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Background Transthyretin (TTR) Cardiomyopathy (ATTR-CM) is characterized by the deposition of misfolded TTR monomers in the heart, leading to progressive heart failure. TTR-specific therapies offer a pharmacological approach to slow disease progression. However, there remains limited data on the efficacy, comparative effectiveness, and safety of these therapies. Therefore, we aim to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing TTR-specific therapies with placebo in patients with ATTR-CM. Methods We searched through Pubmed, Cochrane, and Embase databases. Our primary outcome was: (1) All Cause Mortality. We also performed a subgroup analysis comparing TTR stabilizers versus TTR knock-down therapies (RNA inhibitors and antisense oligonucleotides). Results Nine RCTs were included, involving 2,713 patients, of whom 1,160 (59.34%) were assigned to the TTR-specific therapies group. In the pooled analysis, TTR-specific therapies were associated with a significant reduction in all-cause mortality (RR 0.70; 95% CI 0.60, 0.83; p  < 0.01; I² = 0%), with both TTR stabilizers and knock-down therapies showing equally effective reductions ( p  = 0.97). Additionally, TTR-specific therapies improved LV longitudinal strain (SMD − 0.22; 95% CI -0.34, -0.10; p  < 0.01; I² = 17%) and reduced LV mass (SMD − 9.11 g; 95% CI -16.4 g, -1.82 g; p  = 0.01; I² = 0%). Conclusion This meta-analysis highlights the potential of TTR-targeting therapies as an effective option for managing ATTR-CM, with significant improvements in survival. No efficacy differences were found between TTR stabilizers and knock-down therapies.

Amyloid transthyretin (ATTR) amyloidosis with polyneuropathy (PN) is a progressive, debilitating, systemic disease wherein transthyretin protein misfolds to form amyloid, which is deposited in the endoneurium. ATTR amyloidosis with PN is the most serious hereditary polyneuropathy of adult onset. It arises from a hereditary mutation in the TTR gene and may involve the heart as well as other organs. It is critical to identify and diagnose the disease earlier because treatments are available to help slow the progression of neuropathy. Early diagnosis is complicated, however, because presentation may vary and family history is not always known. Symptoms may be mistakenly attributed to other diseases such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), idiopathic axonal polyneuropathy, lumbar spinal stenosis, and, more rarely, diabetic neuropathy and AL amyloidosis. In endemic countries (e.g., Portugal, Japan, Sweden, Brazil), ATTR amyloidosis with PN should be suspected in any patient who has length-dependent small-fiber PN with autonomic dysfunction and a family history of ATTR amyloidosis, unexplained weight loss, heart rhythm disorders, vitreous opacities, or renal abnormalities. In nonendemic countries, the disease may present as idiopathic rapidly progressive sensory motor axonal neuropathy or atypical CIDP with any of the above symptoms or with bilateral carpal tunnel syndrome, gait disorders, or cardiac hypertrophy. Diagnosis should include DNA testing, biopsy, and amyloid typing. Patients should be followed up every 6–12 months, depending on the severity of the disease and response to therapy. This review outlines detailed recommendations to improve the diagnosis of ATTR amyloidosis with PN.

Transthyretin amyloidosis (ATTR) is a rare, life-threatening systemic disorder. We present first findings on the cardiac hereditary ATTR in Poland. Sixty-eight consecutive patients with suspected or known cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography (ECG) and transthoracic echocardiography. ATTR was confirmed histologically or non-invasively using 99mTc-DPD scintigraphy. Transthyretin (TTR) gene sequencing was performed. In 2017-2019, 10 unrelated male patients were diagnosed with hereditary ATTR. All patients had very uncommon TTR gene mutations: 7 patients had p.Phe53Leu mutation, 2 patients had p.Glu109Lys mutation and 1 patient had p.Ala101Val mutation. The age of onset ranged from 49 to 67 years (mean [SD] age, 58.7 [6.4] years). On ECG, most patients (70%) had pseudoinfarct pattern and/or low QRS voltage. The maximal wall thickness (MWT) on echocardiography varied considerably among the patients from moderate (16 mm) to massively increased (30 mm). Most patients (90%) had decreased left ventricular ejection fraction (mean [SD], 43 [11] %). On follow-up, we observed progressive heart failure in almost all cases. The first patient with p.Phe53Leu mutation died of heart failure, the second died suddenly, the third successfully underwent combined heart and liver transplant with 15 months survival from the surgery. The patient with p.Ala101Val mutation died of stroke. According to available data, this is the first time that the types of TTR mutations and the clinical characteristics of Polish patients with cardiac hereditary ATTR have been described. Previous literature data about Polish background in families with p.Phe53Leu mutation and the present results, suggest that this TTR mutation might be endemic in the Polish population.

