomarkers with a mechanistic basis.

A case of a 67-year-old male with a history of hypertension, diabetes, and hyperlipidemia presented to the hospital because of chest discomfort, preceded by a gradual onset of diminished exercise tolerance, exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, and bilateral lower extremity swelling. An electrocardiogram showed no acute ischemic changes, though he had very mild troponin elevation. Cardiac catheterization showed nonobstructive coronary artery disease. A transthoracic echocardiogram revealed reduced left ventricular systolic function with elevated left ventricular filling pressure. Cardiac magnetic resonance imaging demonstrated abnormal contrast kinetics, consistent with cardiac amyloidosis. A technetium-99m pyrophosphate scan unveiled diffuse cardiac amyloidosis of the transthyretin type. Myocardial biopsy showed amyloid deposition by positive Congo red stain and confirmed by apple-green birefringence on polarized light. He was started on medical therapy for heart failure and coronary artery disease. He was eventually started on an oral transthyretin stabilizer that significantly improved his heart failure symptoms and exercise capacity, with no readmission to the hospital since then. He had been evaluated and deemed a candidate for cardiac transplantation.

Transthyretin cardiac amyloidosis (ATTR-CA) involves the buildup of transthyretin protein in the heart muscle in the form of amyloid fibrils, which can affect heart structure and function. Common ECG findings of ATTR-CA include low QRS voltage and a pseudo-myocardial infarction (MI) pattern, defined as pathological Q waves or QS complexes in two consecutive leads without a history of MI or echocardiographic evidence of akinetic areas. Here, we present a case of ATTR-CA in a very elderly patient, in whom pathological Q waves on ECG were true indicators of a prior inferior MI. A 96-year-old woman with a history of inferior MI presented to her primary care clinic with a one-week history of nocturnal dyspnea. She had undergone coronary stent placement in the distal right coronary artery five years earlier for inferior MI. An ECG revealed abnormal Q waves, ST elevation of 0.5 mm, and T wave inversion in limb leads III and aVF, with no significant findings suggestive of left ventricular (LV) hypertrophy. Over a two-year period, QRS voltage progressively decreased in all leads, while the ST-T changes remained unchanged. Transthoracic echocardiogram (TTE) showed LV concentric hypertrophy with an increased wall thickness of 14 mm, except in the infero-septal region. In basal and mid-short-axis views, infero-septal wall motion was severely reduced, with notable wall thinning in contrast to the global LV hypertrophy observed elsewhere - findings consistent with prior inferior MI. The patient was ultimately diagnosed with ATTR-CA based on technetium-99m-pyrophosphate scintigraphy and monoclonal protein detection tests. Clinicians should recognize that pathological Q waves in ATTR-CA do not always indicate a pseudo-MI pattern. When both ECG and TTE suggest an MI pattern, further evaluation for coronary artery disease is warranted as part of the ATTR-CA diagnostic workup. In patients with both ATTR-CA and prior MI, a comprehensive clinical approach addressing both conditions is essential for optimizing prognosis.

Quantification of cardiac [99mTc]-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) uptake enhances diagnostic capabilities and may facilitate prognostic stratification in patients with transthyretin cardiac amyloidosis (ATTR-CA). This study aimed to evaluate the association of quantitative left ventricular (LV) DPD uptake with myocardial structure and function, and their implications on outcome in ATTR-CA.

