Heart Failure Therapy Research Articles

Guideline-Directed Medical Therapy and Survival After TEER for Secondary Mitral Regurgitation With Right Ventricular Impairment

BackgroundRight ventricular impairment is common among patients undergoing transcatheter edge-to-edge repair for secondary mitral regurgitation (SMR). Adherence to guideline-directed medical therapy (GDMT) for heart failure is poor in these patients. ObjectivesThe aim of this study was to evaluate the impact of GDMT on long-term survival in this patient cohort. MethodsWithin the EuroSMR (European Registry of Transcatheter Repair for Secondary Mitral Regurgitation) international registry, we selected patients with SMR and right ventricular impairment (tricuspid annular plane systolic excursion ≤17 mm and/or echocardiographic right ventricular–to–pulmonary artery coupling <0.40 mm/mm Hg). Titrated guideline-directed medical therapy (GDMTtit) was defined as a coprescription of 3 drug classes with at least one-half of the target dose at the latest follow-up. The primary outcome was all-cause mortality at 6 years. ResultsAmong 1,213 patients with SMR and right ventricular impairment, 852 had complete data on medical therapy. The 123 patients who were on GDMTtit showed a significantly higher long-term survival vs the 729 patients not on GDMTtit (61.8% vs 36.0%; P < 0.00001). Propensity score–matched analysis confirmed a significant association between GDMTtit and higher survival (61.0% vs 43.1%; P = 0.018). GDMTtit was an independent predictor of all-cause mortality (HR: 0.61; 95% CI: 0.39-0.93; P = 0.02 for patients on GDMTtit vs those not on GDMTtit). Its association with better outcomes was confirmed among all subgroups analyzed. ConclusionsIn patients with right ventricular impairment undergoing transcatheter edge-to-edge repair for SMR, titration of GDMT to at least one-half of the target dose is associated with a 40% lower risk of all-cause death up to 6 years and should be pursued independent of comorbidities.

A Case-based Implementation of Heart Failure Therapies, a Consensus Pathway by the Saudi Heart Failure Working Group.

The implementation of guideline-directed medical therapy (GDMT) in heart failure (HF) has many challenges in real-world clinical practice. The consensus document is written considering the variability of the clinical presentation of HF patients. HF medical therapies need frequent dose adjustment during hospital admission or when patients develop electrolyte imbalance, acute kidney injury, and other acute illnesses. The paper describes clinical scenarios and graphs that will aid the managing physicians in decision-making for HF therapy optimization.

Urate-lowering therapy in patients with hyperuricemia and heart failure: A retrospective cohort study using the UK Clinical Practice Research Datalink.

Elevated serum uric acid (sUA) is associated with heart failure (HF). Urate-lowering therapy (ULT) in HF is associated with lower risk of HF hospitalization (hHF) and mortality. Data on patients with HF and gout or hyperuricemia in the Clinical Practice Research Datalink database linked to the Hospital Episode Statistics and the Office for National Statistics in the United Kingdom were analyzed. Risks of hHF and all-cause mortality or cardiovascular-related mortality by ULT exposure (ULT initiated within ≤6 months of gout or hyperuricemia diagnosis) were analyzed in a propensity score-matched cohort using adjusted Cox proportional hazards regression models. Of 2174 propensity score-matched pairs, patients were predominantly male, aged >70 years, with mean ± standard deviation sUA 9.3 ± 1.8 (ULT-exposed) and 9.4 ± 1.9 mg/dL (ULT-unexposed). At 5 years, ULT-exposed patients had a 43% lower risk of hHF or all-cause mortality (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.51-0.65) and a 19% lower risk of hHF or cardiovascular-related mortality (adjusted HR: 0.81; 95% CI: 0.71-0.92) versus no ULT exposure. ULT was associated with reduced risk of adverse clinical outcomes in patients with HF and gout or hyperuricemia over 5 years.

