DPD Quantification Correlates With Extracellular Volume and Disease Severity in Wild-Type Transthyretin Cardiac Amyloidosis.

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 99mTc-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, ß = 0.139, P < 0.001), native T1 time (r = 0.432, ß = 0.020, P = 0.005), RV-LS (r = 0.445, ß = 0.204, P = 0.004), NT-proBNP (log10) (r = 0.458, ß = 2.842, P = 0.003), troponin T (r = 0.422, ß = 0.048, P = 0.007), 6MWD (r = 0.385, ß = -0.007, P = 0.017), and NAC stage (r = 0.490, ß = 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.

Health-related quality of life is an independent predictor of mortality and hospitalisations in transthyretin amyloid cardiomyopathy: a prospective cohort study.

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.

Patients with transthyretin amyloid cardiomyopathy, a condition causing heart failure and mostly seen in the elderly, suffer from shortness of breath and reduced maximum physical performance. Disease assessment is currently based on blood analysis for markers of heart failure. However, standardised patient questionnaires also allow to estimate disease severity. In this study, we analyse different standardised patient questionnaires for their ability to predict adverse events including death and heart failure-related hospitalisations. The analysis demonstrates that an increase of ten points in the Kansas City Cardiomyopathy questionnaire, a tool specifically designed for patients with heart failure, implies a reduction of mortality risk of close to 20%. Interestingly, even the very simple visual analogue scale, a quality-of-life measurement tool which asks the patient to rate their health on a scale from zero (worst) to one hundred (best) has demonstrated remarkable predictive utility. An increase of ten points on this scale resulted in a reduction of risk for death from any cause of almost a quarter. This analysis suggests that standardised patient questionnaires for the assessment of quality of life may play an important role in the evaluation of patients with transthyretin amyloid cardiomyopathy and estimation of prognosis.

Cardiopulmonary exercise testing in transthyretin amyloid cardiomyopathy patients: a long-term follow-up study.

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.

Evaluation of the 2021 ESC recommendations for family screening in hereditary transthyretin cardiac amyloidosis.

AIMS: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement. METHODS AND RESULTS: We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%. CONCLUSIONS: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common.

Diagnosis and prognosis of abnormal cardiac scintigraphy uptake suggestive of cardiac amyloidosis using artificial intelligence: a retrospective, international, multicentre, cross-tracer development and validation study.

BACKGROUND: The diagnosis of cardiac amyloidosis can be established non-invasively by scintigraphy using bone-avid tracers, but visual assessment is subjective and can lead to misdiagnosis. We aimed to develop and validate an artificial intelligence (AI) system for standardised and reliable screening of cardiac amyloidosis-suggestive uptake and assess its prognostic value, using a multinational database of 99mTc-scintigraphy data across multiple tracers and scanners. METHODS: In this retrospective, international, multicentre, cross-tracer development and validation study, 16 241 patients with 19 401 scans were included from nine centres: one hospital in Austria (consecutive recruitment Jan 4, 2010, to Aug 19, 2020), five hospital sites in London, UK (consecutive recruitment Oct 1, 2014, to Sept 29, 2022), two centres in China (selected scans from Jan 1, 2021, to Oct 31, 2022), and one centre in Italy (selected scans from Jan 1, 2011, to May 23, 2023). The dataset included all patients referred to whole-body 99mTc-scintigraphy with an anterior view and all 99mTc-labelled tracers currently used to identify cardiac amyloidosis-suggestive uptake. Exclusion criteria were image acquisition at less than 2 h (99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid, 99mTc-hydroxymethylene diphosphonate, and 99mTc-methylene diphosphonate) or less than 1 h (99mTc-pyrophosphate) after tracer injection and if patients' imaging and clinical data could not be linked. Ground truth annotation was derived from centralised core-lab consensus reading of at least three independent experts (CN, TT-W, and JN). An AI system for detection of cardiac amyloidosis-associated high-grade cardiac tracer uptake was developed using data from one centre (Austria) and independently validated in the remaining centres. A multicase, multireader study and a medical algorithmic audit were conducted to assess clinician performance compared with AI and to evaluate and correct failure modes. The system's prognostic value in predicting mortality was tested in the consecutively recruited cohorts using cox proportional hazards models for each cohort individually and for the combined cohorts. FINDINGS: The prevalence of cases positive for cardiac amyloidosis-suggestive uptake was 142 (2%) of 9176 patients in the Austrian, 125 (2%) of 6763 patients in the UK, 63 (62%) of 102 patients in the Chinese, and 103 (52%) of 200 patients in the Italian cohorts. In the Austrian cohort, cross-validation performance showed an area under the curve (AUC) of 1·000 (95% CI 1·000-1·000). Independent validation yielded AUCs of 0·997 (0·993-0·999) for the UK, 0·925 (0·871-0·971) for the Chinese, and 1·000 (0·999-1·000) for the Italian cohorts. In the multicase multireader study, five physicians disagreed in 22 (11%) of 200 cases (Fleiss' kappa 0·89), with a mean AUC of 0·946 (95% CI 0·924-0·967), which was inferior to AI (AUC 0·997 [0·991-1·000], p=0·0040). The medical algorithmic audit demonstrated the system's robustness across demographic factors, tracers, scanners, and centres. The AI's predictions were independently prognostic for overall mortality (adjusted hazard ratio 1·44 [95% CI 1·19-1·74], p<0·0001). INTERPRETATION: AI-based screening of cardiac amyloidosis-suggestive uptake in patients undergoing scintigraphy was reliable, eliminated inter-rater variability, and portended prognostic value, with potential implications for identification, referral, and management pathways. FUNDING: Pfizer.