Consecutive ATTR-CA patients (n = 100) undergoing planar DPD scintigraphy with Perugini grade 2 or 3, alongside quantitative DPD single-photon emission computed tomography/computed tomography imaging and speckle-tracking echocardiography between 2019 and 2023, were included and divided into two cohorts based on median DPD retention index (low DPD uptake: ≤5.4, n = 50; high DPD uptake: >5.4, n = 50). The DPD retention index showed significant, albeit weak to modest, correlations with LV global longitudinal strain (LV-GLS: r = 0.366, P < 0.001), right ventricular free wall longitudinal strain (RV-FW-LS: r = 0.316, P = 0.002), LV diastolic function (E/e' average: r = 0.304, P = 0.013), NT-proBNP (r = 0.332, P < 0.001), troponin T (r = 0.233, P = 0.022), 6 min walk distance (6MWD: r = -0.222, P = 0.033), and National Amyloidosis Centre (NAC) stage (r = 0.294, P = 0.003). ATTR-CA patients in the high DPD uptake cohort demonstrated more advanced disease severity regarding longitudinal cardiac function (LV-GLS: P = 0.012, RV-FW-LS: P = 0.036), LV diastolic function (E/e' average: P = 0.035), cardiac biomarkers (NT-proBNP: P = 0.012, troponin T: P = 0.044), exercise capacity (6MWD: P = 0.035), and disease stage (NAC stage I: P = 0.045, III: P = 0.006), and experienced adverse outcomes compared with the low DPD uptake cohort [composite endpoint: all-cause death or heart failure hospitalization, HR: 2.873 (95% CI: 1.439-5.737), P = 0.003; DPD retention index: adjusted HR 1.221 (95% CI: 1.078-1.383), P = 0.002].

In ATTR-CA, enhanced quantitative LV DPD uptake indicates advanced disease severity and is associated with adverse outcome. DPD quantification may facilitate prognostic stratification when diagnosing patients with ATTR-CA.

Significant advances in the treatment of transthyretin (ATTR) amyloidosis has led to an evolving understanding of the epidemiology of this condition. This systematic literature review (SLR) aims to synthesize current evidence on epidemiology and mortality outcomes in ATTR amyloidosis, addressing the need for a comprehensive understanding of its current global impact.

An SLR of the literature from January 2018 to April 2023 was conducted using the Medline and Embase databases. The review followed the PRISMA guidelines. Studies evaluating populations with genotypes and phenotypes of ATTR amyloidosis (variant and wild-type cardiomyopathy, polyneuropathy, and mixed) were included. Observational studies, systematic reviews, and meta-analyses were eligible, while reports, commentaries, clinical trials, and non-ATTR amyloidosis studies were excluded. Extracted data included prevalence, incidence, and mortality rates.

Of the 1,458 studies identified, 113 met the inclusion criteria. Forty-nine studies reported on epidemiology, while 64 focused on mortality rates in cohorts of patients with ATTR amyloidosis from Europe (n = 16), North America (n = 26), Asia (n = 5), and Australia (n = 2). No studies were found that exclusively focused on ATTR amyloidosis in Africa or South America. ATTR prevalence ranged from 6.1/million in the US to 232/million in Portugal with very limited data on ATTR-PN. The 2-year mortality risk ranged from 10 to 30% among wild-type ATTR-CM and from 10 to 50% for variant type of ATTR-CM.

This SLR demonstrated heterogeneity in ATTR epidemiology and mortality rates across global regions. Further investigation is needed to address knowledge gaps of the epidemiology and burden of ATTR, which may improve early diagnosis and management.

Nearly 3% to 4% of Black individuals in the United States carry the transthyretin V142I variant, which increases their risk of heart failure. However, the role of cardiovascular (CV) risk factors (RFs) in influencing the risk of clinical outcomes among V142I variant carriers is unknown.

This study aimed to assess the impact of CV RFs on the risk of heart failure in V142I carriers.

This study included self-identified Black individuals without prevalent heart failure from 6 TOPMed (Trans-Omics for Precision Medicine) cohorts, the REGARDS (Reasons for Geographic And Racial Differences in Stroke) study, and the All of Us Research Program. The cohort was stratified based on the V142I genotype and the number of CV RFs (hypertension, diabetes, obesity, and hypercholesterolemia). Adjusted Cox models were used to assess the association of heart failure with the V142I genotype and CV RF profile, taking noncarriers with a favorable CV RF profile as reference.

