Mineralcorticoid Receptor Antagonist Research Articles

Medical use of finererone in patients with diabetes mellitus and chronic kidney disease

Chronic hyperglycemia is one of the factors that contributes significantly to the complications associated with diabetes mellitus. Excess glucose causes an imbalance in cellular oxidation/reduction reactions, as well as systemic inflammation and inflammation in the renal parenchyma, playing a critical role in the pathogenesis of diabetic kidney disease, which today is the main reason for dialysis (hemodialysis/peritoneal) in the world. The pathogenesis of the disease is a difficult process to understand and is integrated with other organic and systematic factors; despite the different mechanisms involved in diabetes mellitus-related kidney damage, the biochemical and cellular mechanisms involving the oxidative and inflammatory pathways are widely recognized by science. There is evidence that the persistent state of hyperglycemia triggers oxidative stress and inflammation mediated by deregulated metabolic pathways, in a cycle that repeats itself, promoting the progression of cell damage and kidney disease. Chronic kidney disease (CKD) is an extremely serious condition that is often underdiagnosed. It is one of the most frequent and serious complications of diabetes. More than 40% of patients with type 2 diabetes mellitus develop CKD. Despite the existence of therapies recommended by the guidelines, patients with CKD and type 2 diabetes have a high risk of CKD progression and cardiovascular events with unfavorable outcomes. It is estimated that CKD affects more than 160 million people with diabetes worldwide. Chronic kidney disease resulting from type 2 diabetes is one of the main causes of advanced kidney disease, requiring dialysis or kidney transplantation. For these reasons, science has set itself the goal of conducting serious and impactful studies into the evolution of kidney disease, in which the key points are the use of drugs aimed at reducing the severity and the rapid natural history of the disease, which as a rule evolves into outcomes that are not always favorable to the patient. Many scientific studies have advanced in this century with an important impact on medicine, such as the FIGARO-DKD and FIDELIO-DKD studies, which seriously analyzes the impact and relevance of the use of mineralcorticoid receptor antagonists, specifically finerenone, in patients with type 2 diabetes mellitus and chronic kidney disease.

Medical use of finererone in patients with diabetes mellitus and chronic kidney disease

Chronic hyperglycemia is one of the factors that contributes significantly to the complications associated with diabetes mellitus. Excess glucose causes an imbalance in cellular oxidation/reduction reactions, as well as systemic inflammation and inflammation in the renal parenchyma, playing a critical role in the pathogenesis of diabetic kidney disease, which today is the main reason for dialysis (hemodialysis/peritoneal) in the world. The pathogenesis of the disease is a difficult process to understand and is integrated with other organic and systematic factors; despite the different mechanisms involved in diabetes mellitus-related kidney damage, the biochemical and cellular mechanisms involving the oxidative and inflammatory pathways are widely recognized by science. There is evidence that the persistent state of hyperglycemia triggers oxidative stress and inflammation mediated by deregulated metabolic pathways, in a cycle that repeats itself, promoting the progression of cell damage and kidney disease. Chronic kidney disease (CKD) is an extremely serious condition that is often underdiagnosed. It is one of the most frequent and serious complications of diabetes. More than 40% of patients with type 2 diabetes mellitus develop CKD. Despite the existence of therapies recommended by the guidelines, patients with CKD and type 2 diabetes have a high risk of CKD progression and cardiovascular events with unfavorable outcomes. It is estimated that CKD affects more than 160 million people with diabetes worldwide. Chronic kidney disease resulting from type 2 diabetes is one of the main causes of advanced kidney disease, requiring dialysis or kidney transplantation. For these reasons, science has set itself the goal of conducting serious and impactful studies into the evolution of kidney disease, in which the key points are the use of drugs aimed at reducing the severity and the rapid natural history of the disease, which as a rule evolves into outcomes that are not always favorable to the patient. Many scientific studies have advanced in this century with an important impact on medicine, such as the FIGARO-DKD and FIDELIO-DKD studies, which seriously analyzes the impact and relevance of the use of mineralcorticoid receptor antagonists, specifically finerenone, in patients with type 2 diabetes mellitus and chronic kidney disease.

Roles of aldosterone on ventricular arrhythmias, and associated gap junction and ion channel remodeling in hypertrophic heart

Abstract Background Ventricular arrhythmias are critical causes of death in patients with chronic heart failure (CHF). Aldosterone (Ald) is an exacerbating factor of CHF and mineral corticoid receptor antagonist (MRA) is usual drug for the management of CHF. MRA also suppressed sudden cardiac death, however, mechanisms of these effects remain unknown. We investigated the effects of MRA on ventricular arrhythmias and arrhythmogenic factors using Dahl Salt sensitive (DS) rats. Methods (in vivo) DS rats were divided into three groups; low salt group (LS), high salt group (HS), and eplerenone-, an MRA, treated high salt group (HS+EPL). Low salt (0.3% NaCl) or high salt (8% NaCl) were administrated for 8 weeks and EPL was administrated in the last 4 weeks. Cardiac geometry and function were assessed by echocardiography. Susceptibility of ventricular arrhythmias were assessed using programmed stimulation. Myocyte hypertrophy and cardiac fibrosis were examined by Masson’s trichrome staining. Expression and distribution of connexin43 (Cx43) were examined by immunostaining and western blotting. mRNA expression of Ca transient-related factors, such as phospholamban, SERCA2a, and ryanosin 2, and potassium ion channel-related factors, such as KCNE1 and KCNQ1, was examined by RT-PCR. (in vitro) Ald (1-100 nM) was administrated to cultured rat neonatal cardiomyocytes. Expression of Cx43, Ca transient-related, and potassium ion channel-related factors are also examined as mentioned above. Effects of Src tyrosin kinase inhibitor, PP2, and ERK inhibitor, PD98059, on Ald-induced Cx43 reduction were examined by RT-PCR and immunostaining. Results Systolic blood pressure and Ald concentrations in cardiac tissue were higher in HS group than LS group, and EPL did not affect them. In HS group left ventricular hypertrophy, dilatation and systolic dysfunction were observed in association with myocyte hypertrophy and interstitial fibrosis. EPL significantly recovered cardiac function and histological impairments. In addition, elongation of QTc in ECG and susceptibility of ventricular tachycardia were remarkable in HS group rather than LS and EPL attenuated them. Distribution of Cx43 was scattered in HS group, and EPL attenuated these changes. Decrease in SERCA2a and increase in KCNE1/KCNQ1 mRNA expression were found in HS group, and these changes were attenuated by EPL. In cultured myocytes, Ald decreased Cx43 mRNA and protein expression in a dose dependent fashion. Ald-induced Cx43 reduction was inhibited by PP2 and PD98059. In addition, Ald (100 nM) also decreased SERCA2a and increased KCNE1/KCNQ1 mRNA expression. Conclusion These results indicate that Ald reduced and dispersed the Cx43 expression reduction and dispersion through Src tyrosin kinase and ERK signaling pathways, and also mediated SRECA2A and KCNE1/KCNQ1 expression, which induced QTc prolongation and susceptibility of lethal ventricular arrhythmias in hypertensive cardiac hypertrophy.

