Search Results (42)

Focal Adhesion Kinase (FAK) is a key regulator of tumor cell migration and survival, and its persistent overexpression in aggressive cancers has motivated ongoing efforts to identify novel small-molecule inhibitors. Despite this interest, progress in discovering new potent scaffolds has been limited. In this work, we applied a multistep computational workflow followed by experimental testing to refine hit selection and reduce the false positives typically associated with docking. DrugBank and several commercial libraries were screened using Exponential Consensus Ranking (ECR) docking, and molecular dynamics simulations were used to assess pose stability and interaction persistence. A subset of predicted binders was then tested in MG-63 (bone cancer) and MDA-MB-231 (breast cancer) cells using cell viability and wound-healing assays, followed by direct autophosphorylation assays with recombinant FAK. Several repurposed compounds, including clofazimine and tafamidis, produced clear dose-dependent effects on cell migration, although their inhibitory activity in biochemical assays remained weak (${\mathrm{IC}}_{50}$ values above 100 $\mu$M), far from the potency of the reference inhibitor TAE226. Retrospective analysis of the computational workflow showed that standard MM-GBSA calculations did not correlate with these experimental outcomes. However, incorporating explicit water molecules through the NWAT-MMGBSA approach improved agreement with the biochemical data and helped to rationalize the limited affinity observed experimentally. Taken together, the results underline the relevance of explicit solvation in modeling the FAK active site and suggest that refined solvent-aware protocols may provide more reliable guidance for future screening efforts. 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

This review article aims to provide an overview of the pathophysiology, diagnosis, and contemporary management of cardiac amyloidosis (CA) as well as identify the knowledge gaps and areas of potential research. CA can be divided into two main groups: transthyretin cardiac amyloidosis (ATTR-CA) and light chain cardiac amyloidosis (AL-CA). The former further separates into wild-type transthyretin (ATTRwt) and hereditary transthyretin (ATTRv). African Americans, males, and people older than 75 are the most common demographics affected by this disease. Thanks to an increased understanding of this disease combined with better diagnostic techniques, there is growing awareness and a surge of clinical trials aimed at improving outcomes of CA. The diagnosis and treatment of CA is multifaceted and complex, relying on multiple imaging modalities and the cooperation of specialists to deliver effective treatments. While some disease-modifying agents have been introduced recently, their extraordinary cost limits their benefit or they are supported by limited evidence. Other agents are currently undergoing phase 3 trials. To date, there is scarce data surrounding optimal diagnostic and treatment strategies, including a potential role for combination therapies. Critically, it is imperative that physicians develop close relationships with the patient that addresses not only their individual health needs but also their unique psychosocial situation. Therefore, more clinical trials, protocols and patient resources are needed to better inform and guide providers managing these complex patient needs. Full article

Background: Transthyretin cardiac amyloidosis (ATTR-CM) is an infiltrative cardiomyopathy that frequently progresses to symptomatic heart failure (HF), often with mildly reduced or reduced ejection fraction (EF). Standard therapies are limited in NYHA III–IV, and Tafamidis is approved only for the early stages. Cardiac contractility modulation (CCM) therapy has shown promise in HF with reduced EF, but its role in ATTR-CM remains unexplored. Methods: This multicentric, prospective pilot study evaluated the safety and efficacy of CCM therapy in ten patients (n = 10) with ATTR-CM, EF between 25 and 45%, and NYHA class III–IV symptoms refractory to optimal medical therapy. All patients underwent implantation of the Optimizer CCM system and were followed for at least 12 months. The primary endpoint was the incidence of worsening heart failure (WHF); secondary endpoints included changes in EF, NYHA class, 6-minute walk test (6MWT), and quality of life metrics. Results: In this cohort (n = 10), CCM therapy significantly reduced WHF episodes (from 0.18 ± 0.09 to 0.025 ± 0.08 hospitalizations/patient-year, p < 0.001) and improved NYHA class and 6MWT (p < 0.001). EF increased by an average of 4.8 ± 6.1%, and 6MWT improved by 31.3 ± 53.3%. Importantly, all patients became eligible for Tafamidis after CCM therapy due to improved functional status. Conclusion: This pilot study suggests that CCM therapy is a feasible and potentially effective option for ATTR-CM patients with advanced HF who are not candidates for existing disease-modifying treatments. These findings support the rationale for larger studies, including the ongoing AMY-CCM registry (NCT05167799), to validate CCM’s therapeutic role in this population. Full article