Cardiac Resynchronization Therapy. Long-Term Evolution of Responder and Non-Responder Patients

Background: Cardiac resynchronization therapy (CRT) is an effective treatment in patients with heart failure (HF), low left ventricular ejection fraction (LVEF) and wide QRS. However, there are a percentage of these patients who are non-responders, implying worse clinical outcomes. Objectives: The aim of this study was to assess the differences in echocardiographic parameters of reverse remodeling and event rates [hospitalization for heart failure (HHF), all-cause mortality (ACM), heart transplantation (HTX) and appropriate therapies (AT)] between responder vs. non-responder patients to CRT. Methods: A total of 343 patients with CRT, classified into responders and non-responders according to clinical and echocardiographic parameters, were included in the study. A 2-year follow-up was performed, in which reverse remodeling and the incidence of HHF, ACM, HTX and AT were evaluated. Results: Among the 343 patients, 17% were non-responders and 83% responders. At 6 and 12 months there were no significant differences in ventricular diameters, but significant differences in LVEF (p&lt;0.001), with greater increase in responders. At 24 months, responders had smaller diastolic diameter (p=0.004), smaller systolic diameter (p=0.003) and higher LVEF (p&lt;0.001). Non-responders had significantly higher incidence of HHF (p&lt;0.001), HTX (p=0.001) and AT (p=0.002), and an excess of ACM at the limit of statistical significance (p= 0.056). Conclusions: Patients responding to CRT presented greater reverse remodeling and better clinical evolution, in accordance with the results of international observational studies.

Histone methyltransferase MLL4 protects against pressure overload-induced heart failure via a THBS4-mediated protection in ER stress

Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.

A Novel Decision Support Tool Aimed at Improving Heart Failure Therapy on Discharge

A Novel Decision Support Tool Aimed at Improving Heart Failure Therapy on Discharge

User Feedback and Experiences of a Novel Decision Support Tool to Improve Rates of Heart Failure Therapy

User Feedback and Experiences of a Novel Decision Support Tool to Improve Rates of Heart Failure Therapy

Initiation of self-care practices in heart failure patients: a phenomenological study

Introduction: The incidence of heart failure continues to rise with advancing age, unabated by advancements in healthcare technology. Patients with heart failure are required to manage their care independently at home for the remainder of their lives. This study aimed to delve into the experiences of heart failure patients regarding self-care management at home. Methods: Nineteen patients with heart failure were chosen through purposive sampling and thorough interviews were conducted to collect their self-care treatment experiences. Content analysis was carried out to scrutinize the acquired data. Results: The analysis revealed four themes: patients' perception of heart failure diagnosis, efforts in self-care, readiness for self-care, and adoption of new healthy behaviors in heart failure. Eight categories were formulated within these themes, including “transitioning into a heart failure patient;” “recognizing the need for self-care;” “seeking information and heart failure therapy;” “facilitators and barriers in seeking information regarding self-care;” “social support and belief in engaging in self-care at home;” “self-confidence in engaging in self-care at home;” “efforts to develop self-care strategies;” and “engaging in new healthy behaviors as heart failure patients independently.” Conclusions: Patients become aware of the necessity for self-care upon experiencing discomfort due to symptoms resulting from their heart failure. Family support and the patient's belief system play pivotal roles in initiating self-care practices at home. Nurses should provide support to patients in fostering self-care practices within their homes.

Preoperative examination of inflammatory biomarkers in relation to the prognosis of postoperative complications after heart transplantation

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Semmelweis University Heart transplantation (HTX) is the definitive therapy for end-stage heart failure. Although complications have drastically decreased with modern immunosuppressive therapy, surgical and anesthetic techniques, significant complications such as graft failure, acute rejection or infection must still be expected. The purpose of the study is to examine cytokine pathways linked to inflammation from direct preoperative serum samples, which can serve as prognostic factors in relation to septic events and mortality in the early postoperative period. The study was conducted using the blood samples of 102 patients who underwent HTX. Blood samples were taken from the patients immediately before HTX. The amounts of a total of 32 cytokines and related proteins were determined using LEGENDplex assays. After that, we correlated the biomarker amounts determined in the serum samples with the end points we indicated. In patients undergoing HTX who developed septic events during postoperative intensive care, the preoperative MMP2 serum concentration was significantly higher compared to other patients undergoing HTX (n=23, p=0.04). Independent predictors of mortality in the intensive care unit (n=5) were preoperative MRP8/14 (AUC=0.8), NGAL (AUC=0.75), IGFBP-4 (AUC=0.73), cystatin C (AUC=0.7) and the MMP2 (AUC=0.74) serum concentrations. Patients transplanted from left ventricular mechanical circulatory support (LVAD) (n=11) were examined as a separate group, where early postoperative mortality was significantly higher (n=4, p=0.02), the independent predictor of which was the concentration of IGFBP-4 (p=0.04 , AUC=0.73). Based on our results, it can be said that the differences in the preoperative concentration of certain inflammatory biomarkers that can be measured in the serum show correlations with the postoperative septic events and mortality of patients undergoing HTX.