Role of renal function in patients with advanced heart failure: insights from the help-hf registry

Abstract Background Chronic kidney disease (CKD) and heart failure (HF) strongly interact in determining patients prognosis. However, the prevalence and impact of CKD in advanced HF is still poorly characterized. Objective To determine the prevalence and prognostic impact of CKD and how estimated glomerular filtration rate (eGFR) might limit the use of guideline directed medical therapy in a large cohort of HF patients with at least one high-risk I NEED HELP marker. Methods 1120 patients enrolled in the HELP-HF registry were included in the analysis; eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration formula. Patients were stratified according to eGFR into three categories (> 60 ml/min, 30-60 ml/min, <30 ml/min). The primary endpoint was a composite of all-cause death and HF-hospitalization. Secondary endpoints were all-cause death, HF-hospitalization and cardiovascular death. Results 291 patients (25.98%) had an eGFR>60 ml/min, whereas 497 (44.37%) had eGFR between 30 and 60 ml/min and 332 (29.64%) had <30 ml/min. The risk of the primary endpoint was increased in patients with worse renal function (eGFR 30-60, HR 1.34, 95%CI 1.05-1.71, p = 0.017; eGFR<30, HR 1.88, 95%CI 1.47-2.42, p<0.001), whereas only patients with eGFR<30 ml/min demonstrated higher risk of all-cause death (HR = 2.36, 95%CI 1.68-3.31, p<0.001) and CV death (HR = 3.08, 95%CI 2.00-4.75, p<0.001). No difference in HF hospitalizations was seen with respect to patients with eGFR>60 ml/min. Once analyzed as a continuous variable, eGFR was significantly associated with each outcome. The impact of CKD was also confirmed in patients fulfilling the 2018 ESC-HFA definition of advanced HF. Logistic regression showed that patients with lower eGFR and with HF with reduced (HFrEF) and mildly reduced ejection fraction (HFmrEF) were less frequently discharged on maximal tolerated dose of mineral corticoid receptor antagonists (p= 0.001 for HrEF, p= 0.013 for HFmrEF), while lower eGFR was associated with less frequent use of maximal tolerated dose of a renin-angiotensin inhibitors (including angiotensin receptor-neprilysin inhibitors) only among patients with HFmrEF (p = 0.018). Conclusions Chronic kidney disease is highly prevalent among patients with advanced HF and impacts on patients’ prognosis and survival. The use of GDMT was significantly limited in patients with lower eGFR only in patients with HFrEF and HFmrEF.

Abstract 11995: Contemporary Guideline-Directed Medical Therapy (GDMT) for Heart Failure is Associated With A Reduced Incidence of New-Onset Atrial Fibrillation

Backgrounds: Heart Failure (HF) is a risk factor for new-onset atrial fibrillation (AF), and the new-onset AF is associated with a worse prognosis in HF patients. It has been reported that renin-angiotensin system inhibitor (RASi), β-blocker, mineral-corticoid receptor antagonist (MRA) and Sodium-glucose cotransporter 2 inhibitors (SGLT2i) prevent the new-onset AF in HF patients. However, significance of contemporary guideline-directed medical therapy (GDMT) for HF (RASi/ARNI + β-blocker + MRA + SGLT2i) on new-onset AF is unknown. We investigated the impact of GDMT for HF on new-onset AF. Methods and Results: We retrospectively studied the long-term (The mean follow-up was 603 ± 410 days) incidence of new-onset AF in HFrEF and HFmrEF patients without episode of AF (n=410) admitted to our hospital due to decompensated HF between 2015 and 2022. Patients were divided into 2 groups; patients treated with ≦2 HF drugs (n=192) and patients with ≧3 HF drugs (n=218) after discharge. The incidence of new-onset AF was significantly fewer in the ≧3 HF drugs group (HR 0.36, 95%CI 0.16-0.82). A multivariate analysis revealed that ≧3 HF drugs use was an independent negative predictor of new-onset AF (HR 0.38, 95%CI 0.15-0.98, P=0.04). Even after a propensity score matching of clinical variables, the incidence of new-onset AF was consistently fewer in the ≧3 HF drugs group (HR 0.39, 95%CI 0.15-1.00, P=0.04). Finally, comparing between patients with and without new-onset AF, new-onset AF was significantly associated with re-hospitalization for HF (HR 5.41, 95%CI 3.32-8.89, P<0.001) and all-cause death (HR 2.36, 95%CI 0.98-5.68, P=0.047) in the studied population. Conclusion: The contemporary GDMT is associated with a reducing of new-onset AF in HF patients, which may be involved in the better outcomes with it.

