Changing paradigm in the treatment of amyloidosis: From disease-modifying drugs to anti-fibril therapy.

Cardiac amyloidosis is a rare, debilitating, and usually fatal disease increasingly recognized in clinical practice despite patients presenting with non-specific symptoms of cardiomyopathy. The current standard of care (SoC) focuses on preventing further amyloid formation and deposition, either with anti-plasma cell dyscrasia (anti-PCD) therapies in light-chain (AL) amyloidosis or stabilizers of transthyretin (TTR) in transthyretin amyloidosis (ATTR). The SoC is supplemented by therapies to treat the complications arising from organ dysfunction; for example, heart failure, arrhythmia, and proteinuria. Advancements in treatments have improved patient survival, especially for those whose disease is detected and for whom treatment is initiated at an early stage. However, there still are many unmet medical needs, particularly for patients with severe disease for whom morbidity and mortality remain high. There currently are no approved treatments to reverse amyloid infiltration and deplete the amyloid fibrils already deposited in organs, which can continue to cause progressive dysfunction. Anti-fibril therapies aimed at removing the deposited fibrils are being investigated for safety and efficacy in improving outcomes for patients with severe disease. However, there is no clinical evidence yet that removing deposited amyloid fibrils will improve organ function, thereby improving quality of life or extending life. Nevertheless, anti-fibril therapies are actively being investigated in clinical trials to evaluate their ability to complement and synergize with current SoC.This manuscript was funded by Alexion AstraZeneca Rare Disease. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.S

Practical Guidance for Diagnosing and Treating Iron Deficiency in Patients with Heart Failure:Why, Who and How?

Iron deficiency (ID) is a comorbid condition frequently seen in patients with heart failure (HF). Iron has an important role in the transport of oxygen, and is also essential for skeletal and cardiac muscle, which depend on iron for oxygen storage and cellular energy production. Thus, ID per se, even without anaemia, can be harmful. In patients with HF, ID is associated with a poorer quality of life (QoL) and exercise capacity, and a higher risk of hospitalisations and mortality, even in the absence of anaemia. Despite its negative clinical consequences, ID remains under-recognised. However, it is easily diagnosed and managed, and the recently revised 2021 European Society of Cardiology (ESC) guidelines on HF provide specific recommendations for its diagnosis and treatment. Prospective randomised controlled trials in patients with symptomatic HF with reduced ejection fraction (HFrEF) show that correction of ID using intravenous iron (principally ferric carboxymaltose [FCM]) provides improvements in symptoms of HF, exercise capacity and QoL, and a recent trial demonstrated that FCM therapy following hospitalisation due to acute decompensated HF reduced the risk of subsequent HF hospitalisations. This review provides a summary of the epidemiology and pathophysiology of ID in HFrEF, and practical guidance on screening, diagnosing, and treating ID

screening for transthyretin amyloid cardiomyopathy in everyday practice

Abstract Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, progressive, infiltrative disease caused by the deposition of transthyretin amyloid fibrils in the heart, and can often be overlooked as a common cause of heart failure. Delayed diagnosis due to lack of disease awareness and misdiagnosis results in a poorer prognosis. Early accurate diagnosis is therefore key to improving patient outcomes, particularly in the context of both the recent approval of tafamidis in some countries (including the United States) for the treatment of ATTR-CM, and of other promising therapies under development. With the availability of scintigraphy as an inexpensive, noninvasive diagnostic tool, the rationale to screen for ATTR-CM in high-risk populations of patients is increasingly warranted. Here the authors propose a framework of clinical scenarios in which screening for ATTR-CM is recommended, as well as diagnostic "red flags" that can assist in its diagnosis among the wider population of patients with heart failure

Transthyretin cardiac amyloidosis in continental Western Europe: an insight through the Transthyretin Amyloidosis Outcomes Survey (THAOS)

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073 Right Ventricle Contractile Reserve as a Pre-operative Tool for Assessing RV failure after Continuous Flow LVAD Implantation

IntroductionLatest generation continuous flow left ventricular assist devices (LVADs) have been proposed as an alternative to heart transplantation for end-stage heart failure. However, postoperative right ventricle (RV) dysfunction remains common and has a negative impact on prognosis. Purpose of our study was to identify echocardiographic or hemodynamic parameters that could predict early RV failure after LVAD implantation in patients with biventricular dysfunction.MethodsFourteen patients with biventricular dysfunction who have been evaluated for LVAD implantation were included. Right and left ventricular dysfunction were respectively defined as: tricuspid annular plane excursion < 16 mm (TAPSE) and LV ejection fraction < 35%. In all patients, preoperative measurements were obtained at rest. In 7 patients, right heart catheterization was performed simultaneously with increasing doses of dobutamine (15γ/Kg/min). Primary endpoint was death caused by right ventricle systolic dysfunction or need for right ventricle mechanical support within 30 days after surgery (RVSD+).ResultsMean recipient age was 58±7 years. Primary end-point (RVSD+) was noted in five patients. Preoperative demographic, echocardiographic and hemodynamic data were similar between RVSD+ and RVSD- patients (Table). Percent increase of TAPSE and systolic PAP between basal and high dobutamine dose was significantly lower in RVSD+ than in RVSD- patients.ConclusionPercent increase of TAPSE and systolic PAP induced by high dose dobutamine infusion might be two interesting criteria to assess RV contractile reserve and predict RV outcome after LVAD implantation in patient with biventricular dysfunction.Baseline Measurement (n=14)Change after Dobutamine infusion,% (n=7)RVSD-RVSD+pRVSD-RVSD+pN95TAPSE, mm14±214±20.955±526±20.03Systolic PAP, mmHg51±753±60.842±84±70.05Cardiac Output, l/min3.3±0.53.5±0.50.987±1093±470.7Pulm Vasc Res, Wood3.9±14.3±10.62±41-36±70.

Screening, diagnosis and treatment of iron deficiency in chronic heart failure:putting the 2016 European Society of Cardiology heart failure guidelines into clinical practice

Iron deficiency is common in patients with chronic heart failure (CHF) and is associated with reduced exercise performance, impaired health-related quality of life and an increased risk of mortality, irrespective of whether or not anaemia is present. Iron deficiency is a serious but treatable condition. Several randomized controlled clinical trials have demonstrated the ability of intravenous (IV) iron, primarily IV ferric carboxymaltose (FCM), to correct iron deficiency in patients with heart failure with reduced ejection fraction (HFrEF), resulting in improvements in exercise performance, CHF symptoms and health-related quality of life. The importance of addressing the issue of iron deficiency in patients with CHF is reflected in the 2016 European Society of Cardiology (ESC) heart failure guidelines, which recognize iron deficiency as an important co-morbidity, independent of anaemia. These guidelines recommend that all newly diagnosed heart failure patients are routinely tested for iron deficiency and that IV FCM should be considered as a treatment option in symptomatic patients with HFrEF and iron deficiency (serum ferritin</p

Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid

BACKGROUND Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.)

World Heart Federation consensus on transthyretin amyloidosis cardiomyopathy (ATTR-CM)

COPYRIGHT: © 2023 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/ licenses/by/4.0/.Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.info:eu-repo/semantics/publishedVersio