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Purpose: Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with severely impaired health-related quality of life (HRQL). HRQL is an independent predictor of outcome in heart failure (HF), but data on patients with ATTR-CM is scarce. This study therefore aims to evaluate the association of HRQL with outcome in ATTR-CM., Methods: Patients from our prospective ATTR-CM registry were assessed using the Kansas City cardiomyopathy questionnaire (KCCQ), the Minnesota living with HF questionnaire (MLHFQ), and the EuroQol five dimensions questionnaire (EQ-5D). Cox regression analysis was utilised to assess the impact of HRQL on all-cause mortality., Results: 167 patients [80 years; interquartile range (IQR): 76-84; 80.8% male] were followed for a median of 27.6 (IQR: 9.7-41.8) months. The primary endpoint of all-cause mortality was met by 43 (25.7%) patients after a median period of 16.2 (IQR: 9.1-28.1) months. In a univariate Cox regression for mortality, a 10-point change in the KCCQ implied a hazard ratio (HR) of 0.815 [95%-confidence interval (CI): 0.725-0.916; p = 0.001], in the EQ-5D VAS of 0.764 (95%-CI: 0.656-0.889; p < 0.001), and 1.163 (95%-CI: 1.114-1.433; p < 0.001) in the MLHFQ. After adjustment for established biomarkers of HF, all-cause mortality was predicted independently by the EQ-5D VAS (HR: 0.8; 95%-CI: 0.649-0.986; p = 0.037; per 10 points) and the MLHFQ (HR: 1.228; 95%-CI: 1.035-1.458; p = 0.019; per 10 points)., Conclusion: HRQL is a predictor of outcome in ATTR-CM. The EQ-5D VAS and the MLHFQ predict survival independent of biomarkers of HF., (© 2024. The Author(s).)

Background: The pathophysiological hallmark of wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is the deposition of amyloid within the myocardium., Objectives: This study aimed to investigate associations between quantitative cardiac 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) uptake and myocardial amyloid burden, cardiac function, cardiac biomarkers, and clinical status in ATTRwt-CM., Methods: Forty ATTRwt-CM patients underwent quantitative DPD single photon emission computed tomography/computed tomography to determine the standardized uptake value (SUV) retention index, cardiac magnetic resonance imaging to determine extracellular volume (ECV) and cardiac function (RV-LS), and assessment of cardiac biomarkers (N-terminal prohormone of brain natriuretic peptide [NT-proBNP], troponin T) and clinical status (6-minute walk distance [6MWD], National Amyloidosis Centre [NAC] stage). ATTRwt-CM patients were divided into 2 cohorts based on median SUV retention index (low uptake: <5.19 mg/dL, n = 20; high uptake: ≥5.19 mg/dL, n = 20). Linear regression models were used to assess associations of the SUV retention index with variables of interest and the Mann-Whitney U or chi-squared test to compare variables between groups., Results: ATTRwt-CM patients (n = 40) were elderly (78.0 years) and predominantly male (75.0%). Univariable linear regression analyses revealed associations of the SUV retention index with ECV (r = 0.669, β = 0.139, P  < 0.001), native T1 time (r = 0.432, β = 0.020, P  = 0.005), RV-LS (r = 0.445, β = 0.204, P  = 0.004), NT-proBNP (log 10 ) (r = 0.458, β = 2.842, P  = 0.003), troponin T (r = 0.422, β = 0.048, P  = 0.007), 6MWD (r = 0.385, β = -0.007, P  = 0.017), and NAC stage (r = 0.490, β = 1.785, P  = 0.001). Cohort comparison demonstrated differences in ECV ( P  = 0.001), native T1 time ( P  = 0.013), RV-LS ( P  = 0.003), NT-proBNP ( P  < 0.001), troponin T ( P  = 0.046), 6MWD ( P  = 0.002), and NAC stage (I: P  < 0.001, II: P  = 0.030, III: P  = 0.021)., Conclusions: In ATTRwt-CM, quantitative cardiac DPD uptake correlates with myocardial amyloid load, longitudinal cardiac function, cardiac biomarkers, exercise capacity, and disease stage, providing a valuable tool to quantify and monitor cardiac disease burden., Competing Interests: Dr Rettl has received speaker fees and congress support from Akcea Therapeutics, Alnylam Pharmaceuticals, and Pfizer Inc, as well as research grants from 10.13039/100004319Pfizer Inc. Dr Duca has received speaker fees and congress support from 10.13039/501100015086AOP Orphan Pharmaceuticals GmbH, 10.13039/100006400Alnylam Pharmaceuticals, 10.13039/100004326Bayer AG, 10.13039/100004336Novartis AG, 10.13039/100004319Pfizer Inc and, as well as research grants from the 10.13039/501100015797Austrian Society of Cardiology and 10.13039/100004319Pfizer Inc. Dr Beitzke has received speaker fees from GE Healthcare and Siemens. Dr Nitsche receives speaker fees and research grants from 10.13039/100004319Pfizer Inc. Dr Badr Eslam has received speaker fees from Merck Sharp & Dohme Ges.m.b.H., AOP Orphan Pharmaceuticals GmbH, and OrphaCare GmbH, as well as research grants from OrphaCare GmbH and Astra Zeneca GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Aims: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience reduced functional capacity. We evaluated changes in functional capacity over extensive follow-up using cardiopulmonary exercise testing (CPX)., Methods: ATTR-CM patients underwent CPX and blood testing at baseline, first [V1, 8 (6-10) months] and second follow-up (V2) at 35 (26-41) months after start of disease-specific therapy., Results: We included 34 ATTR-CM patients, aged 77 (±6) years (88.2% men). CPX showed two patterns with functional capacity improvement at V1 and deterioration at V2. Peak work capacity ( P = 0.005) and peak oxygen consumption (VO 2 , P = 0.012) increased at V1 compared with baseline and decreased at V2. The ventilation to carbon dioxide relationship slope (VE/VCO 2 ) increased at V2 compared with baseline and V1 ( P = 0.044). A cut-off for peak VO 2 at 14 ml/kg·min showed more events (composite of death and heart failure hospitalization): less than 14 vs. greater than 14 ml/kg·min ( P  = 0.013). Cut-offs for VE/VCO 2 slope at 40 showed more events greater than 40 vs. less than 40 ( P  = 0.009)., Conclusion: ATTR-CM patients showed an improvement and deterioration in the short-term and long-term follow-up, respectively, with a better prognosis for those with peak VO 2 above 14 ml/kg·min and for a VE/VCO 2 slope below 40., (Copyright © 2024 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with heart failure (HF) hospitalizations and death. Previous studies have shown that altered muscle composition is associated with higher risk of adverse outcome in HFpEF patients., Aim: The purpose of our study was to investigate the association between skeletal muscle composition, as measured by skeletal muscle T1-times on cardiac magnetic resonance (CMR) imaging, and adverse outcome., Methods: We measured skeletal muscle T1-times of the back muscles on standard CMR images in a prospective cohort of HFpEF patients. Cox regression models were used to test the association of skeletal muscle T1-times and adverse outcome defined as hospitalization for HF and/or cardiovascular death., Results: We included 101 patients (mean age 72±7 years, 71 % female) in our study. The median skeletal muscle T1-times were 842 ms (IQR 806-881 ms). In univariate analysis high muscle T1-time was associated with adverse outcome (HR=1.96 [95 % CI, 1.31-2.94] per every 100 ms increase; p=.001). After adjustment for age, sex, body mass index, left- and right ventricular ejection fraction, N-terminal pro-brain natriuretic peptide and myocardial native T1-times, native skeletal muscle T1-time remained an independent predictor for adverse outcome (HR=1.94 [95 % CI, 1.24-3.03] per every 100 ms increase; p=.004)., Conclusion: In patients with HFpEF, high skeletal muscle T1-times on standard CMR scans are associated with higher rates of HF hospitalizations and cardiovascular death., Condensed Abstract: Skeletal muscle abnormalities are common in patients with heart failure with preserved ejection fraction (HFpEF). The present study evaluates skeletal muscle composition, as quantified by native skeletal muscle T1-times of the back muscles on standard cardiac magnetic resonance imaging, and assessed the association with adverse outcome, defined as hospitalization for heart failure and/or cardiovascular death. In a prospective cohort of 101 patients with HFpEF, we found that high native skeletal muscle T1-times are associated with an increased risk for adverse outcome. These findings suggest that native skeletal muscle T1-time may serve as marker for improved risk prediction., Competing Interests: Declaration of competing interest The authors declare they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). We aimed to determine the impact of RNAi therapeutics on myocardial amyloid load using quantitative single photon emission computed tomography/computed tomography (SPECT/CT) imaging in patients with ATTRv-related cardiomyopathy (ATTRv-CM). We furthermore compared them with wild-type ATTR-CM (ATTRwt-CM) patients treated with tafamidis. Methods and results: ATTRv-CM patients underwent [ 99m Tc]-radiolabeled diphosphono-1,2-propanodicarboxylic acid ( 99m Tc-DPD) scintigraphy and quantitative SPECT/CT imaging before and after 12 months (IQR: 11.0-12.0) of treatment with RNAi therapeutics (patisiran: n  = 5, inotersen: n  = 4). RNAi treatment significantly reduced quantitative myocardial uptake as measured by standardised uptake value (SUV) retention index (baseline: 5.09 g/mL vs. follow-up: 3.19 g/mL, p  = .028) in ATTRv-CM patients without significant improvement in cardiac function. Tafamidis treatment resulted in a significant reduction in SUV retention index (4.96 g/mL vs. 3.27 g/mL, p  < .001) in ATTRwt-CM patients (historical control cohort: n  = 40) at follow-up [9.0 months (IQR: 7.0-10.0)] without beneficial impact on cardiac function. Conclusions: RNAi therapeutics significantly reduce quantitative myocardial uptake in ATTRv-CM patients, comparable to tafamidis treatment in ATTRwt-CM patients, without impact on cardiac function. Serial 99m Tc-DPD SPECT/CT imaging may be a valuable tool to quantify and monitor response to disease-specific therapies in both ATTRv-CM and ATTRwt-CM.