Abstract 11591: Mechanism of Finerenone-Induced Vasorelaxation in Arteries From Human Visceral Adipose Tissue

Introduction: Inadequate perfusion has emerged as a main determinant of adipose tissue (AT) dysfunction in obesity, sparking interest about possible ways to improve it. Among several mechanisms, mineralcorticoid receptor (MR) signaling has been shown to play a key role in the cross-talk between AT and the vasculature. Hypothesis: This study, therefore, tested the vasoactive properties of finerenone, a nonsteroidal MR antagonist, in arteries harvested from human AT. Methods: Small arteries (<1 mm in diameter) were isolated from visceral AT and studied ex vivo in a wire myograph. After vessels had been contracted, changes in vascular tone were determined under different experimental conditions. Results: Finerenone elicited a concentration-dependent relaxation in arteries of obese individuals contracted with the thromboxane A2 analogue U46619 (n=9; P<0001 vs. baseline); the steroidal MR antagonist potassium canrenoate, by contrast, did not induce any vasorelaxation (n=3; P>0.05). The relaxing effect of finerenone on U46619-induced constriction was not different in arteries from lean (n=3) and obese subjects (P=0.155). Mechanistically, the vasorelaxing response to finerenone was not influenced by pre-incubation with the nitric oxide (NO) synthase inhibitor L-NAME (n=4; P=0.19 vs. saline), hence ruling out an involvement of NO. Interestingly, finerenone was also able to relax arteries contracted with endothelin-1 (n=7; P<0.001) or with high-K + solution (n=4; P<0001), as well as those contracted with the L-type Ca 2+ -channel agonist BayK8644 (n=5; P=0.007); similarly, the calcium-channel blocker nifedipine induced relaxation of arteries contracted with BayK8644 (n=3; P<0.001). Conclusions: Finerenone induces NO-independent vasorelaxation in arterioles from human visceral AT, likely through antagonism of L-type Ca2 + -channels. This finding identifies a novel action of finerenone to improve AT perfusion, thereby potentially expanding the emerging observations about the cardiovascular benefits of this agent.

Patients With AMI and Severely Reduced LVEF, a Well-Defined, Still Extremely Vulnerable Population (Insights from AMIS Plus Registry)

Left ventricular ejection fraction (LVEF) represents one of the strongest predictors of both in-hospital and long-term prognosis in acute myocardial infarction (AMI). Temporal trends data coming from real-world experiences focused on patients with AMI with severely reduced LVEF (i.e., <30%) are lacking. In a total of 48,543 screened patients with AMI included in the Acute Myocardial Infarction in Switzerland Plus Registry between 2005 and 2020, data on LVEF were available for 23,510 patients. Study patients were classified according to LVEF as patients with AMI with or without severely reduced LVEF (i.e., patients with LVEF <30% and ≥30%, respectively). Overall, 1,657 patients with AMI (7%) displayed severely reduced LVEF. The prevalence of severe LVEF reduction constantly decreased over the study period (from 11% to 4%, p<0.001). In the subgroup of patients with severely reduced LVEF, a significant increase in revascularization rate was observed (from 61% to 84%, p<0.001); however, in-hospital mortality did not significantly decrease and remained well above 20% over the study period (from 23% to 26%, p=0.65). At discharge, prescription of optimal cardioprotective therapy (defined as an association of renin-angiotensin-aldosterone-system inhibitors, β-blocker, and mineral corticoid receptor antagonist) remained low across the study period (from 17% in 2011 to 20%, p=0.96). In conclusion, patients with AMI with severely reduced LVEF remain a fragile subgroup of patients with an in-hospital mortality that did not significantly decrease and remained well above 20% over the study period. Moreover, access at discharge to optimal cardioprotective therapy remains suboptimal. Efforts are, therefore, needed to improve prognosis and access to guidelines-directed therapies in this fragile population.

P71 SGLT2I IN THE REAL WORLD: DATA FROM THE PONTE (BRIDGE) HF PROJECT (PDTA FOR INTEGRATED TERRITORY HOSPITAL FOLLOW–UP OF PATIENTS WITH HEART FAILURE)

Abstract Background The DAPA–HF and the EMPEROR reduced trials showed that sodium–glucose cotransporter type 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin, on best medical therapy, resulted in a reduced incidence of the combined primary outcome cardiovascular death and worsening heart failure (–26%) and a preventive effect on renal function decline. Based on this evidence, the 2021 ESC guidelines have included SGLT2i in class I recommendations in combination with angiotensin and neprilysin receptor inhibitors (ARNI) or ACE inhibitors (ACEi) or angiotensin receptor blockers (ARB), beta–blockers (BB), and mineral corticoid receptor antagonists (MRA). However, the effect of adding SGLT2i in real–life patients is just partly known. The aim of the study was therefore to evaluate the impact of SGLT2i in a real world population of patients with heart failure and reduced left ventricular ejection fraction (HFrEF). Methods 220 consecutive patients with HFrEF, treated with SGLT2i and with 6 months of follow–up already enrolled in the PONTE (BRIDGE) HF project (PDTA FOR THE INTEGRATED FOLLOW–UP IN THE HOSPITAL TERRITORY OF THE PATIENT WITH HEART FAILURE), a care model implemented in Puglia region (Italy) based on hospital–territory integration aimed at the optimized management of patient with HF after hospitalization, were considered for the study. Demographic, clinical, laboratory and instrumental characteristics and changes in NYHA class, creatinine, NT proBNP, loop diuretic dose, LVEF after initiation of therapy with SGLT2i were evaluated. Results The 220 enrolled patients (mean age of 62 years, 72% hypertensive, 38% diabetic, 67% with ischemic heart disease, 50% with ICD/CRT, 44% with atrial fibrillation, 5.6% in NYHA class I, 61% class II, 33% class III, mean LVEF 30±11%) were in treatment with BB in 93% of cases, with MRA in 94%, with ACE/ARB in 24% and with ARNI in 80%. At 6–month follow–up of, a reduction of patients in NYHA class III from 33 to 20%, an increase in patients in NYHA class II from 61 to 70%, and in NYHA class I from 5.6 to 10% were observed; the LVEF (30 vs 37.2%) and creatinine values (1.3 vs 1.5) increased significantly, while loop diuretic doses decreased (35 vs 97.5). Conclusions Data from patients treated with SGLT2i from real world seem to confirm the efficacy of this class of drugs already in a short term follow–up, with a positive effect on NYHA class, LVEF, and renal function.