The cross-sectional analysis, including 1,625 V142I carriers among 48,365 Black individuals, found that the prevalence of CV RFs did not vary by V142I carrier status. In the longitudinal analysis, there were 587 (3.2%) V142I carriers among 18,407 Black individuals (median age: 60 years [Q1-Q3: 52-68 years], 63.0% female). Among carriers, the heart failure risk was attenuated with a favorable (0 or 1 RF) CV RF profile (adjusted HR: 2.26; 95% CI: 1.58-3.23) compared with an unfavorable (3 or 4 RFs) CV RF profile (adjusted HR: 4.14; 95% CI: 2.79-6.14).

A favorable CV RF profile lowers but does not abrogate V142I variant-associated heart failure risk. This study highlights the importance of having a favorable CV RF profile among V142I carriers for risk reduction of heart failure.

Cardiac amyloidosis is characterized by amyloid fibril deposition in the heart, leading to restrictive cardiomyopathy and heart failure. Early diagnosis and monitoring are crucial for effective management. This systematic review and meta-analysis evaluates the utility of various biomarkers in the early detection, disease progression, and prognosis of cardiac amyloidosis.

We conducted a comprehensive search of PubMed, Scopus, and Web of Science databases for studies published between 2000 and 2024 that assessed the diagnostic and prognostic value of biomarkers in cardiac amyloidosis. Data were extracted and analyzed to determine the sensitivity, specificity, and prognostic significance of each biomarker. The correlation between biomarker levels and imaging findings was also explored.

A total of 45 studies were included in the meta-analysis. NT-proBNP and troponins had high sensitivity and specificity for early diagnosis of cardiac amyloidosis. Novel biomarkers, such as serum amyloid P component and light-chain assays, showed promise in distinguishing between amyloidosis subtypes and predicting disease progression. However, significant variability existed in the correlation between biomarkers and imaging findings.

Biomarkers are crucial for early diagnosis and prognosis of cardiac amyloidosis. NT-proBNP and troponins are well-established markers, while novel biomarkers offer additional insights into disease progression and subtype differentiation.

High-sensitivity cardiac troponin T (hs-cTnT) was proposed as a simple and useful diagnostic tool for cardiac amyloidosis (CA). We performed exploratory systemic screening using hs-cTnT to detect wild-type transthyretin CA (ATTRwt-CA) in outpatient and community-based settings.

This study was a prospective multicenter study including 8 internal medicine clinics in Kochi Prefecture, Japan. Consecutive individuals aged ≥70 years who visited those clinics as outpatients were enrolled. Patients with a prior diagnosis of CA or a history of heart failure hospitalization were excluded. We measured hs-cTnT levels in the enrolled individuals at each clinic, and those with elevated hs-cTnT levels (≥0.03ng/mL) received further detailed examination, including remeasurement of hs-cTnT. The diagnosis of ATTRwt-CA was confirmed by biopsy-proven transthyretin. Of 1,141 individuals enrolled in the study, 55 (4.8%) had elevated hs-cTnT levels. Of the 33 patients who underwent further examination, 22 had elevated hs-cTnT levels at remeasurement. Finally, 2 men were diagnosed with ATTRwt-CA. The prevalence of ATTRwt-CA was 9.1% (2/22) among patients with elevated hs-cTnT levels at two examinations, and at least 0.18% (2/1,141) in the whole study population.

Measurement of hs-cTnT will help to screen for patients with undiagnosed ATTRwt-CA in primary care practice.