Amyloid Burden Correlates with Electrocardiographic Findings in Patients with Cardiac Amyloidosis-Insights from Histology and Cardiac Magnetic Resonance Imaging.

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.

Reduction in 99mTc-DPD myocardial uptake with therapy of ATTR cardiomyopathy.

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 [99mTc]-radiolabeled diphosphono-1,2-propanodicarboxylic acid (99mTc-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 99mTc-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.

Myocardial structural and functional changes in cardiac amyloidosis: insights from a prospective observational patient registry.

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.

Unveiling Cardiac Amyloidosis, its Characteristics, and Outcomes Among Patients With MR Undergoing Transcatheter Edge-to-Edge MV Repair.

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 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid bone scintigraphy and echocardiography and immunoglobulin light chain assessment. Transthyretin CA (ATTR) was diagnosed by 99mTc-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.

Reverse Remodeling Following Valve Replacement in Coexisting Aortic Stenosis and Transthyretin Cardiac Amyloidosis.

BACKGROUND: Dual pathology of severe aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR) is increasingly recognized. Evolution of symptoms, biomarkers, and myocardial mechanics in AS-ATTR following valve replacement is unknown. We aimed to characterize reverse remodeling in AS-ATTR and compared with lone AS. METHODS: Consecutive patients referred for transcatheter aortic valve replacement (TAVR) underwent ATTR screening by blinded 99mTc-DPD bone scintigraphy (Perugini Grade-0 negative, 1-3 increasingly positive) before intervention. ATTR was diagnosed by DPD and absence of monoclonal protein. Reverse remodeling was assessed by comprehensive evaluation before TAVR and at 1 year. RESULTS: One hundred twenty patients (81.8±6.3 years, 51.7% male, 95 lone AS, 25 AS-ATTR) with complete follow-up were studied. At 12 months (interquartile range, 7-17) after TAVR, both groups experienced significant symptomatic improvement by New York Heart Association functional class (both P<0.001). Yet, AS-ATTR remained more symptomatic (New York Heart Association ≥III: 36.0% versus 13.8; P=0.01) with higher residual NT-proBNP (N-terminal pro-brain natriuretic peptide) levels (P<0.001). Remodeling by echocardiography showed left ventricular mass regression only for lone AS (P=0.002) but not AS-ATTR (P=0.5). Global longitudinal strains improved similarly in both groups. Conversely, improvement of regional longitudinal strain showed a base-to-apex gradient in AS-ATTR, whereas all but apical segments improved in lone AS. This led to the development of an apical sparing pattern in AS-ATTR only after TAVR. CONCLUSIONS: Patterns of reverse remodeling differ from lone AS to AS-ATTR, with both groups experiencing symptomatic improvement by TAVR. After AS treatment, AS-ATTR transfers into a lone ATTR cardiomyopathy phenotype.