Background: Cardiac amyloidosis (CA) is an increasingly recognized but historically underdiagnosed cause of restrictive cardiomyopathy and heart failure with preserved ejection fraction (HFpEF). It results from the extracellular deposition of misfolded protein fibrils, most commonly transthyretin (ATTR) or immunoglobulin light chains (AL), leading to progressive myocardial dysfunction and multi-organ involvement. Objective: This review provides a comprehensive, cardiology-centered overview of cardiac amyloidosis, with an emphasis on early recognition, diagnostic strategies, subtype differentiation, and the evolving therapies. Content: We summarize the epidemiology, pathophysiology, and clinical manifestations of both ATTR and AL subtypes. Key diagnostic tools, including echocardiography, cardiac magnetic resonance imaging, bone scintigraphy, monoclonal protein screening, and endomyocardial biopsy, are reviewed in the context of a stepwise diagnostic approach. Special attention is given to clinical presentation, electrocardiographic and imaging “red flags,” and to differentiating CA from mimickers such as hypertrophic cardiomyopathy, hypertension-induced left ventricular hypertrophy, and aortic stenosis. Staging systems are detailed, highlighting the prognostic role of cardiac biomarkers. Therapeutic strategies are explored, including subtype-specific regimens (e.g., daratumumab-based therapy for AL; tafamidis and gene silencers for ATTR), the judicious use of conventional heart failure medications, and emerging therapies such as CRISPR-based gene editing. Conclusions: Timely recognition and accurate diagnosis of cardiac amyloidosis are critical to improving outcomes. As diagnostic tools and disease-modifying therapies evolve rapidly, cardiologists must remain at the forefront of multidisciplinary care. A structured biomarker- and imaging-guided approach can enhance diagnostic yield, inform prognosis, and optimize patient-specific management. Full article

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive form of restrictive cardiomyopathy caused by the misfolding and deposition of transthyretin protein. What was once a condition that had little by way of treatment other than liver transplantation has now become a manageable disease due to revolutionary novel therapies. This review outlines therapeutic strategies aimed at halting or reversing disease progression. Current approaches include transthyretin (TTR) stabilizers such as tafamidis and acoramidis, as well as TTR silencers such as vutisiran. In addition, novel therapies under clinical investigation are emerging, such as gene-editing strategies and monoclonal antibodies targeting amyloid deposits. The aim of this paper is to investigate the current literature and ongoing clinical trials exploring treatment options for ATTR-CM. Transthyretin stabilizers and RNA silencers improve survival, functional capacity, and quality of life. Early-phase studies of gene-editing and monoclonal antibody therapies demonstrate promising amyloid-lowering effects. Stabilizers and silencers continue to constitute the standard therapy, while gene-editing and monoclonal antibodies offer potential as future treatments. The advent of a multitude of therapies for ATTR-CM holds promise for a future of targeted, personalized medicine for the treatment of this not-so-uncommon cause of heart failure. Full article

Background/Objectives: Heart failure (HF) often develops from a prolonged asymptomatic phase where early detection could prevent progression. Pre-heart failure (pre-HF) populations—those with risk factors (Stage A) or subclinical myocardial changes (Stage B)—are critical for intervention. Cardiac magnetic resonance (CMR) with T1 and extracellular volume (ECV) mapping offers a non-invasive approach to detect early myocardial changes in these groups. This systematic review evaluates the role of T1 and ECV mapping in pre-HF populations, focusing on their diagnostic and prognostic utility. Methods: A systematic search of PubMed, EMBASE, and Cochrane was conducted up to April 2025, identifying 17 studies that met inclusion criteria. Data was extracted directly into Excel, and methodological quality was assessed using the Newcastle–Ottawa Scale (NOS) for cohort and cross-sectional studies and AMSTAR-2 for systematic reviews and meta-analyses. A meta-analysis was performed using Review Manager (RevMan) to compare T1 and ECV values between pre-HF and control groups. Results: Studies consistently reported elevated T1 (989.6–1415.41 milliseconds) and ECV (25.7–42.81%) in pre-HF groups compared to controls (T1: 967–1310.63 ms, ECV: 23.5–29.9%). Meta-analysis showed a significant increase in T1 (MD: 27.62 ms, 95% CI: 8.04–47.19, p < 0.006) and ECV (MD: 2.97%, 95% CI: 1.88–4.06, p < 0.00001) in pre-HF groups. RQS scores ranged from 17.2% to 77.8% (mean: 37.9%), and NOS scores ranged from 5 to 8 (mean: 6.2), reflecting variability in study quality. The AMSTAR-2 rating for the systematic review was moderate. Conclusions: T1 and ECV mapping enhance CMR-based detection of early myocardial changes in pre-HF, offering a promising non-invasive approach to predict HF risk. However, variability in study quality, small sample sizes, and methodological inconsistencies limit generalisability. Future research should focus on standardised protocols, prospective designs, and multi-center studies to integrate these techniques into clinical practice, potentially guiding preventive therapies such as SGLT2is and tafamidis. Full article

Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils. Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes. The condition is increasingly recognized as an underdiagnosed contributor to heart failure, particularly in elderly patients. ATTR amyloidosis exists in two major forms: hereditary (ATTRv), resulting from mutations in the TTR gene, and wild-type (ATTRwt), typically affecting men over 70 years of age. Advances in disease understanding have led to a paradigm shift in management, with the introduction of targeted therapies that slow disease progression and improve prognosis. First-generation therapies such as tafamidis have demonstrated survival benefits in ATTR-CM. More recently, second-generation agents—such as the TTR stabilizer acoramidis and RNA silencers including vutrisiran and eplontersen—have shown promising efficacy in clinical trials. Additional strategies under investigation include gene editing and monoclonal antibodies targeting TTR amyloid deposits. This review outlines current diagnostic strategies and therapeutic options for ATTR amyloidosis, emphasizing the need for early detection and individualized treatment approaches. The expanding therapeutic landscape highlights the importance of accurate phenotyping and timely intervention to optimize clinical outcomes. Full article

Background/Objectives: Having serum biomarkers available for cardiac transthyretin amyloidosis (ATTR-CA) would be beneficial for diagnosis and prognosis. This study aimed to identify potential ATTR-CA biomarkers through proteomic analysis. Patients and Methods: Serum proteomic analyses were conducted on 15 ATTR-CA patients before receiving treatment, 11 ATTR-CA patients who had received tafamidis treatment for at least six months, and 13 patients with suspected cardiac amyloidosis who were later ruled out. All patients underwent blood tests, standard 12-lead electrocardiography, transthoracic echocardiography, and ^99mTc-DPD scintigraphy. Results: Proteomic analysis revealed significant differences in protein levels among the study groups. Key findings revealed increased levels of several proteins, including ceruloplasmin, apolipoprotein E, SERPINA1, and cDNA FLJ54111 (which is highly similar to serum transferrin), in ATTR-CA patients before receiving specific treatment. There was also a reduction in prothrombin, transferrin, CD14, and alpha-2-macroglobulin. In the ATTR-CA group treated with tafamidis, elevated levels of SERPINA1, paraoxonase 1, and complement C2 were observed. Notably, levels of cDNA FLJ54111 and SERPINA3 were reduced in this group. Compared to the control group, patients with ATTR-CA exhibited higher levels of ceruloplasmin, SERPINA3, and VCAM1, as well as lower levels of ApoA-I, ApoA-II, clusterin, and gelsolin. Controls exhibited elevated levels of transthyretin and prothrombin. Conclusions: This study identified candidate serum biomarkers for diagnosing ATTR-CA and monitoring the effectiveness of tafamidis treatment. Full article

The hypertrophic cardiomyopathy (HCM) clinical phenotype includes sarcomeric HCM, which is the most common form of inherited cardiomyopathy with a population prevalence of 1:500, and phenocopies such as cardiac amyloidosis and Anderson–Fabry disease, which are considered rare diseases. Identification of cardiac and non-cardiac red flags in the context of multi-organ syndrome, multimodality imaging, including echocardiography, cardiac magnetic resonance, and genetic testing, has a central role in the diagnostic pathway. Identifying the specific disease underlying the hypertrophic phenotype is very important since many disease-modifying therapies are currently available, and phase 3 trials for new treatments have been completed or are ongoing. In particular, many chemotherapy agents (alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting clonal cells) allowing one to treat AL amyloidosis, transthyretin stabilizers (tafamidis and acoramidis), and gene silencers (patisiran and vutrisiran) are available in transthyretin cardiac amyloidosis, and enzyme replacement therapies (agalsidase-alpha, agalsidase-beta, and pegunigalsidase-alpha) or oral chaperone therapy (migalastat) can be used in Anderson–Fabry disease. In addition, the introduction of cardiac myosin inhibitors (mavacamten and aficamten) has deeply modified the treatment of hypertrophic obstructive cardiomyopathy. The aim of this review is to describe the new disease-modifying treatments available in HCM and phenocopies in light of current scientific evidence. Full article