P273 THE RATIO BETWEEN LEFT ATRIAL RESERVOIR AND SEPTAL E/E’: A NEW PARAMETER REFLECTING ATRIO–VENTRICULAR FUNCTION WHICH IS ASSOCIATED WITH A WORSE OUTCOME AMONG HEART FAILURE OUTPATIENTS

Abstract Background Two–dimensional speckle tracking (2D–ST) analysis allows to evaluate both atrial and ventricular function. Recently, it has been demonstrated that the ratio between left atrial reservoir (LAr) assessed by 2D–ST and the E/e’ ratio could allow a more accurate estimation of left ventricular filling pressure. Aim of the study. To evaluate if the ratio between LAr and E/e’ is also associated with heart failure progression among chronic heart failure (CHF) outpatients. Methods All patients enrolled underwent a medical visit, an ECG and an echocardiographic examination. LAr was assessed by 2D–ST. The early diastolic peak at pulsed Doppler (E) and at the level of septal (e’s) and lateral (e’l) mitral annulus by Tissue Doppler Imaging (TDI) were also evaluated. Then the ratio between E and e’s (E/es) and between E and the mean of e’s and e’l (E/em) were also calculated. Finally, the ratio between LAr and E/es (LAr/Ees) and E/em (LAr/Eem) were computed. During follow–up the progression of heart failure, defined as heart failure hospitalization or death, were evaluated. Results Among 256 patients, LAr/Eem and LA/Ees were available in 191 patients (age 64±13 years,80 % males, mean LVEF 39±11%, NYHA class 2.3±0.5). All patients were in conventional medical therapy (sacubitril/valsartan or ACE–inhibitors or Angiotensin II receptor blockers in 85%, beta–blockers in 94%, mineralcorticoid receptor antagonists in 73%, diuretics in 81%, SGLT2 inhibitors in 21%). During a mean follow–up of 13±7 months, 25 patients experienced death (9) and/or hospitalization (21) for heart failure worsening. At univariate Cox univariate regression analysis, both LAr/Eem (HR 0.61; 95%CI: 0.43–0.87; p:0.006) and LAr/Ees (HR 0.43; 95%CI: 0.25–0.71; p:0.001) were associated with the events. However, LAr/Ees showed a greater accuracy than LAr/Eem (C–index 0.76 vs. 0.73) and remained significantly associated with the events at multivariate analysis after correction for age, LVEF, NYHA class and estimated glomerular filtration rate (HR: 0.55; 95%CI: 0.33–0.92; p:0.22). Figure shows Kaplan–Meier curves according with the median value of LAr/Eem (panel A) and LAr/Ees (panel B). Conclusions The ratio between LAr and E/es is a new echocardiographic parameter able to reflect both left ventricular filling pressure and worse prognosis among patients affected by CHF. Further studies should evaluate its incremental value in stratifying patients’ prognosis.

P469 UP TO 12 MONTH TRENDS IN CLINICAL AND BIOCHEMICAL PARAMETERS AFTER SGLT2I THERAPY IN PATIENTS AFFECTED BY HEART FAILURE PATIENTS WITH REDUCED EJECTION FRACTION

Abstract Background The type–2 sodium–glucose cotransporters inhibitors (SGLT2i) are a new relevant therapeutic option for patients affected by chronic heart failure with reduced ejection fraction (HFrEF). The aim of this study was to evaluate the effects of SGLT2i on some clinical and biochemical parameters as well as the persistence of SGLT2i therapy up to 12 months. Methods We evaluated the consecutive patients affected by HFrEF in whom the SGLT2i therapy was prescribed since December 2021. The patients were followed–up after 1, 3, 6 and 12 months with a clinical visit, ECG, echocardiography, assessment of sodium, potassium, fasting glucose, hemoglobin, hematocrit and glomerular filtration rate (GFR) by creatinine. The data were analyzed by linear mixed models. Results Ninety patients were enrolled (age 60±9 years, 83% males, 20% diabetics, 38% affected by ischemic cardiomyopathy, NYHA class 2.24±0.43, 98% with ACEi/ARB/ARNi, 99% with beta–blockers, 84% with mineralcorticoid receptor antagonists). During the follow–up SGLT2i therapy was well tolerated in most of the patients. Five patients withdrew the therapy, 2 for hypotension, 2 for poor adherence, 1 for genital infection. As shown in the Figure, after SGLT2i therapy a significant reduction in weight and fasting glucose and a slight increase in LVEF were observed. Systolic arterial pressure did not show significant differences. As expected a significant short–term reduction in estimated GFR occurred, associated with a reduction of sodium serum levels. Hemoglobin and hematocrit progressively and significantly increased during follow–up. Conclusions In this “real world” study, among patients with HFrEF, the administration of SGLT2i resulted well tolerated in most of the patients. It was associated with the improvement of metabolic parameters (weight and fasting glucose), a slight temporary reduction in GFR, an increase in hemoglobin and systolic function. These data further support the use of this therapeutic approach in routine clinical practice.