Cardiac amyloidosis (CA) is associated with several distinct electrocardiographic (ECG) changes. However, the impact of amyloid depositions on ECG parameters is not well investigated. We therefore aimed to assess the correlation of amyloid burden with ECG and test the prognostic power of ECG findings on outcomes in patients with CA. Consecutive CA patients underwent ECG assessment and cardiac magnetic resonance imaging (CMR), including the quantification of extracellular volume (ECV) with T1 mapping. Moreover, seven patients underwent additional amyloid quantification using immunohistochemistry staining of endomyocardial biopsies. A total of 105 CA patients (wild-type transthyretin: 74.3%, variant transthyretin: 8.6%, light chain: 17.1%) were analyzed for this study. We detected correlations of total QRS voltage with histologically quantified amyloid burden (r = -0.780, p = 0.039) and ECV (r = -0.266, p = 0.006). In patients above the ECV median (43.9%), PR intervals were significantly longer ( p = 0.016) and left anterior fascicular blocks were more prevalent ( p = 0.025). In our survival analysis, neither Kaplan-Meier curves ( p = 0.996) nor Cox regression analysis detected associations of QRS voltage with adverse patient outcomes (hazard ratio: 0.995, p = 0.265). The present study demonstrated that an increased amyloid burden is associated with lower voltages in CA patients. However, baseline ECG findings, including QRS voltage, were not associated with adverse outcomes.

