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.

Background/Objectives: Transthyretin cardiac amyloidosis (ATTR-CA) is an infiltrative cardiomyopathy caused by transthyretin (TTR) amyloid deposition in the myocardium, increasingly recognized in patients with aortic stenosis (AS). This study aims to investigate the diagnostic challenges and therapeutic strategies for patients with both conditions, focusing on shared pathophysiological mechanisms and key diagnostic indicators. Methods: A multimodal diagnostic approach was applied, utilizing cardiac magnetic resonance (CMR) and bone scintigraphy with technetium-99m-labeled tracers to assess AS patients with suspected ATTR-CA. Clinical signs, such as disproportionate heart failure symptoms, conduction abnormalities, and low-flow, low-gradient AS, were evaluated. Electrocardiographic findings, including low-voltage QRS complexes and pseudo-infarction patterns, were also assessed. Treatment options, including transcatheter aortic valve replacement (TAVR) and emerging pharmacotherapies for ATTR-CA, were analyzed. Results: The study found that ATTR-CA is increasingly prevalent in AS patients, with shared mechanisms like oxidative stress and amyloid-induced tissue remodeling. Key diagnostic signs include disproportionate heart failure symptoms, conduction abnormalities, and specific electrocardiographic patterns. TAVR was effective in both isolated AS and AS with ATTR-CA, although patients with both conditions had a higher risk of heart failure hospitalization and persistent symptoms. Emerging pharmacotherapies, such as TTR stabilizers and gene-silencing agents, showed promise in slowing disease progression. Conclusions: A multimodal diagnostic approach is essential for the early detection of ATTR-CA in AS patients. Combining TAVR with emerging pharmacotherapies may improve long-term outcomes for this high-risk group, enhancing patient care in those with both conditions.

While early diagnosis is crucial, as new treatments can significantly slow the progression of the disease, there is growing evidence on the application of novel imaging techniques for detecting transthyretin amyloidosis (ATTR) in pre-symptomatic stages. This study aimed to evaluate the utility of pre-symptomatic scintigraphic imaging cascade screening for early detection of ATTR.

During the period from 2020 to 2024, we conducted a prospective study that enrolled 100 consecutive adults. The study utilized a multimodal cascade screening approach to assess asymptomatic relatives of individuals with ATTR (ClinicalTrials.gov Identifier: NCT05814380). The analysis incorporated clinical data, genetic testing, echocardiography, scintigraphy and single-photon emission computed tomography/computed tomography (SPECT/CT) with [99mTc]Tc-DPD, regardless of the predicted age of disease onset.

Overall, scintigraphy identified cardiac amyloidosis (CA) in 8.2% of relatives, while 20.5% carried a pathogenic transthyretin variant without radiotracer uptake, with Phe53Leu being predominant. Notably, no relatives of wild-type ATTR patients exhibited CA on scintigraphy or carried a transthyretin variant. Additionally, newly-diagnosed relatives with ATTR CA presented elevated high-sensitivity troponin levels and exhibited a higher incidence of pathological electrocardiographic Q waves, greater thickness of the intraventricular septum and left ventricular posterior wall, a notable decline in lateral wall and intraventricular septal E' tissue velocities measured by TDI, and the "5-5-5" sign (p < 0.05).

The presented findings demonstrate that implementing a systematic screening protocol, which integrates genetic and scintigraphic testing, facilitates the early detection of ATTR. Crucially, a significant proportion of asymptomatic relatives of patients with hereditary ATTR may suffer from underlying CA.

ClinicalTrials.gov Identifier: NCT05814380.

Genetic mutations are increasingly recognized as significant contributors to post-transplant complications. Common genetic conditions, such as short telomere syndrome (STS), lymphangioleiomyomatosis, cystic fibrosis (CF), and alpha-1 antitrypsin deficiency (AAT), have been documented to influence outcomes in lung transplant recipients. Here, we present a case of hereditary transthyretin (ATTR) cardiac amyloidosis leading to heart failure in a 71-year-old female, six years after undergoing a single-lung transplantation (LTx) for interstitial lung disease. This case report highlights the need for awareness of genetic predispositions, including rare conditions such as hereditary ATTR amyloidosis, among individuals being considered for solid organ transplantation.

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.

The demographics of patients with transthyretin amyloidosis with cardiomyopathy have evolved over the past decade, mostly driven by improved awareness of the disease among clinicians, noninvasive imaging tools for diagnosis, and new, effective treatments. Patients are now diagnosed earlier in their disease course, and treatment is initiated in those with milder disease, leading to improved outcomes. Earlier treatment of patients with milder disease may lead to accelerated disease stabilization and greater preservation of function. In addition, identification of patients with transthyretin amyloidosis with cardiomyopathy at an earlier disease stage translates to healthier study populations at enrollment in clinical trials, with slower disease progression compared with patients in prior trials. In this context, effect sizes between active treatment and placebo arms will likely be smaller than those seen in historic trials, although it is still possible to observe clinically relevant differences. In this review, we discuss how patient characteristics have changed from the ATTR-ACT trial to the more recent APOLLO-B, ATTRibute-CM, and HELIOS-B studies. In addition, we consider how measures of the minimal clinically important difference for particular end points can assist in clinical decision-making and targeting treatment goals. Treatment goals are evolving over time with the need for evidence-based recommendations in this clinical space. Lastly, we address unmet needs and future expectations for the management of transthyretin amyloidosis with cardiomyopathy.