Prevalence and Outcomes of Cardiac Amyloidosis in All-Comer Referrals for Bone Scintigraphy.

The prevalence of cardiac amyloidosis (CA) in the general population and associated prognostic implications remain poorly understood. We aimed to identify CA prevalence and outcomes in bone scintigraphy referrals. Methods: Consecutive all-comers undergoing 99mTc-3,3-diphosphono-1,2-propanodicarboxylic-acid (99mTc-DPD) bone scintigraphy between 2010 and 2020 were included. Perugini grade 1 was defined as low-grade uptake and grade 2 or 3 as confirmed CA. All-cause mortality, cardiovascular death, and heart failure hospitalization (HHF) served as endpoints. Results: In total, 17,387 scans from 11,527 subjects (age, 61 ± 16 y; 63.0% women, 73.6% cancer) were analyzed. Prevalence of 99mTc-DPD positivity was 3.3% (n = 376/11,527; grade 1: 1.8%, grade 2 or 3: 1.5%), and was higher among cardiac than noncardiac referrals (18.2% vs. 1.7%). In individuals with more than 1 scan, progression from grade 1 to grade 2 or 3 was observed. Among patients with biopsy-proven CA, the portion of light-chain (AL)-CA was significantly higher in grade 1 than grade 2 or 3 (73.3% vs. 15.4%). After a median of 6 y, clinical event rates were: 29.4% mortality, 2.6% cardiovascular death, and 1.5% HHF, all independently predicted by positive 99mTc-DPD. Overall, adverse outcomes were driven by confirmed CA (vs. grade 0, mortality: adjusted hazard ratio [AHR] 1.46 [95% CI 1.12-1.90]; cardiovascular death: AHR 2.34 [95% CI 1.49-3.68]; HHF: AHR 2.25 [95% CI 1.51-3.37]). One-year mortality was substantially higher in cancer than noncancer patients. Among noncancer patients, also grade 1 had worse outcomes than grade 0 (HHF/death: AHR 1.45 [95% CI 1.01-2.09]), presumably because of longer observation and higher prognostic impact of early infiltration. Conclusion: Positive 99mTc-DPD was identified in a substantial number of consecutive 99mTc-DPD referrals and associated with adverse outcomes.

Comparison of Hepatic Tissue Characterization between T1-Mapping and Non-Contrast Computed Tomography.

Background: Non-contrast computed tomography (CT) is frequently used to assess non-alcoholic/metabolic fatty liver disease (NAFLD/MAFLD), which is associated with cardiovascular risk. Although liver biopsy is considered the gold standard for diagnosis, standardized scores and non-contrast computed tomography (CT) are used instead. On standard cardiac T1-maps on cardiovascular imaging (CMR) exams for myocardial tissue characterization hepatic tissue is also visible. We hypothesized that there is a significant correlation between hepatic tissue T1-times on CMR and Hounsfield units (HU) on non-contrast CT. Methods: We retrospectively identified patients undergoing a non-contrast CT including the abdomen, a CMR including T1-mapping, and laboratory assessment within 30 days. Patients with storage diseases were excluded. Results: We identified 271 patients (62 ± 15 y/o, 49% female) undergoing non-contrast CT and CMR T1-mapping within 30 days. Mean hepatic HU values were 54 ± 11 on CT and native T1-times were 598 ± 102 ms on CMR and there was a weak, but significant, correlation between these parameters (r = −0.136, p = 0.025). On age and sex adjusted regression analysis, lower liver HU values indicated a dismal cardiometabolic risk profile, including higher HbA1C (p = 0.005) and higher body mass index (p < 0.001). In contrast, native hepatic T1-times yielded a more pronounced cardiac risk profile, including impaired systolic function (p = 0.045) and higher NT-proBNP values (N-Terminal Brain Natriuretic Peptide) (p = 0.004). Conclusions: Hepatic T1-times are easy to assess on standard T1-maps on CMR but only weakly correlated with hepatic HU values on CT and clinical NAFLD/MAFLD scores. Liver T1-times, however, are linked to impaired systolic function and higher natriuretic peptide levels. The prognostic value and clinical usefulness of hepatic T1-times in CMR cohorts warrants further research.