Aims: The pathophysiological hallmark of cardiac amyloidosis (CA) is the deposition of amyloid within the myocardium. Consequently, extracellular volume (ECV) of affected patients increases. However, studies on ECV progression over time are lacking. We aimed to investigate the progression of ECV and its prognostic impact in CA patients., Methods and Results: Serial cardiac magnetic resonance (CMR) examinations, including ECV quantification, were performed in consecutive CA patients. Between 2012 and 2021, 103 CA patients underwent baseline and follow-up CMR, including ECV quantification. Median ECVs at baseline of the total (n = 103), transthyretin [(ATTR) n = 80], and [light chain (AL) n = 23] CA cohorts were 48.0%, 49.0%, and 42.6%, respectively. During a median period of 12 months, ECV increased significantly in all cohorts [change (Δ) +3.5% interquartile range (IQR): -1.9 to +6.9, P < 0.001; Δ +3.5%, IQR: -2.0 to +6.7, P < 0.001; and Δ +3.5%, IQR: -1.6 to +9.1, P = 0.026]. Separate analyses for treatment-naïve (n = 21) and treated (n = 59) ATTR patients revealed that the median change of ECV from baseline to follow-up was significantly higher among untreated patients (+5.7% vs. +2.3%, P = 0.004). Survival analyses demonstrated that median change of ECV was a predictor of outcome [total: hazard ratio (HR): 1.095, 95% confidence interval (CI): 1.047-1.0145, P < 0.001; ATTR: HR: 1.073, 95% CI: 1.015-1.134, P = 0.013; and AL: HR: 1.131, 95% CI: 1.041-1.228, P = 0.003]., Conclusion: The present study supports the use of serial ECV quantification in CA patients, as change of ECV was a predictor of outcome and could provide information in the evaluation of amyloid-specific treatments., Competing Interests: Conflict of interest: Fr.D.: Speaker fees and congress support from Bayer, Novartis, Alnylam, Pfizer, and AOP, as well as research grants from the Austrian Society of Cardiology and Pfizer. R.R.: Speaker fees and congress support from Akcea, Alnylam, and Pfizer, as well as research grants from Pfizer. C.B.: none. C.M.: none. Fa.D.: none. L.S.: none. D.D.: Speaker fees and congress support from Abbott, Bristol Myers Squibb, and Pfizer, as well as research grants from Alnylam and the Austrian Society of Cardiology. B.Ö.: none. T.M.D.: none. B.C.: none. L.C.L.: none. H.A.: none. R.K.: none. M.K.: none. C.D.: none. R.B.-E.: none. J.K.: none. Die.B.: none. C.L.: none. C.N.: none. C.H.: none. A.A.K.: none. Dia.B.: Speaker fees and congress support from Bayer, Novartis, Alnylam, Pfizer, AOP, Ionis, Zoll, Jansen, and Sanofi Aventis, as well as research grants from the Austrian Society of Cardiology and Pfizer., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Cardiac amyloidosis (CA) often mimics heart failure with preserved ejection fraction (HFpEF). Due to very different treatment strategies, an exact diagnosis and differentiation between pure HFpEF and CA-related heart failure (HF) is important. In the present study, we assessed the recently published H2FPEF score in patients with pure HFpEF, transthyretin (ATTR), as well as light chain (AL) amyloidosis-related HFpEF and tested whether it differentiates between these entities., Methods: The H2FPEF scores consists of easy-to-assess clinical (Body Mass Index, number of hypertensive drugs, presence of atrial fibrillation, age) and echocardiographic (systolic pulmonary arterial pressure, E/E´) parameters. It can be computed in a categorical way resulting in scores between 0 and 9 points (0-1: HFpEF rule out, 2-5: further testing required, 6-9: HFpEF rule in), or in a continual way providing an exact percentage of a patient's HFpEF probability. Continuous and categorical variables were compared using the Kruskal-Wallis, Mann-Whitney-U, and χ 2 -tests. Diagnostic accuracy was computed from 2x2 tables. Survival analysis was performed with Kaplan-Meier curves. A P value of <0.05 was set as the level of significance., Results: A total of 100 patients with pure HFpEF, 53 patients with ATTR, and 34 patients with AL CA were included in the present study. Median age (HFpEF: 71.5 years; ATTR CA: 77.0 years; AL CA: 60.0 years; P<0.001), gender distribution (HFpEF [female]: 73.0%, ATTR (female): 18.9%, AL [female]: 38.2%; P<0.001), and N-terminal prohormone of brain natriuretic peptide (HFpEF: 1045pg/mL; ATTR CA: 1927pg/mL; AL CA: 4308pg/mL; P<0.001) differed significantly between study cohorts. Median H2FPEF scores were highest among HFpEF (categorical: 5.0 points; continual: 95.1%), followed by ATTR (categorical: 4.0 points; continual: 89.0%), and AL CA (categorical: 3.0 points; continual: 31.2%). Respective P values were <0.001. Low H2FPEF scores (0-1 points) were found among patients in the AL CA cohort (29.4%), but not among HFpEF or ATTR CA patients (P<0.001). The majority of patients, irrespective of disease entity were in the intermediate score range (2-5 points, HFpEF: 80.0% ATTR CA: 94.3%, AL CA: 67.9%; P=0.006). High scores (6-9 points) were most often found among HFpEF patients (20.0%), followed by ATTR CA (5.7%) and AL CA (2.9%), (P=0.007)., Conclusions: The H2FPEF score should be used with caution, as there is a significant overlap between HFpEF and CA-related HF.

Background: Bone scintigraphy plays an important role in the diagnosis of cardiac Transthyretin-Related Amyloidosis (ATTR). The mechanism of myocardial tracer accumulation and its dependence over time are not fully understood. Recently, a scintigraphic quantification of the cardiac amyloid deposition has been discussed. Nevertheless, little is known regarding the right time of quantitative imaging., Methods: The geometrical mean of decay corrected total counts over the heart and the heart/whole-body ratio (H/WB) were evaluated in 23 patients undergoing DPD-bone scan with planar whole-body images 1 and 3 hours post injection (p.i.). Myocardial standard uptake values (SUV)peak were assessed in another 15 patients with quantitative SPECT/CT imaging 1 hours and 3 hours p.i.., Results: Total counts over the heart (1 hours p.i.: 81,676 cts, range 69,887 to 93,091 cts and 3 hours p.i.: 64,819 cts, range 52,048 to 86,123 cts, P = .0005) and H/WB ratio (1 hours p.i.:0.076 ± 0.020 and 3 hours p.i. 0.070 ± 0.022; P = .0003) were significantly increased 1 hours p.i.. Furthermore median myocardial SUVpeak (1 hours p.i.:12.2, range 9.6 to 18.9 and 3 hours p.i.: 9.6, range 8.2 to 15.0, P = 0.0012) was also significantly higher after 1 hours p.i. compared to 3 hours p.i.., Conclusion: Cardiac DPD activity and myocardial SUVpeak are time-dependent, which should be considered when using quantitative bone scintigraphy in ATTR patients., (© 2022. The Author(s).)