Heart failure (HF) is a prevalent and critical cardiac condition that leads to profound structural and functional changes in the heart. Although traditional treatments have shown partial efficacy, the long-term outcomes remain suboptimal. Emerging research has highlighted the pivotal role of oxidative stress and ferroptosis in HF progression. This study investigates a new therapeutic approach utilizing antioxidant polyphenol nanoparticles loaded with a STAT3 agonist (PN@Col) to target these pathways and improve age-related HF.

Key cells and genes contributing to HF progression were identified via analysis of the GEO database, with single-cell RNA sequencing (scRNA-seq) and AUCell analysis used to evaluate differential gene expression. The STAT3 gene was highlighted as essential, and its functionality was further validated in vitro through cell experiments, confirming its impact on cardiomyocytes (CMs) in HF. Following the development of PN@Col, in vitro experiments showed that PN@Col effectively reduced oxidative stress and ferroptosis in CMs. In vivo studies in elderly HF mice demonstrated significant improvements in cardiac function following PN@Col treatment.

PN@Col offers a promising therapeutic approach to age-related HF by mitigating oxidative stress and ferroptosis in cardiomyocytes. These findings provide a solid scientific foundation for PN@Col as a potential novel treatment strategy for HF, supporting further exploration toward clinical application.

Patients with amyloid transthyretin (ATTR) amyloidosis typically experience rapid disease progression, poor treatment outcomes, irreversible loss of health-related quality of life (HRQoL), and premature mortality. Early diagnosis is vital. However, diagnostic delays and misdiagnosis are common due to under-recognition of early signs and symptoms.

ANTHOLOGY is an ATTR amyloidosis program, evidence generation, and quality improvement opportunity comprised of two multi-country, longitudinal, observational, real-world evidence studies: OverTTuRe (ClinicalTrials.gov identifier, NCT06355934) and MaesTTRo (NCT06465810). OverTTuRe will retrospectively extract and analyze secondary data from a broad spectrum of sources, and MaesTTRo will prospectively collect and analyze data from patient-reported outcome questionnaires, electronic health records, and insurance claims.

The primary objectives of OverTTuRe are to describe contemporary patient characteristics, treatment patterns and disease outcomes, and to characterize healthcare resource utilization (HCRU) and HRQoL in patients diagnosed with ATTR amyloidosis. Describing patient characteristics and HCRU before diagnosis is a secondary objective. The primary objectives of MaesTTRo are to describe patient characteristics, disease history and treatment patterns from diagnosis, and to prospectively define and assess the real-world effectiveness of current therapies. Secondary objectives are to compare the characteristics of patients according to the therapy received and compare the real-world effectiveness of current therapies. Exploratory objectives are to identify risk factors for disease progression and to describe healthcare costs.

ANTHOLOGY aims to broaden understanding of the contemporary epidemiology of ATTR amyloidosis, identify opportunities to accelerate diagnosis, and assess real-world comparative effectiveness of treatments. This knowledge will be used to define world-class patient care, improve treatment outcomes and HRQoL, inform updates to clinical practice guidelines and treatment pathways, and transform ATTR amyloidosis management through evidence aimed at improving the quality of the current standard of care TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT06355934 (OverTTuRe) and NCT06465810 (MaesTTRo).

The most common form of hereditary transthyretin cardiac amyloidosis (hATTR-CA) in the United States and the United Kingdom is the p.V142I variant. About 3% to 4% of patients with African ancestry carry this genetic predisposition to develop signs and symptoms of hATTR-CA. Nevertheless, clinical manifestations of hATTR-CA appear only late in the fifth and sixth decades of life, despite its clear genetic background. Imbalances in native protein-stabilizing and elementary breakdown cellular mechanisms are postulated as potential causes for affecting transthyretin structural integrity and myocardial fibril deposition. Noncoding variants, epigenetic and environmental factors, as well as gut microbiome derangements may serve as disease-modifying factors that feature detrimental amyloidogenic organ involvement and impact disease severity. Organ amyloid deposition varies widely among different carriers of a genetic transthyretin variant. The genotype-phenotype interdependence causes unpredictable phenotypic penetrance that results in a variety of signs and symptoms and patient outcomes. Cardiovascular biomarkers and multimodality imaging may identify initial amyloidogenic organ involvement. These early clinical clues through the course of hATTR-CA offer a window of opportunity for early treatment onset to cease disease progression and alter prognosis. Identifying at-risk patients requires information on the genetic background of probands and their relatives. Initiatives to reveal asymptomatic gene carriers early in the disease should be encouraged, as it necessitates stringent patient follow-up and immediate treatment onset to reduce the burden of heart failure hospitalization and mortality in hATTR-CA.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease caused by the pathological deposition of misfolded transthyretin (TTR) protein in the myocardium, leading to restrictive cardiomyopathy and heart failure. While TTR stabilizers such as tafamidis and acoramidis are the only FDA-approved treatments, novel gene-modulating therapies are emerging as transformative approaches. Small interfering RNA (siRNA) and antisense oligonucleotide (ASO) therapies effectively reduce TTR production and have demonstrated promising clinical outcomes, though their use in cardiac amyloidosis remains investigational. CRISPR-Cas9 therapies represent a paradigm shift, offering a potential one-time treatment by permanently silencing the TTR gene. Recent clinical trials have shown significant TTR reduction and stabilization of disease biomarkers, although long-term safety and efficacy require further evaluation. Despite the lack of direct comparisons among these modalities, their emergence highlights a promising future for ATTR-CM management. This review discusses the pathogenesis of ATTR-CM, mechanisms of novel gene-modulating therapies, clinical evidence, challenges, and the future outlook for advancing treatment options.