Tafamidis treatment delays structural and functional changes of the left ventricle in patients with transthyretin amyloid cardiomyopathy.

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.

Impact of afterload and infiltration on coexisting aortic stenosis and transthyretin amyloidosis.

OBJECTIVE: The coexistence of wild-type transthyretin cardiac amyloidosis (ATTR) is common in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). However, the impact of ATTR and AS on the resultant AS-ATTR is unclear and poses diagnostic and management challenges. We therefore used a multicohort approach to evaluate myocardial structure, function, stress and damage by assessing age-related, afterload-related and amyloid-related remodelling on the resultant AS-ATTR phenotype. METHODS: We compared four samples (n=583): 359 patients with AS, 107 with ATTR (97% Perugini grade 2), 36 with AS-ATTR (92% Perugini grade 2) and 81 age-matched and ethnicity-matched controls. 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy was used to diagnose amyloidosis (Perugini grade 1 was excluded). The primary end-point was NT-pro Brain Natriuretic Peptide (BNP) and secondary end-points related to myocardial structure, function and damage. RESULTS: Compared with older age controls, the three disease cohorts had greater cardiac remodelling, worse function and elevated NT-proBNP/high-sensitivity Troponin-T (hsTnT). NT-proBNP was higher in AS-ATTR (2844 (1745, 4635) ng/dL) compared with AS (1294 (1077, 1554)ng/dL; p=0.002) and not significantly different to ATTR (3272 (2552, 4197) ng/dL; p=0.63). Diastology, hsTnT and prevalence of carpal tunnel syndrome were statistically similar between AS-ATTR and ATTR and higher than AS. The left ventricular mass indexed in AS-ATTR was lower than ATTR (139 (112, 167) vs 180 (167, 194) g; p=0.013) and non-significantly different to AS (120 (109, 130) g; p=0.179). CONCLUSIONS: The AS-ATTR phenotype likely reflects an early stage of amyloid infiltration, but the combined insult resembles ATTR. Even after treatment of AS, ATTR-specific therapy is therefore likely to be beneficial.

Convolutional Neural Networks for Fully Automated Diagnosis of Cardiac Amyloidosis by Cardiac Magnetic Resonance Imaging.

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.

Heart failure with preserved ejection fraction after left-sided valve surgery: prevalent and relevant.

AIMS: To investigate the epidemiological and prognostic relationship between heart failure with preserved ejection fraction (HFpEF) and left-sided valve surgery using all-cause mortality as a primary endpoint. METHODS AND RESULTS: We studied a total of 973 patients, of whom 673 had undergone left-sided valve surgery (time from surgery to enrolment 50 ± 30 months after valve surgery) and 300 patients with HFpEF without prior surgery served as control group. Among patients after surgery, 67.4% fulfilled all criteria of HFpEF according to current guideline recommendations, 20.6% had no heart failure (HF), and 12.0% had HF with mid-range or reduced ejection fraction (HFmrEF/HFrEF). During 83 ± 39 months of follow-up, a total of 335 (34.4%) patients died. Compared to surgical patients with no subsequent HF, patients with HFpEF and HFmrEF/HFrEF after surgery showed significantly higher all-cause mortality rates [hazard ratio (HR) 1.80, 95% confidence interval (CI) 1.25-2.57, P = 0.001; and HR 1.86, 95% CI 1.16-2.98, P = 0.010, respectively]. This increased mortality rate was similar to the control HFpEF group without surgery (HR 2.05, 95% CI 1.38-3.02, P < 0.001). Results remained consistent after adjustment for clinical and imaging risk factors and when using the established HFA-PEFF risk score for HFpEF diagnosis. Notably, only 12.5% of HFpEF patients after surgery were diagnosed with HF despite regular follow-up visits by board-certified cardiologists. In contrast, 92.1% of HFmrEF/HFrEF patients after surgery were diagnosed correctly. CONCLUSIONS: Heart failure with preserved ejection fraction following left-sided valve surgery is highly prevalent, associated with unfavourable outcomes, but rarely recognized.

