There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%).
Objective
To evaluate the effect of sacubitril/valsartan on N-terminal pro–brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication–based individualized comparators in patients with chronic heart failure and LVEF of more than 40%.
Design, Setting, and Participants
A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019).
Interventions
Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication–based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor.
Main Outcomes and Measures
Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks.
Results
Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88;P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, −2.5 m; 95% CI, −8.5 to 3.5;P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, −0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%).
Conclusions and Relevance
Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro–brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients.
Adiponectin may play an important role in the interplay between metabolic changes and cardiovascular risks. Our aim was to establish if plasma adiponectin can be used to detect the metabolic syndrome (MetS) in women without a history of major cardiovascular events and to evaluate its correlation with the global cardiovascular risk expressed by the Reynolds risk score (RRS).148 consecutive women without a history of cardiovascular events with or without MetS have been investigated. Clinical risks factors as well as plasma levels of lipids, fasting glucose and adiponectin were determined.As expected, circulating adiponectin was lower in women with MetS: 26.8 +/- 20.4 versus 44.3 +/- 26.7 microg/ml (p < 0.001) and inversely related to the number of MetS features (r = -0.33, p < 0.001). The latter was further associated with the total cardiovascular risk calculated using RRS (r = 0.49, p < 0.001). However, there was no relationship between circulating adiponectin and this score (r = -0.14, p = NS).Plasma adiponectin levels are significantly lower in women with MetS, but as a stand-alone tool plasma adiponectin may be of little value in the diagnosis MetS. Circulating adiponectin levels are not associated with the global cardiovascular risk calculated using RRS.
Abstract Erdheim-Chester syndrome, a non-Langerhans histiocytosis, is a very rare disease, in the present approximately 500 cases being reported in literature. It is characterized by the histiocytic infiltration of various organs and systems, therefore clinical signs and symptoms are miscellaneous. Despite that, there are a few patognomonic elements that help recognizing the disease: symmetrical involvement in the long bones of the lower limbs, bilateral perirenal infiltration (“hairy kidneys”) and circumferential aortic infiltration (“coated aorta”). However, in order to confirm the diagnosis, biopsy is required, histopathologic examination revealing “foamy” histiocytes. Currently, interferon alpha serves as the first line of treatment, most literature data showing that it might improve survival rate in patients diagnosed with Erdheim-Chester syndrome.
Abstract Introduction Fabry disease (FD) is an X-linked rare lysosomal storage disease caused by mutations in the GLA gene which lead to decrease in α Gal A enzyme activity and tissue accumulation of lysosomal globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Due to X linked transmission, males are hemizygous, and females are heterozygous and were initially thought to be unaffected. However, women with FD can vary from asymptomatic, mildly symptomatic, to severely symptomatic as males. The aim of this study is to evaluate the particularities of FD presentation, cardiac imaging and management in females from the full Romanian FD cohort as compared to male patients. Methods This study included all consecutive patients diagnosed in or referred to our center with FD between 2014–2021. All patients had a complete clinical, biological and cardiac imaging workup. Results During the inclusion interval, data from 66 consecutive Romanian FD patients (37 women and 29 men) from 29 unrelated families were collected. Diagnosing mode in FD women differs compared to men (p<0.001): most women were diagnosed through family screening or by a cardiologist, while most men were diagnosed by nephrologists. Women had higher levels of α Gal A levels (1.3±0.8 μmol/L/h vs 0.5±0.7 μmol/L/h, normal cutoff >1.2) (p<0.001) and smaller levels of lyso-GB3 (5.8±2.6 ng/ml vs 110±35.6 ng/ml, normal cutoff<3.8) (p<0.001). More women are asymptomatic carriers than men (27% vs 3.4%), but when symptoms were present, they could be as severe as in men. Enrolled women were older (50.9±16.3 vs 41±14.9 years, p=0.014), diagnosed later (46.8±16.8 vs 32.7±14.3 years, p<0.001) and had later symptom onset of the disease compared with men (38.1±14.4 vs 20.3±14.9 years, p<0.001). Women had less angiokeratomas (p=0.001) and hypohydrosis (p=0.04), with no difference in cornea verticillata or ENT involvement. Both women and men developed cardiac symptoms starting from the fifth decade, with no differences in terms of angina, NYHA class, syncope between sexes. Women tend to have a lower prevalence of LVH compared to men (p=0.052), with no differences regarding ejection fraction or global longitudinal strain between genders. Regarding other organs involved, women were equally affected as men from acroparesthesia and stroke, with similar age at first cerebrovascular event. Women had milder kidney involvement (stages 1 and 2) when compared to men (56.8% vs 37.9%, p=0.004). Regardless of these findings, it appeared that women were less treated with pathogenic therapy comparing to men (48.6% vs 82.7%) (p=0.004). Conclusions Women with FD are not merely genetic carriers as they can be as affected as men. However, they benefit later from diagnosis and less of pathogenic therapy. Further studies with more female participations are needed to better understand the Fabry burden and needs in women. Funding Acknowledgement Type of funding sources: None.