Amyloidogenic transthyretin (ATTR) amyloidosis is a systemic disease characterized by the deposition of amyloid fibrils made of transthyretin. Transthyretin is primarily produced in tetrameric form by the liver, but also by retinal epithelium and choroid plexus. The deposition of these fibrils in the myocardium and peripheral nerves causes cardiomyopathies and neuropathies, respectively. Using cryoelectron microscopy (cryo-EM), we investigated fibrils extracted from cardiac and nerve tissues of an ATTRv-V30M patient. We found consistent fibril structures from both tissues, similar to cardiac fibrils previously described, but different from vitreous humor fibrils of the same genotype. Our findings, along with previous ATTR fibrils structural studies, suggest a uniform fibrillar architecture across different tissues when transthyretin originates from the liver. This study advances our understanding of how deposition and production sites influence fibril structure in ATTRv-V30M amyloidosis.

Amyloids consist of fibrils that can be formed by a large variety of different precursor proteins. In localized amyloidosis, amyloids accumulate at the production site with a single organ being affected, whereas in systemic amyloidosis several organs are affected, with the heart being the most common, followed by the kidneys, liver, and the nervous system. The two most frequent systemic amyloidosis types affecting the heart in the vast majority (>95%) of cases are immunoglobulin light chain (AL) amyloidosis and transthyretin (TTR) amyloidosis (ATTR amyloidosis). Patients with amyloid cardiopathy (CA) often present with non-specific heart failure symptoms as well as other clinical manifestations depending on the organ or systems involved. However, there are some findings associated with amyloidosis called "red flags" (clinical, echocardiographic, magnetic resonance imaging), which may assist in guiding the physician to the correct diagnosis. The present state-of-the-art review summarizes the features of the various cardiac phenotypic expressions of amyloidosis, proposes a simplified pathway for its diagnosis, and highlights the rapidly evolving therapeutic landscape.

The electrocardiogram (ECG) is routinely used in patients with suspected infiltrative cardiomyopathies; heart diseases characterized by the abnormal deposition of pathological substances in the myocardium. This study presents a review of ECG features attributable to various infiltrative cardiomyopathies and analyzes the prevalence and overlap of electrocardiographic abnormalities in patients with adjudicated CHF.

The study included 573 consecutive CHF patients without severe aortic stenosis, further stratified by LV hypertrophy (LVH) and preserved or decreased LV ejection fraction. Comprehensive ECG analysis revealed at least one ECG abnormality typically associated with infiltrative cardiomyopathies in 95% of patients, and more than one ECG abnormality in 70%. An average number of ECG abnormalities was 2.2 ± 1.2 per patient. There was substantial overlap in ECG abnormalities in individual patients, particularly those attributable to Fabry's disease and hemochromatosis (51.5%) or cardiac amyloidosis (46.1%), and hemochromatosis and cardiac amyloidosis (44.2%). Prevalence of various ECG abnormalities was similar across various patient demographics and co-morbidities, including LVH status and/or history of CAD which did not increase the number of ECG abnormalities (2.155 ± 1.238 vs. 2.228 ± 1.192 in patients without CAD history, p = 0.969). Patients with reduced LV ejection fraction had a higher prevalence of widened QRS and premature ventricular complexes.

ECG abnormalities attributable to infiltrative cardiomyopathies are common in heart failure patients, with a significant overlap in findings classically attributed to various infiltrative cardiomyopathies. The presence of LVH and decreased LV ejection fraction do not significantly affect the prevalence of ECG abnormalities.

Cardiac amyloidosis is a rarely reported and potentially fatal variant of the systemic disease. Its early diagnosis could potentially lead to significantly improved clinical outcomes.

A 56-year-old female presented with dyspnea and palpitations. Her physical exam and non-invasive evaluation with cardiac magnetic resonance imaging (CMRI) revealed restrictive cardiomyopathy, and the bone marrow biopsy results showed systemic amyloidosis.

The diagnosis of cardiac amyloidosis is not always straightforward, and delay can cause the progression of the disease and an increased risk of morbidity and mortality. Electrocardiograms, echocardiograms, cardiac magnetic resonance imaging, and histopathologic evaluation are the main methods for diagnosing cardiac amyloidosis. The treatment consists of controlling heart failure symptoms and disease-modifying interventions, including medical and surgical therapeutic methods.

