Fibroblast growth factor 23 (FGF23), a bone-derived hormone, is emerging as a potential biomarker in cardiovascular disease. However, its role in transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive infiltrative cardiomyopathy, remains poorly defined. This study examined the relationship between circulating FGF23 levels and cardiac and renal function markers in patients with ATTR-CM. In 114 patients with confirmed ATTR-CM, intact FGF23 levels were measured in venous ethylenediaminetetraacetic acid blood samples using a chemiluminescent immunoassay on the DiaSorin LIAISON XL system. Associations between FGF23 levels, cardiac biomarker levels, and disease severity were evaluated across FGF23 tertiles and National Amyloidosis Centre (NAC) stages. N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin T levels were significantly associated with FGF23 tertiles. NT-proBNP medians across tertiles were 1,608, 2,920, and 1,948.5 pg/mL, respectively (P = 0.0084). Higher FGF23 levels were significantly associated with advanced NAC classification, and cumulative probability modeling supported its association with disease stage. After adjustment for eGFR, FGF23 remained significantly associated with NT-proBNP (Spearman's ρ = 0.16; p = 0.084). However, the association with troponin T did not reach statistical significance (ρ = 0.19; p = 0.043), representing a non-significant trend. This is the first study to demonstrate a significant association between FGF23 and established markers of cardiac injury and disease staging in ATTR-CM, supporting FGF23 as a potential complementary biomarker for risk stratification.

Background/Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a heterogeneous multisystem disease caused by pathogenic transthyretin gene (TTR) variants. Increased awareness and availability of disease-modifying therapies have resulted in increased diagnoses, even in previously nonendemic regions. The aim of this study was to update the nationwide Austrian ATTRv registry by characterizing the clinical, genetic, and regional distribution of TTR variants. Methods: This multicenter, observational analysis examined ATTRv cases diagnosed in Austria between 2014 and 2025. Individuals were included according to the presence of pathogenic or likely pathogenic variants or variants of uncertain significance (VUSs) in TTR. Results: In total, 100 individuals were identified, including symptomatic and asymptomatic carriers. Compared with our previously presented data, the number of genetically confirmed ATTRv cases has more than doubled. Twenty-three TTR variants were identified. The most frequent pathologic variants were p.His108Arg (26%), p.Ile127Phe (11%), and p.Thr69Ile (9%), while p.Val113Leu (9%) represented the most frequent VUS. Significant regional clustering of p.His108Arg was documented in Vienna and Lower Austria. Other findings included a rising number of p.Val142Ile carriers and phenotypically relevant VUSs in 20 patients. Conclusions: Our findings revealed an increasing detection rate of ATTRv in a nonendemic European region. These data underscore the importance of multidisciplinary evaluation, cascade testing, and long-term monitoring to improve early diagnosis and timely management in hereditary amyloidosis.