Cardiac sympathetic neuronal dysfunction is an early marker in wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt-CM). Iodine-123-labeled norepinephrine analog meta-iodobenzylguanidine ([123I]-MIBG) imaging evaluates cardiac sympathetic innervation but lacks volumetric activity quantification in current methods. This study aims to quantify cardiac sympathetic neuronal dysfunction in ATTRwt-CM using [123I]-MIBG single-photon emission computed tomography/ computed tomography (SPECT/CT) and correlate findings with functional and structural cardiac parameters from echocardiogram and cardiac magnetic resonance imaging (CMR).

We conducted a single-center, descriptive, cross-sectional study to quantify absolute myocardial sympathetic function in ATTRwt-CM using [123I]-MIBG SPECT/CT. Retrospective reconstruction allowed for absolute tracer-uptake quantification of the left ventricle, overall and segmented, in kBq/mL, standard uptake value (SUV), and percentage of the injected dose (%ID). Echocardiography, CMR, and bone scintigraphy were performed according to clinical standards. Segmented [123I]-MIBG SPECT/CT values were correlated with global longitudinal systolic strain (GLSS) on echocardiography, native-T1, and extracellular volume (ECV) on CMR using SPECT/CT fused with CMR.

Twenty-nine ATTRwt-CM patients (75.8 ± 6.6 years, 90% male) were prospectively included. All exhibited cardiac sympathetic neuronal dysfunction, with a median late heart-to-mediastinum ratio of 1.69 (1.45-1.89) and a washout rate of 22.7% (16.4%-27.3%). SUVmean, SUVpeak, SUVmax, and %ID were 1.80 ± .78, 3.84 ± 1.41, 4.46 ± 1.68, and .46 ± .18, respectively, correlating with semiquantitative [123I]-MIBG measures. No correlations were found with GLSS on echocardiography or native T1 and ECV on CMR.

The current study demonstrates the feasibility of volumetric quantification of [123I]-MIBG SPECT/CT in ATTRwt-CM. SUVmean, SUVpeak, SUVmax, and %ID correlate with semi-quantitative measures but not with key cardiac parameters on echocardiography or CMR. This confirms the sensitivity of [123I]-MIBG SPECT/CT to different aspects of cardiac function or pathology.

EudraCT ref. 2020-003350-72, retrospectively registered March 20, 2023. https://classic.

gov/ct2/show/NCT05776212.

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.

Left ventricular thrombosis (LVT) is one of the most feared complications of both ischemic and non-ischemic cardiopathy, and despite its incidence having decreased over the years (mostly due to novel reperfusion therapies in acute coronary syndromes), it is still not negligible. If transthoracic echocardiography, possibly with the adjunction of echo contrast, represents the cornerstone in LVT diagnosis, sometimes it is found to be nonconclusive and advanced cardiovascular imaging, namely cardiac magnetic resonance, needs to be performed to fully exclude intraventricular masses or to better characterize them. Vitamin K antagonists always represented the anticoagulant of choice for the treatment of LVT; however, the recent spread of direct oral anticoagulants (DOACs) pushed clinicians to adopt them also in this setting despite the absence of robust evidence in their favor. If the optimal duration of anticoagulation for the treatment of LVT in non-ischemic cardiopathy is still a matter of debate, an initial treatment of 3-6 months seems to be reasonable in the setting of ischemic cardiopathy, with possible extension according to the follow-up findings. High-quality randomized studies are strongly needed to evaluate the potential role of prophylactic anticoagulation in high-risk patients and provide conclusive evidence for the use of DOACs in LVT treatment.

To determine whether transthyretin (TTR) influences the prognosis of patients with colorectal cancers and establish a predictive model based on TTR.

Between January 2013 and February 2019, the clinical data of 1322 CRC patients aged from 18 years to 80 years who underwent surgical treatment were retrospectively analyzed. The preoperative TTR level, clinicopathological data, and follow-up data were recorded. The X-tile program was used to determine the optimal cut-off value. Cox proportional hazard regression analysis was conducted to evaluate the correlation between the TTR and the cumulative incidence of cancer-specific survival (CSS). Nomograms were then developed to predict CSS. Furthermore, an additional cohort of 377 CRC patients enrolled between January 2014 and December 2015 was included as an external validation.

Based on the optimal cut-off value of 121.3 mg/L, we divided the patients into the TTR-lower group (<121.3 mg/L) and the TTR-higher group (≥121.3 mg/L). Comparative analysis revealed that the TTR-higher group exhibited a younger demographic, a higher prevalence of low colorectal cancers, an elevated R0 resection rate, superior differentiation, earlier stage and lower levels of carcinoembryonic antigen (CEA) in contrast to the TTR-lower group. The Cox multivariable analysis underscored the significance of TTR and various clinicopathological factors, encompassing age, tumor location, R0 resection status, differentiation grade, disease stage, postoperative chemoradiotherapy, and preoperative CEA levels, as substantial prognostic indicators. The postoperative survival nomogram, when internally and externally assessed, demonstrated commendable performance across multiple metrics, including the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis (DCA). Compared with other models, the proportional hazards model combined with TTR demonstrates superior performance in terms of C-index, AUC, calibration chart, and DCA within the prognostic column chart.

