Aims Tafamidis improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is not yet known whether tafamidis affects cardiac amyloid deposition and structural changes in the myocardium. We aimed to determine disease-modifying effects on myocardial amyloid progression and to identify imaging parameters that could be applied for specific therapy monitoring. Methods and results ATTR-CM patients underwent serial cardiac magnetic resonance (CMR) imaging using T1 mapping techniques to derive extracellular volume (ECV). Patients receiving tafamidis 61 mg (n = 35) or 20 mg (n = 15) once daily showed stable measurements at follow-up (FU) {61 mg: 9.0 [interquartile range (IQR) 7.0–11.0] months, 20 mg: 11.0 (IQR 8.0–18.0) months} in left ventricular (LV) ejection fraction (LVEF; 61 mg: 47.6% vs. 47.5%, P = 0.935; 20 mg: 52.4% vs. 52.1%, P = 0.930), LV mass index (LVMI; 61 mg: 110.2 vs. 106.2 g/m2, P = 0.304; 20 mg: 114.5 vs. 115.4 g/m2, P = 0.900), and ECV (61 mg: 47.5% vs. 47.7%, P = 0.861; 20 mg: 56.7% vs. 57.5%, P = 0.759), whereas treatment-naïve ATTR-CM patients (n = 19) had clear signs of disease progression at the end of the observation period [12.0 (IQR 10.0–21.0) months; LVEF: 53.3% vs. 45.7%, P = 0.031; LVMI: 98.9 vs. 106.9 g/m2, P = 0.027; ECV: 49.3% vs. 54.6%, P = 0.023]. Between-group comparison at FU revealed positive effects in tafamidis 61 mg-treated compared to treatment-naïve patients (LVEF: P = 0.035, LVMI: P = 0.036, ECV: P = 0.030), while those treated with 20 mg showed no difference in the above LV measurements when compared with treatment-naïve (P = 0.120, P = 0.287, P = 0.158). However, both treatment groups showed clinically beneficial effects compared to the natural course [61 mg, 6-min walk distance (6-MWD): P = 0.005, N-terminal prohormone of brain natriuretic peptide (NT-proBNP): P = 0.002; 20 mg, 6-MWD: P = 0.023, NT-proBNP: P = 0.003]. Conclusion Tafamidis delays myocardial amyloid progression in ATTR-CM patients, resulting in structural, functional, and clinical benefits compared to the natural course. Serial CMR including measurement of ECV may be appropriate for disease-specific therapy monitoring.
Aims The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF. Methods and Results The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by −0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred. Conclusion The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period.
Background: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria. Methods: Within the period of 2014–2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene. Results: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations. Conclusions: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy.
Background: Current diagnosis of Transthyretin-related Amyloidosis (ATTR) using bone scintigraphy is primarily based on visual scoring and semi-quantitative indices. With the introduction of new potential life-prolonging drugs for ATTR, a more precise quantification of myocardial amyloid burden is desirable for improved response prediction and therapy monitoring. Methods: At first, quantification experiments using an anthropomorphic thorax phantom were performed. Second, 32 patients underwent both planar whole body [99mTc]- 3,3-Diphosphono-1,2-Propanodicarboxylic Acid (DPD)-scintigraphy and quantitative Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) of the thorax. SPECT/CT standardized myocardial uptake values SUVpeak and SUVpeak normalized to bone uptake (nSUVpeak) were determined. Results: Phantom measurements showed a strong linear relationship between the activity in the myocardial insert and the measured activity (r = 0.9998, p = 0.01), but the measured activity was systematically underestimated by approximately 30%. Receiver operating characteristics (ROC) analysis revealed a 100% sensitivity and specificity at a cut-off of 3.1 for SUVpeak for the differentiation of both patient groups. Conclusion: SUV quantification of ATTR amyloid burden is feasible using novel SPECT/CT technology. With a SUVpeak cut-off of 3.1, patients with Perugini grade 2 and 3 could be clearly separated from those with Perugini grade 0 and 1. Besides ATTR diagnostics, quantification of amyloid deposits could potentially be used for therapy monitoring and prognostication in patients with cardiac ATTR.
Background Pericardial and pleural effusion are common findings in patients with cardiac amyloidosis (CA). It is not known, whether effusions correlate with right ventricular (RV) function in these patients. Furthermore, data on the prognostic significance of pleural and pericardial effusion in CA is scarce. Methods Patients with transthyretin (ATTR) and light chain (AL) CA were included in a clinical registry. All patients underwent transthoracic echocardiography at baseline. The presence of pericardial and pleural effusion was determined in every patient. The clinical endpoint was defined as cardiac death or heart failure hospitalization. Results In total, 143 patients were analysed. Of these, 85 patients were diagnosed with ATTR and 58 patients with AL. Twenty-four patients presented with isolated pericardial effusion and 35 with isolated pleural effusion. In 19 patients, both pericardial and pleural effusion were found and in 65 patients no effusion was present at baseline. The presence of pleural effusion correlated well with poor RV function, measured by global RV free-wall strain (p = 0.007) in patients with AL, but not in ATTR. No such correlation could be found for pericardial effusion in either amyloidosis subtype. Patients with AL presenting with pleural effusion had worse outcomes compared to patients with pericardial effusion alone or no effusion at baseline. In the ATTR group, there was no difference in outcomes according to presence and type of effusion. Conclusion More than 50% of patients with CA presented with pleural and/or pericardial effusions. While pleural effusion was clearly associated with poor RV function in AL, we were not able to detect this association with pericardial effusion.
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