Purpose A planar Perugini grade 1 scan is equivocal for transthyretin amyloid cardiomyopathy (ATTR-CM), has no dedicated management pathway and is biologically heterogeneous, spanning early or low-burden ATTR, AL amyloidosis and non-amyloid blood-pool activity. Rather than investigating grade 1 as a step toward amyloid confirmation, we characterized the clinical phenotype it marks and tested whether that phenotype, rather than amyloid, drives its prognosis. Methods We studied 9,170 consecutive patients who underwent [99mTc]Tc-DPD bone scintigraphy between 2010 and 2020, graded on planar imaging by blinded expert consensus. Using an imaging-phenotype association (IPA) framework analogous to genome-wide association analysis, we related Perugini grade to 1,243 clinical, laboratory, echocardiographic, cardiac magnetic resonance and ICD-10 comorbidity variables from electronic health records, adjusting for age, sex and cancer history. The outcome was a composite of heart failure hospitalization or death. Results Grade 1 occurred in 175 (1.9%) and grade ?2 in 142 (1.6%) patients. Grade ?2 reproduced the canonical infiltrative ATTR phenotype, with greater septal thickness, higher extracellular volume, neuropathy and atrial fibrillation, validating the framework. Grade 1 instead marked a non-infiltrative cardiometabolic phenotype dominated by hypertension, chronic ischemic heart disease, high BMI, anemia, reduced eGFR and atrial enlargement, with low extracellular volume and septal thickness arguing against meaningful infiltration. Grade 1 carried worse outcomes than grade 0 (adjusted HR 1.30, 95% CI 1.07 to 1.59). Within grade 1, a cardiometabolic phenotype defined by hypertension, high BMI and low hematocrit, with or without chronic ischemic heart disease, identified patients whose risk matched or exceeded that of grade ?2 (median HR 2.46 versus HR 1.76), indicating that grade 1 prognosis is driven substantially by comorbid cardiometabolic disease rather than amyloid burden. Conclusions Perugini grade 1 is neither uniform early amyloid nor a benign artifact but a mixed-etiology, predominantly non-infiltrative cardiometabolic phenotype that carries clinically meaningful risk. A simple cardiometabolic phenotype stratifies this risk, supporting reinterpretation of grade 1 and a management focus on cardiorenal comorbidity alongside selective amyloid workup. The IPA framework provides a scalable approach to characterizing cardiovascular imaging biomarkers. ### Competing Interest Statement CPS: speaker honoraria and/or consulting fees from Pfizer, Hermes Medical Solutions, MedPhys Consulting, the European School of Molecular Imaging and Technology (ESMIT) and the European Society for Radiology (ESR). CN: speaker/consulting honoraria from Pfizer, Bayer, Prothena and Böhringer Ingelheim and research contracts with Pfizer, AstraZeneca, the Austrian Society of Cardiology, the European Association of Cardiovascular Imaging and the Austrian Science Fund. DK: research grant from Pfizer, personal fees from Alnylam, GE Healthcare, Novartis and Pfizer and travel grants from Life Molecular Imaging and Sanofi, all outside of the submitted work. MH: Associate Editor at the European Journal of Nuclear Medicine and Molecular Imaging. The remaining authors declare no conflicts of interest. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was performed in line with the principles of the Declaration of Helsinki. Approval was obtained from the Ethics Committee of the Medical University of Vienna (No. 2278/2024). The institutional review board waived the requirement for informed consent owing to the retrospective design of the study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The current ethical approval of this study does not permit the sharing of study data. If you would like to access the data, please contact the corresponding author.

AIM:This study aimed to characterize circulating renin-angiotensin-aldosterone system (RAAS) patterns in transthyretin amyloid cardiomyopathy (ATTR-CM), examine their relationship with clinical and echocardiographic parameters and determine their prognostic value. METHODS:In this prospective study, ATTR-CM patients underwent serum quantification of classical (angiotensin I-IV, aldosterone) and alternative (angiotensin 1-7, angiotensin 1-5) RAAS peptides and angiotensin converting enzyme 2 (ACE2) activity using mass spectrometry. RAAS inhibitor use was recorded. Associations of RAAS peptides with N-terminal pro brain natriuretic peptide (NT-proBNP) and echocardiographic parameters were analyzed. Prognostic associations with the composite endpoint of HF hospitalization or cardiac death were assessed using Kaplan-Meier curves stratified by median peptide values. RESULTS:Among 137 patients, RAAS inhibitor use included ACEi (21.2%), ARBs (34.3%), ARNIs (7.3%) and none (26.0%). RAAS profiles were consistent with the expected effects of the respective RAAS inhibitors. During a median follow-up of 1.6 years, 49 patients (36%) experienced the composite endpoint. Patients with adverse cardiac events had higher ACE2 activity (p<0.001) and alternative RAAS peptides (angiotensin 1-7: p=0.007; angiotensin 1-5: p<0.001). Higher ACE2 activity was associated with higher NT-proBNP (p<0.001) and more advanced echocardiographic markers of biventricular dysfunction. In Kaplan Meier analysis, ACE2 above median predicted adverse cardiac outcomes (p=0.017), while classical RAAS peptides were not predictive. CONCLUSION:ATTR-CM patients exhibit distinct RAAS profiles, with increased ACE2 activity and a shift toward the alternative RAAS axis in more advanced disease. Higher ACE2 activity is associated with higher NT-proBNP, biventricular dysfunction and adverse cardiac outcomes, suggesting that ACE2 may represent a promising marker for risk stratification in ATTR-CM.

