Heart Failure Medications Research Articles

Approach to Estimating Adherence to Heart Failure Medications Using Linked Electronic Health Record and Pharmacy Data.

Medication non-adherence, which is common in chronic diseases such as heart failure, is often estimated using proportion of days covered (PDC). PDC is typically calculated using medication fill information from pharmacy or insurance claims data, which lack information on when medications are prescribed. Many electronic health records (EHRs) have prescription and pharmacy fill data available, enabling enhanced PDC assessment that can be utilized in routine clinical care. To describe our approach to calculating PDC using linked EHR-pharmacy data and to compare to PDC calculated using pharmacy-only data for patients with heart failure. We performed a retrospective cohort study of adult patients with heart failure who were prescribed guideline-directed medical therapy (GDMT) and seen in a large health system. Using linked EHR-pharmacy data, we estimated medication adherence by PDC as the percent of days in which a patient possessed GDMT based on medication pharmacy fills over the number of days the prescription order was active. We also calculated PDC using pharmacy-only data, calculated as medications possessed over days with continued medication fills. We compared these two approaches for days observed and PDC using a paired t-test. Among 33,212 patients with heart failure who were prescribed GDMT, 2226 (6.7%) never filled their medications, making them unavailable in the assessment of PDC using pharmacy-only data (n = 30,995). Linked EHR-pharmacy data had slightly longer days observed for PDC assessment (164.7 vs. 163.4days; p < 0.001) and lower PDC (78.5 vs. 90.6, p < 0.001) as compared to assessment using pharmacy-only data. Linked EHR-pharmacy data can be used to identify patients who never fill their prescriptions. Estimating adherence using linked EHR-pharmacy data resulted in a lower mean PDC as compared to estimates using pharmacy-only data.

Effects of Tirzepatide on the Clinical Trajectory of Patients with Heart Failure, a Preserved Ejection Fraction, and Obesity.

Patients with heart failure, a preserved ejection fraction (HFpEF), and obesity have significant disability and suffer frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical endpoints, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden in these patients. 731 patients in class II-IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m2 were randomized(double-blind) to tirzepatide(titrated up to 15mg subcutaneously weekly)(n=364) or placebo(n=367), added to background therapy for a median of 104 weeks (Q1=66, Q3=126 weeks). tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score(KCCQ-CSS). The current expanded analysis included sensitivity analyses of the primary endpoints, 6-minute walk distance(6MWD), EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health(PGIS), NYHA class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in KCCQ-CSS and 6MWD. Patients were aged 65.2±10.7, 53.8%(n=393) were female; BMI 38.2±6.7kg/m2, KCCQ-CSS 53.5±18.5, 6MWD 302.8±81.7meters, and 53%(n=388) had a worsening heart failure event in the prior 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time-to-first-event (hazard ratios 0.41-0.67). At 52 weeks, tirzepatide increased KCCQ-CSS 6.9 points (95%CI, 3.3, 10.6, P<0.001), 6MWD 18.3 meters (95%CI, 9.9, 26.7, P<0.001) and EQ-5D-5L 0.06 (95%CI, 0.03, 0.09, P<0.001). The tirzepatide group shifted to a more favorable PGIS (proportional odds ratio 1.99 (95%CI, 1.44, 2.76) and NYHA class (proportional odds ratio 2.26 (95%CI, 1.54, 3.31), both P<0.001 and required less heart failure medications (P=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio 1.63, 95%CI, 1.17, 2.28;P=0.004). Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance and well-being; and reduced symptoms and medication burden in patients with HFpEF and obesity.

Case Ascertainment in Pediatric Heart Failure Using International Classification of Disease Clinical Modification (ICD-CM) Codes.