Transthyretin (TTR) variant (V30M) polyneuropathy (ATTRv-PN) is a progressive systemic amyloidosis caused by transthyretin aggregation, leading to a variety of debilitating manifestations, including neuropathy and cardiomyopathy. We investigated the plasma proteome of heterozygotic V30M TTR asymptomatic carriers and heterozygotic V30M ATTRv-PN patients (before and after tafamidis treatment) versus WT TTR healthy control plasma using an organic solvent-induced shift in solubility assay to identify biosignatures for disease progression and therapeutic response. We identified many proteins, including TTR, apolipoproteins, ceruloplasmin, and proteins with functions in innate immunity that displayed changes in either their abundances or their sensitivity to precipitation. Elevated oxidative modifications of TTR and APOE in ATTRv-PN patients suggest a role for oxidative stress in disease pathogenesis/progression. Tafamidis treatment mitigated these pathology-associated changes, suggesting that alleviating proteotoxic stress impacts these other pathways. Although our study was limited to a Portuguese cohort, these findings nevertheless provide a comprehensive plasma proteomic profile of V30M ATTRv-PN patients, V30M TTR carriers, and tafamidis-treated ATTRv-PN patients over up to 60 months; provide insights into ATTRv-PN pathophysiology; identify potential biomarkers for disease progression and therapeutic response; and highlight the utility of proteomics in advancing personalized treatments for amyloidosis. Full article

Background/Objectives: A 43-year-old male presented with neurological symptoms and asymptomatic cardiac dysfunction, left ventricular hypertrophy, and impaired global longitudinal strain with apical sparing, associated with elevated NT-proBNP. Methods: Multimodality imaging (bone scintigraphy and cardiac magnetic resonance) revealed cardiac amyloid deposition. Genetic testing confirmed variant transthyretin amyloidosis (ATTR) with mixed phenotype. Results: Treatment with tafamidis 20 mg for stage I polyneuropathy, available at that moment, was initiated with good neurological outcome. Three years later, cardiac function deteriorated, following a moderate COVID-19 infection, with heart failure symptoms and reduced ventricular and atrial functions. For progressive ATTR cardiomyopathy, we intensified therapy to tafamidis free acid 61 mg, associated with SGLT2 inhibitor, spironolactone, and furosemide with subsequent improvements of symptoms and stabilization of imaging findings. Conclusions: This case emphasizes the importance of multimodal imaging in early detection, monitoring, and guiding individualized management in ATTR cardiomyopathy. Full article

Background/Objectives: In patients with transthyretin amyloid cardiomyopathy (ATTR-CM), the effect of tafamidis on right ventricular (RV) dysfunction has been poorly investigated. The purpose of this study was to evaluate the effect of tafamidis on RV free wall global longitudinal strain (RV FW-GLS) and right ventricular and pulmonary artery (RV-PA) coupling over 12 months of treatment. Methods: Ninety-three patients with ATTR-CM treated with 61 mg of tafamidis daily who underwent multimodality imaging evaluation at baseline by cardiovascular magnetic resonance (CMR) and speckle-tracking echocardiography were retrospectively studied. The 12-month follow-up included an echocardiographic assessment of RV FW-GLS and RV-PA coupling. RV reverse remodeling was defined as a >10% improvement in RV FW-GLS and/or in RV-PA coupling from baseline. RV-PA coupling was assessed using the tricuspid annular plane systolic excursion/ pulmonary artery systolic pressure (TAPSE/PASP) ratio. Results: Over 12 months of tafamidis treatment, RV reverse remodeling was documented in 22.6% of patients. In these patients, RV FW-GLS improved significantly from 14.5 ± 2.1% to 17.3 ± 2%, p < 0.001, whereas the TAPSE/PASP ratio improved from 0.42 ± 0.05 mm/mmHg to 0.54 ± 0.07 mm/mmHg, p = 0.001. Patients who experienced RV reverse remodeling were at an earlier stage of disease prior to tafamidis treatment with less dilated RV and less severe RV-PA uncoupling (TAPSE/PASP ratio: 0.43 ± 0.06 mm/mmHg vs. 0.39 ± 0.06 mm/mmHg, p = 0.040). CMR-derived baseline RV end-systolic volume (HR 0.83, 95% CI 0.73–0.94, p = 0.005) and NT-proBNP (HR 0.989, 95% CI 0.988–0.999, p = 0.024) were the strongest independent predictors of RV reverse remodeling, followed by PASP (HR 0.82, 95% CI 0.69–0.98, p = 0.030). Conclusions: Patients with ATTR-CM treated with tafamidis at an earlier stage of the disease experienced RV reverse remodeling with significant improvement in RV FW-GLS and RV-PA coupling. Full article

