Journal of the American College of Cardiology最新文献

Background: Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease with a significant burden of recurrent cardiovascular (CV) events. Acoramidis, an approved oral therapy for ATTR-CM, achieves early, near-complete (≥90%) TTR stabilization. In the phase 3 ATTRibute-CM (Efficacy and Safety of Acoramidis in Participants with Transthyretin Amyloid Cardiomyopathy) study, acoramidis significantly reduced the composite of all-cause mortality or first CV-related hospitalization (CVH), with an effect observed at month 3. Its efficacy on the burden of cumulative CV outcome events has not been reported.

Objectives: This study was a post hoc exploratory recurrent-event analysis of the efficacy of acoramidis on the cumulative incidence of CV outcomes from ATTRibute-CM and its open-label extension.

Methods: Cumulative incidences of centrally adjudicated CV-related mortality (CVM) or recurrent CVH (first and, if applicable, subsequent CVH), recurrent CVH alone (month 30), and CVM (month 42) were measured in the modified intention-to-treat population (acoramidis, n = 409; placebo, n = 202). Mean cumulative events by treatment, and the difference between treatment groups were estimated by using a modified Andersen-Gill model.

Results: Acoramidis significantly reduced the cumulative risk of CVM or recurrent CVH through month 30 vs placebo (HR: 0.51; 95% CI: 0.43-0.62; P < 0.0001). A notable proportion of CV outcome events (19% of CVM or recurrent CVH events, 22% of CVH) occurred within the first 6 months. Numerically fewer cumulative events were observed with acoramidis compared with placebo at month 1, and the difference increased progressively, resulting at month 30 in 53 events avoided per 100 treated participants (95% CI: 29-79). At month 42, CVM was reduced with continuous acoramidis vs placebo-to-acoramidis (HR: 0.55; 95% CI: 0.39-0.79; P = 0.0011). The annualized frequency of recurrent CVH was significantly decreased through month 30 (relative risk ratio: 0.50; 95% CI: 0.35-0.69; P < 0.0001).

Conclusions: Acoramidis significantly reduced the cumulative burden of CV outcomes in ATTR-CM over 30 months. Numerically fewer events were observed with acoramidis vs placebo by month 1, and the difference increased progressively over time, resulting in 53 events avoided per 100 treated patients at month 30. Almost one-fourth of the cumulative CV events occurred within the first 6 months. These exploratory findings suggest that cumulative event burden may occur early, highlighting the importance of timely evaluation, diagnosis and treatment in ATTR-CM.

Background: Timely diagnosis and treatment are critical to reduce morbidity and mortality for patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). Limited existing data suggest underdiagnosis of ATTR-CM and inequity in predictors of diagnosis patterns.

Objective: This study sought to describe the time from heart failure (HF) diagnosis to ATTR-CM diagnosis and identify predictors for delayed diagnosis of ATTR-CM.

Methods: This retrospective cohort study used Veterans Health Administration (VHA) data. We identified patients with HF and ATTR-CM diagnosed between 2016 and 2022 using an algorithm based on diagnoses and medications. The primary outcome was the time to diagnosis of ATTR-CM and was defined as the number of days between each patient's first HF diagnosis and their first ATTR-CM diagnosis. We also evaluated the number of days between first HF hospitalization or first loop diuretic prescription and ATTR-CM diagnosis. We used multivariable logistic regression to assess demographic, clinical, and socioeconomic predictors of time to ATTR-CM diagnosis using >6 months as a meaningful delay.

Results: A total of 2,557 patients with HF and ATTR-CM were identified. The mean age at the time of ATTR-CM diagnosis was 81 years. Most veterans were male (2,544; 99.5%) and White (1,440; 56%). The median time to diagnosis to ATTR-CM was 490 days. For the 1,882 veterans with a loop diuretic prescription before ATTR-CM diagnosis, the median time between initial loop prescription and ATTR-CM diagnosis was 835 days (Q1-Q3: 250-1850). Across Department of Veterans Affairs sites, the median number of days to diagnosis ranged from 169 to 1,070 days. After adjustment, Black race (OR: 0.71; 95% CI: 0.57-0.88) and older age (OR: 0.66; 95% CI: 0.59-0.73) were associated with a shorter time to diagnosis, whereas a history of atrial fibrillation (OR: 1.21; 95% CI: 1.00-1.45), coronary artery disease (OR: 1.38; 95% CI: 1.15-1.64), or chronic kidney disease (OR: 1.79; 95% CI: 1.50-2.15) was associated with longer time to diagnosis.

Conclusions: There are clinically important delays between incident HF and diagnosis of ATTR-CM. Carrying a diagnosis of atrial fibrillation, coronary artery disease, or chronic kidney disease was associated with a longer delay to diagnosis. These findings uncover an opportunity for clinicians to consider concomitant ATTR-CM in patients with alternate etiologies for their cardiomyopathy, as expediting evaluation for ATTR-CM following HF diagnosis is critical to reduce the morbidity of this progressive condition.