The preoperative TTR was identified as a prognostic factor for predicting the long-term prognosis of CRC patients who underwent surgical treatment, supporting its role as a prognostic biomarker in clinical practice.

This 2025 updated consensus outlines the diagnostic strategy for transthyretin amyloid cardiomyopathy (ATTR-CM). Given that ATTR-CM is a significant contributor to heart failure, this article emphasizes the importance of making an early and precise diagnosis, particularly as new therapeutic options become available. Highlighting the critical importance of an early and accurate diagnosis, particularly in light of emerging therapeutic modalities, this consensus underscores the central role of 99mTc-pyrophosphate (PYP) scintigraphy as a non-invasive diagnostic tool. The consensus calls for the adoption of standardized imaging protocols and interpretation criteria to ensure consistency and reliability across diverse clinical settings. The integration of qualitative and quantitative imaging techniques within a structured diagnostic framework places particular focus on the use of single-photon emission computed tomography/computed tomography (SPECT/CT) imaging to enhance diagnostic precision by minimizing blood pool activity and eliminating overlapping interference. Three-hour imaging is considered to be critical for accurate evaluations and to reduce false-positive findings, and it is recommended for its superior diagnostic accuracy. Moreover, quantitative assessments are also considered to be essential for evaluating myocardial amyloid deposition. This updated consensus provides comprehensive guidelines for clinicians, with the aim of optimizing patient outcomes through precise diagnosis and effective management of ATTR-CM. The consensus concludes by advocating for continued research and refinement of imaging methodologies, particularly to enhance the clinical applicability of 99mTc-PYP scintigraphy and other future developments in nuclear molecular imaging.

Cardiac amyloidosis (CA) is a form of infiltrative, restrictive cardiomyopathy that presents a diagnostic and therapeutic challenge in clinical practice. Historically, it has led to poor prognosis due to limited treatment options. However, advancements in disease awareness, diagnostic tools, and management approaches have led to the beginning of an era characterized by earlier diagnosis and a broader range of treatments. This article examines the advances in treating the two primary forms of cardiac amyloidosis: transthyretin cardiac amyloidosis (ATTR-CA) and light chain mediated cardiac amyloidosis (AL-CA). It highlights therapies for ATTR-CA that focus on interrupting the process of amyloid fibril formation. These therapies include transthyretin stabilizers, gene silencers, and monoclonal antibodies, which have shown the potential to improve patient outcomes and survival rates significantly. As of this writing, tafamidis is the sole Food and Drug Administration (FDA)--approved drug for ATTR-CA; however, experts anticipate several other drugs will gain approval within 1-2 years. Treatment strategies for AL-CA typically involve chemotherapy to inhibit the clonal cell type responsible for excessive AL amyloid fibril production. The prognosis for both types of amyloidosis primarily depends on how much the heart is affected, with most deaths occurring due to progressive heart failure. Effective care for CA patients requires collaboration among specialists from multiple disciplines, such as heart failure cardiology, electrophysiology, hematology/oncology, nephrology, neurology, pharmacology, and palliative care.

To estimate the burden of transthyretin cardiac amyloidosis (ATTR-CA) through a cross- sectional 'snapshot' of Australian Amyloidosis Network (AAN) and New Zealand (NZ) specialist amyloidosis clinics.

A prospective survey was performed of seven AAN/ specialist amyloidosis clinics across Australia and NZ. All centres were invited to contribute data; participating centres provided clinical and demographic data for patients with ATTR-CA reviewed in the 2022 calendar year. Patients with new or previously confirmed ATTR-CA reviewed in the 2022 calendar year were included. Diagnosis was established through a positive cardiac scintigraphy scan in the absence of a monoclonal gammopathy or through a cardiac biopsy staining positive with transthyretin (TTR).

A total of 515 patients were reviewed across seven sites. A total of 302/515 (59%) were wild type TTR (ATTRwt), 63/515 (12%) were variant ATTR (ATTRv) and the remaining 150 (29%) had not undergone genetic testing at the time of data collection. A total of 455/515 (88%) patients were male. Compared to ATTRwt, patients with ATTRv had smaller left ventricular (LV) wall thickness (IVSd 14±3 mm vs 16±3mm, p<0.001), and better LV systolic function (LVGLS -15.4±5% vs -11.7±3%, p<0.001). Most patients, 387/515 (75%) were on at least one ATTR specific treatment, including EGCG (157), diflunisal (139), doxycycline (68) and tafamidis (78), acoramidis (33) and gene silencer therapies or monoclonal antibodies (23).

A significant number of patients with ATTR-CA are seen in specialist amyloidosis clinics across Australia and NZ. Most patients received specific amyloidosis therapy, thorough enrollment in clinical trials. With increased recognition of amyloidosis and newer therapies becoming available, the volume of patients seen in these clinics is likely to increase.