Abstract Aims Systemic amyloidosis represents a heterogeneous group of diseases resulting from amyloid fibre deposition. The purpose of this study is to establish a differential diagnosis algorithm targeted towards the two most frequent subtypes of CA. Methods and results We prospectively included all consecutive patients with ATTR and AL evaluated between 2018 and 2022 in two centres in a score derivation cohort and a different validation sample. All patients had a complete clinical, biomarker, electrocardiographic, and imaging evaluation. Confirmation of the final diagnosis with amyloid typing was performed according to the current international recommendations. The study population included 81 patients divided into two groups: ATTR (group 1, n = 32: 28 variant and 4 wild type) and AL (group 2, n = 49). ATTR patients were younger (50.7 ± 13.9 vs. 60.2 ± 7.3 years, P = 0.0001), and significantly different in terms of NT‐proBNP [ATTR: 1472.5 ng/L (97–4218.5) vs. AL 8024 ng/L (3058–14 069) P = 0.001], hs‐cTn I [ATTR: 10 ng/L (4–20) vs. AL 78 ng/L (32–240), P = 0.0002], GFR [ATTR 95.4 mL/min (73.8–105.3) vs. AL: 68.4 mL/min (47.8–87.4) P = 0.003]. At similar left ventricular (LV) wall thickness and ejection fraction, the ATTR group had less frequently pericardial effusion (ATTR: 15% vs. AL: 33% P = 0.0027), better LV global longitudinal strain (ATTR: −13.1% ± 3.5 vs. AL: −9.1% ± 4.3 P = 0.04), RV strain (ATTR: −21.9% ± 6.2 vs. AL: −16.8% ± 6 P = 0.03) and better reservoir function of the LA strain (ATTR: 22% ± 12 vs. AL: 13.6% ± 7.8 P = 0.02). Cut‐off points were calculated based on the Youden method. We attributed to 2 points for parameters having an AUC > 0.75 (NT‐proBNP AUC 0.799; hs‐cTnI AUC 0.87) and 1 point for GFR (AUC 0.749) and TTE parameters (GLS AUC 0.666; RV FWS AUC 0.649, LASr AUC 0.643). A score of equal or more than 4 points has been able to differentiate between AL and ATTR (sensitivity 80%, specificity 62%, AUC = 0.798). The differential diagnosis score system was applied to the validation cohort of 52 CA patients showing a sensitivity of 81% with specificity of 77%. Conclusions CA is a complex entity and requires extensive testing for a positive diagnosis. This study highlights a series of non‐invasive checkpoints, which can be useful in guiding the decision‐making process towards a more accurate and rapid differential diagnosis.
Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Romanian Ministry of National Education, CNCS-UEFISCDI. Background Atrial fibrillation (AF) is the most frequent arrhythmia in hypertrophic cardiomyopathy (HCM), with a major impact on overall survival, thromboembolic risk, and quality of life. Early recognition and treatment of AF are essential to improve the outcome of HCM patients (pts). Despite the existence of several independent predictors of AF development, the identification of HCM pts at risk for AF is still inconsistent. The identification, quantification, and interpretation of the relationships between different clinical and imaging-derived variables may lead to improved risk stratification and prognosis. Predictive models based on machine learning (ML) could reduce variability while providing useful new medical knowledge. Purpose Develop a ML model (emerging from the integration of clinical and echocardiographic data) capable of accurately detecting HCM pts with AF. Methods A comprehensive clinical and echocardiographic assessment was performed in 151 consecutive pts (52±16 years, 72 men) with HCM, in sinus rhythm. Pts were divided into two groups according to the presence (38 pts) or absence (113 pts) of documented paroxysmal AF (24/48 h ambulatory ECG recordings). 81 features (clinical and echocardiographic parameters) were considered as input to the ML models. Four different ML models were evaluated: Deep Learning (DL), Linear Logistic Regression (LLR), Support Vector Machine (SVM) and Random Forest (RF). Ensemble learning and four-fold cross-validation were employed in all experiments. For each experiment the training dataset was augmented and balanced using the Synthetic Minority Over-sampling Technique. The models were fine-tuned using the following hyper-parameters: learning rate, batch size, number of hidden layers, and number of features used as input. The features were first ranked using the Recursive Feature Elimination method, and the top N features were selected during the hyper-parameter tuning. Results Each ML model was trained for 100 epochs, and the results were extracted from the epoch that led to the best results when combining all four folds. DL was the best performing model, with a learning rate of 0.01, a batch size of 32, 4 hidden layers (256/128/128/64 neurons), and 15 input features. The DL model had 5% higher accuracy compared to LLR, 10% higher than SVM and 8% higher than RF, with consistently higher sensitivity. The performance of the various models is detailed in the table below. Moreover, the DL model had significantly higher accuracy compared to conventional imaging parameters consistently related to the presence of AF in previous studies, such as maximum LA volume (AUC 0.66, accuracy 59%) or LA strain (AUC 0.61, accuracy 62%). Conclusions The DL based model can detect the presence of paroxysmal AF in patients with HCM with an accuracy of 84% (5% higher than the best classic ML model, and significantly higher than independent conventional imaging parameters).
