Search Results (81)

Transthyretin amyloidosis (ATTR) is a multisystemic disorder associated with extracellular accumulation of misfolded transthyretin (TTR) protein forming insoluble amyloid deposits. Depending on the TTR genotype, ATTR is classified as hereditary ATTR (ATTRv) with pathogenic gene variants and wild-type ATTR (ATTRwt) with a normal TTR genotype. Two cardinal clinical manifestations of ATTR are amyloid cardiomyopathy and peripheral neuropathy, but multisystemic deposition of amyloid may also manifest with ocular and leptomeningeal amyloidosis, various orthopedic complications (carpal tunnel syndrome, spinal stenosis), nephropathy, and gastrointestinal and pulmonary amyloidosis. The natural history of untreated ATTR is characterized by progressive worsening and 25% of patients may die within 24 months from the onset. The first treatment for ATTR was liver transplantation which slows the disease progression, but its use was limited by the scarcity of available liver allografts and complex post-transplant morbidities associated with immunosuppression and various metabolic disturbances. Recent introduction of TTR stabilizers and gene silencing has significantly changed the outcomes and reduced ATTR-related morbidities and mortality, and early diagnosis remains important for improved outcomes. In our narrative expert review, we are discussing epidemiological and clinical features of ATTR, its pathophysiology and available treatments as rapidly progressive fatal disease is being transformed into a treatable chronic disease. Full article

Background: The care of patients with transthyretin amyloid cardiomyopathy (ATTR-CM) is often fragmented and routine datasets rarely capture real-world clinical trajectories and reasons for diagnosis. We introduce a novel approach, called forensic data acquisition and pathway analysis, to examine the real-world experiences of patients with ATTR-CM in our district general hospital. Methods: We retrospectively evaluated inpatient and outpatient healthcare records for our hospital between 2019 to 2025 as a part of a quality improvement project. Results: We identified 26 cases of confirmed or likely wild-type ATTR-CM and four hereditary cases from two families carrying the S77Y variant and estimate the prevalence of transthyretin cardiac amyloidosis to be 1 per 10,000 patients. Many red flags were present in patients, including carpal tunnel syndrome (63.3%) and lumbar spinal stenosis (26.7%), as well as echocardiographic features of left ventricular hypertrophy (86.7%), left atrial dilatation (76.7%), right ventricular hypertrophy (43.3%), and a dense or speckled myocardial appearance (43.3%). Among patients with wild-type disease, the most frequent trigger for further investigation was the presence of suspicious features on transthoracic echocardiography, accounting for 13 cases. Incidental abnormalities detected on cardiac MRI contributed to another six diagnoses. In two patients, non-invasive imaging did not provide sufficient diagnostic certainty, and myocardial biopsy was required to confirm ATTR-CM. Conclusions: Forensic data acquisition and pathway analysis provides a powerful approach for revealing real-world clinical activity in ATTR-CM, exposing diagnostic patterns and missed opportunities that remain hidden in routine datasets. Full article

Transthyretin (TTR) amyloidosis is a systemic, progressive, and fatal disease. TTR is integral in vitamin A (retinol) transport via its binding to retinol binding protein 4 (RBP4). Current and emerging therapies for TTR amyloid cardiomyopathy (ATTR-CM), including RNAi therapies and potentially CRISPR-based therapies, reduce hepatic transthyretin production and hence decrease serum RBP4, which decreases circulating vitamin A levels. However, despite these reductions in circulating vitamin A, hepatic reserves and alternative delivery mechanisms may prevent clinical manifestations of vitamin A deficiency. Vitamin A functions as a key regulator of immunity, antioxidant function, cell growth and differentiation and vision. This paper aims to serve as a comprehensive review of vitamin A and its metabolites, their transport, and their function in human health and disease. Additionally, we seek to synthesize the relevant outcomes and safety data of TTR silencing therapies and how they relate to circulating vitamin A levels and vitamin A-related clinical outcomes in a manner that is relevant to the cardiac amyloidosis specialist. Full article