Long-range gene editing of LMNA

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Hartstichting (Dutch Heart Foundation) Background Mutations in the LMNA gene commonly affect the cardiac muscle tissue, which leads to the development of a severe dilated cardiomyopathy with life-threatening arrhythmias. The lack of response to conventional heart failure therapy in these patients indicates the urgent need for new therapies. Gene editing has the potential to become a curative treatment for these patients by correcting the genetic cause of the disease. Prime editing is a promising new gene editing technology, which uses a prime editing guide RNA (pegRNA) to target a specific genetic locus and creates edits using a reverse-transcriptase enzyme linked to a Cas9-nickase. Purpose Conventional prime-editing technology targets one mutation per pegRNA. However, with more than 600 disease-causing mutations described in LMNA, the feasibility of applying this technology to each mutation is limited. Therefore, we aim to target not a single, but a set of mutations with one single pegRNA. Methods The pegRNAs are optimised by selecting the optimal target regions, improving their stability and 3D structure. The in vitro editing efficiency is assessed using the fluoPEER reporter plasmid, transfected into HEK293T cells. Using flow cytometry, expression of mCherry fluorescent protein is detected following successful editing of the target mutation. Results Flow-cytometry analysis of treated cells revealed an editing efficiency of 12% with a long-range pegRNA targeting a full exon, compared to 15% with a conventional short pegRNA targeting the same mutation &amp;lt;10bp downstream of the Cas9 nick site. This editing efficiency using the same long-range pegRNA was retained at 9% when editing at a distant position &amp;gt;100bp downstream of the nick site. To increase the editing efficiency, we improved the stability of the pegRNAs by the addition of different 3’ structural motifs. This resulted in an increased editing efficiencies of 15% and 17% for nearby and distant mutations, respectively. Conclusion We show that it is possible to edit different mutations within a range of up to 120 bp with a single pegRNA. By optimisations of the pegRNA 3D structure and optimal selection of target locations we aim to further improve the editing efficiency of this system. This work could eventually provide a prime editing therapy able to cure disease in a subset of patients carrying different mutations in the same genetic region. For LMNA-associated diseases this would substantially reduce the number of pegRNAs that have to be developed to cover all mutations, greatly improving the feasibility of prime editing therapy.

Evaluation and Management of Chronic Heart Failure in Children and Adolescents With Congenital Heart Disease: A Scientific Statement From the American Heart Association.

With continued medical and surgical advancements, most children and adolescents with congenital heart disease are expected to survive to adulthood. Chronic heart failure is increasingly being recognized as a major contributor to ongoing morbidity and mortality in this population as it ages, and treatment strategies to prevent and treat heart failure in the pediatric population are needed. In addition to primary myocardial dysfunction, anatomical and pathophysiological abnormalities specific to various congenital heart disease lesions contribute to the development of heart failure and affect potential strategies commonly used to treat adult patients with heart failure. This scientific statement highlights the significant knowledge gaps in understanding the epidemiology, pathophysiology, staging, and outcomes of chronic heart failure in children and adolescents with congenital heart disease not amenable to catheter-based or surgical interventions. Efforts to harmonize the definitions, staging, follow-up, and approach to heart failure in children with congenital heart disease are critical to enable the conduct of rigorous scientific studies to advance our understanding of the actual burden of heart failure in this population and to allow the development of evidence-based heart failure therapies that can improve outcomes for this high-risk cohort.

Physician Perceptions of Medication Prescribing in Heart Failure: A Scoping Review.