Aims: Tafamidis treatment positively affects left ventricular (LV) structure and function and improves outcomes in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). We aimed to investigate the relationship between treatment response and cardiac amyloid burden identified by serial quantitative 99mTc-DPD SPECT/CT. We furthermore aimed to identify nuclear imaging biomarkers that could be used to quantify and monitor response to tafamidis therapy., Methods and Results: Forty wild-type ATTR-CM patients who underwent 99mTc-DPD scintigraphy and SPECT/CT imaging at baseline and after treatment with tafamidis 61 mg once daily [median, 9.0 months (interquartile range 7.0-10.0)] were divided into two cohorts based on the median (-32.3%) of the longitudinal percent change in standardized uptake value (SUV) retention index. ATTR-CM patients with a reduction greater than or equal to the median (n = 20) had a significant decrease in SUV retention index (P < 0.001) at follow-up, which translated into significant benefits in serum N-terminal prohormone of brain natriuretic peptide levels (P = 0.006), left atrial volume index (P = 0.038), as well as LV [LV global longitudinal strain: P = 0.028, LV ejection fraction (EF): P = 0.027, LV cardiac index (CI): P = 0.034] and right ventricular (RV) [RVEF: P = 0.025, RVCI: P = 0.048] functions compared with patients with a decrease less than the median (n = 20)., Conclusion: Treatment with tafamidis in ATTR-CM patients results in a significant reduction in SUV retention index, associated with significant benefits for LV and RV function and cardiac biomarkers. Serial quantitative 99mTc-DPD SPECT/CT imaging with SUV may be a valid tool to quantify and monitor response to tafamidis treatment in affected patients., Translational Perspective: 99mTc-DPD SPECT/CT imaging with determination of SUV retention index as part of a routine annual examination can provide evidence of treatment response in ATTR-CM patients receiving disease-modifying therapy. Further long-term studies with 99mTc-DPD SPECT/CT imaging may help to evaluate the relationship between tafamidis-induced reduction in SUV retention index and outcome in patients with ATTR-CM and will demonstrate whether highly disease-specific 99mTc-DPD SPECT/CT imaging is more sensitive than routine diagnostic monitoring., Competing Interests: Conflict of interest: R.R. received speaker fees and congress support from Akcea, Alnylam, and Pfizer, as well as research grants from Pfizer. F.D. received speaker fees and congress support from Bayer, Novartis, Alnylam, Pfizer, and AOP, as well as research grants from the Austrian Society of Cardiology and Pfizer. D.D. received speaker fees and congress support from BMS and Pfizer, as well as research grants from Alnylam and the Austrian Society of Cardiology. D.BE. received speaker fees from Bayer, MSD, and Medis Medical Imaging. D.B. received speaker fees and congress support from Bayer, Novartis, Alnylam, Pfizer, and AOP, as well as research grants from the Austrian Society of Cardiology and Pfizer. All other authors have nothing to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: The one-minute sit-to-stand-test (1-min STST) is a quick, space saving test to evaluate functional capacity. Exercise testing plays an important role in the long-term follow-up of pulmonary hypertension (PH) patients and is currently evaluated using the six-minute-walk-test (6MWT). The aim of the study was to assess the convergent validity of the 1-min STST in patients with PH and its association with markers of PH severity., Methods: We evaluated 106 PH patients with the 1-min-STST and 6MWT and measured cardiorespiratory parameters (heart rate, blood pressure, oxygen saturation) before and after test conduction. N-terminal pro brain-type natriuretic peptide (NT-proBNP), WHO functional class (WHO-FC) and mean pulmonary artery pressure (mPAP) were defined as markers of PH severity., Results: Strong correlation was found between performances of 1-min STST and 6MWT (r = .711, p < .001), indicating convergent validity. Both tests were inversely associated with NT-proBNP (STST: r = -.405, p < .001; 6MWT: r = -.358, p < .001), WHO-FC (STST: r = -.591, p < .001; 6MWT: r = -.643, p < .001) and mPAP (STST: r = -.280, p < .001; 6MWT: r = -.250, p < .001). Significant changes in cardiorespiratory parameters were observed in both tests (all p < 0.001). Further the post-exercise cardiorespiratory parameters correlated strongly between the 1-min STST and 6MWT (all r ≥ .651, all p < .001)., Conclusion: The 1-min STST demonstrated good convergent validity with the 6MWT and was associated with markers of PH severity. Furthermore, both exercise tests caused similar cardiorespiratory responses., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kronberger et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aims: The impact of tafamidis on myocardial strain in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) have been barely investigated. We aimed to determine tafamidis-induced changes using serial speckle tracking echocardiography and to identify imaging parameters for specific therapy monitoring., Methods and Results: ATTR-CM patients underwent serial TTE with two-dimensional (2 D) speckle tracking imaging. Patients receiving tafamidis free acid 61 mg ( n  = 62) or tafamidis meglumine 20 mg ( n  = 21) once daily (QD) showed stable measurements at follow-up (61 mg: 8.5 months, 20 mg: 7.0 months) in LV global longitudinal strain (GLS) (61 mg: -11.75% vs. -11.58%, p  = 0.534; 20 mg: -10.61% vs. -10.12%, p  = 0.309), right ventricular (RV) GLS (61 mg: -14.18% vs. -13.72%, p  = 0.377; 20 mg: -14.53% vs. -13.99%, p  = 0.452) and left atrial (LA) reservoir strain (LASr; 61 mg: 8.80% vs. 9.42%, p  = 0.283; 20 mg: 8.23% vs. 8.67%, p  = 0.589), whereas treatment-naïve ATTR-CM patients ( n  = 54) had clear signs of disease progression at the end of the observation period (10.5 months; LV-GLS: -11.71% vs. -10.59%, p  = 0.001; RV-GLS: -14.36% vs. -12.99%, p  = 0.038; LASr: 10.67% vs. 8.41%, p  = 0.005). Between-group comparison at follow-up revealed beneficial effects of tafamidis free acid 61 mg on LASr ( p  = 0.003) and the LV (LV-GLS: p  = 0.030, interventricular septum (IVS): p  = 0.006), resulting in clinical benefits (six-minute walk distance (6-MWD): p  = 0.006, NT-proBNP: p= <0.001), while patients treated with tafamidis meglumine 20 mg QD showed positive effects on LASr ( p  = 0.039), but no differences with respect to the LV (LV-GLS: p  = 0.274, IVS: p  = 0.068) and clinical status (6-MWD: p  = 0.124, NT-proBNP: p  = 0.053) compared to the natural course., Conclusions: Treatment with tafamidis free acid 61 mg in ATTR-CM patients delays the deterioration of LA and LV longitudinal function, resulting in significant clinical benefits compared with natural history. Serial TTE with 2 D speckle tracking imaging may be appropriate for disease-specific therapy monitoring.