Background: The clinical significance of circulating serum transthyretin (sTTR) levels in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) remains incompletely defined, particularly in patients treated with tafamidis in real-world clinical practice. We aimed to evaluate the relationship between sTTR levels, disease severity, longitudinal changes during tafamidis therapy, and clinical outcomes. Methods: We conducted a retrospective, exploratory study based on prospectively collected data, including consecutive patients with ATTR-CM initiating tafamidis therapy at a tertiary referral center. sTTR levels were measured at baseline and after six months. Associations between sTTR, markers of disease severity, functional status, and outcomes were assessed. Cox regression, receiver operating characteristic (ROC) analysis, and Kaplan–Meier survival analysis were performed. Results: A total of 107 patients (mean age 79.6 ± 8.5 years, 84 males) were enrolled and followed for 24 ± 6 months. Tafamidis therapy was associated with a significant increase in sTTR levels at six months (from 24.7 ± 8.8 to 36.9 ± 6.4 mg/dL; p = 0.006). Baseline sTTR levels were inversely correlated with NT-proBNP (ρ = –0.349; p = 0.037) and were significantly lower in non-survivors compared with survivors (14.2 ± 3.1 vs. 23.5 ± 5.2 mg/dL; p < 0.001). Each 1 mg/dL increase in baseline sTTR was associated with a 13% reduction in all-cause mortality risk (HR 0.87, 95% CI 0.83–0.91; p < 0.001). A baseline sTTR cut-off of 20 mg/dL was associated with an increased risk of mortality (AUC 0.85), and patients with sTTR < 20 mg/dL showed significantly reduced survival. Higher on-treatment sTTR levels at six months were associated with better functional capacity (r = 0.52; p = 0.009) and, when >26 mg/dL, with lower observed mortality during follow-up. Conclusions: In a real-world cohort of patients with ATTR-CM treated with tafamidis, serum transthyretin levels were associated with disease severity, functional status, and survival. Baseline and early on-treatment sTTR measurements may represent useful biomarkers for risk stratification and treatment monitoring. Full article

Background: The number of patients with transthyretin amyloid cardiomyopathy (ATTR-CM) has been increasing recently, and the early diagnosis and treatment of it are important. ^99mTc pyrophosphate scintigraphy (^99mTc-PYP) plays a key role in the early diagnosis of ATTR-CM. In patients who underwent ^99mTc-PYP, the early diagnosis of ATTR-CM by echocardiography was evaluated, focusing on left ventricular myocardial form and left ventricular wall thickness. Methods: The present study was conducted on 144 patients who underwent ^99mTc-PYP between February 2020 and March 2024. A comparison was made between the ^99mTc-PYP positive (P) and negative (N) groups, and significant factors were subjected to multivariate analysis. Results: 17 of 144 patients were positive (14.9%), and 15 patients were diagnosed with ATTR-CM by myocardial or skin (fat) biopsy. Other positive patients were also clinically considered to have ATTR-CM based on findings such as poor cardiac function and cerebral hemorrhage. ^99mTc-PYP positive had a significantly larger CTR (60.3% in the P group vs. 53.9% in the N group, p = 0.007) and a larger left atrial diameter (42.8 mm in the P group vs. 40.0 mm in the N group, p = 0.047). On the other hand, the mean LV wall thickness was significantly thicker (15.7 mm in the P group vs. 12.8 mm in the N group, p < 0.001); however the LV end-diastolic diameter was smaller (41.9 mm in the P group vs. 48.4 mm in the P group, p < 0.001). The LV mass was similar in both groups, thus the relative left ventricular wall thickness (RWT), which indicates relative wall thickening, was significantly higher in the P group (0.85 in the P group vs. 0.52 mm in the N group, p < 0.001). The receiver operating characteristic curve of RWT for assessing ^99mTc-PYP positivity had a cut-off value of 0.717 (area under the curve 0.862, 95%CI 0.763–0.961). Conclusions: The evaluation of wall thickness and RWT on echocardiography is important for diagnosing ATTR-CM. Full article