The swift uptake of new medications into clinical practice has many benefits; however, slow uptake has been seen previously with other guideline-directed medical therapies (GDMT) in heart failure (HF). Sodium glucose co-transporter 2 inhibitors are a novel therapy in HF proven to be efficacious and will have beneficial clinical outcomes if prescribed. Understanding physician perspectives on prescribing GDMT in HF can help target strategies to bridge the gap between guidelines and practice. The study followed the PRISMA guide for scoping reviews. A search was conducted using EMBASE, Medline, and PubMed databases in April 2024. Studies included were those using qualitative methods to assess physician perspectives towards prescribing any HF medication. Common themes were identified through thematic synthesis following the methods from Cochrane Training and using software MAXQDA Analysis Pro. 708 studies were found in the search, with 23 full studies included. The most pertinent barriers identified were concern for medication adverse effects, unclear role responsibilities between physicians of different specialities, patient co-morbidities, and unwillingness to alter therapies of stable patients. The most identified enablers included awareness of efficacy, influence from colleagues, and the use of multi-media approaches for information dissemination. Perceptions were also found to change over time and vary among prescriber groups. Physicians perceive common barriers and enablers of prescribing GDMT in HF, despite differences in prescriber groups and time periods. The identified barriers and enablers may be targeted to improve implementation of GDMT into clinical practice.

Modified Ross score and echocardiographic score in children with heart failure: a subgroup analysis

Background Over the past two decades, heart failure in children has increased in terms of symptom recognition and prevalence. The initial clinical manifestations of heart failure in children are non-specific. Therefore, diagnosis requires the support of echocardiography. The symptomatic severity of heart failure in children can be classified through a simple scoring system such as Ross score. The duration of heart disease, duration of therapy, and cardiac remodeling status may have clinical and anatomical effects on the disease. Objective To analyze for a possible correlation between modified Ross score and echocardiographic score by subgroup analysis consisting of duration of heart disease, duration of therapy, and cardiac remodeling. Methods This cross-sectional study included children aged 1 month - 18 years with heart failure who sought treatment at Prof.Dr. I.G.N.G Ngoerah Hospital, Denpasar from June 2019 to February 2020. Cardiac remodeling was defined as &gt;20% increase in left ventricle internal end diastolic dimension (LVIDd) compared to normal values, ??based on body surface area. Spearman’s correlation test was used for statistical analysis. Results A total of 30 subjects were analyzed in this study. The median modified Ross score and echocardiography score were 3 points (range 2-11) and 4 (range 2-6), respectively. The median durations of heart disease and preventive heart failure therapy were 2 years (range 7 days-15 years) and 1 year (range 7 days-15 years), respectively. The mean LVIDd was 4.3 (SD 1.4) cm. Twenty-one out of 30 subjects experienced a ? 20% increase of LVIDd from baseline. The modified Ross score and echocardiographic score had no significant correlation (r=0.18; P=0.33). However, the modified Ross score had significant correlations with duration of heart disease (r=-0.632; P&lt;0.001) as well as duration of therapy (r=-0.584; P=0.001). In addition, no correlation was found between echocardiographic score with heart disease and therapy duration (P&gt;0.05). Echocardiography score and remodelling process was significantly correlated (r=0.64; P&lt;0.001). Conclusion There is no correlation between modified Ross score and echocardiographic score. Duration of heart disease and duration of therapy are significantly negatively correlated with modified Ross scores. The remodelling process is positively correlated with echocardiographic score. Further research on acute symptomatic and validated echocardiographic scores are needed.

Iron deficiency in new onset heart failure: association with clinical factors and quality of life.

