Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a life‐threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR‐CM has stimulated increased ...awareness of the disease and patient identification. Stratification of patients with ATTR‐CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best‐practice guidance. In this report, experts with experience in treating amyloidosis and ATTR‐CM developed consensus recommendations for monitoring the course of patients with ATTR‐CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR‐CM will help to elucidate, refine and define these and other measurements.
This consensus document from an international expert panel recommends a set of clinically feasible tools for the long‐term monitoring of patients with transthyretin amyloid cardiomyopathy (ATTR‐CM), including meaningful thresholds for defining disease progression and the frequency of measurements. 6MWT, 6‐min walk test; ECG, electrocardiogram; EQ‐5D, EuroQol five dimensions; GLS, global longitudinal strain; HF, heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricular; LVEF, LV, left ventricular ejection fraction; NAC, UK National Amyloidosis Centre; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; QoL, quality of life.
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.
Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone ...thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancementImaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirmatory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.
Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various ...tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.
Transthyretin (TTR) amyloidosis is an underdiagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of ...disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation.
This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure.
ATTR-CM, New York Heart Association functional class II to III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400 mg, AG10 800 mg, or placebo twice daily for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR, and 2 established ex vivo assays (fluorescent probe exclusion and Western blot).
AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by fluorescent probe exclusion of 92 ± 10% (mean ± SD) at trough and 96 ± 9% at peak (both p < 10−12 vs. placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 and 800 mg, respectively (both p < 0.0001 vs. placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects.
AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A phase 3 trial is ongoing. (Study of AG10 in Amyloid Cardiomyopathy; NCT03458130)
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Transthyretin‐mediated amyloidosis (ATTR) is a rare, under‐recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) ...fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue‐specific delivery of these nucleic acid‐based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low‐density lipoprotein receptor‐mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N‐acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor‐mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor‐targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.
Objective
To identify predictors of 30‐day all‐cause mortality for patients with cardiogenic shock secondary to acute coronary syndrome (ACS‐CS) who require short‐term mechanical circulatory support ...(ST‐MCS).
Background
ACS‐CS mortality is high. ST‐MCS is an attractive treatment option for hemodynamic support and stabilization of deteriorating patients. Mortality prediction modeling for ACS‐CS patients requiring ST‐MCS has not been well‐defined.
Methods
The Utah Cardiac Recovery (UCAR) Shock database was used to identify patients admitted with ACS‐CS requiring ST‐MCS devices between May 2008 and August 2018. Pre‐ST‐MCS clinical, laboratory, echocardiographic, and angiographic data were collected. The primary endpoint was 30‐day all‐cause mortality. A weighted score comprising of pre‐ST‐MCS variables independently associated with 30‐day all‐cause mortality was derived and internally validated.
Results
A total of 159 patients (mean age, 61 years; 78% male) were included. Thirty‐day all‐cause mortality was 49%. Multivariable analysis resulted in four independent predictors of 30‐day all‐cause mortality: age, lactate, SCAI CS classification, and acute kidney injury. The model had good calibration and discrimination (area under the receiver operating characteristics curve 0.80). A predictive score (ranging 0–4) comprised of age ≥ 60 years, pre‐ST‐MCS lactate ≥2.5 mmol/L, AKI at time of ST‐MCS implementation, and SCAI CS stage E effectively risk stratified our patient population.
Conclusion
The ACS‐MCS score is a simple and practical predictive score to risk‐stratify CS secondary to ACS patients based on their mortality risk. Effective mortality risk assessment for ACS‐CS patients could have implications on patient selection for available therapeutic strategy options.
Hereditary transthyretin-mediated amyloidosis, also known as ATTRv amyloidosis (v for variant), is a rare, autosomal dominant, fatal disease, in which systemic amyloid progressively impairs multiple ...organs, leading to disability and death. The recent approval of disease-modifying therapies offers the hope of stabilization or eventual reversal of disease progression, and yet highlights a lack of disease-management guidance. A multidisciplinary panel of expert clinicians from France and the US came to consensus on monitoring the disease and identifying progression through a clinical opinion questionnaire, a roundtable meeting, and multiple rounds of feedback.