Atrial and ventricular arrhythmias are common in patients with Infiltrative heart diseases. This review discusses ablative techniques for arrhythmias in amyloidosis, sarcoidosis, hemochromatosis, and glycogen storage disorders, primarily focusing on atrial fibrillation (AF). A thorough literature review was conducted on the MEDLINE database to synthesize current knowledge and propose future research directions. AF is the most common arrhythmia identified in patients with amyloidosis due to cellular infiltration and atrial dilation. While catheter ablation is associated with a significantly lower rate of all-cause mortality and admission rate, conflicting data exist regarding the higher risk of pericardial effusion, in-hospital mortality, length of stay, and cost of hospitalization. Cardiac sarcoid predisposes AF due to granulomas, atrial dilation, and scarring. Studies demonstrate encouraging outcomes and low recurrence rates in these patients who undergo ablation for AF, with no difference in complications compared to those without sarcoidosis. AF is the most common arrhythmia in hereditary hemochromatosis (HH), secondary to increased myocardial iron stores and elevated oxidative stress, and is primarily managed by chelation. Scant reports regarding ablation are described for HH and glycogen storage disorders. Catheter ablation is a safe and effective modality for the treatment of AF in infiltrative cardiomyopathy. Future large-scale trials are needed to confirm these findings.

Technetium Tc 99m pyrophosphate scintigraphy (99mTc PYP imaging) is a diagnostic tool for transthyretin amyloid cardiomyopathy (ATTR-CM). Cardiac biomarkers, particularly high-sensitivity cardiac troponin (hs-cTn) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), may help identify patients at low or high risk for ATTR-CM.

The authors sought to evaluate the predictive value of hs-cTnT and NT-proBNP in patients undergoing 99mTc PYP imaging for suspected ATTR-CM in a large U.S. cohort.

This was a retrospective study of patients who underwent 99mTc PYP imaging between May 2013 and September 2022, including those with at least 1 hs-cTnT measurement within 6 months of the scan.

ATTR-CM was diagnosed in 427 of 1,442 patients (29.6%). A hs-cTnT level <6 ng/L (n = 50, 3.5%) showed a negative predictive value of 100% (95% CI: 93%-100%) and sensitivity of 100% (95% CI: 99%-100%) for ruling out ATTR-CM. As the hs-cTnT threshold increased, the number of patients who could be ruled out also increased, but false negatives emerged. The positive predictive value for ruling in ATTR-CM remained low. NT-proBNP showed similar results (n = 1,378). The combination of hs-cTnT <14 ng/L and NT-proBNP <60 ng/L identified 45 patients (3.3%) without ATTR-CM.

In patients undergoing 99mTc PYP imaging for suspected ATTR-CM, very low hs-cTnT levels can effectively rule out the diagnosis, although in a small subset of patients. Higher thresholds increase the risk of false negatives. NT-proBNP and combined biomarker strategies showed similar trends, the utility of hs-cTnT and NT-proBNP for ruling in the disease is limited.

The prognostic implications of cerebral microbleeds (CMBs) in patients who undergo transcatheter aortic valve replacement (TAVR) have not been fully elucidated. Therefore, we aimed to investigate the association between the presence of CMBs and adverse outcomes post-TAVR.

In this single-center retrospective study, we included 124 patients who underwent brain magnetic resonance imaging before TAVR. The outcomes of interest were the subsequent incidences of stroke and all-cause death or admission for heart failure.

CMBs were identified in 32.2 % of the included patients. The median follow-up duration was 954 (interquartile range, 553-1306) days. The incidence of stroke after TAVR was comparable between patients with and without CMBs. Conversely, all-cause death or admission for heart failure was significantly higher in patients with CMBs than in those without (log-rank P = 0.010). Multivariate Cox regression analysis revealed that the presence of CMBs was independently correlated with the occurrence of all-cause death or admission for heart failure after adjusting for other prognostic predictors (hazard ratio 4.016, 95 % confidence interval 1.572-10.259, P = 0.007).

The presence of CMBs predicts the incidence of all-cause death or admission for heart failure in patients undergoing TAVR. Evaluating CMBs could provide useful information for post-TAVR management.

Transthyretin cardiac amyloidosis (ATTR-CA) is most often associated with heart failure with preserved ejection fraction (HFpEF). However, patients may present with impaired systolic function at the time of diagnosis, which has not been widely investigated. We sought to explore the prevalence of various heart failure (HF) phenotypes and their associated clinical characteristics at the time of ATTR-CA diagnosis.

We performed a single-centre retrospective cohort study of consecutive patients with ATTR-CA evaluated between February 2016 and December 2022. Data on patient demographics, comorbidities, imaging and laboratory findings were compared across HF phenotypes (age: 78.1 ± 8.6 years, with 91.1% male). A total of 21.6% (n = 46) presented with heart failure with reduced ejection fraction (HFrEF), 17.8% (n = 38) with heart failure with mildly reduced ejection fraction (HFmrEF) and 60.6% (n = 129) with HFpEF at the time of diagnosis with ATTR-CA. Those presenting with HFrEF or HFmrEF were more likely to be African American and had significantly worse New York Heart Association (NYHA) functional class, higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and higher serum creatinine levels as compared with those with HFpEF.

Although ATTR-CA is traditionally thought to be seen primarily among patients with HFpEF, our data suggest that ATTR-CA has a higher prevalence among patients with HFrEF, which underscores the importance of heightened clinical suspicion regardless of ejection fraction when considering ATTR-CA. Furthermore, although comorbidities are similar, patients with HFmrEF and HFrEF had a worse symptom burden.