Background: Early diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) remains challenging. Although ECG and morphological abnormalities at diagnosis are well-described, their temporal evolution has not been systematically evaluated. This study characterized the prevalence and longitudinal progression of electrical and structural cardiac abnormalities preceding ATTR-CM diagnosis. Methods: We retrospectively analyzed patients with confirmed ATTR-CM evaluated at a specialist amyloidosis center between 2006 and 2023. Diagnosis was established by grade 2–3 myocardial uptake on 99mTc-DPD scintigraphy. Standard 12-lead ECGs and transthoracic echocardiograms were reviewed at diagnosis and at baseline, 3–5 years earlier. Results: Sixty-three patients (79% men; mean age 77 ± 8 years) were studied, including 33 (52%) with hereditary ATTR (ATTRv) and 30 (48%) with wild-type ATTR (ATTRwt). Overall, 95% had a NAC score ≤ 2, consistent with less advanced disease at diagnosis. During the prediagnostic phase, 79% of patients exhibited pathological ECGs. Non-specific ST–T abnormalities (40%), prolonged QTc (38%), left-axis deviation (35%), first-degree AV block (33%) and anterior infarction pattern (33%) were each observed in at least one-third of patients. From baseline to diagnosis, significant prolongation was observed in the PR interval (+26 ms), QRS duration (+11 ms), and QTc interval (+22 ms) (p < 0.001 for all), and a leftward shift observed in the electrical axis (−12.03°, p = 0.011). Low voltage was uncommon at both time points. Although interventricular septal thickness increased significantly (+3.42 mm; p < 0.001), left ventricular ejection fraction and dimensions were relatively stable. Conclusions: In this proof-of-concept study, electrical remodeling precedes functional changes and outperforms low voltages to raise clinical suspicion of ATTR-CM. Full article

Introduction: Cardiac amyloidosis, primarily comprising transthyretin amyloid cardiomyopathy (ATTR-CM) and light-chain amyloidosis with cardiac involvement (AL-cardiac), is an increasingly recognized contributor to the global heart failure burden. Management has shifted from supportive care to disease-modifying agents targeting specific stages of the amyloid cascade. This registry-based review qualitatively characterizes the current pharmacological clinical trial landscape through a registry-based analysis. Methods: A structured qualitative analysis of ClinicalTrials.gov was conducted for interventional trials registered between January 2015 and November 2025. Following PRISMA principles, studies were screened to include pharmacological interventions with explicit cardiac targeting while excluding neuropathy-dominant amyloidosis. Trial-level data regarding therapeutic classes, study phases, enrollment, and primary outcome domains were extracted and synthesized. Results: A total of 18 trials met the inclusion criteria (14 ATTR-CM; 4 AL-cardiac), representing a total enrollment of 4924 participants across 11 unique agents. Five therapeutic classes were identified: amyloid-clearing monoclonal antibodies (44.4% of trials), TTR silencers, TTR stabilizers, fibril-modifying agents, and cardiac phenotype-directed therapies. Monoclonal antibodies represented the largest class by both trial count and enrollment (3075 participants). Clinical events (n = 7) and safety/tolerability (n = 5) were the most frequent primary outcome domains. ATTR-CM trials dominated the landscape, accounting for 77.7% of the total study population, while parallel-group placebo-controlled designs were the most common study architecture (n = 10). Conclusions: The therapeutic landscape for cardiac amyloidosis is transitioning toward stage-specific, mechanism-based interventions. While ATTR-CM currently dominates research efforts, the expansion of silencers and monoclonal antibodies reflects an increasing capacity to intercept the amyloid cascade at distinct molecular checkpoints. However, significant heterogeneity in outcome measures and the shift toward diagnosing milder disease pose challenges for demonstrating clinical efficacy. Future priorities include standardized progression markers and addressing barriers to global access for these high-cost therapies. Full article

