Gender differences in reverse cardiac remodeling following initiation of sacubitril/valsartan in heart failure with reduced ejection fraction: real world experience

Background Gender related differences in physiology and pharamocokinetics have long been appreciated; however, the clinical relevance of these differences are unclear (1). Sacubitril/Valsartan has become established as a guideline directed therapy for the treatment of heart failure with reduced ejection therapy (HFref) and NYHA class II-IV symptoms. Interestingly; recent secondary analysis of key trials such as PARAGON-HF and PARADIGM, have highlighted possible differential gender specific benefits from Sacubitril/Valsartan therapy (2). We therefore sought to evaluate if there were gender specific effects of Sacubitril/Valsartan on both quantitative and qualitative measures of heart failure outcomes. Methods We performed a retrospective data interrogation of all patients commenced on Sacubitril/valsartan therapy in the SHSCT between 2016 and 2019. Data was extracted using electronic care records. Local ethical approval was granted. The primary endpoint were change in LVEF% on echocardiography and improvement in QOL (defined as NYHA score) at one year following initiation of Sacubitril/Valsartan. Differences in means between baseline and one year were assessed using a paired student's t-test. Interaction of gender on respective outcomes was assessed using a two way ANOVA. Significance defined as p<0.05. Data expressed as mean ± SD. Analysis performed using SPSS™. Results A total of 422 patients were included (mean age 69.1±12.1 years; 66% male). The predominant NYHA class' were II (n=298, 67.7%) and III (n=118, 26.8%). Aetiology and comorbidities were similar across male and females. In both groups, there was a statistically significant improvement in LVEF% at one year following initiation of Sacubitril/Valsartan (female; 27.1±8.6 to 34.6±9.5, n=40 p<0.01) (male; 27.4±7.5% to 32.6±9.3%, n=91, p<0.01). There was a statistically significant interaction between gender and degree of reverse cardiac remodeling defined as LVEF% on echocardiography following initiation of Sacubitril/Valsartan (F[2,52]=8.280, p=0.04, partial n2=0.27) (Figure 1). Similarly, there was a significant improvement in NYHA scores in both groups (male; 2.2±0.5 to 2.02±0.6, n=331, p<0.05) (female; 2.29±0.6 to 2.07±0.5, n=91, p<0.05) (Figure 2). However; there was no statistically significant interaction between gender and NYHA score following initiation of Sacubitril/Valsartan (F[2,52]=0.133, P=0.716, partial n2≤0.0). Conclusion Sacubitril/Valsartan produced significant improvement in reverse cardiac remodelling and QOL measures in both groups. Notably, had a stronger effect of reverse cardiac remodelling in women – suggesting possible gender specific differential benefits. FUNDunding Acknowledgement Type of funding sources: None.

Longitudinal analysis of cardiac abnormalities in pediatric patients with sickle cell anemia and effect of hydroxyurea therapy

Cardiac abnormalities such as left ventricular hypertrophy, dilation and pulmonary hypertension in sickle cell anemia, have been previously described. Hydroxyurea, a disease modifying therapy for sickle cell anemia, has been used for several decades. Longitudinal assessment of echocardiographic abnormalities in children and young adults with sickle cell anemia on hydroxyurea therapy is lacking. In this retrospective study, we aim to determine the prevalence of echocardiographic abnormalities in children and young adults with sickle cell anemia and to examine the effects of hydroxyurea on reverse cardiac remodeling. We reviewed the records of patients with sickle cell anemia who underwent routine cardiac screening at Cohen Children's Medical Center between 2010 and 2017, followed by retrospective longitudinal analysis of echocardiograms performed on patients receiving treatment with hydroxyurea. Data on a total of 100 patients with sickle cell anemia were analyzed; 60 (60%) were on hydroxyurea. Twenty-five (41.6%) of the patients on hydroxyurea had been treated for less than 1 year; these patients had a significantly greater prevalence of left ventricular dilation compared to those who had been on treatment for more than 1 year. Serial echocardiograms were then analyzed on patients receiving hydroxyurea. Left ventricular dilation and hypertrophy improved significantly with hydroxyurea treatment. Additionally, the left ventricular volume and mass correlated negatively with duration of treatment with hydroxyurea. Our study provides evidence that prolonged hydroxyurea therapy may lead to reverse cardiac remodeling. Future studies should attempt to follow this patient cohort for a longer duration.

Five-year survival and biomarkers of sympatho-adrenal, neurohumoral, immune activation, fibrosis in patients with early and late superresponse to cardiac resynchronization therapy