Cardiac amyloidosis (CA) is a serious condition that results in infiltrative cardiomyopathy and heart failure with preserved ejection fraction (HFpEF) that is caused by the extracellular deposition of amyloid fibrils within heart tissue. While many important features of CA have been known for years, its prevalence in elderly patients with HF is increasingly being recognized. Plasma cells produce monoclonal immunoglobulin light chains which results in the formation and aggregation of amyloid fibrils that are responsible for AL amyloidosis. CA is classified as originating from either transthyretin (ATTR) or light chain (AL) amyloidosis. ATTR CA may result from a genetic mutation in the TTR gene, which is inherited (ATTRv), or from age-related deposition from wild-type ATTR (ATTRwt). Cardiac involvement in AL amyloidosis is attributed to either of two mechanisms: the extracellular deposition of amyloid fibril in the myocardium, or direct cardiotoxicity from the fibril aggregates. Typing of amyloid fibrils, a critical determinant of therapy, has also improved with wider availability of laser capture and mass spectrometry of histologic specimens. Specific and accurate evaluation of CA is now possible using cardiac magnetic resonance imaging and bone scintigraphy tracers. Survival in CA has improved markedly as novel chemotherapy agents have become available, but challenges remain in advanced disease. Broadening the amyloid-specific therapeutic landscape to include RNA inhibitors, fibril formation stabilizers and inhibitors, and immunotherapeutic targeting of amyloid deposits holds promise and may improve outcomes in systemic and cardiac amyloidoses. Treatment strategies for CA has recently undergone transformative changes, leading to some progress in outcomes for certain patients. Here, we discuss the basic features of CA as well as the emergence of novel, disease-modifying strategies that have been recently evaluated in clinical trials for the treatment of CA.

Amyloidosis with cardiac involvement is a fatal disease leading to progressive heart failure. The most common forms of amyloidosis with cardiac involvement are light chain (AL) and transthyretin (ATTR) amyloidosis. To allow effective specific treatment for both forms, precise and early diagnosis is important. This review focuses on diagnostic approaches for AL and ATTR amyloidosis with cardiac involvement, including different strategies, the role of imaging and biomarkers and possible pitfalls.

Anemia is prevalent in transthyretin amyloid cardiomyopathy (ATTR-CM), but its prognostic significance remains uncertain because of conflicting data mainly in patients not receiving disease-modifying therapy. Additionally, the effect of anemia on morbidity in this population has not been studied. This retrospective study included 270 patients diagnosed with ATTR-CM, receiving disease-modifying treatment (tafamidis), of which 30% (n = 80) were anemic (defined as a hemoglobin level <13 g/100 ml for males and <12 g/100 ml for females according to the World Health Organization). At baseline, patients with anemia were on average older (mean age 79 vs 77 years), more likely to be female (21% vs 12%), and exhibited higher symptom severity based on the New York Heart Association class (42% in class III vs 27%) compared with those without anemia. Additionally, they had a worse Columbia score (mean score 3 vs 5) and Columbia stage (12% in late-stage vs 7.1%) than those without anemia. Kaplan-Meier analysis indicates that anemia was associated with a higher likelihood of mortality, all-cause, and cardiovascular (CV) hospitalizations (p <0.05). However, in the Cox regression analysis, after adjusting for baseline age, ATTR genotype, and Columbia score, anemia was only associated with a higher risk of all-cause hospitalizations (hazard ratio 1.9 (1.3 to 2.7), p <0.001) and CV-related hospitalizations (hazard ratio 1.9 (1.2 to 2.9), p = 0.006). In conclusion, this study indicates that anemic patients with ATTR-CM have higher risks of CV and all-cause hospitalizations compared with nonanemic ATTR-CM patients. Further research is needed to understand how treating anemia may improve outcomes in this high-risk patient population.

Systemic amyloidosis represents a heterogeneous group of diseases resulting from amyloid fibre deposition. The purpose of this study is to establish a differential diagnosis algorithm targeted towards the two most frequent subtypes of CA.

We prospectively included all consecutive patients with ATTR and AL evaluated between 2018 and 2022 in two centres in a score derivation cohort and a different validation sample. All patients had a complete clinical, biomarker, electrocardiographic, and imaging evaluation. Confirmation of the final diagnosis with amyloid typing was performed according to the current international recommendations. The study population included 81 patients divided into two groups: ATTR (group 1, n = 32: 28 variant and 4 wild type) and AL (group 2, n = 49). ATTR patients were younger (50.7 ± 13.9 vs. 60.2 ± 7.3 years, P = 0.0001), and significantly different in terms of NT-proBNP [ATTR: 1472.5 ng/L (97-4218.5) vs. AL 8024 ng/L (3058-14 069) P = 0.001], hs-cTn I [ATTR: 10 ng/L (4-20) vs. AL 78 ng/L (32-240), P = 0.0002], GFR [ATTR 95.4 mL/min (73.8-105.3) vs. AL: 68.4 mL/min (47.8-87.4) P = 0.003]. At similar left ventricular (LV) wall thickness and ejection fraction, the ATTR group had less frequently pericardial effusion (ATTR: 15% vs. AL: 33% P = 0.0027), better LV global longitudinal strain (ATTR: -13.1% ± 3.5 vs. AL: -9.1% ± 4.3 P = 0.04), RV strain (ATTR: -21.9% ± 6.2 vs. AL: -16.8% ± 6 P = 0.03) and better reservoir function of the LA strain (ATTR: 22% ± 12 vs. AL: 13.6% ± 7.8 P = 0.02). Cut-off points were calculated based on the Youden method. We attributed to 2 points for parameters having an AUC > 0.75 (NT-proBNP AUC 0.799; hs-cTnI AUC 0.87) and 1 point for GFR (AUC 0.749) and TTE parameters (GLS AUC 0.666; RV FWS AUC 0.649, LASr AUC 0.643). A score of equal or more than 4 points has been able to differentiate between AL and ATTR (sensitivity 80%, specificity 62%, AUC = 0.798). The differential diagnosis score system was applied to the validation cohort of 52 CA patients showing a sensitivity of 81% with specificity of 77%.