Background: With the introduction of several drugs for the therapy of transthyretin-related amyloidosis (ATTR) which slow down the disease, early detection of polyneuropathy (PNP) is becoming increasingly of interest. [99mTc]-3,3-Diphosphono-1,2-Propanodicarboxylic Acid (DPD) bone scintigraphy, which is used for the diagnosis of cardiac (c)ATTR, can possibly make an important contribution in the identification of patients at risk for PNP., Methods: Fifty patients with cATTR, who underwent both planar whole-body DPD scintigraphy and nerve conduction studies (NCS) were retrospectively evaluated. A subgroup of 22 patients also underwent quantitative SPECT/CT of the thorax from which Standardized Uptake Values (SUVpeak) in the subcutaneous fat tissue of the left axillar region were evaluated., Results: The Perugini score was significantly increased in patients with cATTR and additional diagnosis of PNP compared to patients without (2.51 ± 0.51 vs 2.13 ± 0.52; P = 0.03). Quantitative SPECT/CT revealed that DPD uptake in the subcutaneous fat of the left axillar region was significantly increased in cATTR patients with compared to patients without (1.36 ± 0.60 vs 0.74 ± 0.52; P = 0.04)., Conclusion: This study suggests that DPD bone scintigraphy is a useful tool for identification of patients with cATTR and a risk for PNP due to increased DPD soft tissue uptake., (© 2022. The Author(s).)

Objective: We sought to develop a clinical model to identify heart failure patients with preserved ejection fraction (HFpEF) at highest risk for acute HF events or death., Methods and Results: Between 2010 and 2019, 422 patients with HFpEF were followed. Acute HF events occurred in 190 patients (45%), including 110 (58%) with recurrent hospitalizations. Those with recurrent events had worse 6-min walk test ( p < 0.001), higher brain N-terminal prohormone natriuretic peptide (NT-proBNP, p < 0.001), and higher New York Heart Association functional class (NYHA, p < 0.001). Overall survival rates in patients with 1 HF event vs > 1 HF events were: at 1-year 91.6 vs. 91.8%, at 3-years 84.7 vs. 68.3% and at 5-years 67.4 vs. 42.7%, respectively ( p < 0.04). The Hfpef survivAL hOspitalization (HALO) score revealed best predictive capability for all-cause mortality combining the variables age ( p = 0.08), BMI ( p = 0.124), NYHA class ( p = 0.004), need for diuretic therapy ( p = 0.06), left atrial volume index ( p = 0.048), systolic pulmonary artery pressure ( p = 0.013), NT-proBNP ( p = 0.076), and number of prior hospitalizations ( p = 0.006). HALO score predicted future HF hospitalizations in an ordinal logistic regression model (OR 3.24, 95% CI: 2.45-4.37, p < 0.001). The score performance was externally validated in 75 HFpEF patients, confirming a strong survival prediction (HR 2.13, 95% CI: 1.30-3.47, p = 0.002)., Conclusions: We developed a model to identify HFpEF patients at increased risk of death and HF hospitalization. NYHA class and recurrent HF hospitalizations were the strongest drivers of outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schrutka, Seirer, Rettl, Dachs, Binder, Duca, Dalos, Badr-Eslam, Kastner, Hengstenberg, Frommlet and Bonderman.)