Methods. 82 SR (80.5% men; mean age 60.4±9.3; 45 (54.9%) with CAD) were divided according to period of LVESV maximum decrease: Gr.1 (n=19)- <24months (14.0 [8.0; 21.0]), Gr.2 (n=63)->24 months (59[43.0; 84.0]). Dynamics of echocardiography, adrenaline (ADR) plasma levels, norepinephrine (NE), interleukins (IL) 1β, 6, 10, TNF-α, NT-proBNP, MMP-9, TIMP-1, 4, were examined. Five-year survival was estimated by Kaplan-Meier method. ROC analysis and logistic regression were applied to identify late CRT response factors.Results. Initially, groups didn’t differ by clinical and echocardiographic findings. At baseline, Gr.2 had larger ADR (p=0.049) and NE (p=0.061). Rate of change in NE was opposite in groups during CRT: ΔNE increased in Gr.1 and decreased in Gr.2. (p=0.015), which was associated with better reverse cardiac remodeling (lower LV end systolic diameter, LV end diastolic diameter, LVESV, LV end diastolic volume), decrease in activity of immune inflammation (decrease in levels of IL-1β, 6, 10, TNF-α) and fibrosis formation (decrease in TIMP- 1, enhancement of MMP-9/TIMP-1). Cut-off value of 2.55 ng/ml for NE complied with the highest sensitivity (80%), specificity (60%), AUC=0.693 (p=0.011) for predicting late CRT response. Proportion of patients with NE<2.55 ng/ml was 21.1% in Gr.1 and 59.7% in Gr.2, (p=0.003), mean follow-up period was 45.8±0.3 and 94.9±35.9 months (p<0.001), respectively All SR of Gr.2 were alive within 5 years, survival rate was 50% in Gr.1 (Log-Rank test<0.001). NE was associated with late CRT response (OR 8.0 (95%CI 1.5-42.8), p=0.015).Conclusion. Late CRT response was accompanied by increased life expectancy, better 5-year survival, associated with greater reverse cardiac remodeling, decreased fibrosis activity, immune, neurohumoral, sympathoadrenal activation. When NE level was less than 2.55 ng/ml, probability of late response increased 8-fold.

Reduction of extracellular volume and reverse cardiac remodeling during sacubitril/valsartan therapy assessed by cardiac magnetic resonance in patients with heart failure (REMODELING CMR-HF)

Funding Acknowledgements Type of funding sources: None. OnBehalf REMODELING HF Background/Introduction: Extracellular volume (ECV) expansion is a major determinant of cardiac remodeling in heart failure. Cardiac magnetic resonance (CMR) T1 mapping has been developed as a noninvasive technique to estimate ECV. Purpose The objective of this study is to assess the response to Sacubitril/Valsartan by measuring changes in myocardial ECV and their association with reverse cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF). Methods Prospective, single-center, open-label study of two hundred-four HFrEF patients underwent CMR T1 mapping using the modified Look-Locker inversion recovery (MOLLI) sequence for ECV calculation, and initiated with sacubitril-valsartan treatment according to Guideline-Directed Medical Therapy. Absolute change in myocardial ECV, serum levels of procollagen type I amino-terminal peptide (PINP) and procollagen type III amino-terminal peptide (PIIINP), left ventricular end-diastolic volume index, left ventricular end-systolic volume index and left ventricle ejection fraction (LVEF) were analyzed from baseline to 12-month follow-up. Results Baseline MOLLI-ECV was 48.2% ± 2.4 in 106 patients with ischemic cardiomyopathy (ICM) and 38.7% ± 2.7 in 98 with idiopathic dilated cardiomyopathy (DCM), decreasing to 34% ± 2.4 for ICM and 29.5% ± 2.7 for DCM (P &lt; 0.001), at 12 months with sacubitril-valsartan therapy. These changes were correlated with a reduction of -36 μg/L for PINP (CI 95% 78-93, P &lt; 0.001), and -3.0 μg/L for PIIINP (CI 95% 73-91, P &lt; 0.001), -20 ml/m² in left ventricle end-diastolic and -18 ml/m² in end-systolic volumes, and an improvement in LVEF from 29% to 36% in both groups (P &lt; 0.001). Conclusions For the first time, we observe that changes in extracellular volume induced by sacubitril-valsartan therapy are related to reverse cardiac remodeling in patients with in HFrEF. These findings suggest that there may be an opportunity to decrease adverse remodeling with the use of a CMR-guided therapeutic approach aimed at decreasing fibrogenic activity and modulate the remodeling process.

Inhibition of ADAM10 ameliorates doxorubicin-induced cardiac remodeling by suppressing N-cadherin cleavage

The present research was designed to examine the effects of disintegrin metalloproteinases 10 (ADAM10) on the doxorubicin (DOX)-induced dilated cardiomyopathy (DCM) and the mechanisms involved, with a focus on ADAM10-dependent cleavage of N-cadherin. The present study constructed recombinant lentiviral vectors expressing short hairpin RNA (shRNA) targeting the ADAM10 gene. H9C2 cells were treated with the recombinant lentivirus or GI254023 (an ADAM10 inhibitor). The expression level of N-cadherin and its C-terminal fragment1 (CTF1) was tested by western blotting and flow cytometry. The adhesion ability was analyzed using a plate adhesion model. Cardiac function and morphology were assessed in control and lentivirus-transfected rats with or without DOX treatment. The inhibition of ADAM10 activity significantly increased the expression of full-length N-cadherin on the cellular surface and reduced CTF1 generation in vivo and in vitro. The adhesion ability was also increased in ADAM10-knockdown H9C2 cells. Furthermore, DOX-induced myocardial dysfunction was ameliorated in rats transfected with ADAM10-shRNA lentivirus. These findings demonstrated that ADAM10 specifically cleaves N-cadherin in cardiomyocytes. ADAM10-induced N-cadherin cleavage results in changes in the adhesive behavior of cells. Therefore, ADAM10 may serve as a therapeutic target to reverse cardiac remodeling in DCM.