Olga Azevedo

BACKGROUND: In HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy), vutrisiran reduced the risk of all-cause mortality (ACM) and recurrent cardiovascular events and slowed disease progression measures versus placebo in patients with TTR (transthyretin) amyloidosis with cardiomyopathy after 33 to 36 months. We report the long-term efficacy and safety of vutrisiran from an ongoing open-label extension of HELIOS-B. METHODS: Patients who completed HELIOS-B could enroll in the open-label extension, continuing with vutrisiran 25 mg every 3 months (continuous vutrisiran) or, if previously receiving placebo, initiating vutrisiran 25 mg every 3 months (placebo/vutrisiran). Prespecified end points assessed in the open-label extension are the composite of ACM and cardiovascular events, ACM, Kansas City Cardiomyopathy Questionnaire–Overall Summary score, New York Heart Association class, and NT-proBNP (N-terminal pro–B-type natriuretic peptide) and troponin I levels. Outcomes were assessed through month 48 in this analysis. RESULTS: Of 654 participants in HELIOS-B (vutrisiran, n=326; placebo, n=328), 478 completed double-blind treatment and 466 (vutrisiran, n=243; placebo, n=223) entered the open-label extension. In the continuous vutrisiran group, the risk of first cardiovascular event or ACM was reduced by 37% (hazard ratio, 0.63 [95% CI, 0.51, 0.79]; P =0.0001) and ACM by 37% (hazard ratio, 0.63 [95% CI, 0.46, 0.84]; P =0.0023) versus the placebo/vutrisiran group. Through month 48, patients in the continuous vutrisiran group had preserved health status and quality of life per Kansas City Cardiomyopathy Questionnaire–Overall Summary score (least squares mean difference, 9.0 [95% CI, 5.3, 12.6]; P P =0.0084) versus the placebo/vutrisiran group. Benefits in the continuous vutrisiran group were maintained for NT-proBNP and troponin I levels (adjusted geometric mean fold change ratios, 0.66 [95% CI, 0.58, 0.74]; P P <0.0001, respectively) versus the placebo/vutrisiran group. Similar benefits were observed in the vutrisiran monotherapy population. No new safety signals were observed. CONCLUSIONS: Long-term vutrisiran resulted in clinically meaningful benefits across mortality, cardiovascular events, cardiac biomarkers, functional status, and quality of life in patients with TTR amyloidosis with cardiomyopathy through month 48. Patients initially treated with vutrisiran had better outcomes than those first receiving placebo, highlighting the importance of early diagnosis and treatment in TTR amyloidosis with cardiomyopathy. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04153149.

Aim: To develop a microfluidic workflow for extracting extracellular vesicle (EV)-associated nucleic acids (NAs) from biofluids, such as blood plasma and serum, for downstream molecular analysis. Methods: Healthy serum and plasma samples were spiked with EVs obtained from Hec-1-A cells carrying defined mutations and characterized in accordance with MISEV guidelines. The spiked samples were then processed using either the standard centrifugation-based ExoGAG protocol or a microfluidic workflow. The latter combines ExoGAG mediated aggregation of EVs with mechanical entrapment of the resulting EV aggregates in a microfluidic filtration device (EVNA-chip). The retained material was washed and on-chip lysed to release its NA cargo. NAs were subsequently purified using a commercial silica column, producing an output suitable for molecular analysis through droplet digital PCR (ddPCR). Results: The EVNA-chip recovery yield was 42.0 ± 4.28% and 38.1 ± 1.46% for double-stranded DNA (dsDNA) and microRNA respectively. The recovered dsDNA remained compatible with ddPCR detection of the KRAS p.G12D variant (c.35G>A) and with the assessment of MSI-associated alterations using BAT25, BAT26, NR21, NR24, and MONO27. The method was demonstrated for pilot cohort of patients with endometrial cancer. The RNA workflow supported reverse transcription and was demonstrated for the quantification of miR-X, a potential marker of Fabry disease, using patient samples and healthy controls. Conclusion: Although recovery was lower than with the standard protocol, the centrifugation-free EVNA- chip workflow demonstrates the compatibility of the method with downstream NA molecular analyses and is advantageous for the development of an integrated, automated platform for EV-based liquid biopsy applications.