Cardiac involvement is the main cause of death in systemic amyloidosis. Early suspicion, diagnosis, and treatment are crucial in improving patients' survival. CMRI can play an essential role in the diagnosis of cardiac Amyloidosis. A graphical abstract is provided for visual summary.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the accumulation of transthyretin (TTR) protein in the myocardium. The aim of this scoping review is to provide a descriptive summary of the clinical trials and observational studies that evaluated the clinical efficacy and safety of various agents used in ATTR-CM, with a goal of identifying the contemporary gaps in literature and to reveal future research opportunities.

The search was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A literature search using several databases for observational and clinical trials investigating the treatment modalities for ATTR-CM was undertaken. We extracted data including study characteristics, primary endpoints, and adverse events from each study. A total of 19 studies were included in our scoping review. Out of which, 8 were clinical trials and 11 were observational analyses. The drugs evaluated included tafamadis, acoramidis, revusiran, doxycycline and tauroursodeoxycholic acid and doxycycline, diflusinil, inotersan, eplontersen, and patisiran. Tafamidis has shown to be efficacious in the management of ATTR-CM, particularly when initiated at earlier stages. RNA interference and antisense oligonucleotide drugs have shown promising impacts on quality of life. Additionally, this review identified gaps in the literature, particularly among long-term outcomes, comparative effectiveness, and the translation of research into economic contexts.

Multiple pharmacological options are potential disease-modifying therapies for ATTR-CM. However, many gaps exist in the understanding of these various drug therapies, warranting further research. The future directions for management of ATTR-CM are promising in regard to improving prognostic implications.

Medical image classification using convolutional neural networks (CNNs) is promising but often requires extensive manual tuning for optimal model definition. Neural architecture search (NAS) automates this process, reducing human intervention significantly. This study applies NAS to [18F]-Florbetaben PET cardiac images for classifying cardiac amyloidosis (CA) sub-types (amyloid light chain (AL) and transthyretin amyloid (ATTR)) and controls. Following data preprocessing and augmentation, an evolutionary cell-based NAS approach with a fixed network macro-structure is employed, automatically deriving cells' micro-structure. The algorithm is executed five times, evaluating 100 mutating architectures per run on an augmented dataset of 4048 images (originally 597), totaling 5000 architectures evaluated. The best network (NAS-Net) achieves 76.95% overall accuracy. K-fold analysis yields mean ± SD percentages of sensitivity, specificity, and accuracy on the test dataset: AL subjects (98.7 ± 2.9, 99.3 ± 1.1, 99.7 ± 0.7), ATTR-CA subjects (93.3 ± 7.8, 78.0 ± 2.9, 70.9 ± 3.7), and controls (35.8 ± 14.6, 77.1 ± 2.0, 96.7 ± 4.4). NAS-derived network performance rivals manually determined networks in the literature while using fewer parameters, validating its automatic approach's efficacy.

This study aimed to describe baseline characteristics and adherence among patients with transthyretin amyloid cardiomyopathy (ATTR-CM) treated with tafamidis (VYNDAQEL®) in Japan using the Japanese Medical Data Vision (MDV) database.