CA is a complex entity and requires extensive testing for a positive diagnosis. This study highlights a series of non-invasive checkpoints, which can be useful in guiding the decision-making process towards a more accurate and rapid differential diagnosis.

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.

This study investigated the prevalence, incidence, and prognosis of cardiac amyloidosis (CA) in Korea.

This retrospective nationwide population-based study used the Health Insurance Review and Assessment Service databases between 2008 and 2020. All patients diagnosed with amyloidosis were included, and those with a diagnosis of heart failure or cardiomyopathy were classified as having CA. Both the special code for amyloidosis (V121), which enables coverage of medical expenses, and the corresponding International Classification of Diseases, 10th revision codes for amyloidosis (E850- E854, E858, E859) were used to improve the reliability of amyloidosis diagnosis.

Among 2,239 patients with amyloidosis, 758 met the criteria for CA (mean age, 64.4±11.9 years; 59.1% male). The mean age of patients with CA increased from 59.5±14.7 years in 2009 to 68.1±13.9 years in 2020. The incidence and prevalence increased from 0.09 (95% confidence interval [CI], 0.06 to 0.12) to 0.22 (95% CI, 0.18 to 0.27) per 100,000 person-years and 0.20 (95% CI, 0.16 to 0.25) to 1.30 (95% CI, 0.12 to 0.42) per 100,000 persons, respectively (all p<0.001). Patients with light-chain CA showed similar trends. In-hospital mortality decreased from 17.3% (95% CI, 9.23 to 29.6) to 6.10% (95% CI, 4.21 to 8.48) between 2009 and 2020. While age-specific in-hospital mortality was significantly higher in patients aged ≥70 years (p=0.004), no significant age-specific difference in in-hospital mortality was observed in patients with CA aged <70 years (p=0.981).

The prevalence and incidence of CA have increased in Korea, predominantly affecting older individuals, particularly males. Notably, in-hospital mortality decreased significantly.

The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt.

The aetiology of heart failure with preserved ejection fraction (HFpEF) is heterogenous and overlaps with that of several comorbidities like atrial fibrillation, diabetes mellitus, chronic kidney disease, valvular heart disease, iron deficiency, or sarcopenia. The diagnosis of HFpEF involves evaluating cardiac dysfunction through imaging techniques and assessing increased left ventricular filling pressure, which can be measured directly or estimated through various proxies including natriuretic peptides. To better narrow down the differential diagnosis of HFpEF, European and American heart failure guidelines advocate the use of different algorithms including comorbidities that require diagnosis and rigorous treatment during the evaluation process. Therapeutic recommendations differ between guidelines. Whilst sodium glucose transporter 2 inhibitors have a solid evidence base, the recommendations differ with regard to the use of inhibitors of the renin-angiotensin-aldosterone axis. Unless indicated for specific comorbidities, the use of beta-blockers should be discouraged in HFpEF. The aim of this article is to provide an overview of the current state of the art in HFpEF diagnosis, clinical evaluation, and treatment.

Cardiac amyloidosis represents a spectrum of conditions characterized by the accumulation of insoluble fibrils, resulting in progressive deposition and myocardial dysfunction. The exact mechanisms contributing to the heightened risk of thromboembolic events and bleeding tendencies in cardiac amyloidosis remain unclear. Proteins such as transthyretin in transthyretin amyloidosis and light chains in light-chain amyloidosis, along with acute phase proteins in amyloid A (AA) amyloidosis, play complex roles in the coagulation cascade, affecting both coagulation initiation and fibrinolysis regulation. The increased occurrence of atrial fibrillation, systolic and diastolic left ventricular dysfunction, and atrial myopathy in patients with cardiac amyloidosis may predispose them to thrombus formation. This predisposition can occur regardless of sinus rhythm status or even with proper anticoagulant management. Bleeding events are often linked to amyloid deposits around blood vessels, which may increase capillary fragility and cause coagulation disturbances, leading to unstable international normalized ratio levels during anticoagulant therapy. Thus, comprehensive risk assessment for both thrombotic and hemorrhagic complications, especially before commencing anticoagulant therapy, is imperative. This review will explore the essential pathophysiological, epidemiologic, and clinical aspects of thromboembolic and bleeding risk in cardiac amyloidosis, evaluating the existing evidence and uncertainties regarding thrombotic and bleeding risk assessment and antithrombotic treatment.