Background Cardiac transthyretin amyloidosis (ATTR‐CA) is frequently underdiagnosed and commonly presents as heart failure with preserved ejection fraction (HFpEF). Early identification enables disease‐modifying therapy but remains challenging in routine practice, so simple, widely available screening tools are needed. Methods In this multicenter validation study, 885 patients with HF from 2 European centers were included. The internal validation cohort comprised 560 patients with preserved ejection fraction and analyzable ECGs: 149 with ATTR‐CA, 318 with HFpEF, and 93 with hypertrophic cardiomyopathy. External validation used an independent cohort of 107 patients (72 ATTR‐CA, 31 HFpEF, 4 hypertrophic cardiomyopathy). Standard 12‐lead ECGs were analyzed blindly by 3 independent observers using a previously developed, 2‐step, artificial intelligence–derived, visually interpretable ECG algorithm. Results The ECG pattern was present in 82.6% of patients with ATTR‐CA, versus 10.2% with HFpEF and 6.5% with hypertrophic cardiomyopathy ( P <0.001). Internal‐cohort accuracy was high: area under the curve 0.87 (95% CI, 0.84–0.90), sensitivity 83% (95% CI, 76%–88%), specificity 91% (95% CI, 88%–93%), and negative predictive value 93% (95% CI, 91%–96%). In the external cohort, the area under the curve was 0.84 (95% CI, 0.76–0.92), with sensitivity 89% (95% CI, 78%–94%) and specificity 79% (95% CI, 63%–90%). The pattern was strongly associated with ATTR‐CA (odds ratio, 46 [95% CI, 27–80]; P <0.001) and with reduced 3‐year survival (log‐rank P =0.007). Conclusions A visually interpretable, artificial intelligence–derived ECG algorithm enables effective screening for ATTR‐CA among patients with HFpEF. Its simplicity and compatibility with standard ECG systems support broad clinical implementation.

INTRODUCTION:Cardiac amyloidosis (CA) is a progressive cardiomyopathy caused by amyloid deposition, leading to heart failure and increased mortality. Cardiac magnetic resonance (CMR) identifies myocardial involvement via elevated native T1 relaxation time and extracellular volume (ECV). Although amyloid infiltration has also been observed in thoracic skeletal muscle, the diagnostic and prognostic relevance of thoracic skeletal muscle T1 time and ECV remain unclear. AIM:To compare native thoracic skeletal muscle T1 time and ECV between CA patients and controls and assess their diagnostic and prognostic value. METHODS:In a prospective CMR registry, consecutive CA patients and controls underwent CMR with T1-mapping. Native and post-contrast T1 relaxation time and ECV were quantified in myocardium and thoracic skeletal muscles. Diagnostic performance was evaluated using ROC analysis and associations with mortality were assessed using Cox regression. RESULTS:Among 1976 participants (267 CA, 1709 controls), CA patients showed significantly higher native myocardial T1 time and ECV, as well as elevated native thoracic skeletal muscle T1 time (919.4 vs. 868.5 ms, p < 0.001) and ECV (16.4 vs. 12.9%, p < 0.001). Native thoracic skeletal muscle T1 time demonstrated moderate diagnostic performance for CA (AUC = 0.70), with an optimal cutoff of 895 ms yielding a sensitivity of 61% and specificity of 59%. Higher native thoracic skeletal muscle T1 time predicted increased mortality (HR = 1.65 per 100 ms, p < 0.001), and this association remained significant after adjusting for age, sex and ventricular function (HR = 1.21 per 100 ms, p = 0.008). CONCLUSION:Native skeletal muscle T1 relaxation time and ECV indicate systemic amyloid involvement and provide additional diagnostic and prognostic information beyond myocardial assessment, potentially supporting improved detection and risk stratification in CA.