This study was a non-interventional, retrospective cohort study of adult (≥18 years old) patients in the Japanese MDV claims database diagnosed with ATTR-CM and with at least two tafamidis prescriptions of dose strength 4 × 20 mg/day between 1 March 2019 and 31 August 2021. The date of the first prescription was defined as the index date, with follow-up time defined as the time between the first and last prescription plus the days' supply from the last refill. Baseline characteristics were assessed during a 12 month pre-index period. Adherence was measured using two metrics: (i) the modified medication possession ratio (mMPR), calculated by taking the sum of days supplied for all fills within the follow-up period, divided by the number of days of follow-up, and reported as a percentage, with patients classified as adherent with an mMPR of ≥80%, and (ii) the proportion of days covered (PDC), calculated by taking the total number of days' supply dispensed during the follow-up period divided by the number of days of follow-up, adjusting for any days' supply overlap. A total of 210 patients were identified; the mean (standard deviation) age of the cohort was 77 (5.9) years, and the majority (89%) were male. The most common baseline cardiovascular comorbidities were heart failure (85%), ischaemic heart disease (66%), hypertensive diseases (49%), and diabetes (35%); 75% of patients received heart failure medications in the 12 months prior to index, with the most common being beta-blockers (49%), diuretics (48%), angiotensin receptor blockers (30%), angiotensin-converting enzyme inhibitors (22%), and sodium-glucose cotransporter-2 inhibitors (8.1%). Over an average 14 month follow-up, mean mMPR was 96% with a median of 100% [inter-quartile range (IQR): 97-101%]; 93% of patients were adherent (defined as an mMPR ≥ 80%). In the same follow-up period, mean PDC was 93.6% with a median of 99% (IQR: 93-100%). Persistence was high with 78% of patients having a 0 day gap between prescription refills.

This study found high adherence rates to tafamidis in this real-world Japanese patient population. Adherence rates in this study were similar to those reported by the tafamidis clinical trial and a previously published US commercial claims adherence analysis. Further studies should be conducted to assess the impact of real-world adherence on real-world outcomes.

The pathophysiological hallmark of wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is the deposition of amyloid within the myocardium.

This study aimed to investigate associations between quantitative cardiac 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) uptake and myocardial amyloid burden, cardiac function, cardiac biomarkers, and clinical status in ATTRwt-CM.

Forty ATTRwt-CM patients underwent quantitative DPD single photon emission computed tomography/computed tomography to determine the standardized uptake value (SUV) retention index, cardiac magnetic resonance imaging to determine extracellular volume (ECV) and cardiac function (RV-LS), and assessment of cardiac biomarkers (N-terminal prohormone of brain natriuretic peptide [NT-proBNP], troponin T) and clinical status (6-minute walk distance [6MWD], National Amyloidosis Centre [NAC] stage). ATTRwt-CM patients were divided into 2 cohorts based on median SUV retention index (low uptake: <5.19 mg/dL, n = 20; high uptake: ≥5.19 mg/dL, n = 20). Linear regression models were used to assess associations of the SUV retention index with variables of interest and the Mann-Whitney U or chi-squared test to compare variables between groups.

ATTRwt-CM patients (n = 40) were elderly (78.0 years) and predominantly male (75.0%). Univariable linear regression analyses revealed associations of the SUV retention index with ECV (r = 0.669, β = 0.139, P < 0.001), native T1 time (r = 0.432, β = 0.020, P = 0.005), RV-LS (r = 0.445, β = 0.204, P = 0.004), NT-proBNP (log10) (r = 0.458, β = 2.842, P = 0.003), troponin T (r = 0.422, β = 0.048, P = 0.007), 6MWD (r = 0.385, β = -0.007, P = 0.017), and NAC stage (r = 0.490, β = 1.785, P = 0.001). Cohort comparison demonstrated differences in ECV (P = 0.001), native T1 time (P = 0.013), RV-LS (P = 0.003), NT-proBNP (P < 0.001), troponin T (P = 0.046), 6MWD (P = 0.002), and NAC stage (I: P < 0.001, II: P = 0.030, III: P = 0.021).

In ATTRwt-CM, quantitative cardiac DPD uptake correlates with myocardial amyloid load, longitudinal cardiac function, cardiac biomarkers, exercise capacity, and disease stage, providing a valuable tool to quantify and monitor cardiac disease burden.

There is limited data on the safety and efficacy of left atrial appendage occlusion (LAAO) devices in patients with cardiac amyloidosis. We examined the outcomes of patients with cardiac amyloidosis undergoing LAAO device implantation in a nationally representative cohort of patients.