Global left ventricular (LV) myocardial work (MW) indexes can be recognized at ultrasound imaging from the LV pressure/global longitudinal strain (GLS) loop analysis. A total of 4 indexes, global work index (GWI), global constructive work (GCW), global wasted work (GWW), and global work efficiency (GWE), have been demonstrated to overcome the methodological limitations of GLS and provide useful information on myocardial dysfunction in some clinical settings. Although impaired MW indexes have been demonstrated in patients with transthyretin cardiac amyloidosis (ATTR) or with nonobstructive hypertrophic cardiomyopathy (HCM), there are no comparative studies at present. This study aimed to describe the characteristics of MW in both these clinical settings compared with patients with well-controlled hypertension (HTN). A total of 83 patients, 32 with ATTR (aged 70 ± 11 years, 32% mutated, 68% wild-type, 72% men), 29 with HCM (aged 57 ± 17 years), and 22 HTN controls (aged 56 ± 5.6 years, 59% men) were prospectively enrolled at 2 clinical centers. All participants had New York Heart Association class I or II. Overall, the LV mass index was greater in both study groups than in HTN, whereas the LV ejection fraction (EF) was significantly lower in ATTR compared with other groups. Based on this finding, patients with ATTR were further divided into 2 subgroups: ATTR1 (LVEF ≤0.50), n = 14 (44%) and ATTR2 (LVEF >0.50), n = 18 (56%). Overall, the GWI and GCW were lower in all ATTR patients (mostly in ATTR1) than in the other groups (p <0.001), whereas only small differences in GWE and none in GWW were found among the groups. Of interest, the pairwise comparison and receiver operating characteristic analysis in preserved LVEF patients showed that GWI was a better discriminator of ATTR2 from HCM patients than GLS, with the cut-off value ≤1,419 mm Hg% (89% sensitivity; 55% specificity; p = 0.013). In conclusion, MW analysis was confirmed to be a modern way to investigate myocardial function in patients with hypertrophic phenocopies. GWI and GCW were more impaired in patients with ATTR compared with HCM and HTN controls. Furthermore, this study likely revealed an additional discriminative value of GWI over GLS alone in preserved LVEF settings.

Amyloid transthyretin (ATTR) amyloidosis is a clinically heterogeneous and fatal disease that results from deposition of insoluble amyloid fibrils in various organs and tissues, causing progressive loss of function. The objective of this review is to increase awareness and diagnosis of ATTR amyloidosis by improving recognition of its overlapping conditions, misdiagnosis, and multiorgan presentation. Cardiac manifestations include heart failure, atrial fibrillation, intolerance to previously prescribed antihypertensives, sinus node dysfunction, and atrioventricular block, resulting in the need for permanent pacing. Neurologic manifestations include progressive sensorimotor neuropathy (e.g., pain, weakness) and autonomic dysfunction (e.g., erectile dysfunction, chronic diarrhea, orthostatic hypotension). Non-cardiac red flags often precede the diagnosis of ATTR amyloidosis and include musculoskeletal manifestations (e.g., carpal tunnel syndrome, lumbar spinal stenosis, spontaneous rupture of the distal tendon biceps, shoulder and knee surgery). Awareness and recognition of the constellation of symptoms, including cardiac, neurologic, and musculoskeletal manifestations, will help with early diagnosis of ATTR amyloidosis and faster access to therapies, thereby slowing the progression of this debilitating disease.