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease that has emerged as a significant cause of heart failure. Advances in the understanding of ATTR-CM pathophysiology have revolutionised its therapeutic landscape over the past decade, with the development of targeted therapies that are able to improve survival and quality of life. TTR stabilizers, such as tafamidis and acoramidis, can reduce TTR instability and subsequent amyloid fibril formation. Clinical trials have demonstrated their efficacy both in improving survival and quality of life in patients with ATTR-CM. Gene-silencing therapies using small interfering RNAs (siRNAs), such as patisiran and vutrisiran, or antisense oligonucleotide inhibitors (ASOs), such as inotersen and eplontersen, serve as powerful therapeutic options by decreasing TTR production; trials on patients with ATTR-CM have been recently published or are ongoing. Novel, emerging therapies aim to enhance fibril clearance using monoclonal antibodies, such as NI006, that target amyloid deposits in the myocardium, promoting their depletion, plausibly with regression of the structural and functional impairments caused by the disease. Concurrently, advancements in diagnostic modalities have facilitated earlier detection of this disease, allowing the timely initiation of treatment with a more significant impact on patients’ survival and quality of life. Despite these strides, challenges remain, including the high cost of disease-modifying therapy and the need for response criteria to monitor treatment’s efficacy. Future directions will involve improving patients’ screening to achieve earlier diagnoses, optimising patients’ selection for disease-modifying therapy and identifying criteria for the treatment’s response or lack thereof to possibly consider therapy switch or associations. In this review, we will explore the more recent therapeutic advancements in ATTR-CM, starting from traditional heart failure therapies and moving to disease-modifying therapies with a detailed evaluation of the registration trials to explore the strengths and shortcomings of each treatment. Full article

Background/Objectives: Cardiac amyloidosis (CA) is a rare and severe multisystem disorder, associated with an average survival of approximately five years. Recently, Tafamidis has emerged as a promising treatment for transthyretin-related CA. This retrospective study aimed to assess disease progression through echocardiographic findings in patients with transthyretin-related CA, with a specific focus on evaluating the impact of Tafamidis in a cohort managed at our Cardiomyopathy Clinic. Methods: A total of 39 patients were included, of whom 28 received Tafamidis treatment, while 11 did not. Clinical, electrocardiographic, echocardiographic, biological, and other imaging data were collected at diagnosis. Comprehensive echocardiographic data were collected every six months over a two-year period (2021–2023). Results: At 1-year follow-up, the Tafamidis-treated cohort demonstrated stable global systolic and diastolic function. Left ventricular (LV) global longitudinal strain (GLS) and global work index (GWI) showed minimal change (GLS −12.9% (−15.6; −10.7) vs. −13.0% (−14.0; −10.7), p = 0.054; GWI 1113 mmHg/% (963; 1301) vs. 1208 mmHg/% (850; 1420), p = 0.054), and there was no significant increase in indexed LV mass (135.0 g/m² (118.0; 167.0) vs. 148.0 (128.0; 173.0), p = 0.25). Similarly, valvular heart disease severity remained unchanged. Longitudinal analysis using generalized linear mixed models further confirmed the stability of echocardiographic parameters over the 2-year follow-up period. Systolic function metrics, including LV ejection fraction (slope: −0.0098 ± 0.011, p = 0.38) and GLS (slope: 0.0036 ± 0.0041, p = 0.39) showed no significant decline. Diastolic function assessed through E/A ratio (slope: −0.0007 ± 0.0013, p = 0.59) and E/e’ (slope: −0.0042 ± 0.0073, p = 0.57) also remained stable. Indexed LV mass exhibited no significant progression (slope: 0.050 ± 0.061, p = 0.41). These findings were consistent across the various subgroups. Conclusions: Tafamidis appears to effectively stabilize transthyretin-related CA, limiting disease progression over the follow-up period. Full article