The prevalence of iron deficiency (ID) in newly diagnosed heart failure (HF) and the progression of ID in patients after initiation of HF therapy are unknown. We aimed to describe the natural trajectory of ID in patients with new onset HF during the first year after HF diagnosis, assessing associations between ID, clinical factors, and quality of life (QoL). A prospective cohort of patients with new onset HF in hospitals or outpatient clinics at five major hospitals in Stockholm, Sweden, during 2015-2018 were analysed with clinical assessment, electrocardiogram, blood samples including iron levels, Minnesota living with heart failure questionnaire (MLHFQ), and echocardiogram at baseline and after 12months. Of 547 patients with new-onset HF, 482 (88%) had complete iron data at baseline. Median age was 70years (interquartile range 61-77) and 311 (65%) were men; 55% of patients had ejection fraction (EF)≤40%, 19% had EF 41-49%, and 26% had HF with preserved EF (HFpEF) [Correction added on 26 June 2024, after first online publication: The 'Mean age was 70 years' has been corrected to 'Median age was 70 years' in this version.]. At baseline, 163 patients (34%) had ID defined as ferritin <100μg/L or ferritin 100-299μg/L and transferrin saturation <20%. After 12months of follow-up, 119 (32%) had ID of the 368 patients who had complete iron data both at baseline and after 12months and did not receive intravenous (i.v.) iron during follow-up. During the first year after HF diagnosis, 19% had persistent ID, 13% developed ID, 11% resolved ID, and 57% never had ID, consequently 24% changed their classification. Anaemia at baseline was the strongest independent predictor of ID 1year after diagnosis [odds ratio (OR) 3.91, 95% confidence interval (CI) 1.88-8.13, P<0.001], followed by HF hospitalization (OR 2.21, 95% CI 1.24-3.95, P<0.01), female sex (OR 2.04, 95% CI 1.25-3.32, P<0.01), HFpEF (OR 1.96, 95% CI 1.13-3.39, P<0.05), and diabetes mellitus (OR 1.92, 95% CI 1.06-3.48, P<0.05). ID was associated with low QoL at baseline (MLHFQ score mean difference 7.4 points, 95% CI 3.1-11.7, P<0.001), but not at follow-up. About one third of patients with new onset HF had ID both at the time of HF diagnosis and after 1year, though a quarter of the patients changed their ID status. Patients with anaemia, HF hospitalization, female gender, HFpEF, or diabetes mellitus at baseline were more likely to have ID after 1year implying that these should be carefully screened for ID to find those in need of i.v. iron treatment.

Accelerated pacing reduces left heart filling pressures: a novel therapy for heart failure with preserved ejection fraction?

Abstract Background The recent MyPACE trial demonstrated significant improvement of quality-of-life, physical activity, and atrial fibrillation (AF) burden with accelerated pacing as compared to the standard 60bpm back-up rate setting in patients with heart failure with preserved ejection fraction (HFpEF) and indication for pacemaker therapy. We hypothesized that a potential working mechanism underlying these improved outcomes lies in the reduction of left heart filling pressures during accelerated pacing, reducing congestion and atrial stretch. Aim To assess the acute effects of accelerated atrial pacing on left heart filling pressures in consecutive AF patients undergoing catheter ablation. Methods Fifty AF patients undergoing catheter ablation were prospectively enrolled for accelerated atrial pacing. As illustrated in Figure 1, pacing was performed proximally in coronary sinus (CS). Pacing rate was increased incrementally from resting heart rate by 10-bpm increments up to Wenckebach rhythm, with 30-sec intervals of pacing on and off for hemodynamic stabilization. Left atrial pressure (LAP) was continuously monitored via a fluid-filled transseptal sheath (SL0 sheath, Abbott). Acute pacing-induced changes in mean LAP and PR-interval were evaluated at each pacing rate and compared between resting heart rate, the patient-specific optimal heart rate (i.e., the rate resulting in the lowest mean LAP), and the maximum pacing rate. Results Atrial pacing acutely decreased mean LAP from 14.8[9.8; 18.4] to 12.8[8.5; 15.8]mmHg (median[IQR], p&amp;lt;0.001) as heart rate increased from 51[47; 61] to 90[70; 100]bpm (p&amp;lt;0.001) (Figure 2, resting versus optimal category). Among the 50 patients included, only 4 did not exhibit a decrease in LAP. Further increasing pacing rate to a maximum of 130[100; 140]bpm resulted in an acute LAP increase to 16.2[12.7; 19.9]mmHg (p&amp;lt;0.001) to values above resting mean LAP. Accelerated pacing induced negative AV dromotropy, i.e., lengthening of the PR-interval from 169[150; 185] to 186[164; 209]ms (p=0.003) and 270[217; 310]ms (p&amp;lt;0.001). Conclusion Our study demonstrated that moderately accelerated atrial pacing reduced mean LAP in AF patients undergoing catheter ablation. While our primary focus was on acute response in AF patients, the reduction in mean LAP during moderate pacing rates may suggest a promising therapeutic approach for managing HFpEF patients. However, caution is warranted as pacing rates beyond the optimal range led to a marked increase in LAP. Additionally, increasing pacing rates were observed to induce varying degrees of AV-node dromotropy, which potentially modulates therapy response.Fig 1. Overview of clinical protocolFig 2. Response to accelerated pacing