Background: Cardiac amyloidosis (CA) is mainly characterized by diastolic dysfunction, with gradually worsening functional capacity and poor prognosis. Left atrial (LA) strain by speckle tracking echocardiography (STE) is an index of diastolic function and heart failure (HF) symptoms. The aim of this study was to evaluate the relationship of LA strain with functional capacity in CA and the potential prognostic value of speckle tracking variables. Methods: In this single-center study, we prospectively enrolled consecutive outpatients with CA (n = 75). Clinical, echocardiographic evaluation, six-minute-walking-test (6MWT) and Kansas City Cardiomyopathy Questionnaire (KCCQ) were performed on the same day. The primary endpoint was the correlation between global peak atrial longitudinal strain (PALS) and NTproBNP, 6MWT score, and KCCQ. The secondary endpoint was a combination of all-cause or cardiovascular death and HF hospitalization. Results: Overall, 48 ATTR and 27 AL patients (74 ± 11 years, 84% male) were enrolled. Global PALS showed a significant direct correlation with N-terminal-pro-brain natriuretic peptide (NTproBNP, p = 0.3, p = 0.017) and 6MWT (p = 0.4, R² = 0.2, p = 0.004), but no significant correlation with KCCQ (p = −0.13, p = 0.3). GLS showed a significant direct correlation with NTproBNP (p = 0.3, p = 0.017) but not with 6MWT and/or KCCQ. Over a mean follow up of 12 ± 3 months, 42 patients reached the combined endpoint. With ROC curves, both global PALS < 13.5% and GLS > −12% provided a good prediction of the combined endpoint (AUC = 0.72 [0.6–0.82] and 0.73 [0.63–0.83], respectively, p < 0.0001), higher than NTproBNP and other echocardiographic parameters. Conclusions: Global PALS is associated with congestion and functional capacity in CA, suggesting its role as a more objective marker of disease severity in CA. Speckle tracking parameters may be used to enhance prognostic stratification in CA. Full article

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins, most commonly immunoglobulin light chains (AL) or transthyretin (ATTR), with rarer forms occurring less frequently. AL amyloidosis arises from plasma cell-derived light chains and typically follows an aggressive clinical course, whereas ATTR amyloidosis results from misfolded wild-type or variant transthyretin and progresses more indolently. Extracellular vesicles (EVs) have recently been recognized as mediators of amyloid propagation, inflammation, and myocardial remodeling, particularly at later stages of disease. Despite growing evidence, no comprehensive reviews have focused on this relationship. We conducted a structured narrative review (PubMed and Scopus, 2020–2025) following Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines to synthesize emerging data. EVs act as scaffolds for transthyretin and serum amyloid A aggregation and carry disease-specific protein and RNA cargo detectable in blood and urine. Experimental models also demonstrate EV-mediated transport of serum amyloid A under conditions of cardiac stress, representing a reactive amyloidogenic pathway rather than a common cause of human cardiac amyloidosis. Preclinical studies show regenerative and anti-fibrotic effects of stem-cell-derived EVs, and early clinical trials demonstrate the feasibility of EV-based cardiac therapy. While methodological and translational challenges persist, EVs represent promising diagnostic and therapeutic tools that could transform the precision management of cardiac amyloidosis. Full article

Amyloidosis is a group of disorders caused by extracellular deposition of insoluble fibrillar proteins, leading to progressive organ dysfunction. Cardiac amyloidosis is clinically significant, as myocardial infiltration results in restrictive cardiomyopathy, arrhythmias, and heart failure. The main subtypes are light-chain (AL) and transthyretin (ATTR) amyloidosis, while AA and isolated atrial amyloidosis (IAA) are less common. Accurate subtype identification is crucial for management and prognosis. Diagnosis requires a multimodal approach combining imaging and tissue-based techniques. Echocardiography is usually first-line, showing increased wall thickness, biatrial enlargement, and apical sparing. Cardiac magnetic resonance (CMR) provides superior tissue characterization through late gadolinium enhancement and elevated extracellular volume. Nuclear scintigraphy with 99mTc-labeled tracers enables non-invasive ATTR detection, while amyloid-specific PET tracers show potential for early diagnosis. Histochemical confirmation remains essential. Congo Red staining with apple-green birefringence under polarized light is the diagnostic gold standard, supported by Thioflavin T, PAS, and Alcian Blue stains. Immunohistochemistry and mass spectrometry aid amyloid typing, while electron microscopy provides ultrastructural confirmation. Integrating imaging, histochemical, immunohistochemical, and proteomic techniques enhances early recognition and precise classification, improving therapeutic strategies and patient outcomes. Full article