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., Competing Interests: Conflict of interest: E.G. received grants/contracts from Bayer, MSD, United Therapeutics and OMT; consulting fees from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics; payments/honoraria from Bayer, Janssen and MSD; support for attending meetings and/or travel from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics. E.G. participated on data monitoring/advisory boards for Janssen, United Therapeutics, and Acceleron. I.P. has received honoraria for lectures from Orion, AOP Orphan and Amomed. D.B. received financial support for the present manuscript in form of an unrestricted research grant by Bayer (all payments were made to the Medical University of Vienna); research grants by Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi (all payments were made to the Medical University of Vienna); and payments/honoraria from Bayer AG, Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi, Astra Zeneca, Boehringer Ingelheim, Zoll, Janssen, AOP Orphan, and MSD. All other authors declare that there is no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Background: Mitral regurgitation (MR) and cardiac amyloidosis (CA) both primarily affect older patients. Data on coexistence and prognostic implications of MR and CA are currently lacking., Objectives: This study sought to identify the prevalence, clinical characteristics, and outcomes of MR CA compared with lone MR., Methods: Consecutive patients undergoing transcatheter edge-to-edge repair (TEER) for MR at 2 sites were screened for concomitant CA using a multiparametric approach including core laboratory 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid bone scintigraphy and echocardiography and immunoglobulin light chain assessment. Transthyretin CA (ATTR) was diagnosed by 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (Perugini grade 1: early infiltration; grades 2/3: clinical CA) and the absence of monoclonal protein, and light chain (AL) CA via tissue biopsy. All-cause mortality and hospitalization for heart failure (HHF) served as the endpoints., Results: A total of 120 patients (age 76.9 ± 8.1 years, 55.8% male) were recruited. Clinical CA was diagnosed in 14 patients (11.7%; 12 ATTR, 1 AL, and 1 combined ATTR/AL) and early amyloid infiltration in 9 patients (7.5%). Independent predictors of MR CA were increased posterior wall thickness and the presence of a left anterior fascicular block on electrocardiography. Procedural success and periprocedural complications of TEER were similar in MR CA and lone MR (P for all = NS). After a median of 1.7 years, 25.8% had experienced death and/or HHF. MR CA had worse outcomes compared with lone MR (HR: 2.2; 95% CI: 1.0-4.7; P = 0.034), driven by a 2.5-fold higher risk for HHF (HR: 2.5; 95% CI: 1.1-5.9), but comparable mortality (HR: 1.6; 95% CI: 0.4-6.1)., Conclusions: Dual pathology of MR CA is common in elderly patients with MR undergoing TEER and has worse postinterventional outcomes compared with lone MR., Competing Interests: Funding Support and Author Disclosures This study received financial support from Pfizer. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality. Precise risk stratification remains challenging. The one-minute sit-to-stand-test (1-min STST), a quick, objective test of functional capacity may be helpful for stratification of clinical profile in HFpEF patients., Objective: The aim of this initial investigation was to prospectively examine whether the 1-min STST can be used for the evaluation of exercise capacity in HFpEF patients and whether it is in line with echocardiographic as well as quality of life (QoL) findings., Methods: 39 HFpEF patients were prospectively studied. Functional performance was examined with the 1-min STST and QoL with the CAMPHOR questionnaire. Clinical parameters including echocardiographic measurements [estimated pulmonary artery systolic pressure (ePASP), tricuspid regurgitation velocity (TRV)] were obtained. Patients were divided into two groups based on their number of 1-min STST repetitions (Group I: ≤50% of predicted 1-min STST repetitions using the norm-reference values developed by Strassmann et al. for healthy people, N=24; Group II: >50% of predicted 1-min STST repetitions, N=15)., Results: Patients in group I with limited 1-min STST performance showed worse echocardiographic parameters [higher ePASP (p=0.038), higher TRV (p=0.018) and more reduced tricuspid annular plane systolic excursion (TAPSE) (p=0.001)], worse six-minute walk test (6MWT) (p<0.001) and worse QoL (p<0.001) compared to patients in group II., Conclusion: Our study shows potential usefulness of the 1-min STST as an evaluative tool for exercise capacity in HFpEF patients, because patients with worse 1-min STST performance have worse clinical parameters and QoL., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In patients with transthyretin amyloid cardiomyopathy, tafamidis was shown to slow the decline in 6-minute walking distance as compared with placebo. We aimed to define the impact of tafamidis and optimal background treatment on functional capacity as determined by cardiopulmonary exercise testing (CPET)., Methods: Seventy-eight consecutive patients were enrolled in the study. They underwent CPET at baseline, and outcome defined as death or heart failure hospitalization was obtained for a time period of up to 30 months. Fifty-four patients completed a follow-up CPET at 9±3 months (range, 4-16 months). Improvement in peak VO 2 at follow-up was defined as ∆peak VO 2 ≥1.0 mL/(kg·min), stable peak VO 2 was defined as 0≤∆peak VO 2 <1.0 mL/(kg·min), and decline in peak VO 2 was defined by ∆peak VO 2 <0 mL/(kg·min)., Results: Baseline peak VO 2 >14 mL/(kg·min) as well as minute ventilation/carbon dioxide production slope≤34 were associated with a lower risk of death or heart failure hospitalization ( P =0.002, P =0.007, respectively). In 54 patients, who received tafamidis and underwent repeat CPET testing, an improvement in physical performance ( P =0.002) was observed at follow-up. When comparing pre and post-treatment parameters, 29 patients (54%) showed an increase in percent predicted peak VO 2 ( P <0.0001), an improvement of peak VO 2 ( P <0.0001), and better physical performance at follow-up ( P <0.0001). Patients with stable or improved peak VO 2 had less advanced heart disease at baseline ( P =0.046)., Conclusions: Our findings demonstrate that baseline peak VO 2 and baseline minute ventilation/carbon dioxide production slope predict outcomes and an improvement in physical performance as measured by CPET was observed in patients receiving tafamidis, who had less advanced disease at baseline, emphasizing the importance of early diagnosis.

