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

Development of a human model for the study of effects of hypoxia, exercise, and sildenafil on cardiac and vascular function in chronic heart failure

Background: Pulmonary hypertension is associated with poor outcome in patients with chronic heart failure (CHF) and may be a therapeutic target. Our aims were to develop a noninvasive model for studying pulmonary vasoreactivity in CHF and characterize sildenafil's acute cardiovascular effects. Methods and Results: In a crossover study, 18 patients with CHF participated 4 times [sildenafil (2 × 20 mg)/or placebo (double-blind) while breathing air or 15% oxygen] at rest and during exercise. Oxygen saturation (SaO2) and systemic vascular resistance were recorded. Left and right ventricular (RV) function and transtricuspid systolic pressure gradient (RVTG) were measured echocardiographically. At rest, hypoxia caused SaO2 (P = 0.001) to fall and RVTG to rise (5 ± 4 mm Hg; P = 0.001). Sildenafil reduced SaO2 (−1 ± 2%; P = 0.043), systemic vascular resistance (−87 ± 156 dyn·s−1·cm−2; P = 0.034), and RVTG (−2 ± 5 mm Hg; P = 0.05). Exercise caused cardiac output (2.1 ± 1.8 L/min; P < 0.001) and RVTG (19 ± 11 mm Hg; P < 0.0001) to rise. The reduction in RVTG with sildenafil was not attenuated by hypoxia. The rise in RVTG with exercise was not substantially reduced by sildenafil. Conclusions: Sildenafil reduces SaO2 at rest while breathing air, this was not exacerbated by hypoxia, suggesting increased ventilation–perfusion mismatching due to pulmonary vasodilation in poorly ventilated lung regions. Sildenafil reduces RVTG at rest and prevents increases caused by hypoxia but not by exercise. This study shows the usefulness of this model to evaluate new therapeutics in pulmonary hypertension

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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Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study.

Aims Tafamidis is an effective treatment for transthyretin amyloid cardiomyopathy (ATTR-CM) in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). While ATTR-ACT was not designed for a dose-specific assessment, further analysis from ATTR-ACT and its long-term extension study (LTE) can guide determination of the optimal dose. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods and results In ATTR-ACT, patients were randomized (2:1:2) to tafamidis 80 mg, 20mg, or placebo for 30months. Patients completing ATTR-ACT could enrol in the LTE (with placebo-treated patients randomized to tafamidis 80 or 20 mg; 2:1) and all patients were subsequently switched to high-dose tafamidis. All-cause mortality was assessed in ATTR-ACT combined with the LTE (median follow-up 51 months). In ATTR-ACT, the combination of all-cause mortality and cardiovascular-related hospitalizations over 30 months was significantly reduced with tafamidis 80mg (P = 0.0030) and 20mg (P = 0.0048) vs. placebo. All-cause mortality vs. placebo was reduced with tafamidis 80mg [Cox hazards model (95% confidence interval (CI): 0.690 (0.487–0.979), P = 0.0378] and 20mg [0.715 (0.450–1.137), P = 0.1564]. The mean (standard error) change in N-terminal pro-B-type natriuretic peptide from baseline to Month 30 was −1170.51 (587.31) (P = 0.0468) with tafamidis 80 vs. 20 mg. In ATTR-ACT combined with the LTE there was a significantly greater survival benefit with tafamidis 80 vs. 20 mg [0.700 (0.501–0.979), P = 0.0374]. Incidence of adverse events in both tafamidis doses were comparable to placebo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion Tafamidis, both 80 and 20mg, effectively reduced mortality and cardiovascular-related hospitalizations in patients with ATTR-CM. The longer-term survival data and the lack of dose-related safety concerns support tafamidis 80mg as the optimal dose. Clinical Trial Registration: ClinicalTrials.gov NCT01994889; NCT02791230post-print369 K

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 ferriti