Background: This study assessed the prognostic value of submaximal cardiopulmonary exercise testing (CPET) in cardiac amyloidosis and explored CPET as an alternative to the 6-min walk test (6MWT). Methods and Results: In this single-center prospective observational study, 160 patients with cardiac amyloidosis (87% male; mean age 78 +/- 7 years) were evaluated. A total of 145 performed maximum symptom limited CPET. The VE/VCO(2)slope was 39 +/- 8, submaximal power output (SPO) was 24.75 +/- 11.50 W, and VO(2)at anaerobic threshold (AT) was 8.13 +/- 2.29 mL/min/kg. During follow up, 34 (21.25%) patients died, and another 34 (21.25%) experienced heart failure (HF)-related hospitalization, with 15 (9.38%) patients experiencing both events. Univariate analysis showed that VE/VCO(2)slope (hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.86-0.93; P<0.001) and SPO (HR 0.91; 95% CI 0.87-0.96; P<0.001) were predictors of mortality. In multivariate analysis, VE/VCO(2)slope remained a significant predictor (HR 0.92; 95% CI 0.88-0.97; P<0.001) for both all-cause mortality and HF-related hospitalization independently. A SPO cut-off of <28 W predicted a worse outcome for both measures independently. Moderate correlations for VE/VCO(2)slope (-0.56 [CI -0.67, -0.42]) and SPO (0.55 [CI 0.42, 0.67]) with 6MWT distance have been found. Conclusions: These findings highlight CPET parameters, particularly VE/VCO(2)slope and SPO with a cut-off <28 W, as predictors of survival and HF-related hospitalization in cardiac amyloidosis.

Background/Objectives: Cardiac amyloidosis (CA) as well as coronary artery disease (CAD) are both highly prevalent among the elderly. However, both the prevalence and risk factors associated with significant CAD among patients with CA, as well as potential outcome disparities, remain mainly unexplored. This study aimed to show the prevalence of CAD in patients with CA, as well as to assess outcomes and differences in late gadolinium enhancement (LGE) in comparison to patients with lone CA. Methods: We retrospectively assessed CA patients who underwent CAD assessment between 2013 and 2023. The primary endpoint was all-cause death. A subgroup underwent cardiac magnetic resonance imaging (CMR) with LGE assessment. Results: Of 255 consecutive patients with CA, 81 patients had significant CAD. Differences could be found with respect to age, sex, arterial hypertension, and hyperlipidemia. Significant differences in CMR features could only be found with respect to indexed left-ventricular end-diastolic volume, as well as left-ventricular mass. CAD-specific LGE was present only in 17.7% of patients with CAD, while most patients showed typical amyloid LGE, making a viability diagnosis difficult via CMR, especially in patients with end-stage CA. No differences in outcomes could be observed according to the prevalence of CAD. Conclusions: Concomitant obstructive CAD is highly prevalent among patients with CA. However, the presence of CAD does not influence patient outcomes. Furthermore, our data suggests that CAD viability testing by CMR might be complicated in patients with concomitant CA due to the high prevalence of amyloid-specific LGE.

Background: Heart failure (HF) and chronic kidney disease (CKD) create a mutually reinforcing cycle, escalating disease development, and increasing morbidity and mortality rates. Both are common comorbidities promoting AF and contributing to heightened symptom burden and poorer outcomes in AF. Here our aim was to investigate the relationship of HF and CKD with cardiorenal outcomes in patients with atrial fibrillation (AF). Methods: Patients with AF, treated at a tertiary centre between January 2005 and July 2019, were included. The primary endpoint was a composite of cardiovascular (CV) death and hospitalization for HF (HHF). Secondary outcomes were the individual components of the primary endpoint, all-cause death, renal death, and dialysis. Results: We included a total of 7,412 patients (median age 70 years, 39.7% female) with AF and followed them over a median of 4.5 years. There was a significant stepwise increase in 5-year event rates for the composite of CV death/HHF (no CKD and no HF: 23%, HF: 61%, CKD: 63%, CKD and HF: 82%; P log-rank <0.001). Both CKD (adjusted hazard ratio [HR]: 1.87, 95% confidence interval [CI]: 1.55–2.25) and HF (adjusted HR: 2.57, 95% CI: 2.22–2.98) were significantly associated with CV death/HHF after multivariable adjustment. A similar association was observed for the individual components of the primary endpoint and renal death/dialysis. Conclusions: Both CKD and HF significantly increase the risk of CV death and HHF, as well as renal death/dialysis in patients with AF. Risk assessment should expand beyond stroke and bleeding to cardiorenal complications including HHF, CV, and renal death, as well as kidney failure.