New risk stratification after colorectal polypectomy reduces burden of surveillance without increasing mortality.

BACKGROUND: The 2020 postpolypectomy surveillance guideline update of European Society for Gastrointestinal Endoscopy defines a more restrictive group of individuals in need for surveillance 3 years after colonoscopy. AIM: The aim of this cohort study was to validate the new guideline recommendation. METHODS: Based on a national quality assurance program, we compared the 2020 risk group definition with the previous 2013 recommendations for their strength of association with (1) colorectal cancer death, and (2) all-cause death. RESULTS: A total of 265,608 screening colonoscopies were included in the study. Mean age was 61.1 years (SD ±9.0), and 50.6% were women. During a mean follow-up of 59.3 months (SD ±35.0), 170 CRC deaths and 7723 deaths of any cause were identified. 62.4% of colonoscopies were negative and 4.9% were assigned to surveillance after 3 years according to the 2020 guidelines versus 10.4% following the 2013 guidelines, which corresponds to a relative reduction in colonoscopies by 47%. The strength of association with CRC mortality was markedly higher with the 2020 surveillance group as compared to the 2013 guidelines (HR 2.56, 95% CI 1.62-4.03 vs. HR 1.73, 95% CI 1.13-2.62), while the magnitude of association with CRC mortality for low risk individuals was lower (HR 1.17, 95% CI 0.83-1.63 vs. 1.25, 95% CI 0.88-1.76). CONCLUSIONS: Adherence to the updated guidelines reduces the burden of surveillance colonoscopies by 47% while preserving the efficacy of surveillance in preventing CRC mortality.

Association of Adenoma Detection Rate and Adenoma Characteristics With Colorectal Cancer Mortality After Screening Colonoscopy.

BACKGROUND & AIMS: The adenoma detection rate (ADR) and characteristics of previously resected adenomas are associated with colorectal cancer (CRC) incidence and mortality. However, the combined effect of both factors on CRC mortality is unknown. PATIENTS AND METHODS: Using data of the Austrian quality assurance program for screening colonoscopy, we evaluated the combined effect of ADR and lesion characteristics on subsequent risk for CRC mortality. We analyzed mortality rates for individuals with low-risk adenomas (1-2 adenomas <10 mm), individuals with high-risk adenomas (advanced adenomas or ≥3 adenomas), and after negative colonoscopy (negative colonoscopy or small hyperplastic polyps) performed by endoscopists with an ADR <25% compared with ≥25%. Cox regression was used to determine the association of combined risk groups with CRC mortality, adjusted for age and sex. RESULTS: We evaluated 259,885 colonoscopies performed by 361 endoscopists. A total of 165 CRC-related deaths occurred during the follow-up period, up to 12.2 years. In all risk groups, CRC mortality was higher when colonoscopy was performed by an endoscopist with an ADR <25%. Compared with negative colonoscopy with an ADR ≥25%, CRC mortality was similar for individuals with low-risk adenomas irrespective of ADR (for ADR ≥25%: adjusted hazard ratio [HR], 1.22; 95% confidence interval [CI], 0.59-2.49; for ADR <25%: adjusted HR, 1.25; 95% CI, 0.64-2.43) and after negative colonoscopy with ADR <25% (adjusted HR, 1.27; 95% CI, 0.81-2.00). Individuals with high-risk adenomas were at significantly higher risk for CRC death if colonoscopy was performed by an endoscopist with an ADR <25% (adjusted HR, 2.25; 95% CI, 1.18-4.31) but not if performed by an endoscopist with an ADR ≥25% (adjusted HR, 1.35; 95% CI, 0.61-3.02). CONCLUSIONS: Our study adds important evidence for mandatory assessment and monitoring of performance quality in screening colonoscopy. High-quality colonoscopy was associated with a lower risk for CRC death, and the impact of ADR was strongest for individuals with high-risk adenomas.

Prevalence and Outcomes of Concomitant Aortic Stenosis and Cardiac Amyloidosis.