Most epidemiological studies in pediatric heart failure (HF) use administrative database sources, defining patient cohorts by presence of a single HF ICD code. However, the ability of ICD codes to identify true HF patients is unknown in pediatrics.Here we describe the accuracy of HF ICD-10-CM code search algorithms, in identifying pediatric patients with HF from electronic data sources. Based on the adult HF literature, search algorithms were designed to incorporate HF ICD codes, imaging, and medications. Sensitivity, specificity, positive and negative predictive value and accuracy of the algorithms were tested among children in an advanced HF clinic ("Clinic cohort"). Top-performing algorithms were then tested in a large-scale regional electronic data warehouse (EDW), 01/2017 to 01/2020, generating the "EDW Cohort". False positive cases were identified and characterized by chart review. Within the Clinic Cohort, 78/378 patients (21%) had gold standard HF diagnoses. A search algorithm with one HF ICD coded visit was more sensitive but less specific than > 1 HF ICD coded visit, (sensitivity 94% and specificity 89% versus 69% and 97%, respectively). Correspondingly, > 1 ICD coded visit had a higher PPV than one ICD coded visit; 84% vs. 69%. Accuracy was similar (90% vs 91%). Presence of 1 HF ICD code combined with HF medication had high sensitivity, specificity, PPV, NPV and accuracy, all higher than the single ICD code algorithm. The "1 HF coded visit + any medication" algorithm resulted in highest accuracy (93%). Top-performing algorithms were tested in the EDW: the algorithm with > 1 HF ICD coded visit, and the algorithm with one HF ICD coded visit combined with HF medication. In the EDW Cohort, 133/248 (53.6%) patients had gold standard HF diagnoses though 115/248 (46.3%) were false positive cases; 41% of those had pulmonary over-circulation from congenital heart disease. Excluding children < 30days old and those with a history of an isolated VSD repair, complete AVSD repair, or PDA closure further reduced the proportion of false positives to 50/248 (20%). A search algorithm using a single HF ICD code can have acceptable sensitivity, specificity, PPV, NPV and accuracy in identifying children with HF from within electronic medical records. Similar to adult HF literature, specificity improves by including HF medication. When applied to large data sources, however, the search algorithms result in a high proportion of patients with pulmonary overcirculation related to congenital heart disease. To narrow the population to those with myocardial dysfunction, case identification may require use of ICD codes with linked of administrative, surgical, and/or imaging databases.

Abstract 4113961: Contemporary Guideline Directed Medical Therapy in Heart Failure in Clinical Practice - Results from the EMPACE Study

Background: Guideline directed medical therapy (GDMT) for heart failure (HF) evolves, incorporating newer therapies such as SGLT2i within recommendations for HFmrEF and HFpEF. Understanding the contemporary profile of real-world HF patients, in combination with real-world utilization of GDMT, is important for informing GDMT implementation and quality improvement strategies. The EMPACE study aims to improve our comprehension of HF GDMT utilization in real-world settings during post-2020 . Objectives: To describe baseline demographic and clinical characteristics, including baseline treatments, of patients with HF hospitalization (HHF). Methods: This non-interventional, retrospective cohort study used patient data standardized to the OMOP Common Data Model from the Optum Market Clarity, an integrated EHR and Claims database in the U.S. The study period spanned from Jun-2020 to Oct-2023. Adult patients with a primary diagnosis of HF during hospitalization were stratified by HF phenotypes (HFrEF, HFmrEF, HFpEF) based on left ventricular ejection fraction (EF). Results: A total of 30,762 patients with HHF were included (74% HFrEF, 4% HFmrEF, and 22% HFpEF). The mean age was 70.1 years, 60% were male, mean BMI was 30.6 kg/m 2 , and mean eGFR was 58.7 mL/min/1.73m 2 . Of them, 72% had a history of HF and 43% has been previously hospitalized for HF in the past 1 year. The prevalence of baseline comorbidities was as follows: hypertension (90%), coronary artery disease (54%), chronic kidney disease (38%), atrial fibrillation (40%), peripheral artery disease (9%), stroke history (9%), and end-stage renal disease (1%). Medication prior to HF hospitalization are described in the figure 1. Overall, prior comorbidities and HF medication use in the last 365 days prior to HHF were similar between all HHF patients and the HFrEF, HFmrEF, and HFpEF phenotypes, except for the lower use of MRA and ARNI in HFmrEF, and HFpEF patients. Conclusion: This study showed a high comorbidity burden and a low utilization of many GDMT prior to hospitalization, especially for novel GDMT (ARNI and SGLT2i) and in HFmrEF and HFpEF. Despite many medications having a varying strength of guideline recommendation depending on EF, absolute differences in rates of GDMT utilization were relatively small across the EF phenotypes. Across the spectrum of EF, further efforts are needed to improve use of GDMT and reduce the missed opportunities for GDMT implementation that are occurring prior to HHF.

