Amyloid cardiomyopathy could be related to AL amyloidosis, wild-type transthyretin amyloidosis (ATTRwt) or hereditary amyloidosis (ATTRm). It is crucial to distinguish and accurately type the precu...
Background: Wild-type transthyretin (ATTRwt) cardiac amyloidosis is a progressive restrictive cardiomyopathy, characterized by the extracellular deposition of amyloid protein fibrils derived from g...
Abstract: Transthyretin (ATTR) amyloidosis is a multisystem disease caused by organ deposition of amyloid fibrils derived from the misfolded transthyretin (TTR) protein. The purpose of this article is to provide an overview of current treatment regimens and summarize important considerations for each agent. A literature search was performed with the PubMed database for articles published through October 2020. Search criteria included therapies available on the market and investigational therapies used for ATTR amyloidosis treatment. Both prospective clinical trials and retrospective studies have been included in this review. Available therapies discussed in this review article are tafamidis, diflunisal, patisiran, and inotersen. Tafamidis is FDA approved for treatment of wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv) cardiomyopathy, and patisiran and inotersen are FDA approved for ATTRv polyneuropathy. Diflunisal does not have an FDA-labeled indication for amyloidosis but has been studied in ATTRv polyneuropathy and ATTRwt cardiomyopathy. Investigational therapies include a TTR stabilizer, AG10; 2 antifibril agents, PRX004 and doxycycline/tauroursodeoxycholic acid; and 2 gene silencers, vutrisiran and AKCEA-TTR-LRx; and clinical trials are ongoing. ATTR amyloidosis treatment selection is based on subtype and presence of cardiac or neurological manifestations. Additional considerations such as side effects, monitoring, and administration are outlined in this review.
Introduction: Case reports and smaller observational studies have suggested an association between monoclonal gammopathy of undetermined significance (MGUS) and various cardiovascular diseases. We aimed to explore the association of MGUS with a broad spectrum of incident cardiovascular disease further, using the Danish nationwide administrative databases. Methods: Between 1995-2018, all patients eighteen years and older with MGUS were matched (10:1) with controls from the general population based on age and sex. Patients with a diagnosis of multiple myeloma were excluded. Incident cardiovascular diseases were identified using ICD coding. Hazard ratios for cardiovascular outcomes were calculated using Cox proportional hazard regression. Results: Patients with MGUS (n= 8,445, mean age 69.9 years, 51.3% male) had a higher risk of developing most cardiovascular diseases after multivariable adjustment, including heart failure (HR 1.65, 95% CI 1.51-1.81), atrial fibrillation (HR 1.47, 95% CI 1.37-1.58), acute myocardial infarction (HR 1.24, 95% CI 1.08- 1.43), stroke (HR 1.25, 95% CI 1.12-1.40), aortic aneurysm (HR 1.49, 95% CI 1.23-1.80), aortic stenosis (HR 1.72, 95% CI 1.52-1.96), aortic regurgitation (HR 1.70, 95% CI 1.36-2.12), conduction disease (HR 1.52, 95% CI 1.25-1.82), pericarditis (HR 1.62, 95% CI 1.03-2.55), peripheral arterial disease (HR 1.86, 95% CI 1.61-2.14), cor pulmonale (HR 2.32, 95% CI 1.76-3.06), venous thromboembolism (HR 1.29, 95% CI 1.12-1.48), and implantation of a cardiac pacemaker or defibrillator (HR 1.34, 95% CI 1.14-1.59). Conclusions: MGUS is associated with a broad spectrum of cardiovascular diseases, with somewhat greater risk estimates observed for cardiovascular disorders that have previously been associated with infiltrative diseases (such as heart failure, pulmonary hypertension, aortic valvular disease, atrial fibrillation, and conduction abnormality) than for atherosclerotic and thrombotic disorders. Further studies are warranted to understand the underlying mechanisms.
Congenital heart disease incidence has remained stable,1 but longevity has improved. There are more than 787 000 adults with congenital heart disease in the United States.2 Adults with congenital heart disease remain at risk for frequent hospitalizations.