Aggregation of aberrant fragment of plasma gelsolin, AGelD187N, is a crucial event underlying the pathophysiology of Finnish gelsolin amyloidosis, an inherited form of systemic amyloidosis. The amyloidogenic gelsolin fragment AGelD187N does not play any physiological role in the body, unlike most aggregating proteins related to other protein misfolding diseases. However, no therapeutic agents that specifically and effectively target and neutralize AGelD187N exist. We used phage display technology to identify novel single-chain variable fragments that bind to different epitopes in the monomeric AGelD187N that were further maturated by variable domain shuffling and converted to antigen-binding fragment (Fab) antibodies. The generated antibody fragments had nanomolar binding affinity for full-length AGelD187N, as evaluated by biolayer interferometry. Importantly, all four Fabs selected for functional studies efficiently inhibited the amyloid formation of full-length AGelD187N as examined by thioflavin fluorescence assay and transmission electron microscopy. Two Fabs, neither of which bound to the previously proposed fibril-forming region of AGelD187N, completely blocked the amyloid formation of AGelD187N. Moreover, no small soluble aggregates, which are considered pathogenic species in protein misfolding diseases, were formed after successful inhibition of amyloid formation by the most promising aggregation inhibitor, as investigated by size-exclusion chromatography combined with multiangle light scattering. We conclude that all regions of the full-length AGelD187N are important in modulating its assembly into fibrils and that the discovered epitope-specific anti-AGelD187N antibody fragments provide a promising starting point for a disease-modifying therapy for gelsolin amyloidosis, which is currently lacking.

Wild-type transthyretin amyloid (ATTRwt) cardiomyopathy is increasingly recognized in the development of heart failure. The link between cardiac performance, hemodynamics, and mitochondrial function in disease stages of ATTRwt has not previously been studied but may provide new insights into the pathophysiology and clinical performance of the patients.

The study investigated 47 patients diagnosed with ATTRwt at Aarhus University Hospital, Denmark. Patients were stratified according to the disease stages of the National Amyloidosis Centre (NAC) as NAC I with low levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) (NAC I-L, n=14), NAC I with high levels NT-proBNP (NAC I-H, n=20), and NAC II-III (n=13). Exercise testing with simultaneous right heart catheterization was performed in all patients. Endomyocardial biopsies were collected from the patients and the mitochondrial oxidative phosphorylation capacity was assessed. All NAC disease groups, even in the NAC I-L group, a significant abnormal increase in biventricular filling pressures were noted during exercise while the filling pressures was normal or near normal at rest. The inotropic response to exercise was reduced with diminished increase in cardiac output which was significantly more pronounced in the NAC I-H (Diff. -2.4, 95% CI (-4.2: -0.7), P=0.00) and the NAC II-III group (Diff: -3.1 L/min, 95% CI (-5.2: -1.1), P=0.00) compared with the NAC I-L group. The pulmonary artery wedge pressure to cardiac output ratio at peak exercise was significantly different between NAC I-L and NAC II-III (Diff: 1.6 mm Hg*min/L, 95% CI (0.01:3.3, P=0.04)). Patients with ATTRwt had a reduced oxidative phosphorylation capacity which correlated to left ventricular mass but not to cardiac output capacity.

An abnormal restrictive left ventricle and right ventricle response to exercise was demonstrated, even present in patients with early-stage ATTRwt. In more advanced disease stages a progressive impairment of the pressure-flow relationship was noted. The myocyte energetics is deranged but not associated to the contractile reserve or restrictive filling characteristics in ATTRwt.

Amyloidosis is a heterogenous group of disorders, caused by the deposition of insoluble fibrils derived from misfolded proteins in the extracellular space of various organs. These proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils with the pathognomonic histologic property of green birefringence when viewed under cross-polarized light after staining with Congo red. Amyloid fibrils are insoluble and degradation-resistant; resistance to catabolism results in progressive tissue amyloid accumulation. The outcome of this process is organ disfunction independently from the type of deposited protein, however there can be organ that are specifically targeted from certain proteins.

Amyloidosis, particularly wild-type transthyretin amyloidosis (ATTRwt), is an increasingly recognized cause of heart failure with preserved ejection fraction in the aging population. The complexity of managing ATTRwt in older patients underscores the necessity for individualized treatment approaches, yet clinical guidelines are lacking. This case report contributes to the understanding of ATTRwt management in the elderly, emphasizing the intricacies of medication tolerance and therapeutic decision-making.

An 83-year-old Korean man with a history of hypertension presented with dyspnea and peripheral edema. Investigations including electrocardiography, transthoracic echocardiography, cardiac magnetic resonance, and Technetium pyrophosphate scintigraphy led to a diagnosis of ATTRwt cardiac amyloidosis. Initial management with heart failure medications, including an angiotensin-converting enzyme inhibitor, diuretic, and mineralocorticoid receptor antagonist, was modified due to evolving clinical presentations, such as hypotension and onset of atrial fibrillation. Challenges included intolerance to beta-blockers and bleeding complications from direct oral anticoagulant therapy. The patient's treatment journey highlighted the need for personalized management strategies in older ATTRwt patients.

This case illustrates the challenges in diagnosing and managing ATTRwt amyloidosis in the elderly, particularly the complexities in medication management due to the patient's age, comorbid conditions, and side effects. It underscores the importance of a tailored approach in managing ATTRwt in older populations and highlights the need for ongoing research and development of treatment strategies tailored to this demographic.