Several randomized, double-blind, placebo-controlled trials (RCT) explore disease-modifying therapeutics in transthyretin amyloid cardiomyopathy (ATTR-CM). However, it is currently unclear whether patients eligible to participate in the RCT are representative of real-world patients. ATTR-CM patients presenting to a tertiary referral center for cardiac amyloidosis at the Medical University of Vienna between March 2012 and May 2024 were included in a prospective registry. Inclusion and exclusion criteria of the ATTRACT, ATTRIBUTE, HELIOS-B, CARDIO-TTRANSFORM, and the DEPLETTR-CM trial were applied, and the baseline characteristics of the hypothetical trial cohorts as well as their survival were compared. 353 patients (80.3 years, IQR: 75.5-84.2, 17.6% female) were included, and 192 (57.8%) patients would have been eligible to participate in ATTRIBUTE, ATTRACT would have recruited 163 (49.1%) patients, HELIOS-B 105 (31.6%) patients, CARDIO-TTRANSFORM 80 (24.1%) subjects, and 71 (21.4%) patients would have been eligible for DEPLETTR-CM. Hypothetical ATTRIBUTE, ATTRACT, HELIOS-B, and CARDIO-TTRANSFORM patients demonstrated only minor differences regarding baseline characteristics, both among each other and compared to the real-world cohort. However, DEPLETTR-CM eligible patients exhibited more severely elevated biomarkers of heart failure (NT-proBNP: 2590pg/mL, IQR: 1614-4423, vs. 2339pg/mL, IQR: 1154-4250; p < 0.001) and more advanced National Amyloidosis Centre stage (p < 0.001). Patients who could have been included in DEPLETTR-CM also showed significantly worse survival. Applied to our real-world ATTR-CM cohort, RCT inclusion and exclusion criteria would have selected patients comparable to the real-world cohort. Only the DEPLETTR-CM trial would have selected patients with more advanced disease and worse prognosis.

Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive, underdiagnosed disease with high morbidity and mortality. While disease-modifying therapies (DMTs) slow progression, early treatment response markers remain scarce. This study assessed AI-quantified thoracic [99mTc]Tc-DPD SPECT/CT markers as potential non-invasive biomarkers for monitoring therapeutic efficacy. This longitudinal study included ATTR-CM patients receiving DMTs (transthyretin stabilizers, RNA interference, or antisense oligonucleotides). [99mTc]Tc-DPD SPECT/CT scans were acquired at baseline and after treatment (median interval 9 months, IQR 7–10). AI-driven segmentation and quantification extracted 26 markers (SUV metrics, retention index, amyloid-affected volume, and amyloid activity). Functional, clinical, and blood parameters, as well as clinical outcomes, were evaluated for their association with changes in imaging markers. In 45 patients (37 ATTRwt-CM, 8 ATTRv-CM), 65

Background:Patients with cardiac amyloidosis undergoing direct current electrical cardioversion (DCCV) are at risk of left atrial appendage thrombus (LAAT). We investigated LAAT formation rates, success rates, and long-term recurrence rates in transthyretin amyloid cardiomyopathy (ATTR-CM) patients. Methods:ATTR-CM patients scheduled to undergo DCCV were included in the study. LAAT exclusion was performed utilizing transesophageal echocardiography or computed tomography. Results:A total of 62 (1.35 per patient) DCCVs were recorded among 46 patients (77 ± 6.5 years, 89 % male) with ATTR-CM. In 39 DCCVs, LAAT exclusion was performed (62.9 %). In total, 10 DCCVs (16.1 %) were canceled due to (I) spontaneous conversion to sinus rhythm (n = 2, 5.1 %) or (II) definitive/suspected LAAT (n = 8, 20.5 %). Of these, five patients with LAAT had been receiving sufficient doses of oral anticoagulants for more than three weeks prior to DCCV. The immediate success rate was 92.3 %, and 3-month rhythm control was achieved in 27 (62.8 %) procedures. Notably, one stroke event was recorded two months following DCCV. Conclusion:A high rate of left atrial appendage thrombus was observed in ATTR-CM, leading to DCCV cancellation in 20.5% of patients. Despite a high immediate success rate (92.3%), sustained sinus rhythm control was achieved in only 62.8% following DCCV. These findings advise using TEE or CT prior to DCCV to exclude LAAT in ATTR-CM patients, even in those with oral anticoagulation.