Background: Cardiac amyloidosis (CA) is characterized by progressive myocardial infiltration leading to restrictive cardiomyopathy and heart failure. While left ventricular assessment has traditionally dominated prognostic evaluation, right ventricular (RV) dysfunction and RV–pulmonary artery (PA) coupling have emerged as critical determinants of outcomes. Objectives: This review synthesizes current evidence on RV–PA coupling as a prognostic marker in cardiac amyloidosis, examining measurement methodologies, prognostic significance, pathophysiological mechanisms, and clinical applications. Methods: We comprehensively reviewed the recent literature on RV–PA coupling in CA, focusing on studies published from 2020 to 2025, including both AL and ATTR subtypes. We analyzed data from multicenter cohorts, prospective registries, and validation studies examining the relationship between RV–PA coupling indices and clinical outcomes. Results: RV–PA coupling, most commonly assessed using the tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, consistently demonstrates strong independent prognostic value for mortality and heart failure outcomes in CA patients. Impaired coupling (TAPSE/PASP < 0.45 mm/mmHg) identifies high-risk patients with hazard ratios ranging from 1.98 to 4.17 for adverse outcomes. In a multicenter cohort of 283 patients, TAPSE/PASP < 0.45 mm/mmHg was independently associated with death or heart failure hospitalization (HR 1.98, 95% CI 1.32–2.96, p = 0.001) and significantly improved risk reclassification (NRI 0.46–0.49). In ATTR-specific populations receiving disease-modifying therapy, impaired coupling (TAPSE/PASP ≤ 0.382 mm/mmHg) predicted three-year mortality with an adjusted HR of 2.99. The coupling index provides incremental value over individual RV parameters by accounting for afterload conditions and demonstrates consistent prognostic performance across both AL and ATTR subtypes. Conclusions: RV–PA coupling represents a robust, easily obtainable prognostic marker that should be routinely assessed in CA patients for risk stratification and clinical decision-making. The TAPSE/PASP ratio can be calculated from standard echocardiographic examinations without additional cost or time, making it practical for widespread implementation. Future research should focus on standardizing measurement protocols, establishing disease-specific thresholds, evaluating coupling trajectories with novel therapies, and integrating coupling assessment into staging systems and management algorithms. The strong prognostic signal, pathophysiological relevance, and ease of measurement position RV–PA coupling as an essential component of comprehensive cardiac amyloidosis evaluation. Full article

Background/Objectives: Transthyretin cardiomyopathy (ATTR-CM) is frequently associated with conduction disease requiring pacing. Conventional right ventricular pacing may worsen cardiac function, whereas left bundle branch area pacing (LBBAP) aims to preserve physiological activation. Evidence for LBBAP in ATTR-CM remains limited. Methods: A structured narrative review of PubMed and Google Scholar was performed through November 2025 using predefined terms related to LBBAP and ATTR-CM. Peer-reviewed articles, case reports, case series, and relevant abstracts were included. Studies exclusively on light-chain cardiac amyloidosis were excluded. Results: Ten publications met inclusion criteria, comprising three case reports, five case series, one retrospective cohort without a comparator, and one cohort comparing LBBAP with cardiac resynchronization therapy (CRT). In total, 56 patients with ATTR-CM underwent LBBAP. Implantation success was high, with stable acute and mid-term electrical parameters. Follow-up (typically 3–12 months) showed stable electrical parameters with narrow paced QRS complexes and preserved or improved left ventricular ejection fraction in most reports. Symptomatic improvement and reductions in natriuretic peptides were variably described. No major lead-related complications were reported. Comparative data remain sparse and inconclusive. Conclusions: This review suggests that LBBAP is a feasible and safe pacing approach in patients with ATTR-CM and may help to stabilize or improve heart failure symptoms. Further prospective studies are needed to confirm its clinical effectiveness. Full article