Background: Diagnosis of cardiac amyloidosis (CA) requires advanced imaging techniques. Typical surface ECG patterns have been described, but their diagnostic abilities are limited., Objective: The aim was to perform a thorough electrophysiological characterisation of patients with CA and derive an easy-to-use tool for diagnosis., Methods: We applied electrocardiographic imaging (ECGI) to acquire electroanatomical maps in patients with CA and controls. A machine learning approach was then used to decipher the complex data sets obtained and generate a surface ECG-based diagnostic tool., Findings: Areas of low voltage were localised in the basal inferior regions of both ventricles and the remaining right ventricular segments in CA. The earliest epicardial breakthrough of myocardial activation was visualised on the right ventricle. Potential maps revealed an accelerated and diffuse propagation pattern. We correlated the results from ECGI with 12-lead ECG recordings. Ventricular activation correlated best with R-peak timing in leads V1-V3. Epicardial voltage showed a strong positive correlation with R-peak amplitude in the inferior leads II, III and aVF. Respective surface ECG leads showed two characteristic patterns. Ten blinded cardiologists were asked to identify patients with CA by analysing 12-lead ECGs before and after training on the defined ECG patterns. Training led to significant improvements in the detection rate of CA, with an area under the curve of 0.69 before and 0.97 after training., Interpretation: Using a machine learning approach, an ECG-based tool was developed from detailed electroanatomical mapping of patients with CA. The ECG algorithm is simple and has proven helpful to suspect CA without the aid of advanced imaging modalities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: We tested the hypothesis that artificial intelligence (AI)-powered algorithms applied to cardiac magnetic resonance (CMR) images could be able to detect the potential patterns of cardiac amyloidosis (CA). Readers in CMR centers with a low volume of referrals for the detection of myocardial storage diseases or a low volume of CMRs, in general, may overlook CA. In light of the growing prevalence of the disease and emerging therapeutic options, there is an urgent need to avoid misdiagnoses., Methods and Results: Using CMR data from 502 patients (CA: n = 82), we trained convolutional neural networks (CNNs) to automatically diagnose patients with CA. We compared the diagnostic accuracy of different state-of-the-art deep learning techniques on common CMR imaging protocols in detecting imaging patterns associated with CA. As a result of a 10-fold cross-validated evaluation, the best-performing fine-tuned CNN achieved an average ROC AUC score of 0.96, resulting in a diagnostic accuracy of 94% sensitivity and 90% specificity., Conclusions: Applying AI to CMR to diagnose CA may set a remarkable milestone in an attempt to establish a fully computational diagnostic path for the diagnosis of CA, in order to support the complex diagnostic work-up requiring a profound knowledge of experts from different disciplines.

Significant expression of neprilysin (NEP) is found on neutrophils, which present the transmembrane integer form of the enzyme. This study aimed to investigate the relationship of neutrophil transmembrane neprilysin (mNEP) with disease severity, adverse remodeling, and outcome in HFrEF. In total, 228 HFrEF, 30 HFpEF patients, and 43 controls were enrolled. Neutrophil mNEP was measured by flow-cytometry. NEP activity in plasma and blood cells was determined for a subset of HFrEF patients using mass-spectrometry. Heart failure (HF) was characterized by reduced neutrophil mNEP compared to controls ( p < 0.01). NEP activity on peripheral blood cells was almost 4-fold higher compared to plasma NEP activity ( p = 0.031) and correlated with neutrophil mNEP ( p = 0.006). Lower neutrophil mNEP was associated with increasing disease severity and markers of adverse remodeling. Higher neutrophil mNEP was associated with reduced risk for mortality, total cardiovascular hospitalizations, and the composite endpoint of both ( p < 0.01 for all). This is the first report describing a significant role of neutrophil mNEP in HFrEF. The biological relevance of neutrophil mNEP and exact effects of angiotensin-converting-enzyme inhibitors (ARNi) at the neutrophil site have to be determined. However, the results may suggest early initiation of ARNi already in less severe HF disease, where effects of NEP inhibition may be more pronounced.

Drugs which interact with the renin angiotensin aldosterone system (RAAS) aim to reduce the negative effects of angiotensin (Ang) II. Treatment with these drugs anticipate a compensatory up-regulation of renin; however, it has been shown that there is a large variability in circulating plasma renin (PRA), even in patients with optimal medical therapy in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Our aim was to measure plasma renin activity (PRA-S), its response to RAAS inhibitor (RAASi) therapies and its effects on outcome in patients with HF with preserved ejection fraction (HFpEF). For this purpose, 150 HFpEF patients were included into a prospective single-center registry. Equilibrium (eq) angiotensin metabolites were measured from serum samples using mass spectroscopy. PRA-S (eqAng I + eqAng II) was calculated and compared in respect to the primary endpoint defined as all-cause death. PRA-S in patients with RAASi therapy was not significantly higher than in patients without RAASi ( p = 0.262). Even after adjusting for confounding factors, PRA-S remained predictive for all-cause death in the multivariable model with a hazard ratio of 2.14 (95%CI 1.20-3.82, p = 0.010). We conclude that high PRA-S is associated with poor prognosis in patients with HFpEF, regardless of RAASi treatment, which could ultimately result in hyperactivated RAAS and consecutive negative effects on the cardiovascular and renal system, leading to poor outcome in patients with HFpEF.

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.

The PARAGON-HF clinical trial suggested that sacubitril/valsartan may become a treatment option for particular subgroups of patients with heart failure and preserved ejection fraction (HFpEF). However, the proportion of real-world HFpEF patients who are theoretically superimposable with the PARAGON-HF population is yet unknown. The present study was performed to define the proportion of real-world PARAGON-HF-like patients and to describe their clinical characteristics and long-term prognosis in comparison with those who would not meet PARAGON-HF criteria. We systematically applied PARAGON-HF inclusion and exclusion criteria to a total of 427 HFpEF patients who have been participating in a prospective national registry between December 2010 and December 2019. In total, only 170 (39.8%) registry patients were theoretically eligible for PARAGON-HF. Patients not meeting inclusion criteria (41.0%) were less impaired with respect to exercise capacity (median 6-min walk distance: 385 m (IQR: 300-450) versus 323 m (IQR: 240-383); p < 0.001) had lower pulmonary pressures (mean pulmonary artery pressure (mPAP): 31.2 mmHg, standard deviation (SD): ±10.2 versus 32.8 mmHg, SD: ±9.7; p < 0.001) and better outcomes (log-rank: p < 0.001) as compared to the PARAGON-like cohort. However, patients theoretically excluded from the trial (19.2%) were those with most advanced heart failure symptoms (median 6-min walk test: 252 m (IQR: 165-387); p < 0.001), highest pulmonary pressures (mPAP: 38.2 mmHg, SD: ±12.4; p < 0.001) and worst outcome (log-rank: p = 0.037). We demonstrate here that < 40% of real-world HFpEF patients meet eligibility criteria for PARAGON-HF. We conclude that despite reasons for optimism after PARAGON-HF, a large proportion of HFpEF patients will remain without meaningful treatment options.