Impact of myocardial phenotype on atrioventricular delay optimization at rest and during exercise: insights from a virtual patient study

Abstract Background The usefulness of atrioventricular delay (AVD) optimization in cardiac resynchronization therapy (CRT) for heart failure (HF) patients with left bundle branch block (LBBB) and reduced left ventricular ejection fraction (LVEF) is still debated. Yet, studies have not explored the role of non-electrical myocardial disease substrates in determining optimal AVD settings among patients. Purpose We first hypothesized that acute response to AVD optimization might be modulated by various myocardial disease substrates. Furthermore, we hypothesized that cardiac function is more sensitive to changes in AV coupling during exercise and that this sensitivity is also modulated by underlying myocardial disease substrates. Methods We used the CircAdapt model of the human heart and circulation to simulate different types of LV remodeling that can be found in CRT candidates. First, an LBBB-like pattern of mechanical activation was imposed by delaying LV free wall (LVFW) and interventricular septal (IVS) activation relative to right ventricular free wall activation. Then, two types of LV remodeling were simulated by LV dilation with preserved or impaired myocardial contractility, resulting in LVEF &amp;lt;35%. To investigate the effect of diastolic dysfunction, we increased passive myocardial stiffness of the IVS and LVFW on both substrates with LV remodeling until a mean left atrial pressure (mLAP) of 14 mmHg was reached. CRT was simulated by resynchronizing IVS and LVFW. AVD optimization was conducted by gradually reducing the paced AVD from 220 ms to 40 ms in steps of 20 ms. In each simulation, the optimal paced AVD at rest (cardiac output (CO) and heart rate (HR) of 4.2 L/min and 80 bpm, respectively) was assessed using stroke volume (SV) and mLAP which is used as a measure of LV filling pressure. To investigate the relative effect of these myocardial phenotypes during AVD optimization under exercise, CO and HR were increased step-wise. Results The gain in SV by AVD optimization was larger in the simulations with healthy myocardium than in those with hypo-contractile and stiff myocardium (Figure 1: top-row). However, mLAP was comparably decreased by AVD optimization in healthy and diseased myocardium (Figure 1: bottom row). During exercise, the optimum AVD shifted to shorter values (Figure 2: top-row), and mLAP was much more sensitive to AVD, particularly in the presence of hypo-contractile and stiff myocardium (Figure 2: bottom row). Conclusion Virtual patient simulations show that both myocardial hypocontractility and stiffness dampen the effect of AVD optimization on SV. Furthermore, simulations suggest that patients benefit more from AVD optimization during exercise than during resting conditions. These mechanistic insights may help to gain more benefit from AVD optimization for patients undergoing CRT.AVD optimization at restAVD optimization during exercise

A time-dependent analysis of sacubitril/valsartan and gliflozins benefits in patients receiving cardiac resynchronization therapy

Abstract Background While sacubitril/valsartan (ARNi), gliflozins (or SGLT2i) and cardiac resynchronization therapy (CRT) are firmly recognized as cornerstones of therapy for heart failure with reduced ejection fraction (HFrEF), robust evidence validating the long-term efficacy of their combination remains elusive. The few data suggesting a synergistic advantage of these drugs alongside CRT have not rigorously considered their time-varying administration, leading to potential selection bias, since only patients with longer initial survival could commence these treatments. As a result, the literature to date lacks a comprehensive and persuasive demonstration of the additional survival benefits conferred by ARNi and gliflozins over CRT alone in HFrEF. Purpose To evaluate the impact of ARNi and gliflozins on reducing cardiovascular and overall mortality among HFrEF patients undergoing CRT. Methods Patients with heart failure and an ejection fraction ≤ 35%, who were referred for CRT-D implantation from 2015 to 2023, were retrospectively recruited for the study. These patients were grouped into two cohorts: those not receiving drugs (no drugs group) and those treated with ARNi and/or SGLT2i (ARNi/SGLT2i group). Importantly, ARNi and SGLT2i treatments were considered as time-dependent covariates in order to account for patients who initiated or discontinued therapy during follow-up. Results The cohort included 183 ischemic and non-ischemic HFrEF patients (148 male [80.9 %], 113 ischemic [61.7 %], median [IQR] age 73 [65-80] years). 117 (74 %) patients started ARNi (61, 52.1 %), gliflozins (7, 6 %) or both drugs (49, 41.9 %) and were assigned to ARNi/SGLT2i group. During a median follow-up of 5.67 (CI 95 %, 5 – 6.5) years, 63 (34.4 %) patients died, of whom 47 (74.6 %) died of cardiovascular HF-related death. Specifically, 44 (of whom 35 (79 %) due to HF-related death) died in the no drugs group vs 19 (12 (63 %) due to HF-related death) in ARNi/SGLT2i patients. At univariable analysis (Panel A in the Figure), ARNi and/or SGLT2i treatments reduced all-cause (HR 0.59 [0.34-1.02], p = 0.056) and cardiovascular (HR 0.47 [0.24-0.92], p = 0.029) mortality. However, after multivariable adjustment for key covariates (1-year CRT response, age, atrial fibrillation, baseline LVEF, chronic obstructive pulmonary disease, glomerular filtration rate), the survival benefits of ARNi and SGLT2i use diminished, and the only factor strongly associated with reduced mortality risk remained 1-year positive response to CRT (Panel B). Conclusions Despite their recognized therapeutic benefits, ARNi and SGLT2i have not demonstrated additional survival benefit compared to CRT alone in patients with HFrEF. A 1-year positive response to CRT remains the most significant prognostic factor. Further studies with larger sample sizes and extended follow-up periods are needed to confirm this hypothesis, also evaluating whether the timing of introduction of these medications may impact survival.