Diflunisal is a non-steroidal anti-inflammatory drug that stabilises transthyretin (TTR) and reduces neurologic deterioration in patients with polyneuropathy caused by hereditary transthyretin amyloidosis (ATTRv).We conducted a retrospective cohort study of patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) treated with diflunisal for at least one year between 2009 and 2016 at the Boston University Amyloidosis Centre. Baseline and one year follow up characteristics were measured, including plasma chemistries and echocardiography. Cox proportional hazards analysis assessed the primary outcome of all-cause mortality.A total of 104 ATTRwt-CM patients were evaluated with 35 patients receiving diflunisal. Patients in the diflunisal group were younger (73.8 vs 76.8 years, p = 0.034), with lower B-type natriuretic peptide (BNP, 335 +/- 67 vs. 520 +/- 296 pg/mL, p = 0.006), similar troponin I (0.1 +/- 0.1 vs 0.2 +/- 0.3 ng/mL, p = 0.09), and better renal function (eGFR 67 +/- 17 vs 53 +/- 18 mL/min/1.73m2, p = 0.0002) at baseline. Over a median follow-up of 3.2 years, 52 deaths occurred. Diflunisal administration was associated with improved survival in unadjusted analysis (HR 0.13, 95% CI 0.05 - 0.36, p < 0.001) that persisted after adjustment for age, baseline BNP, eGFR, troponin I, interventricular septal thickness, and left ventricular ejection fraction (HR 0.18, 95% CI 0.06 - 0.51, p = 0.0006). Over the observation period, no significant changes in BNP, troponin I, interventricular septal thickness or left ventricular ejection fraction were observed with diflunisal treatment. A total of 14 patients (40%) discontinued diflunisal in this study, but only 3 within the first year. Mean eGFR in treated patients was 59 ml/min/1.73m2 at 1 year (change from baseline p = 0.03).Diflunisal administration in ATTRwt-CM was associated with improved survival and overall stability in clinical and echocardiographic markers of disease with decrement renal function.
To define the epidemiology of adverse cardiovascular events among women with congenital heart disease (CHD) hospitalised for childbirth in the USA.
Design and setting
The 1998–2007 Nationwide Inpatient Sample, an administrative dataset representative of overall US hospital admissions, was used to identify hospitalisations for delivery.
Main outcome measures
Logistic regression was used to estimate ORs for cardiovascular outcomes (arrhythmia, heart failure, cerebrovascular accident, embolism, death or a combined outcome) for women with and without CHD. Covariates included age, number of medical comorbidites, pulmonary hypertension, hospital teaching status, insurance status and method of delivery.
Results
Annual deliveries for women with CHD increased 34.9% from 1998 to 2007 compared with an increase of 21.3% in the general population. Women with CHD were more likely to sustain a cardiovascular event (4042/100 000 vs 278/100 000 deliveries, univariate OR 15.1, 95% CI 13.1 to 17.4, multivariable OR 8.4, 95% CI 7.0 to 10.0). Arrhythmia, the most common cardiovascular event, was more frequent among women with CHD (2637/100 000 vs 210/100 000, univariate OR 12.9, 95% CI 10.9 to 15.3, multivariable OR 8.3, 95% CI 6.7 to 10.1). Death occurred in 150/100 000 patients with CHD compared with 8.2/100 000 patients without CHD (multivariable OR 6.7, 95% CI 2.9 to 15.4). Complex CHD was associated with greater odds of having an adverse cardiovascular event than simple CHD (8158/100 000 vs 3166/100 000, multivariable OR 2.0, 95% CI 1.4 to 3.0).
Conclusions
Maternal CHD is associated with a markedly increased risk of adverse cardiovascular events and death during admission for delivery.
Introduction: Transthyretin cardiac amyloidosis (ATTR-CA) is an important cause of heart failure for which tafamidis is the only FDA-approved therapy. Diflunisal is an NSAID that is also effective in improving cardiovascular outcomes in ATTR-CA and is utilized in regions where tafamidis is unavailable or cost-prohibitive. Data comparing the efficacy of these agents are lacking. Research Question: To compare longitudinal changes in cardiac structure by echocardiography and cardiac biomarkers among patients with ATTR-CA treated with tafamidis or diflunisal over 36 months. Methods: Among 425 sequential ATTR-CA patients seen at the Boston University Amyloidosis Center between 2016 and 2022, following exclusion for single visits (194) and for receiving TTR-silencer or multiple therapies (67), the final cohort was 164 patients: 109 were treated with tafamidis (ATTR-CA-T, 86% wild-type) and 55 with diflunisal (ATTR-CA-D, 54% wild-type). Echocardiographic wall thickness was re-measured by a single observer, while LVEF, global longitudinal strain (GLS, expressed in absolute value), NT-proBNP, troponin I, prealbumin, and creatinine were collected from the electronic health record at baseline and 36 months with differences between the measures calculated for each patient and compared using paired t-tests. Results: At baseline, while the ATTR-CA-D cohort was older and had a higher proportion of variant ATTR-CA (p<0.001), the ATTR-CA-T cohort had more advanced disease as demonstrated by increased wall thickness, lower LVEF, worse GLS, higher creatine, and worse cardiac biomarkers (Table 1). After 36 months of treatment compared to baseline (n=23 for ATTR-CA-D and n=36 for ATTR-CA-T), the ATTR-CA-D group showed increase in septal thickness (0.5mm, p=0.04) and posterior wall thickness (0.6mm, p=0.006), while GLS (-5.6%, p<0.001) and LVEF (-5.9%, p=0.02) were decreased. There were no significant echocardiographic changes after 36 months in the ATTR-CA-T group and cardiac biomarker change was similar. Conclusion: These data suggest that tafamidis may be more effective than diflunisal in arresting echocardiographic progression in ATTR-CA. Further studies are necessary to assess the association of these changes with cardiovascular outcomes.