Background: Transthyretin amyloidosis is a multi-system disease that may manifest as cardiomyopathy (ATTR-CM) and/or polyneuropathy. Both disease manifestations are associated with autonomic dysfunction. However, the prevalence of autonomic dysfunction in ATTR-CM remains to be evaluated. Methods: Within the scope of a prospective ATTR-CM registry, the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire was applied to consecutive patients between November 2022 and November 2024. Baseline characteristics are described, and associations of the COMPASS-31 score with markers of disease severity were assessed. Kaplan-Meier analysis was utilized to assess the COMPASS-31 score's association with a combined endpoint of all-cause mortality and heart failure-related hospitalizations. Results: A total of 129 ATTR-CM patients [81.7 years (IQR: 77.4-84.3), 108 male (83.7%)] were included in the final study cohort. After stratification using the COMPASS-31 median [14 points, interquartile range (IQR): 6-29], statistically significant differences with regard to New York Heart Association (NYHA) stage and the Kansas City Cardiomyopathy Questionnaire (KCCQ) were observed. Furthermore, the COMPASS-31 score was moderately correlated with the KCCQ score in Spearman correlation analysis (r = -0.55, p < 0.001). The primary endpoint occurred in 16 patients (13 HF-hospitalizations/3 deaths) after 6.3 (IQR: 2.8-17.1) months. In Kaplan-Meier analysis, a COMPASS-31 score above the median of 14 was also associated with the primary endpoint of all-cause mortality and HF-related hospitalization (log-rank p = 0.047). Conclusions: Autonomic dysfunction is highly prevalent in ATTR-CM, affecting almost two-thirds of patients. As the presence of autonomic dysfunction is likely associated with more severely impaired quality of life, routine screening for this disease manifestation of transthyretin amyloidosis may be advisable.

Background: Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been found to have potential hematopoietic effects in patients with heart failure (HF). However, these benefits have not been studied in patients with cardiac amyloidosis (CA). CA patients present with HF symptoms and often suffer from iron deficiency, which has a negative impact on erythropoiesis and leads to lower hemoglobin and hematocrit levels. We sought to determine the potential effects of SGLT2i on hematological parameters and functional capacity (FC) in CA patients. Methods: A prospective analysis was conducted to compare the effects of SGLT2i in patients who received the best medical therapy (BMT) along with SGLT2i (n = 20), versus patients receiving only BMT without SGLT2i (n = 20) (historical control group). All patients underwent blood testing and cardiopulmonary exercise testing (CPET) at baseline (BL) and after 6 months [interquartile range (IQR): 4.0 to 8.0]. Results: The SGLT2i-based therapy resulted in a significant improvement and difference in hematological parameters at 6 months follow-up compared to the control group. In the SGLT2i group, the mean hemoglobin level increased (+1.2 mg/dL), whereas in the control group, it decreased (–0.8 g/dL) (p < 0.001 for overall group comparison). The hematocrit showed a significant increase in the SGLT2i group (+4.4%) compared to a decrease in the control group (–1.8%) (p < 0.001). Additionally, the serum iron level improved in the SGLT2i-treated group (+ 5.5 [–5.0 to 17.5] μg/dL vs. –6.0 [–15.0 to 4.0] μg/dL, p = 0.121). Although there was no significant change in the peak oxygen consumption (peak VO2, (mL/min)/kg) (p = 0.206), as well as in pulmonary ventilation (VE)/carbon dioxide production (VCO2) slope in both groups (p = 0.964), the SGLT2i group maintained a peak VO2 and VE/VCO2 slope throughout the study. Conclusions: SGLT2i therapy improved hematological parameters and stabilized the FC of CA patients.

Background/Objectives: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) often experience significantly reduced functional capacity due to myocardial involvement. Cardiopulmonary exercise testing (CPET) is the gold standard to quantify functional capacity, and 99mTc-DPD scintigraphy and SPECT/CT have proven to be highly effective tools for diagnostic and disease monitoring. We aimed to investigate the complementary role and correlation between both methods, focusing on their combined potential as a strong prognostic framework for monitoring disease progression and evaluating treatment efficacy. Methods: A total of 44 patients with diagnosed ATTR-CM, who underwent 99mTc-DPD scintigraphy and SPECT/CT imaging as well as CPET, were included. All patients were divided into two groups based on the median DPD retention index (low DPD uptake: ≤5.0, n = 22; high DPD uptake: >5.0, n = 22). Results: The mean age was 78 years, with 82% of participants being male. Significant correlations were observed between peak VO2 and DPD retention index (r = -0.355, p = 0.018) as well as between peak VO2 at anaerobic threshold with DPD retention index (r = -0.391, p = 0.009). Interestingly, there was no strong correlation between VE/VCO2 slope and the retention index. A strong association was identified between cardiac biomarkers and peak VO2, specifically for NT-proBNP (r = -0.530, p < 0.001) and Troponin T (r = -0.431, p < 0.001). Conclusions: In ATTR-CM, significant correlations were observed between key CPET parameters and quantitative cardiac DPD uptake, which further reflects on disease severity and functional impairment. Our findings highlight the utility of integrating CPET and SPECT/CT for comprehensive patient assessment in ATTR-CM.