C56 ACCURACY OF TWO–DIMENSIONAL SPECKLE TRACKING PARAMETERS REFLECTING LEFT ATRIAL FUNCTION IN PREDICTING OUTCOME AMONG OUTPATIENTS AFFECTED BY HEART FAILURE

Abstract Background The two–dimensional speckle tracking analysis (2D–ST) is a new useful tool in order to evaluate both atrial and ventricular function. Aim of the study. To evaluate the accuracy of the 2D–ST measures reflecting atrial and ventricular function in predicting the outcome among outpatients affected by chronic heart failure (CHF). Methods We enrolled 212 outpatients (age 64±13 years, 77% males, mean left ventricular ejection fraction, LVEF, 38±11%, NYHA class 2.4±0.5) affected by CHF in conventional therapy (sacubitril/valsartan or ACE–inhibitors or Angiotensin II receptor blockers in 85%, beta–blockers in 94%, mineralcorticoid receptor antagonists in 74%, diuretics in 72%, SGLT2 inhibitors in 20%). All patients underwent a medical visit, an ECG and an echocardiographic examination. The following 2D–ST parameters reflecting atrial and ventricular function were analyzed: global longitudinal left ventricular strain (LV–GLS, mean –11.4±3.9%), global longitudinal right ventricular strain (RV–GLS, mean –15.2±5.2%), free wall right ventricular longitudinal strain (RV–fwLS, mean –20.2±5.8%); left atrial reservoir (LAr, mean 19±10.8%), conduit (LAcd, mean –10.–8±6.8) and contraction (LAct, mean –8.1±8.2). Moreover, the early diastolic peak at pulsed Doppler (E) and at the level of septal (e’s) and lateral (e’l) mitral annulus by Tissue Doppler Imaging (TDI) were also evaluated. Then the ratio between E and e’s (E/es, mean 13.9±6.4) and between E and the mean of e’s and e’l (E/em, mean 11.1±5.4) were also calculated. Finally, the ratio between LAr and E/es (LAr/Ees, mean 1.98±1.65) and E/em (LAr/Eem, mean 2.51±1.95) were computed. During follow–up the progression of heart failure, defined as heart failure hospitalization or cardiovascular death, were evaluated. Results During a mean follow–up of 13±6, 32 patients experienced death (13) and/or hospitalization (25) for heart failure worsening. The table shows the relationship among echocardiographic variables and outcome At Cox univariate regression analysis and the relative C–index. LAR/Ees showed the greater accuracy (C–index) in predicting heart failure progression. Conclusions 2D–ST is an echocardiographic approach able to more accurately assess both left ventricular and atrial function. In our series, among the 2D–ST parameters, the ratio between LAr and E/es is characterized by the greater accuracy in predicting heart failure progression.

Left ventricular ejection fraction evolution in ischemic and non-ischemic patients with de novo left ventricle dysfunction hospitalized in a tertiary ICCU

Abstract Funding Acknowledgements Type of funding sources: None. Background Aadverse left ventricle remodeling’s natural evolution without proper therapy leads to low left ventricle ejection fraction (LVEF) and high morbidity and mortality. LVEF evolution after discharge in patients with de novo LV dysfunction (≤40%) detected during an intensive cardiac care unit (ICCU) hospitalization is not well known. Purpose To characterize LVEF evolution after discharge in patient with de novo LV dysfunction (≤40%) detected during an Intensive Cardiac Care Unit (ICCU) admission according to etiology: ischemic etiology (IE)Vs non-ischemic etiology (NIE). Methods We retrospectively analyzed clinical, echocardiographyc, pharmacological and coronary angiography -related variables from 154 consecutive patients admitted from May 2020 to July 2022 in the ICCU of a tertiary hospital and whose LVEF at discharge was ≤40%. Patients were grouped according to LV dysfunction etiology in ischemic and non-ischemic. LVEF at follow-up was registered when available. Results This cohort had a mean age of 64.8 ±14 years and 127 (82%) were male. Mean left ventricle ejection fraction was 30 ±6.8%. Among them, 119 (77%) had ischemic etiology (IE) and 35 (23%) non-Ischemic (NIE). Inotropes during admission were required in 29 (19%) and 151 (98%) were studied with coronary angiography. 70 (46%) were also studied with MRI during hospitalization; 35 (23%) had right ventricular dysfunction (RVD) and 39 (25%) had any kind of bundle branch block at discharge’s EKG. At discharge, 121 (78%) received betablockers (BB), 69 (45%) received Angiotensin Converser Enzyme Inhibitor (ACEI), 17 (11%) received Angiotensin Receptor Blocker (ARB), 24 (16%) received sacubitril-valsartan (ARNI), 88 (57%) received Mineralcorticoid Receptor Antagonist (ARM) and 39 (25%) received Sodium-Glucos type-2 inhibitors. At discharge, LVEF in patients with IE was 31 ±6% and 27 ±8% in NIE (p=0,01). Follow-up echocardiography was available in 119 (77%) of them. Mean last available follow-up LVEF was 46% ±11 in NIE while among IE was 40% ±11 (p=0,02). LVEF increase was of 17±11% in NIE and 9±9% in IE (p=0,0004). Among all, 36 patients normalized LVEF, 14 (50%) in NIE group and 22 (25%) in IE (P=0.01). In a multiple linear regression model adjusting by age, sex, QRS duration, left bundle branch block, TRC implantation and modifying-disease drugs, NIE etiology was independently associated with a 7,6% increase in LVEF compared to IE (p=0,003). Conclusions Our findings support that LVEF improvement after admission to ICCU with de novo LV dysfunction is strongly dependent on etiology. Patients with NIE tend to have an initial worse LVEF but greater improvement at follow-up.