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) remain at risk of cerebrovascular events even when in sinus rhythm (SR), yet the majority of these patients are unrecognized.

Objectives: This study sought to identify patients in SR at high risk of cerebrovascular events.

Methods: We analyzed patients diagnosed with ATTR-CM between January 2003 and December 2023 at the UK National Amyloidosis Centre. Left atrial (LA) function was assessed using speckle-tracking strain echocardiography. Atrial electromechanical dissociation (AEMD) was defined as SR on electrocardiogram with absent left atrial strain contraction (LASc). Patients in SR were stratified according to LASc tertiles. The primary outcome was a cerebrovascular event defined as stroke or transient ischemic attack (TIA), whichever occurred first. The secondary outcome was development of atrial fibrillation (AF). Death was treated as a competing event.

Results: The study comprised 2,310 patients with ATTR-CM, of which 873 patients were in SR and not receiving anticoagulation (age 77 years, 82% male, 61% wild type, CHA₂DS₂-VASc 4). AEMD was present in 115 patients (13.2%). Of the patients in SR, over a median of 34 months (Q1-Q3: 18-54 months), 269 patients (30.8%) developed incident AF and 85 (9.7%) experienced stroke/TIA. Patients with baseline AF receiving anticoagulation had a rate of stroke or TIA of 0.7 per 100 person-years. AEMD was associated with a 2.4-fold higher incident AF and 3-fold higher risk of stroke or TIA compared with SR with LA mechanical contraction (8.7 vs 2.5 per 100 person-years, respectively, for stroke or TIA), independent of CHA₂DS₂-based scores and markers of disease severity. Among 758 patients in SR without AEMD, LASc tertiles (<4%, 4%-7%, >7%) exhibited an independent association with 1-year risk of stroke or TIA, with LASc <4% being associated with 10-fold increased risk compared to LASc >7%. This association was consistent after adjustment for NAC stage and prior cerebrovascular events. Adding LASc tertiles to CHA₂DS₂-VASc or CHA₂DS₂-VA significantly improved model fit and risk reclassification at 1 year.

Conclusions: LA dysfunction, particularly AEMD and severely impaired LASc, is associated with increased cerebrovascular events in ATTR-CM. Using LAS analysis may refine risk stratification and help identify patients with ATTR-CM in SR who might potentially benefit from intensified extended rhythm monitoring or prophylactic anticoagulation.

Background: Atrial fibrillation (AF) is heritable and its complex underlying genetic substrate is gradually being unraveled.

Objectives: We sought to explore the impact of disease-causing cardiomyopathy variants on the risk of AF after adjustment for incident ventricular cardiomyopathy and clinical heart failure in 2 cohort studies (UK Biobank [UKB] and All of Us [AoU]) and evaluate the utility of polygenic risk scores (PRS) to further discern the risk of atrial and ventricular phenotypes in carriers.

Methods: Cox regression was used to evaluate for associations between disease-causing variants within genes for 3 cardiomyopathies (dilated cardiomyopathy [DCM], hypertrophic cardiomyopathy [HCM], and arrhythmogenic right ventricular cardiomyopathy) and AF. Disease-specific PRSs for AF, DCM, and HCM stratified study participants into quintiles. A HR random-effects meta-analysis was performed using the DerSimonian-Laird method. The Kaplan-Meier method was used to ascertain cumulative incidence from birth to 75 years of age.

Results: Among 655,796 individuals from UKB and AoU, presence of a disease-causing variant was associated with an increased AF hazard (HR: 1.73; 95% CI: 1.59-1.89; P < 0.001), including after adjustment for incident ventricular cardiomyopathy or clinical heart failure (adjusted to HR: 1.55; 95% CI: 1.46-1.64, P < 0.001). The cumulative AF risk for study participants with a putative disease-causing rare variant and a PRS_AF within the top-risk quintile ranged from 32.5% (UKB) to 32.4% (AoU) relative to 9.8% (UKB) and 11.0% (AoU) for individuals without a putative disease-causing variant and a PRS_AF within the lowest-risk quintile. The absolute cumulative cardiomyopathy risk among study participants with both a putative disease-causing variant and a disease-specific PRS within the top-risk quintile ranged from 5.9% (UKB) to 15.2% (AoU) for DCM and from 11.7% (UKB) to 19.1% (AoU) for HCM.

Conclusions: Genetic variants that cause cardiomyopathy also increase the risk of AF, even in individuals without heart failure or overt ventricular disease. Combining disease-specific PRSs with these variants helps identify whether a person is more likely to develop atrial or ventricular disease. Although discovered as causes of cardiomyopathy, these genes often have an equal or greater impact on the risk of AF.