#1816 CA 125 as a surrogate marker for plasma volume in patients with cardiorenal syndrome

Abstract Background and Aims Assessing volume status in heart failure (HF) and end-stage chronic kidney disease (CKD) is challenging. Plasma volume expansion is an early step in the pathophysiology of decompensated HF and an independent risk factor for death and HF hospitalization, and should be addressed early. Evaluating plasma volume, especially its variation with diuretic therapy, can be a useful clinical tool for guiding decongestive therapy. There's a growing need for accurate and simple tools to guide clinician decisions on patient volume management. Cancer antigen 125 (CA125), a glycoprotein produced in mesothelial cells in the pericardium, pleura, or peritoneum, is primarily associated with ovarian and gynecological malignancies. Recent studies link CA125 to inflammation and congestion. In acute HF, elevated CA125 is associated with fluid overload indicators like increased central venous and pulmonary wedge pressure. Elevated CA125 in acute HF patients is linked to worse outcomes in death and hospital stay length. Evidence supports CA125-guided therapy in acute HF, but its role in managing chronic volume overload is still uncertain. We aim to assess the relationship between CA125 levels and estimated plasma volume (ePV). Method A retrospective unicentric observational study was conducted between June 2022, and April 17, 2023, at the Renocardiac clinic of a tertiary hospital. Clinical data were extracted from electronic patient records. CKD staging was determined following the Kidney Disease Improving Global Outcomes (KDIGO) classification. ePV was calculated using the Kaplan-Hakim formula. CA125 and ePV were assessed for the same patient in 2 different visits and their variation was calculated. The correlation between CA125 and ePV, as well as CA125 and ePV variation, was evaluated using Spearman's rank correlation coefficient for bivariate analysis, conducted with IBM SPSS®. Results This study comprised 65 patients, totaling 124 hospital visits. The patient demographic was 67.7% male, with a mean age of 76.4 (±12.47) years. In terms of CKD staging, 48.5% were classified as KDIGO 5, 40.6% as KDIGO 4, 9.4% as KDIGO 3, and 1.5% as KDIGO 2. HF etiology distribution included 59% ischemic, 9.8% hypertensive, 6.5% valvular, and 24.5% other causes. The mean ejection fraction was 37.35 (±12.36)% and 19% had preserved ejection fraction; 75% of them were treated with prognostic-modifying medication, including SGLT2 inhibitors. This proportion was lower (19%) in patients with reduced ejection fraction, receiving ACE/angiotensin ± neprilysin inhibitor + mineralocorticoid receptor inhibitor + beta-blocker + SGLT2 inhibitor. During the follow-up period, 13 hospitalizations, 1 major adverse cardiovascular event (MACE), and 5 deaths were recorded. The mean CA125 level was 193.98 (±154.55) U/mL, and patients had a mean ePV of 2.41 (±1.19) L. A significant positive correlation was found between CA125 levels and ePV (r = 0.355, p = 0.000). However, there was no significant correlation between the variation of CA125 and ePV levels between visits (p = 0.535). Conclusion This study focuses on a population with limited implementation of disease-modifying therapy due to advanced CKD, complicating the clinical management of volume status, kidney function, potassium levels, and long-term prognosis in both CKD and HF. CA125 shows potential clinical utility as a marker of congestion, aiding clinicians in assessing volume status by correlating with plasma volume. However, this study found no correlation between CA125 variation and changes in plasma volume. The outpatient nature of the studied population, typically euvolemic, may hinder assessing the relationship between CA125 and ePV changes. Future studies with larger sample sizes are essential to clarify this relationship and potentially identify volume-expanded patients early.