The National Readmissions Database (NRD) was analyzed from 2016 to 2019 to identify patients ≥ 18 years old with atrial fibrillation (AF) undergoing LAAO. Patients were divided into those with cardiac amyloidosis and those without cardiac amyloidosis. A multivariable logistic regression model was utilized to assess the independent association of cardiac amyloidosis with in-hospital, 30-day/90-day/180-day outcomes after adjusting for confounders.

Our cohort included 54,900 LAAO implantation procedures, of which 220 (0.4%) had cardiac amyloidosis. Patients with cardiac amyloidosis had a lower proportion of women and a lower prevalence of comorbidities including anemia, obesity, diabetes, and peripheral vascular disorders but a higher prevalence of stroke, as compared to those without cardiac amyloidosis. On multivariable analysis, cardiac amyloidosis was associated with significantly higher odds of peri-procedural major adverse events (adjusted odds ratio [aOR]: 2.69; 95% confidence interval [CI]: 1.41-5.14; p<0.01) and neurological complications (aOR: 5.48; 95% CI: 2.47-12.8; p<0.01). There was no difference in the odds of other peri-procedural complications, in-hospital mortality, hospital resource utilization, and 30/90/180-day all-cause/bleeding/stroke-related readmissions between both groups.

Patients with cardiac amyloidosis undergoing LAAO device implantation have an increased risk of peri-procedural complications without any difference in bleeding/stroke-related readmissions. These hypothesis-generating findings need validation in future prospective studies.

Tafamidis-associated adverse events (AEs) were investigated retrospectively by data mining the US Food and Drug Administration Adverse Event Reporting System (FAERS) to inform clinical safety.

Data were gathered from the FAERS database, which spans the second quarter of 2019 to the fourth quarter of 2023. A total number of 8532 reports of Tafamidis-related adverse events were detected after evaluating 8,432,351 data. Disproportionality analyses were used to quantify the signal and assess the significance of Tafamidis-associated AEs using four algorithms, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the multi-item gamma Poisson shrinker (MGPS) and the Bayesian confidence propagation neural network (BCPNN).

Among the 8532 reports of AEs with Tafamidis as the primary suspected drug, Tafamidis-induced AEs were identified as occurring in 27 system organ classes (SOC). A total of 207 Tafamidis-induced AEs were detected which simultaneously complied with the four algorithms. Our analysis also identified new adverse reactions including Hypoacusis, Deafness, and Essential hypertension. The median onset of adverse reactions associated with Tafamidis was 180 days (interquartile range [IQR] 51-419 days).

Tafamidis is a drug that has shown favorable safety and tolerability results in clinical trials. However, a number of adverse reactions associated with Tafamidis have been identified through analysis of the FAERS database. In clinical applications, it is recommended to closely monitor patients' hearing while using Tafamidis. In addition, it is hoped that further experimental and clinical studies will be conducted in the future to understand the mechanism of occurrence between Tafamidis and adverse reactions such as primary hypertension, hyperlipidemia, and height reduction.

In recent years, several strategies have been developed for the treatment of transthyretin-related amyloidosis, whose complex clinical manifestations involve cardiomyopathy and polyneuropathy. In view of this, transthyretin stabilizers represent a major cornerstone in treatment thanks to the introduction of tafamidis into therapy and the entry of acoramidis into clinical trials. However, the clinical treatment of transthyretin-related amyloidosis still presents several challenges, urging the development of new and improved therapeutics. Bearing this in mind, in this paper, the most promising among the recently published transthyretin stabilizers were reviewed. Their activity was described to provide some insights into their clinical potential, and crystallographic data were provided to explain their modes of action. Finally, structure-activity relationship studies were performed to give some guidance to future researchers aiming to synthesize new transthyretin stabilizers. Interestingly, some new details emerged with respect to the previously known general rules that guided the design of new compounds.