Current And Future Therapeutic Perspective In Chronic Heart Failure

The incidence of heart failure is primarily flat or declining for a presumably reflecting better management of cardiovascular diseases, but that of heart failure with preserved ejection fraction (HFpEF) is probably increasing for the lack of an established effective treatment. Moreover, there is no specific pharmacological treatment for patients with heart failure with mildly reduced ejection fraction (HFmrEF) since no substantial prospective randomized clinical trial has been performed exclusively in such population. According to the recent 2021 European Society of Cardiology (ESC) guidelines, the triad composed of an Angiotensin Converting Enzyme inhibitor or Angiotensin Receptor-Neprilysin Inhibitor (ARNI), a beta-blocker, and a Mineralcorticoid Receptor Antagonist is the cornerstone therapy for all patients with heart failure with reduced ejection fraction (HFrEF) but a substantial gap exists for patients with HFpEF/HFmrEF. Despite the important role of the Renin- Angiotensin-Aldosterone System (RAAS) in heart failure pathophysiology, RAAS blockers were found ineffective for HFpEF patients. Indeed, even the new drug class of ARNI was found effective only in HFrEF patients. In this regard, a therapeutic alternative may be represented by drug stimulating the non-classic RAAS (ACE2 and A1–7) as well as other emerging drug classes (such as SGLT2 inhibitors). Reflecting on this global health burden and the gap in treatments among heart failure phenotypes, we summarize the leading players of heart failure pathophysiology, the available pharmacological treatments for each heart failure phenotype, and that in future development.

Abstract 14354: Prognostic Impact of Low Serum Chloride Level in Elderly Patients With Heart Failure

Background: Patients with heart failure (HF) are known to be stratified the risk of mortality by serum chloride level. However, since large-scaled studies to date have not included the elderly patients, it is still unclear whether serum chloride level well predicts the prognosis of the elderly patients with HF, whose clinical profiles are different from young adult patients. We aimed to test the hypothesis that hypochloremia gave different prognostic impacts in non-elderly and elderly patients with HF. Methods: This observational study included 1,326 elderly patients ( &gt; 65 year-old) without regular hemodialysis who were hospitalized for worsening of HF and discharged alive. They were divided into two subgroups depending on serum chloride levels at admission (Low-chloride group ( &lt; 97 mEq/L, n=244); Normal-chloride group ( &gt; 98 mEq/L, n=1518)), referred to prior reports. Propensity scores were developed and patients in Normal-chloride group were matched with those in Low-chloride group in a 1:1 ratio. The endpoint of this study was death from any cause. Results: Among 1,326 unmatched patients, Low-chloride group included significantly more male patients, and those with higher BUN, CRP, bilirubin levels, dose of furosemide and atrial fibrillation, and prescriptions of oral anticoagulant, and lower BMI, blood pressure, hemoglobin, prescription of mineral corticoid receptor antagonist, thiazide and statins. Following propensity score matching by diverse baseline parameters, 106 pairs in both groups were included in the matched population. During 413 days of median observational period, 62 patients (28.8%) died. Kaplan-Meier analysis showed that patients in the Low-chloride group had a significantly higher mortality rate (p=0.011, Figure ). Conclusion: In this observational study, baseline hypochloremia was associated with an increased mortality in elderly patients hospitalized with heart failure.

Guideline Directed Medical Therapy at Discharge and Further Uptitration Leading to Reduction in Indication for Prophylactic ICD Implantation during Protected Waiting Period.

Heart failure with reduced ejection fraction (LV-EF < 35%) is diagnosed in app. 11,000,000 patients worldwide. For the treatment of these patients, guideline directed medical therapy has proven to reduce mortality and rehospitalization regardless of the disease’s etiology. It is implemented to treat clinical symptoms by improving the left ventricular ejection fraction. Patients with a transient risk of ventricular tachycardia and sudden cardiac death can be protected by a defibrillator vest. The defibrillator vest is capable to detect and terminate ventricular arrhythmias during Guideline Directed Medical Therapy (GDMT). It is based on the recommendations of the European society of cardiology for 3 months. Afterwards, the WCD wear time could be prolonged, or, in case of persistent low ejection fraction (LV-EF ≤ 35%), an implantable cardioverter defibrillator (ICD) should be implanted, as shown in the WEARIT-II-registry. Our goal was to evaluate the effects of GDMT on LV-recovery and reduction of ICD implantations under protection with a defibrillator vest—depending on the uptitration of GDMT. Methods: 339 consecutive patients between August 2017 and September 2020 with newly diagnosed cardiomyopathy and an EF ≤ 35% were analyzed retrospectively by chart review. All patients were protected by a wearable cardioverter defibrillator (WCD). GDMT as recommended by the ESC started at discharge from hospital. The left ventricular ejection fraction (LV-EF) was determined by transthoracic echocardiography at week 4, 8 and at week 12 (in case of prolonged WCD wear time). Uptitration was performed after 4 and 8 weeks during patient visits. We focused on baseline medication as per GDMT and the dosage increase at week 4, 8 and 12. The aim was the uptitration to the maximum dosage tolerated by the patient. We also compared the LV-EF improvement in the group with and without uptitration of medication dosage. Results: The patient age was, on average, 63.2 years (SD ± 11.9 years). A total of 129 pts (38%) had ICM, 196 (58%) had NICM (incl 66 pts (19%) with DCM and 51 pts (15%) with Myocarditis, 79 pts (24%) with unknown origin) and 14 pts (4%) had other entities (e.g., Tachycardiomyopathy). In total, 21 pts (6%) had an LV-EF of less than 16%, 130 pts (38%) between 16–25% and 183 pts (54%) between 26–35%. GDMT started at discharge from the hospital included treatment with beta blocker for 327 pts (96.5%), ACE-inhibitors/Angiotensin/ARNI for 283 pts (83.5%) and Mineralcorticoid receptor antagonists (MRA) for 334 pts (88.4%). Uptitration was performed in all groups at a rate of 82.3%, 91.1% and 81.0% after 4 weeks and 64.7%, 50.3% and 66.3% after 8 weeks, respectively. After 4 weeks, 25 pts (7.4%) and, after 8 weeks, 171 pts (50.4%) had an EF increase of 5% or more (mean 14.2%). After 4 weeks, 81 patients had an LV-EF more than 35%. A total of 169 pts had a wear time of 12 weeks and an improvement of LVEF of more than 35%. Interestingly, in our study we did not find a significant difference in LV-EF improvement between the group with no uptitration and the group with uptitration. Conclusions: Guideline-directed medical therapy under protection with a WCD from ventricular arrhythmia can reduce the need for implantation of an ICD and can lead to an improvement of ejection fraction. Interestingly, the LV-EF improvement depends on the GDMT at discharge. Current guidelines recommend an initiation of all therapy columns of GDMT (sacubitril/valsartan, ACE-inhibitor/AT1-blocker, mineralcorticoidreceptorblocker, beta blocker) at once and further uptitration to the maximal dosage (ESC Guidelines 2021). A further uptitration of all drugs of GDMT should lead to improvement of LV-EF and consequently to a reduction in ICD implantations.