Association of suPAR, ST2, and galectin-3 with eGFR decline and mortality in patients with advanced heart failure with reduced ejection fraction.

Patients with heart failure with reduced ejection fraction (HFrEF) are at risk for chronic kidney disease (CKD). Elevated levels of circulating biomarkers soluble urokinase plasminogen activator receptor (suPAR), galectin-3, soluble suppression of tumorigenicity 2 (ST2), and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) are associated with CKD progression and mortality. The predictive value of these biomarkers in a population with HFrEF and kidney disease is relatively unknown. We sought to determine whether these biomarkers were associated with longitudinal trajectory of estimated glomerular filtration rate (eGFR) in HFrEF and assess their association with mortality using a joint model to account for competing risks of ventricular assist device (VAD) implantation and heart transplantation. We included participants from the Registry Evaluation of Vital Information for Ventricular Assist Devices in Ambulatory Life with repeated eGFR measures over 2 years. Of 309 participants, mean age was 59 years, median eGFR 60 ml/min/1.73 m2, 45 participants died, 33 received VAD, and 25 received orthotopic heart transplantation. Higher baseline serum standardized suPAR (β coefficient = -0.36 √(ml/min/1.73 m2), 95% confidence interval (-0.48 to -0.24), p < 0.001), standardized galectin-3 (-0.14 √(ml/min/1.73 m2) (-0.27 to -0.02), p = 0.02), and log NT-proBNP (-0.23 √(ml/min/1.73 m2) (-0.31 to -0.15), p < 0.001) were associated with eGFR decline. ST2 and log NT-proBNP were associated with mortality. Higher baseline suPAR, galectin-3, and NT-proBNP are associated with eGFR decline in patients with HFrEF. Only ST2 and NT-proBNP are associated with greater mortality after controlling for other factors including change in eGFR. These biomarkers may provide prognostic value for kidney disease progression in HFrEF and inform candidacy for advanced heart failure therapies.

Efficacy of acetazolamide and loop diuretics combinatorial therapy in congestive heart failure: A meta-analysis

Acetazolamide, one of the carbonic anhydrase inhibitors, has been known to improve the efficacy of diuretic therapy in patients with in congestion heart failure. The aim this study was to investigate the effectiveness of acetazolamide when combined with loop diuretics in ameliorating diuresis and natriuresis in congestive heart failure using systematic review and meta-analysis. Randomized controlled trials (RCTs) and cohort studies were searched on PubMed, Scopus, and Embase on March 7, 2023, by using combinations of ‘acetazolamide’, ‘heart failure’ and along with their respective synonyms. The protocol had been registered on PROSPERO (CRD42023409864). The studies must investigate the effect of oral acetazolamide as the add-on to loop diuretic therapy to be included. Successful decongestion, natriuresis, and diuresis were set as the primary outcomes. The quality of the included studies was assessed using the Cochrane risk-of-bias tool for RCTs and Newcastle Ottawa Scale for observational studies. We identified 1176 titles in the initial search, and further reduced to five studies (three RCTs and two cohort studies) after in-depth screening. A total of 625 patients were recruited in the included studies published from 2015 to 2022. Results from meta-analysis revealed that acetazolamide and loop diuretics combination therapy ameliorated natriuresis (n=4; standardized means difference (SMD)=0.65; 95%CI: 0.07–1.24; p=0.03) and diuresis (n=2; SMD=0.29; 95%CI: 0.12–0.46; p=0.0009) when compared to loop diuretics alone. Acetazolamide and loop diuretics combinatorial therapy is efficacious in alleviating congestion in heart failure patients.