Background: ^99mTc pyrophosphate scintigraphy (^99mTc-PYP) is useful for diagnosing transthyretin amyloid cardiomyopathy (ATTR-CA). We examined the characteristics of ^99mTc-PYP-positive patients at our institution. Methods: A total of 76 patients who underwent ^99mTc-PYP from December 2020 and March 2022 were grouped into ^99mTc-PYP-positive (P) and -negative (N) groups and compared. Results: Nine of seventy-six patients were positive (11.8%), and all patients were diagnosed with ATTR-CA by myocardial biopsy or clinical findings. The heart-to-contralateral lung ratio in the P group was significantly higher (N Group: 1.15, P Group: 1.92, p < 0.001). In the P group, the left ventricular posterior wall thickness was significantly thickened (N Group; 12.5 mm, P Group; 15.5 mm, p = 0.003). Electrocardiogram showed left ventricular hypertrophy (LVH) was observed more frequently in the N group (N Group; 30 patients (44.8%) and the P Group; 1 patient (11.1%), p < 0.001). In addition, the QTc interval was significantly prolonged in the P group (N Group; 422 msec, P Group; 456 msec, p = 0.001). Conclusions: In patients who have significant LVH on echocardiogram but not on electrocardiogram, ^99mTc-PYP may be useful for diagnosing ATTR-CA. However, the present study is a single-center retrospective study with a small number of patients, and the results are exploratory and hypothesis-generating. Prospective studies with a larger number of subjects are needed. Full article

Amyloid cardiomyopathy (ACM), driven by transthyretin (TTR) and immunoglobulin light chain (LC) amyloid fibrils, remains a major clinical challenge due to limited mechanistic understanding and insufficient preclinical models. Human-induced pluripotent stem cells (iPSCs) have emerged as a transformative platform to model ACM, offering patient-specific and genetically controlled systems. In this review, we summarize recent advances in the use of iPSC-derived cardiomyocytes (iPSC-CMs) in both two-dimensional (2D) monolayer cultures and three-dimensional (3D) constructs—including spheroids, organoids, cardiac microtissues, and engineered heart tissues (EHTs)—for disease modeling, mechanistic research, and drug discovery. While 2D culture of iPSC-CMs reproduces hallmark proteotoxic phenotypes such as sarcomeric disorganization, oxidative stress, and apoptosis in ACM, 3D models provide enhanced physiological relevance through incorporating multicellularity, extracellular matrix interactions, and mechanical load-related features. Genome editing with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 further broadens the scope of iPSC-based models, enabling isogenic comparisons and the dissection of mutation-specific effects, particularly in transthyretin-related amyloidosis (ATTR). Despite limitations such as cellular immaturity and challenges in recapitulating aging-associated phenotypes, ongoing refinements in differentiation, maturation, and dynamic training of iPSC-cardiac models hold great promise for overcoming these barriers. Together, these advances position iPSC-based systems as powerful human-relevant platforms for modeling and elucidating disease mechanisms and accelerating therapeutic development to prevent ACM. Full article

Background: Conventional HF treatment in transthyretin cardiac amyloidosis (ATTR-CA) resulting in restrictive cardiomyopathy is debated due to absent trial evidence in this specific sub-population of heart failure (HF) patients. Current European Society of Cardiology guidelines recommend the use of diuretics and mineralocorticoid receptor antagonists (MRAs). However, beta-blockers (BBs) and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARBs) are often discontinued due to hypotension or bradycardia. This study assesses real-world HF treatment patterns and their impact on survival in a multinational ATTR-CA cohort. Methods: A retrospective analysis of 794 ATTR-CA patients examined baseline BB, ACEi/ARB, and MRA prescriptions. The cohort was divided based on guideline publication dates. Results: Patients were predominantly male (73.2%) with a median age of 78 years. Prescription of diuretics (52.8%) and disease-modifying therapy (44.9%), mostly tafamidis, was common. BBs (43.7%) and ACEi/ARBs (41.2%) were prescribed more often in patients with higher NYHA class, elevated NT-proBNP, and more comorbidities. Blood pressure and heart rate were similar regardless of BB or ACEi/ARB use. BB prescription and combination therapy with BB and ACEi/ARB increased over time. Neither BB nor ACEi/ARB use significantly impacted mortality when analyzed in a multivariate Cox proportional hazard regression. Conclusions: Use of BBs and ACEi/ARBs has increased over time, particularly in advanced-stage ATTR-CA patients, and although these therapies appear to be reasonably tolerated, survival was not significantly altered. Full article