Cardiac transthyretin amyloidosis (ATTR CA) has been increasingly recognized as an important heart failure (HF) entity, and cardiac magnetic resonance (CMR) imaging is a mainstay in the clinical evaluation of this disease. However, studies evaluating the prognostic values of longitudinal data in ATTR CA patients with disease-modifying therapies are lacking. We aimed to assess the prognostic significance of serial quantification of extracellular volume (ECV) in ATTR CA patients treated with tafamidis. The present study included ATTR CA patients who received ≥ 3 months of tafamidis treatment and underwent baseline and CMR, including ECV quantification. The primary endpoint was a composite of all-cause mortality, cardiac transplantation, or hospitalization due to HF. Between June 2016 and June 2020, 54 patients were included in the present analysis and were representative of a typical ATTR CA cohort (median age: 76.7 years, male participants: 79.6

[This corrects the article DOI: 10.1371/journal.pone.0282697.].

Cardiac amyloidosis (CA) is a severe condition characterized by infiltrative cardiomyopathy and heart failure, primarily with preserved ejection fraction (HFpEF), resulting from the deposition of amyloid fibrils in the myocardial extracellular space. While obesity generally linked with increased health risks, studies in chronic cardiac conditions have shown a relationship between body mass index (BMI) and patient’s outcomes. We therefore sought to investigate the association of BMI and clinical outcomes in patients with diagnosed CA, focusing on whether lower BMI serves as a marker for increased risk in this patient population. In this study, we conducted a retrospectively analysis of CA patients enrolled in a clinical registry. Patients were categorized by baseline BMI into underweight (BMI < 18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25.0–29.9), and obese (BMI ≥ 30.0) groups. We used Kaplan-Meier survival analysis to examine the relationship between BMI categories and patient outcomes over a 10 year follow-up period. A total of 418 patients were included, with a median age of 75.5 years, interquartile range (IQR): 33.6 – 94.0. Of these, 77.5 % were male, and 39.7% were classified as NYHA functional class. Kaplan-Meier curves demonstrated that patients with a lower BMI had a significantly higher risk of both all-cause mortality and/or heart-failure related hospitalizations compared to those in the overweight and obese categories (p < 0.05). These findings underscore that lower BMI is associated with poorer outcomes in patients with CA. This observed "obesity paradox", where higher BMI appears protective, highlights the need for individualized management strategies in CA patients, especially those with lower BMI who may be at elevated risk for adverse outcomes.

Background:The 6-min walk test distance (6MWD) was identified as a predictor of mortality in transthyretin amyloid cardiomyopathy (ATTR-CM). However, its real-world applicability remains uncertain, as only therapy-naïve patients were included in the primary analysis. Methods:Patients from a prospective ATTR-CM registry were analyzed and included if a 6MWT was completed at baseline. Results:A total of 252 patients [79.8 years, interquartile range (IQR): 75.4-83.7] were included. After a median of 21.7 (IQR: 12.7-34.1) months, 61 (24.2%) patients died. A 6MWD of <350 m was associated with worse survival [hazard ratio (HR): 3.29, 95% confidence interval (CI): 1.94-5.55, p < 0.001], even after adjusting for National Amyloidosis Centre stage (HR: 2.30, 95% CI: 1.29-4.10, p = 0.005). The Δ6MWD thresholds of <-35 meters/-5% were only associated with mortality after adjusting for change in treatment status. Conclusion:The 6MWD is independently associated with mortality in ATTR-CM irrespective of treatment status. A baseline 6MWD of <350 m is associated with a ~3-fold risk for all-cause mortality. However, our results suggest that the Δ6MWD should only be used in patients on stable background therapy for the estimation of prognosis.