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Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

In a phase 1 trial of NI006 for transthyretin amyloid cardiomyopathy, no apparent drug-related serious adverse events occurred. At doses of at least 10 mg per kilogram, amyloid-load surrogates appeared to be reduced.

Objective Sodium glucose cotransporter 2 (SGLT2) inhibitors significantly improve cardiovascular outcomes in diabetic patients; however, the mechanism is unclear. We hypothesized that dapagliflozin improves cardiac outcomes via beneficial effects on systemic and cardiac inflammation and cardiac fibrosis. Research and design methods This randomized placebo-controlled clinical trial enrolled 62 adult patients (mean age 62, 17% female) with type 2 diabetes (T2D) without known heart failure. Subjects were randomized to 12 months of daily 10 mg dapagliflozin or placebo. For all patients, blood/plasma samples and cardiac magnetic resonance imaging (CMRI) were obtained at time of randomization and at the end of 12 months. Systemic inflammation was assessed by plasma IL-1B, TNFα, IL-6 and ketone levels and PBMC mitochondrial respiration, an emerging marker of sterile inflammation. Global myocardial strain was assessed by feature tracking; cardiac fibrosis was assessed by T1 mapping to calculate extracellular volume fraction (ECV); and cardiac tissue inflammation was assessed by T2 mapping. Results Between the baseline and 12-month time point, plasma IL-1B was reduced (− 1.8 pg/mL, P  = 0.003) while ketones were increased (0.26 mM, P  = 0.0001) in patients randomized to dapagliflozin. PBMC maximal oxygen consumption rate (OCR) decreased over the 12-month period in the placebo group but did not change in patients receiving dapagliflozin (− 158.9 pmole/min/10 6 cells, P  = 0.0497 vs. − 5.2 pmole/min/10 6 cells, P  = 0.41), a finding consistent with an anti-inflammatory effect of SGLT2i. Global myocardial strain, ECV and T2 relaxation time did not change in both study groups. Clinical Trial.gov Registration NCT03782259.

Background Incretin-based therapies are used in the treatment of type 2 diabetes mellitus (T2DM) and obesity. We investigated the changes in arterial stiffness and left ventricular (LV) myocardial deformation after 6-month treatment with the GLP-1 analogue liraglutide in subjects with newly diagnosed T2DM. Methods We randomized 60 patients with newly diagnosed and treatment-naive T2DM to receive either liraglutide (n = 30) or metformin (n = 30) for 6 months. We measured at baseline and after 6-month treatment: (a) carotid-femoral pulse wave velocity (PWV) (b) LV longitudinal strain (GLS), and strain rate (GLSR), peak twisting (pTw), peak twisting velocity (pTwVel) and peak untwisting velocity (pUtwVel) using speckle tracking echocardiography. LV untwisting was calculated as the percentage difference between peak twisting and untwisting at MVO (%dpTw–Utw MVO ), at peak (%dpTw–Utw PEF ) and end of early LV diastolic filling (%dpTw–Utw EDF ) (c) Flow mediated dilatation (FMD) of the brachial artery and percentage difference of FMD (FMD%) (d) malondialdehyde (MDA), protein carbonyls (PCs) and NT-proBNP. Results After 6-months treatment, subjects that received liraglutide presented with a reduced PWV (11.8 ± 2.5 vs. 10.3 ± 3.3 m/s), MDA (0.92 [0.45–2.45] vs. 0.68 [0.43–2.08] nM/L) and NT-proBNP (p < 0.05) in parallel with an increase in GLS (− 15.4 ± 3 vs. − 16.6 ± 2.7), GLSR (0.77 ± 0.2 vs. 0.89 ± 0.2), pUtwVel (− 97 ± 49 vs. − 112 ± 52°, p < 0.05), %dpTw–Utw MVO (31 ± 10 vs. 40 ± 14), %dpTw–Utw PEF (43 ± 19 vs. 53 ± 22) and FMD% (8.9 ± 3 vs. 13.2 ± 6, p < 0.01). There were no statistically significant differences of the measured markers in subjects that received metformin except for an improvement in FMD. In all subjects, PCs levels at baseline were negatively related to the difference of GLS (r = − 0.53) post-treatment and the difference of MDA was associated with the difference of PWV (r = 0.52) (p < 0.05 for all associations) after 6-month treatment. Conclusions Six-month treatment with liraglutide improves arterial stiffness, LV myocardial strain, LV twisting and untwisting and NT-proBNP by reducing oxidative stress in subjects with newly diagnosed T2DM. ClinicalTrials.gov Identifier NCT03010683