BACKGROUND: Older patients with severe aortic stenosis (AS) are increasingly identified as having cardiac amyloidosis (CA). It is unknown whether concomitant AS-CA has worse outcomes or results in futility of transcatheter aortic valve replacement (TAVR). OBJECTIVES: This study identified clinical characteristics and outcomes of AS-CA compared with lone AS. METHODS: Patients who were referred for TAVR at 3 international sites underwent blinded research core laboratory 99mtechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) bone scintigraphy (Perugini grade 0: negative; grades 1 to 3: increasingly positive) before intervention. Transthyretin-CA (ATTR) was diagnosed by DPD and absence of a clonal immunoglobulin, and light-chain CA (AL) was diagnosed via tissue biopsy. National registries captured all-cause mortality. RESULTS: A total of 407 patients (age 83.4 ± 6.5 years; 49.8% men) were recruited. DPD was positive in 48 patients (11.8%; grade 1: 3.9% [n = 16]; grade 2/3: 7.9% [n = 32]). AL was diagnosed in 1 patient with grade 1. Patients with grade 2/3 had worse functional capacity, biomarkers (N-terminal pro-brain natriuretic peptide and/or high-sensitivity troponin T), and biventricular remodeling. A clinical score (RAISE) that used left ventricular remodeling (hypertrophy/diastolic dysfunction), age, injury (high-sensitivity troponin T), systemic involvement, and electrical abnormalities (right bundle branch block/low voltages) was developed to predict the presence of AS-CA (area under the curve: 0.86; 95% confidence interval: 0.78 to 0.94; p < 0.001). Decisions by the heart team (DPD-blinded) resulted in TAVR (333 [81.6%]), surgical AVR (10 [2.5%]), or medical management (65 [15.9%]). After a median of 1.7 years, 23% of patients died. One-year mortality was worse in all patients with AS-CA (grade: 1 to 3) than those with lone AS (24.5% vs. 13.9%; p = 0.05). TAVR improved survival versus medical management; AS-CA survival post-TAVR did not differ from lone AS (p = 0.36). CONCLUSIONS: Concomitant pathology of AS-CA is common in older patients with AS and can be predicted clinically. AS-CA has worse clinical presentation and a trend toward worse prognosis, unless treated. Therefore, TAVR should not be withheld in AS-CA.

International Multi-Center Analysis of In-hospital Morbidity and Mortality of Low-Voltage Electrical Injuries.

Background : Patients with high- and low-voltage electrical injuries differ in their clinical presentation from minor symptoms to life-threatening conditions. For an adequate diagnosis and treatment strategy a multidisciplinary team is often needed, due to the heterogeneity of the clinical presentation. To minimize costs and medical resources, especially for patients with mild symptoms presenting after low-voltage electrical injuries, risk stratification for the development of further complications is needed. Methods : During 2012-2019 two independent patient cohorts admitted with electrical injuries in two maximum care university hospitals in Germany and Austria were investigated to quantify risk factors for prolonged treatment, the need of surgery and death in low-voltage injuries. High-voltage injuries were used as reference in the analysis of the low-voltage electrical injury. Results : We analyzed 239 admitted patients with low-voltage (75%; 276 ± 118 V), high-voltage (17%; 12.385 ± 28.896 V) or unclear voltage (8%). Overall mortality was 2% (N = 5) associated only with high-voltage injuries. Patients with low-voltage injuries presented with electrocution entry marks (63%), various neurological symptoms (31%), burn injuries (at least second degree) (23%), pain (27%), and cardiac symptoms (9%) including self-limiting thoracic pain and dysrhythmia without any therapeutic need. Seventy three percentage of patients with low-voltage injury were discharged within 24 h. The remaining patients stayed in the hospital (11 ± 10 days) for treatment of entry marks and burns, with an overall need for surgery of 12% in all low-voltage injuries. Conclusions : The only identified risk factors for prolonged hospital stay in patients with low-voltage electrical injuries were the treatment of burns and electric marks. In this multi-center analysis of hospitalized patients, low-voltage electrical injuries were not associated with cardiac arrhythmia or mortality. Therefore, we suggest that asymptomatic patients, without preexisting conditions, with low-voltage injury can be discharged after an initial check-up without prolonged monitoring.