A multidisciplinary team should monitor ATTRv amyloidosis disease course by assessing potential target organs at baseline and during follow-up for signs and symptoms of somatic and autonomic neuropathy, cardiac dysfunction and restrictive cardiomyopathy, and other manifestations. Variability in penetrance, symptoms, and course of ATTRv amyloidosis requires that all patients, regardless of variant status, undergo regular and standardized assessment in all these categories. Progression in ATTRv amyloidosis may be indicated by: worsening of several existing quantifiable symptoms or signs; the appearance of a new symptom; or the worsening of a single symptom that results in a meaningful functional impairment.
We suggest that a multisystem approach to monitoring the signs and symptoms of ATTRv amyloidosis best captures the course of the disease. We hope this work will help form the basis of further, consensus-based guidance for the treatment of ATTRv amyloidosis.
Abstract Background Exercise intolerance is a hallmark symptom of heart failure patients with preserved ejection fraction (HFpEF), which may be related to an impaired ability to appropriately ...increase blood flow to the exercising muscle. Methods We evaluated leg blood flow (LBF, ultrasound Doppler), heart rate (HR), stroke volume (SV), cardiac output (CO), and mean arterial blood pressure (MAP, photoplethysmography) during dynamic, single leg knee-extensor (KE) exercise in HFpEF patients ( n = 21; 68 ± 2 yrs) and healthy controls ( n = 20; 71 ± 2 yrs). Results HFpEF patients exhibited a marked attrition during KE exercise, with only 60% able to complete the exercise protocol. In participants who completed all exercise intensities (0–5-10-15 W; HFpEF, n = 13; Controls, n = 16), LBF was not different at 0 W and 5 W, but was 15–25% lower in HFpEF compared to controls at 10 W and 15 W ( P < 0.001). Likewise, leg vascular conductance (LVC), an index of vasodilation, was not different at 0 W and 5 W, but was 15–20% lower in HFpEF compared to controls at 10 W and 15 W ( P < 0.05). In contrast to these peripheral deficits, exercise-induced changes in central variables (HR, SV, CO), as well as MAP, were similar between groups. Conclusions These data reveal a marked reduction in LBF and LVC in HFpEF patients during exercise that cannot be attributed to a disease-related alteration in central hemodynamics, suggesting that impaired vasodilation in the exercising skeletal muscle vasculature may play a key role in the exercise intolerance associated with this patient population.
Aims
Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive, fatal disorder that remains underdiagnosed. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) was the first ...large clinical trial to include both wild‐type (ATTRwt) and hereditary (ATTRv) patients. A description of the natural history of ATTR‐CM, utilizing data from placebo‐treated patients in ATTR‐ACT, will provide a greater understanding of presentation and progression of ATTR‐CM and may aid in disease awareness, earlier diagnosis and treatment monitoring.
Methods and results
Changes in clinical endpoints (mortality, cardiovascular CV‐related hospitalizations, 6‐min walk test 6MWT distance and Kansas City Cardiomyopathy Questionnaire Overall Summary KCCQ‐OS score) from baseline to Month 30 in the 177 patients (134 ATTRwt, 43 ATTRv) who received placebo in ATTR‐ACT were assessed. ATTRwt patients tended to have less severe disease at baseline. Over the duration of ATTR‐ACT, there were 76 (42.9%) all‐cause deaths, and 107 (60.5%) patients had a CV‐related hospitalization. There was a lower proportion of all‐cause deaths in ATTRwt (49, 36.6%) than ATTRv (27, 62.8%). There was a similar, steady decline in mean (SD) 6MWT distance from baseline to Month 30 in ATTRwt (93.9 93.7 m) and ATTRv (89.1 107.2 m) patients. The decline in mean (SD) KCCQ‐OS score was less severe in ATTRwt (13.8 20.7) than ATTRv (21.0 26.4) patients.
Conclusions
Patients with ATTR‐CM experience a severe, progressive disease. In ATTR‐ACT, placebo‐treated patients with ATTRv, compared with ATTRwt, had more severe disease at baseline, and their disease progressed more rapidly as shown by mortality, hospitalizations and quality of life over time.
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