Purpose This study aims to evaluate the diagnostic value of right ventricular (RV) myocardial assessment using two-dimensional speckle-tracking echocardiography (2D-STE) in differentiating hypertrophic cardiomyopathy (HCM), Fabry cardiomyopathy (FC), and wild-type transthyretin amyloidotic cardiomyopathy (ATTR-CM), given the clinical importance of accurate diagnosis for guiding treatment and prognosis. Methods A retrospective study was performed involving ninety consecutive patients with nonobstructive sarcomeric HCM, FC or wild-type ATTR-CM, thirty from each disease, referred to a tertiary cardiomyopathy consultation. Thirty matched healthy individuals served as controls. All participants underwent echocardiographic evaluation of RV morphology and RV myocardial mechanics using 2D-STE. RV global longitudinal strain, RV free wall longitudinal strain, and the RV apical sparing ratio were derived and diagnostic performance of RV parameters for differentiating ATTR-CM, FC, and HCM was assessed using receiver operating characteristic (ROC) curve analysis. Inter- and intra-observer reproducibility was assessed using Bland-Altman analysis. Results RV hypertrophy was significantly more prevalent in ATTR-CM and FC (100% and 97%, respectively) than in HCM (60%). ATTR-CM patients exhibited the most substantial RV strain impairment compared to FC and HCM. RV strain analysis led to significant reclassification of RV systolic dysfunction prevalence in all groups. RV global longitudinal strain, RV free wall longitudinal strain and RV apical sparing ratio emerged as effective parameters for distinguishing ATTR-CM from FC (AUC 0.91, AUC 0.89 and AUC 0.85; respectively). RV wall thickness (RVWT) was the best discriminative parameter for distinguishing ATTR-CM from HCM (AUC 0.98) and FC from HCM (AUC 0.91), followed by RV apical sparing ratio (AUC 0.94 and AUC 0.75, respectively). Excellent inter- and intra-observer agreement was observed. Conclusions Our study underscores the importance of RV assessment in differentiating HCM phenocopies. RV strain parameters and RVWT may play pivotal roles in distinguishing these conditions, facilitating earlier diagnostic and specific treatment initiation. Further research is required to assess their clinical implications.

Fabry disease (FD) is a rare genetic disorder associated with cardiac abnormalities and often overlooked brain white matter lesions (WMLs). Despite the importance of early WMLs detection, diagnosis is frequently delayed. The aim is to identify electrocardiographic biomarkers linked to WMLs in middle-aged FD patients using machine learning, assessing their potential as non-invasive diagnostic tools. This retrospective study analyzed electrocardiographic data from FD patients aged 40–59. A feature selection process based on variance inflation factor analysis identified nine relevant features, including heart rate variability and QT interval parameters. Machine learning classifiers—logistic regression, support vector machines, random forest, and k-nearest neighbors—were trained and evaluated using accuracy, sensitivity, specificity, and AUC. SHAP (SHapley Additive exPlanations) analysis was used to interpret model predictions. The random forest model achieved the highest accuracy (0.81) using all nine features. A subset consisting of SDANN 5 and QTc Min also performed well (accuracy 0.75) in other models. SHAP analysis highlighted SDANN 5 as a key predictor. Machine learning applied to ECG data shows promise for early WML detection in FD, supporting the integration of computational methods into diagnostics for complex genetic diseases.