Where do we stand with acute myocardial infarction patients with severely reduced left ventricular ejection fraction? insights from AMIS Plus Registry

Abstract Background Left ventricular ejection fraction (LVEF) represents one of the strongest predictors of both in-hospital and long-term prognosis in acute myocardial infarction (AMI). Temporal trends data coming from real-word experiences focused on AMI patients with severely reduced LVEF (i.e. &amp;lt;30%) are lacking. Purpose The present study aims at providing a comprehensive picture on temporal trends in AMI patients with severely reduced LVEF, with a particular focus on prevalence, in-hospital management/prognosis and pharmacological therapy at discharge. These data could shed light on the implementation in the clinical arena of guideline-directed therapies in this fragile subgroup of patients and on their effect on real-word short-term prognosis. Methods On a total of 48,543 screened AMI patients included in AMIS Plus Registry between 2005 and 2020, data on LVEF were available for 23,510 patients. Study patients were classified according to LVEF as AMI patients with or without severely reduced LVEF (i.e. patients with LVEF &amp;lt;30% and ≤30%, respectively). Results Overall, 1657 AMI patients (7%) presented with severely reduced LVEF. Prevalence of severe LVEF reduction constantly decreased over the study period (from 11% to 4%, p&amp;lt;0.001; Figure 1). In the subgroup of patients with severely reduced LVEF a significant increase in revascularisation (percutaneous and/or surgical) rate was observed (from 61% to 84%, p&amp;lt;0.001); in-hospital access to advanced short-term mechanical circulatory support (both ECMO and/or Impella) significantly increased from 0% in 2011 to 17% (p=0.05). Rate of cardiogenic shock developed during hospitalization remained stable over time (from 21% to 16%, p=0.7); in-hospital mortality did not significantly decrease and remained well above 20% all over the study period (from 23% to 26%, p=0.65; Figure 2). At discharge, prescription of optimal anti-ischaemic therapy (defined as an association of dual antiplatelet therapy and statine) significantly increased (from 47% to 75%, p&amp;lt;0.001), mainly driven by an increase in dual antiplatelet therapy prescription; however, prescription of optimal cardio-protective therapy (defined as an association of renin-angiotensin-aldosterone-system inhibitors, beta-blocker and mineralcorticoid receptor antagonist) remained low across the study period (from 17% in 2011 to 20%, p=0.96). Conclusion AMI patients with severely reduced ejection fraction still remain a fragile subgroup of patients; in-hospital mortality did not significantly decrease and remained exceedingly high and well above 20% all over the study period; efforts are, therefore, urgently needed to develop therapeutic strategies focused on this subgroup of patients and aiming at improving short-term prognosis. Moreover, access at discharge to optimal cardio-protective therapy remains suboptimal; efforts are needed to improve access to guidelines-directed therapy both at discharge and follow-up in this fragile population. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Swiss Heart Fundation

Aggressive combined pharmacotherapy for heart failure reduces new onset atrial fibrillation

Abstract Backgrounds Heart failure (HF) is a risk factor for new onset atrial fibrillation (AF), and the new onset AF is associated with a worse prognosis in HF patients. It has been reported that renin-angiotensin system inhibitor (RASi), β-blocker and mineral-corticoid receptor antagonist (MRA) prevent the new onset AF in HF patients. However, the effect of combined pharmacotherapy including angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitor (SGLT2i) on AF is unknown. We investigated the impact of contemporary regimen of combined pharmacotherapy for HF (RASi/ARNI+β-blocker+MRA+SGLT2i) on new onset AF. Methods and results We retrospectively studied rEF and mrEF patients without AF admitted to our hospital due to decompensated HF between 2015 and 2021 (n=366). Long-term (The mean follow-up was 635±421 days) incidence of new onset AF was investigated with regard to medical therapies. Patients were divided into 2 groups; patients with ≤2 HF drugs (n=181) and patients with ≥3 HF drugs (n=185). Patients with ≤2 HF drugs group were older (77.3 vs 67.0 years old, P&amp;lt;0.001), had a poorer renal function (Cre: 1.66 vs 1.09 mg/dl, P&amp;lt;0.001), and had a higher rate of ischemic heart disease (52 vs 38%, P=0.009), whereas left ventricular systolic function was better (EF: 31.9 vs 27.3%, P&amp;lt;0.001). There were 19 (10.5%) new onsets AF in the ≤2 HF drugs group, whereas only 7 (3.8%) had new onsets AF in the ≥3 HF drugs group (HR 0.36, 95% CI 0.15–0.85, P=0.01). All-cause death and hospitalization for HF were fewer in the ≥3 HF drugs group. A multivariate analysis revealed that ≥3 HF drugs use was an independent negative predictor of new onset AF (HR 0.37, 95% CI 0.15–0.93, P=0.03). Even after a propensity score matching of the clinical variables, the incidence of new onset AF was consistently fewer in the ≥3 HF drugs group (HR 0.36, 95% CI 0.13–0.99, P=0.04). Finally, patients with new onset AF had a higher rate of hospitalization for HF in the studied population (HR 9.68, 95% CI 5.67–16.5, P&amp;lt;0.01). Conclusion Aggressive combined pharmacotherapy for HF may be associated with fewer new onset AF in patients with HF. Funding Acknowledgement Type of funding sources: None.