Supporting information Body weights of individual mice before and after photothrombosis (PT) or sham operation. Showing 1/3: pone.0235527.s001.pdf Skip to figshare navigation Body weights (g) animal n. pre d1 animal n. pre d2 animal n. pre d7 61 24.7 23.7 67 25.2 23.2 76 26.5 25.8 62 25.7 23.7 68 25.4 22.2 77 25.8 27.7 63 26.4 25.2 69 25.4 23 78 25.8 24.9 64 25.8 24.1 70 24.3 22.3 109 25.1 25.2 65 25.2 24.4 92 24.2 23.9 110 26.4 25.9 94 25.2 24 93 25.7 25.1 111 26 25.9 98 24.8 23.5 100 25.7 24.9 112 24.6 25.8 99 23.8 22.9 101 26.3 24.9 113 24.7 25 animal n. pre d2 animal n. pre d7 102 26.3 25.4 107 25.5 26.6 103 26.3 25.2 108 25.3 26 104 27.2 25.2 105 25.2 24.9 106 25.5 24.7 PT 24 hours PT 7 days PT 48 hours Sham 48 hours Sham 7 days Body weights (g ) animal n. pre d1 d2 d3 d4 d5 d6 d7 d8 d9 d10 d11 d12 d13 d14 1 22.9 21.9 23.4 23.2 23.8 22.8 23.8 23.6 24 23.5 23.6 23.4 23.5 23.8 23.9 6 20.8 21.6 21.9 22 22.2 20.9 21.5 21.8 21.5 21.6 21.8 21.4 22 22.6 22.2 15 23.8 23.3 23 23.3 23.1 23.2 23.2 23.4 23.6 23.5 23.6 23.6 24.1 24.7 24.7 21 22.6 21.5 21.9 21.3 21.7 21.8 22 21.4 22 21.7 21.7 22.1 22.1 22.4 21.9 38 24.1 22.9 22.5 23.1 23.3 23.6 23.1 23.3 23.5 23.5 23.8 23.8 23.6 23.4 23.3 43 24.1 22.4 21.9 22.4 22.7 22.8 23.8 22.5 23.4 23.5 23.4 23.6 24.2 24.2 23.2 48 24.5 22.6 21.8 21.7 21.4 22.8 22.5 22.6 23.4 23.7 24.2 25 25.1 24.8 24 60 27.6 25.3 24.9 26 26.5 26.9 27.6 27.3 27.3 27.5 27.5 27.7 27.7 27.7 79 26.1 25.4 25.1 25.7 26.2 26.6 26.4 26.7 26.9 27.3 27.1 27.4 28.1 28.5 27.8 83 24 22.4 21.7 21.8 22.3 22.4 22.6 22.6 23.5 23.6 23.6 24 24.4 24.5 23.6 122 21.8 19.7 19.7 20 20.2 20.6 20.6 20.2 21.1 21.2 21.4 21.1 21.2 21.2 21.2 136 22.1 20.8 20.7 21.2 21.3 22 21.8 22.2 22.5 22.1 22.1 22.2 22.4 22 21.8 138 22.6 21.2 21.1 21.5 21.6 22.1 21.7 22.2 22.2 22 21.8 22 22.1 22.4 22.1 147 23.1 21.7 21.7 22.4 22.5 22.7 22.7 22.6 23.7 23.7 23.3 23.3 23.5 23.5 23.2 155 24 22.3 21.9 22.5 23 23 23.4 22.8 23.3 23.8 24.2 24.6 24.2 24.3 23.3 157 26.2 24.9 24.5 25 25 25.6 25.6 25.1 26 26.2 26 25.6 25.2 25.9 25.1 162 26.3 25 24.3 24.5 24.7 25 25 25.1 25.9 25.5 25.3 24.9 25 25.1 24.3 animal n. pre d1 d2 d3 d4 d5 d6 d7 d8 d9 d10 d11 d12 d13 d14 10 23 23.7 23.8 24.2 23.7 23.8 23.4 23.6 23.4 23.7 23.5 24 24.2 24 24.4 54 24.4 24.2 23.6 23.8 24.2 24.6 24.4 23.6 24.7 25.2 25.3 25.4 25.4 25.7 24.9 56 26.3 25.7 25.8 26 26.1 26.2 26.9 26.6 26.8 27.2 26.8 27.7 28 27.2 88 24.5 22.8 22.3 22.6 23.2 24.1 24.1 23.9 24.6 23.9 24.2 24.7 24.6 24.9 23.7 135 22.8 21.5 21.6 21.5 21.5 22.3 23 22.8 23 22.8 22.3 22.5 23 22.7 22.6 139 23.3 22.6 22.6 23 23.3 23 23.2 22.5 22.9 23.7 24.1 23.5 23.6 23.8 23.2 PT 14 days Sham 14 days 1 / 3 Share Download figshare Body weights of individual mice before and after photothrombosis (PT) or sham operation. Body weights of individual mice before and after photothrombosis (PT) or sham operation. https://doi.org/10.1371/journal.pone.0235527.s001 (PDF) S2 File.

In this audio interview, Editor-in-Chief Eric Rubin and Deputy Editor Jane Leopold discuss research being presented at the 2024 European Society of Cardiology annual meeting. . . .

Recent advances in therapeutic strategies have emerged to address transthyretin-related amyloidosis, a progressive disorder characterized by diverse clinical manifestations including cardiomyopathy and polyneuropathy. Cardiac amyloidosis (CA), resulting from myocardial amyloid fibril deposition, induces restrictive cardiomyopathy and severe diastolic dysfunction. Among current treatment modalities, transthyretin (TTR) stabilizers have become therapeutic cornerstones, exemplified by the clinical implementation of tafamidis and ongoing trials with acoramidis. Nevertheless, persistent challenges in disease management necessitate the development of improved therapeutics. Notably, natural compounds have gained prominence as promising candidates for developing safer, less toxic TTR stabilizers that may overcome limitations of existing synthetic drugs. This review critically evaluates the most promising recently reported TTR stabilizers, with particular emphasis on natural products and their derivatives as innovative alternatives to conventional synthetic stabilizers.

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.