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 [ 99m Tc]- 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: Heart failure with preserved ejection fraction (HFpEF) is among the most common forms of heart failure (HF). We aimed to investigate the prognostic significance of serum potassium levels and its interaction with type-2 diabetes mellitus in patients with HFpEF., Methods: Consecutive HFpEF patients were prospectively included in a registry study. The primary endpoint was a composite of cardiac death or HF hospitalization., Results: 363 HFpEF patients were enrolled (median age: 73.0 years; females: 70.3%). Median serum potassium (K+) was 4.3 mmol/L. A total of 128 (35.3%) patients had type-2 diabetes mellitus, of whom 92 were treated with oral anti-diabetic drugs and 35 with insulin. The study population was divided into two groups, according to their serum potassium levels. Significant differences between the groups were detected with regards to combined endpoint [n = 27 (61.4%) versus n = 87 (27.3%); p < 0.0001]. Lower serum potassium levels were significantly associated with adverse outcome in the Cox proportional hazard analysis [hazard ratio (HR): 1.83; 95% confidence interval (CI) 1.14-2.94; p = 0.0118]. Further independent predictors of adverse outcome were a history of HF hospitalizations (HR: 2.77; 95% CI 1.82-4.21; p < 0.0001), higher NT-pro BNP (HR: 1.93; 95% CI 1.82-4.21; p = 0.0084) as well as type-2 diabetes mellitus (HR: 1.57; 95% CI 1.05-2.34; p = 0.0027). Patients with diabetes and K+ ≤ 3.71 mmol/L faced the worst outcome as compared to the remainder of the group (p = 0.0001)., Conclusion: In HFpEF patients, the combination of diabetes and low serum potassium levels are associated with an adverse outcome., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

(1) Background: Cardiac amyloidosis (CA) is a rare and complex condition with poor prognosis. While novel therapies improve outcomes, many affected individuals remain undiagnosed due to a lack of awareness among clinicians. This study was undertaken to develop an expert-independent machine learning (ML) prediction model for CA relying on routinely determined laboratory parameters. (2) Methods: In a first step, we developed baseline linear models based on logistic regression. In a second step, we used an ML algorithm based on gradient tree boosting to improve our linear prediction model, and to perform non-linear prediction. Then, we compared the performance of all diagnostic algorithms. All prediction models were developed on a training cohort, consisting of patients with proven CA (positive cases, n = 121) and amyloidosis-unrelated heart failure (HF) patients (negative cases, n = 415). Performances of all prediction models were evaluated on a separate prognostic validation cohort with 37 CA-positive and 124 CA-negative patients. (3) Results: Our best model, based on gradient-boosted ensembles of decision trees, achieved an area under the receiver operating characteristic curve (ROC AUC) score of 0.86, with sensitivity and specificity of 89.2% and 78.2%, respectively. The best linear model had an ROC AUC score of 0.75, with sensitivity and specificity of 84.6 and 71.7, respectively. (4) Conclusions: Our work demonstrates that ML makes it possible to utilize basic laboratory parameters to generate a distinct CA-related HF profile compared with CA-unrelated HF patients. This proof-of-concept study opens a potential new avenue in the diagnostic workup of CA and may assist physicians in clinical reasoning.

This study sought to characterize cardiac amyloidosis (CA) patients with respect to hemodynamic parameters and asses their prognostic impact in different CA cohorts. Intracardiac and pulmonary arterial pressures (PAPs) are among the strongest predictors of outcomes in patients with heart failure (HF). Despite that, the hemodynamic profiles of patients with CA and their relation to prognosis have rarely been investigated. Invasive hemodynamic, clinical, and laboratory assessment, as well as cardiac magnetic resonance imaging were performed in our CA cohort. A total of 61 patients, 35 (57.4%) with wild-type transthyretin amyloidosis (ATTRwt) and 26 (42.6%) with light-chain amyloidosis (AL) were enrolled. ATTRwt patients had lower N-terminal prohormone of brain natriuretic peptide values and were less frequently in New York Heart Association class ≥ III. Intracardiac and PAPs were elevated, but hemodynamic parameters did not differ between CA groups. Whereas in ATTRwt, the median mean PAP (hazard ratio (HR): 1.130, p = 0.040) and pulmonary vascular resistance (HR: 1.010, p = 0.046) were independent predictors of outcome, no hemodynamic parameter was associated with outcome in the AL group. Cardiac ATTRwt and AL patients feature elevated intracardiac and PAPs and show similar hemodynamic profiles. However, hemodynamic parameters are of greater prognostic relevance in ATTRwt, potentially providing a new therapeutic target.

Aims: Cardiac amyloidosis (CA) leads to signs and symptoms of heart failure (HF). The mechanisms of biventricular dysfunction and their impact on outcome in subtypes of CA are poorly understood. Our aim was to compare right ventricular (RV) and left ventricular (LV) parameters in patients with light chain (AL) and wild-type transthyretin amyloidosis (ATTRw) and evaluate their ability to predict cardiac outcome., Methods and Results: We included patients with CA into a prospective registry. Baseline assessment included biventricular 2D speckle tracking imaging parameters. Patients were followed-up in regular intervals. The composite endpoint was defined as cardiovascular death, heart transplantation or ventricular assist device implantation, and HF hospitalization. We included 122 patients with CA. Sixty-two of these patients (50.8%) were diagnosed with ATTRw and 60 (49.2%) with AL. In ATTRw, parameters of RV size and function correlated well with symptom severity and only morphological and functional parameters of the RV predicted outcome. RV free wall strain was the only independent predictor of outcome with a hazard ratio (HR) of 1.185 [95% confidence interval (CI) 1.047-1.342, P = 0.007]. In AL on the other hand, RV function correlated well with symptoms but was not associated with outcome. In contrast, global longitudinal strain of the LV (LV-GLS) was predictive for outcome. After adjusting in a multivariable model, LV-GLS remained predictive with a HR of 1.180 (95% CI 1.032-1.348, P = 0.015)., Conclusion: Our data suggest that mechanisms underlying HF differ between ATTRw and AL. This may have substantial implications in particular in light of emerging therapies for both subtypes of CA., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)