Introduction Arrhythmia‐induced cardiomyopathy (AIC) is an underrecognized condition resulting in left ventricular systolic dysfunction (LVSD) that is primarily caused by atrial fibrillation (AFib). The relationship between AIC, right ventricular (RV) function, and quality of life (QoL) has not been well studied. Methods We performed a post‐hoc analysis of our AIC trial in which we prospectively screened for patients with tachyarrhythmia and newly diagnosed, otherwise unexplained LVSD. Following rhythm restoration, patients were followed up at 2, 4, and 6 months. Only patients with persistent sinus rhythm were analyzed. RV function was assessed via echocardiography (tricuspid annular plane systolic excursion [TASPE] and fractional area change [FAC]) and QoL by the Minnesota Living with Heart Failure Questionnaire. Results Of a total of 50 patients recovering from LVSD, 41 were diagnosed with AIC and 9 with non‐AIC. Initially, RV function was reduced in the AIC group and recovered after rhythm restoration, whereas no relevant changes were noted in the non‐AIC group. QoL was reduced in both groups and also improved after rhythm restoration. Regression analysis identified low TAPSE as a predictive parameter for AIC diagnosis and worse QoL in AIC patients. Conclusion We demonstrated that RV function and QoL are impaired in patients with AIC. Six months after rhythm restoration, TAPSE may serve as an early indicator of AIC while also correlating with QoL. This underscores the importance of detailed echocardiographic evaluation with a focus on RV function in patients with concomitant tachyarrhythmia and LVSD. Initial tricuspid annular plane systolic excursion (TAPSE), quality of life (QoL) as measured by the Minnesota Living with Heart Failure Questionnaire and left ventricular ejection fraction (LVEF) during atrial fibrillation (AFib) or atrial flutter (AFlut) were reduced in patients with arrhythmia‐induced cardiomyopathy (AIC) compared with values at the end of 6 months of follow‐up in sinus rhythm. In this paper we show that low TAPSE (optimal cut‐off 18.5 mm) has good predictive power for the diagnosis of AIC and that a low quality of life is associated with low TAPSE. Values in red indicate the relative percent the baseline values were reduced compared with the post‐recovery measurement at the end of follow‐up.

Artificial intelligence (AI), and more specifically deep learning, models have demonstrated the potential to augment physician diagnostic capabilities and improve cardiovascular health if incorporated into routine clinical practice. However, many of these tools are yet to be evaluated prospectively in the setting of a rigorous clinical trial–a critical step prior to implementing broadly in routine clinical practice. To describe the rationale and design of a proposed clinical trial aimed at evaluating an AI-enabled electrocardiogram (AI-ECG) for cardiomyopathy detection in an obstetric population in Nigeria. The protocol will enroll 1,000 pregnant and postpartum women who reside in Nigeria in a prospective randomized clinical trial. Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. Women aged 18 and older, seen for routine obstetric care at 6 sites (2 Northern and 4 Southern) in Nigeria will be included. Participants will be randomized to the study intervention or control arm in a 1:1 fashion. This study aims to enroll participants representative of the general obstetric population at each site. The primary outcome is a new diagnosis of cardiomyopathy, defined as left ventricular ejection fraction (LVEF) < 50% during pregnancy or within 12 months postpartum. Secondary outcomes will include the detection of impaired left ventricular function (at different LVEF cut-offs), and exploratory outcomes will include the effectiveness of AI-ECG tools for cardiomyopathy detection, new diagnosis of cardiovascular disease, and the development of composite adverse maternal cardiovascular outcomes. This clinical trial focuses on the emerging field of cardio-obstetrics and will serve as foundational data for the use of AI-ECG tools in an obstetric population in Nigeria. This study will gather essential data regarding the utility of the AI-ECG for cardiomyopathy detection in a predominantly Black population of women and pave the way for clinical implementation of these models in routine practice. Clinicaltrials.gov: NCT05438576.

Introduction Persons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown. Methods In this prespecified subgroup analysis of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) trial, 685 participants with asymptomatic DbCM underwent baseline echocardiography data, laboratory investigations, and functional assessments. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test. Results The median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/E’, or right ventricular systolic pressure. In contrast, NT-proBNP was significantly correlated with overall Kansas City Cardiomyopathy Questionnaire score (rho = − 0.10; p  = 0.007), the Physical Activity Scale in the Elderly (rho = − 0.12; p  = 0.004), duration of cardiopulmonary exercise testing (rho = − 0.28; p  < 0.001), peak VO 2 (rho = − 0.26; p  < 0.001), and ratio of minute ventilation/carbon dioxide production (rho = 0.12; p  = 0.002). After adjustment for known confounders, the correlation with Physical Activity Scale in the Elderly and overall Kansas City Cardiomyopathy Questionnaire score was no longer significant. Conclusion Among patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals. Trial registration ARISE-HF, NCT 04083339 Date Registered August 23, 2019. Graphical abstract Abnormal ECHO defined as Myocardial Global Longitudinal Strain < − 16 or left ventricular mass index > 95 for females or > 115 for males or E/e’ >13 or left atrial volume index > 34. †Normal ECHO is defined as the absence of these abnormalities. Low NT-proBNP is defined as < 71 ng/L while high NT-proBNP is defined as ≥ 71 ng/L.