The evidence for sodium-glucose cotransporter-2 inhibitors (SGLT2i) in heart failure (HF) secondary to transthyretin amyloid cardiomyopathy (ATTR-CM) is limited. Evaluate the impact of SGLT2i on clinical outcomes in ATTR-CM. Single-center, retrospective cohort study of 111 patients with confirmed ATTR-CM between 2014 and 2023. Patients were categorized as SGLT2i-treated or untreated. Propensity score (PS) matching was performed based on 14 clinical variables, yielding 27 matched pairs (n=54). The primary outcome was all-cause mortality; secondary outcomes included HF hospitalization and a composite of mortality and HF hospitalization. Survival was analyzed using Kaplan-Meier estimates and Cox regression, with treatment modeled at baseline and as a time-varying covariate. In the PS-matched cohort (n=54; mean age 81.4±4.3 years, 64.8% male), SGLT2i treatment was associated with lower all-cause mortality (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.13–0.85; p=0.021), the actuarial all-cause mortality rate was 9.3 versus 25.4 per 100 patient-years in untreated patients. Sensitivity analyses supported these findings (HR, 0.37; 95% CI, 0.15–0.93; p=0.034) and after covariate adjustment (HR, 0.35; 95% CI, 0.13–0.97; p=0.044). SGLT2i were linked to numerically fewer HF hospitalizations (HR, 0.39; 95% CI, 0.15–1.01; p=0.052) and a significantly lower composite of mortality and HF hospitalization (HR, 0.36; 95% CI, 0.15–0.88; p=0.025). SGLT2i were well tolerated, with a 7.4% drug discontinuation rate. In this study, SGLT2i treatment was associated with improved survival in ATTR-CM patients. While observational design and sample size limit causal inference, these findings support further evaluation of SGLT2i as adjunctive therapy in this population.

Mavacamten is approved to treat adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). However, its effects in nonobstructive HCM remain uncertain. We conducted a phase 3, international, double-blind, placebo-controlled, clinical trial to determine whether mavacamten improves functional capacity and patient-reported health status among adults with symptomatic nonobstructive HCM. Patients were randomly assigned in a 1:1 ratio to receive mavacamten (starting at 5 mg per day and adjusted up to a maximum of 15 mg per day on the basis of left ventricular ejection fraction) or placebo (with sham dose adjustment) for 48 weeks. The two primary end points were the change from baseline to week 48 in peak oxygen uptake and in the 23-item Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better health status). We randomly assigned 289 patients to receive mavacamten and 291 to receive placebo. The mean (±SD) age of the patients was 56±15 years, and 46% were women. From baseline to week 48, the least-squares mean change in peak oxygen uptake was 0.52 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.09 to 0.95) in the mavacamten group and 0.05 ml per kilogram per minute (95% CI, -0.38 to 0.47) in the placebo group (between-group difference, 0.47 ml per kilogram per minute; 95% CI, -0.03 to 0.98; P = 0.07). The least-squares mean change in the KCCQ-CSS was 13.1 points (95% CI, 10.7 to 15.5) in the mavacamten group and 10.4 points (95% CI, 8.0 to 12.8) in the placebo group (between-group difference, 2.7 points; 95% CI, -0.1 to 5.6; P = 0.06). Reductions in ejection fraction and interruptions in the trial regimen were more common with mavacamten than with placebo. Among patients with nonobstructive HCM, mavacamten did not result in a significantly greater improvement in peak oxygen uptake or decrease in symptoms than placebo. (Funded by Bristol Myers Squibb; ODYSSEY-HCM ClinicalTrials.gov number, NCT05582395.).

In the HELIOS-B randomized clinical trial, the RNA interference therapeutic agent vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). In this secondary analysis of HELIOS-B, we evaluated vutrisiran’s effects on echocardiographic measures of cardiac structure and function in patients with ATTR-CM receiving vutrisiran or placebo (n = 654, 93% men). At 30 months after treatment, as compared to the placebo group, vutrisiran treatment attenuated increases in mean left ventricular (LV) wall thickness (least squares mean difference: −0.4 mm; 95% confidence interval (CI): −0.8, 0.0; P = 0.03) and LV mass index (−10.6 g m^{− 2}; 95% CI: −18.0, −3.3; P < 0.01). Vutrisiran treatment also attenuated declines in LV ejection fraction (2.0%; 95% CI: 0.3, 3.7; P = 0.02), absolute global longitudinal strain (1.2%; 95% CI: 0.7, 1.7; P < 0.01) and LV stroke volume (4.1 ml; 95% CI: 1.7, 6.4; P < 0.01), and decreased both the average ratio of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity (−2.0; 95% CI: −2.9, −1.2; P < 0.01) and the early to late diastolic transmitral flow velocities ratio (−0.3; 95% CI: −0.6, −0.0; P = 0.04), as compared to placebo. Consistent with its clinical benefits, these echocardiographic findings indicate favorable effects of vutrisiran on cardiac structure and function in patients with ATTR-CM. ClinicalTrials.gov registration: NCT04153149.