Refractory Arterial Hypertension: Features of Neurohormonal and Water-salt Imbalanceand Approaches to Antihypertensive Drug Therapy

Refractory arterial hypertension is characterized by a lack of control of target blood pressure, despite the prolonged use &gt;5 antihypertensive drugs with different mechanisms of action, including longacting diuretic chlorthalidone and the mineralcorticoid receptor antagonists (spironolactone or eplerenone). The review presents the results of clinical studies devoted the elucidating peculiarities of the neurohormonal status and water-salt balance in such patients and developing new approaches to antihypertensive drug therapy based on them. According to these studies, individuals with refractory hypertension differ from patients with resistant hypertension with the higher of sympathetic nervous system activity and the absence of an increased of intrathoracic fluid volume, which indirectly indicates a significant decrease in the intravascular fluid volume. In this regard, the review focuses on the data obtained in assessing the clinical efficacy of sympatholytics clonidine and reserpine in patients with resistant and refractory hypertension, as well as renal sodium-glucose co-transporter type 2 inhibitors, which suppress the sympathetic nervous system activity and can be used to overcome refractory hypertension in patients with type 2 diabetes.

Refractory arterial hypertension: hyperactivity of the sympathetic nervous system, kidney and approaches to antihypertensive drug therapy

Improving blood pressure (BP) control and reducing the risk of developing unfavorable cardiovascular and renal outcomes in patients with refractory hypertension (HTN) is an urgent problem of cardiology. According to clinical studies, patients with refractory HTN receiving intensive diuretic therapy with chlorthalidone and a mineralcorticoid receptor antagonist differ from patients with refractory HTN by a higher sympathetic nervous system (SNS) activity. Overactivity of sympathetic nerves may be one of the key pathogenetic factors that is involved in the kidney in the formation of refractory HTN, exerting a direct stimulating effect on the type 3 Na+ / H+ exchanger (NHE3) and type 2 sodium glucose cotransporter (SGLT2), which are involved in BP control by mechanism of pressure natriuresis. The review presents data on the peculiarities of sympathetic regulation of sodium tubular transport and the results of studies devoted the elucidating in the patients with resistant and refractory HTN the clinical efficacy of SGLT2 inhibitors glyflozins, sympatholytic reserpine and brain aminopeptidase A inhibitor firibastat, which suppresses the activity of central structures of SNS.

Heart failure medication and its effect on response to cardiac resynchronisation therapy in patients with pacing-induced cardiomyopathy: an UPGRADE post hoc analysis

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Austrian National Bank Unlimited scientific grant from the Boston Scientific Investigator Sponsored Research (ISR) Committee Background/Introduction Current heart failure (HF) guidelines recommend optimal medical therapy (OMT) in patients with pacing-induced cardiomyopathy (PICM) prior upgrading to cardiac resynchronisation therapy (CRT). It is unknown, whether previous prescription of heart failure medication reduces the effect of CRT upgrading. Purpose To evaluate the effect of HF medication on CRT response in patients suffering from PICM receiving an upgrade to CRT. Methods The UPGRADE trial was a prospective investigator driven trial evaluating the effect of CRT upgrading in patients with PICM. Key inclusion criteria were symptomatic HF with left ventricular ejection fraction (LVEF) below 40% despite OMT and right ventricular pacing (RVP) above 40%. Device programming had to be adjusted to minimize RVP prior to enrolment. Echocardiographic examinations were performed prior to device implantation and 3-5 months after activation of CRT and were analyzed in blinded fashion. CRT response was defined by a reduction of &amp;gt; 15% in left ventricular end systolic volume (LVESV). Heart failure medication was assessed at implantation of the device. Results Overall, 54 patients were enrolled in the UPGRADE trial between 2014 and 2018. Beta-blockers (BB) were prescribed in 43 (79.6%), mineralcorticoid receptor antagonists (MRA) in 29 (53.7%) and either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blockers (ARB) in 45 (83.3%) of the patients. Therapy with CRT has led to significant improvement in LVEF (mean delta: 12.8 ± 7.8%) and LVESV (delta: 30.7 ± 33.2ml), whereas CRT response was achieved in 30 (55.6%) patients. There was no statistically significant difference in patients with BB intake regarding increase of LVEF (12.4 ± 7.5% vs. 14.6 ± 9.4%, p=0.431), decrease of LVESV (42.8 ± 32.8ml vs. 27.8 ± 33.0ml, p=0.201) or CRT response (22 (53.7%) vs. 8 (80%), p=0.167). Similar results were found regarding ACE inhibitor/ARB [LVEF: 13.1 ± 6.8% vs. 11.5 ± 11.8%, p=0.705; LVESV: 32.6 ± 32.6ml vs. 21.7 ± 36.3ml, p=0.373; CRT response: 26 (61.9%) vs. 4 (44.4%), p=0.460] and MRA intake [LVEF: 13.7 ± 7.3% vs. 11.8 ± 8.4%, p=0.382; LVESV: 34.3 ± 36.8ml vs. 26.7 ± 28.8ml, p=0.423; CRT response: 15 (55.6%) vs. 15 (62.5%), p=0.777]. Conclusion Previous prescription of heart failure medication did not reduce the effect of CRT upgrading in patients suffering from PICM. It remains to be proven, whether similar results may be observed for newer HF agents like sodium-glucose co-transporter 2 inhibitors or angiotensin receptor-neprilysin inhibitors as both were not available in clinical routine at the time of study conduct.