IntroductionSepsis-induced left ventricular (LV) dysfunction participates in cardiovascular dysfunction and associated organ failure in patients with septic shock. The tested hypothesis is that dobutamine will reduce tissue hypoperfusion and secondary organ dysfunction in increasing oxygen delivery in fluid-filled patients with septic shock and associated symptomatic septic cardiomyopathy with documented low-flow state.Methods and analysisADAPT–Dobutamine is a blinded, two parallel group, add-on, multicentre, randomised 1:1 and placebo-controlled trial. Patients will be included if hospitalised in the intensive care unit with septic shock (Sepsis-3 definition) and septic cardiomyopathy, identified using echocardiography (LV ejection fraction ≤40% and LV outflow tract velocity–time integral <14±1.5 cm). Non-inclusion criteria will include ventricular rate >130 bpm, severe ventricular arrhythmia, obstructive cardiomyopathy, severe aortic stenosis, ongoing acute coronary syndrome and indication for extracorporeal life support. Primary outcome will be the evolution of a modified Sequential Organ Failure Assessment score (excluding the neurologic system) during the initial intensive care unit stay encompassing screening (before randomisation), and from Day 1 to 3 after randomisation. Randomisation will be stratified on participating centres and previously documented heart failure (ejection fraction ≤40%). The use of open-labelled Dobutamine as a rescue therapy will be allowed in refractory shock based on strict clinical requirements. The use of alternative inotropes will not be allowed.Ethics and disseminationApproved by the Comité de Protection des Personnes Nord-Ouest IV from Lille (France) on 19 December 2019 (approval reference #19.04.05.36321). The results will be published in a peer-reviewed journal and presented in various congresses.Trial registration numberNCT04166331.

Duchenne muscular dystrophy is life-limiting. Cardiomyopathy, which mostly ensues in the second decade of life, is the main cause of death. Treatment options are still limited. The TAMDMD (NCT03354039) trial assessed motor function, muscle strength and structure, laboratory biomarkers, and safety in 79 ambulant boys with genetically confirmed Duchenne muscular dystrophy, 6.5–12 years of age, receiving either daily tamoxifen 20 mg or placebo for 48 weeks. In this post-hoc analysis, available echocardiographic data of ambulant patients recruited at one study centre were retrieved and compared before and after treatment. Data from 14 patients, median 11 (interquartile range, IQR, 11–12) years of age was available. Baseline demographic characteristics were similar in participants assigned to placebo ( n  = 7) or tamoxifen ( n  = 7). Left ventricular end-diastolic diameter in the placebo group (median and IQR) was 39 (38–41) mm at baseline and 43 (38–44) mm at study end, while it was 44 (41–46) mm at baseline and 41 (37–46) mm after treatment in the tamoxifen group. Left ventricular fractional shortening in the placebo group was 35% (32–38%) before and 33% (32–36%) after treatment, while in the tamoxifen group it was 34% (33–34%) at baseline and 35% (33–35%) at study end. No safety signals were detected. Conclusion : This hypothesis-generating post-hoc analysis suggests that tamoxifen over 48 weeks is well tolerated and may help preserving cardiac structure and function in Duchenne muscular dystrophy. Further studies are justified. ClinicalTrials.gov Identifier : EudraCT 2017–004554–42, NCT03354039 What is known: • Duchenne muscular dystrophy (DMD) is life-limiting. Cardiomyopathy ensues in the second decade of life and is the main cause of death. Treatment options are still limited. • Tamoxifen reduced cardiac fibrosis in mice and improved cardiomyocyte function in human-induced pluripotent stem cell-derived cardiomyocytes. What is new: • In this post-hoc analysis of the TAMDMD trial among 14 boys, median 11 years of age, treated with either tamoxifen or placebo for 48 weeks, treatment was well-tolerated. • A visual trend of improved left-ventricular dimensions and better systolic function preservation generates the hypothesis of a potential beneficial effect of tamoxifen in DMD cardiomyopathy.

Aims Aging is influenced by genetic determinants and comorbidities, among which diabetes increases the risk for heart failure with preserved ejection fraction. There is no therapy to prevent heart dysfunction in aging and diabetic individuals. In previous studies, a single administration of the longevity-associated variant (LAV) of the human BPIFB4 gene halted heart decline in older and type 2 diabetic mice. Here, we asked whether orally administered LAV-BPIFB4 protein replicates these benefits. Materials and Methods In two controlled, randomized studies, 18-month-old male C57BL/6 J mice and 9-week-old C57BLKS/J-Leprdb/Leprdb/Dock7 + [db/db] mice of both sexes underwent baseline echocardiography. They then received a recombinant purified LAV-BPIFB4 protein (3 µg/animal, every three days) or vehicle by gavage. After 30 days, the animals underwent echocardiography, and the hearts were collected post-termination for histology. Results All the animals completed the study except one female diabetic mouse, which was culled prematurely because tooth malocclusion caused eating problems. There was no effect of the LAV-BPIFB4 protein on body weight in the two studies or glycosuria in the diabetic study. In aging mice, LAV-BPIFB4 increased myocardial Bpifb4 expression, improving heart contractility and capillarity while reducing perivascular fibrosis and senesce. In male diabetic mice, LAV-BPIFB4 therapy improved systolic function, microvascular density, and senescence, whereas the benefit was limited to systolic function in females. Conclusions This study shows the feasibility and efficacy of a variant protein associated with human longevity in contrasting pivotal risk factors for heart failure in animal models. The diabetic study revealed that sex influences the treatment efficacy.