Abstract 4134957: Survival and Cardiac Recovery in Pediatric Dilated Cardiomyopathy: A Long-term Cohort Study of Risk Factors, Prognosis, and Health Outcomes Followed into Adulthood

Background: Dilated cardiomyopathy (DCM) is the most common cause of pediatric heart failure (HF), but there is limited literature on its long-term prognosis and treatment outcomes. We examined risk factors for long-term morbidity and mortality and outcomes of care in childhood-onset DCM. Methods: Electronic medical records from a tertiary care pediatric hospital (SickKids, Toronto, Canada) were used to retrospectively follow children ages 0–18 years with DCM from January 1, 2001 to July 1, 2017. Provincial healthcare administrative data was used to monitor outcomes recorded outside of SickKids, following patients during the same time period and into adulthood (age &gt;18 years) until August 31, 2023. We compared DCM cases, with or without echocardiographic recovery (LVEDD z score &lt; 2 and LVEF ≥ 55%), and controls matched on sex, age, and urban/rural residence on a range of health and health service outcomes. Primary outcomes included all-cause mortality, heart transplant (HT), and inpatient admission for HF. Among cases, Cox proportional hazards regression with backwards selection was used to identify demographic, disease, and treatment characteristics associated with each primary outcome, with candidate variables selected based on univariate analysis and clinical judgment. Results: We studied 156 patients with DCM and 780 controls for a median of 14.8 years. Median age at the end of follow-up was 16.2 years. Compared with controls, DCM cases had higher rates of all-cause death, HT, and HF admission (all P &lt;0.001), as well as chronic kidney disease ( P &lt;0.001) and diabetes ( P =0.002). Compared to cases with recovered DCM (n=53), non-recovered cases had higher rates of death, HT, and HF admission (all P &lt;0.001). On multivariable analysis, beta blockers were associated with reduced mortality risk (HR 0.343, 95% CI 0.162–0.727). Using any HF medication (HR 0.205, 95% CI 0.102–0.412) and living in an urban versus a rural area (HR 0.166, 95% CI 0.048–0.573) decreased HT risk. Idiopathic (HR 4.16, 95% CI 1.42–12.2) or sarcomeric mutation-related (HR 9.86, 95% CI 2.30–42.3) DCM were associated with higher HT risk than myocarditis-related DCM. Conclusions: While childhood DCM is associated with long-term adverse health and increased health care utilization, patients who recover have improved morbidity and mortality. Treatment (e.g. medication or access to urban specialist care) was associated with lower mortality and HT risk in DCM.

Abstract 4134772: Optimizing Heart Failure with Preserved Ejection Fraction Management: Quality Review of SGTL2 Inhibitor Use

Heart failure with preserved ejection fraction (HFpEF) remains a diagnostic challenge despite a 50% incidence of HF admissions. H2FPEF tool is a validated scoring system that estimates HFpEF probability with a sensitivity of 69% and positive predictive value of 85%. Despite clinical research interest and therapeutic advances in HFpEF, implementation of therapies remain inconsistent. Currently ACC/AHA guidelines classify sodium-glucose cotransporter 2 inhibitors (SGLT2i) use a 2A recommendation with benefits for reducing hospital admissions. We assess the utilization of current guidelines. An observational retrospective analysis was performed of patients &gt;18 years with a left ventricular ejection fraction of &gt;50% seen in cardiology clinic with an ICD.10 code of diastolic heart failure from January 2022 to 2024 at a large tertiary hospital. Electronic records were reviewed for patient demographics, documentation of heart failure diagnosis, medication list and echocardiogram parameters. Primary outcome was HF related hospitalization. The study screened 79 patients, 51% females and 49% males. 20.2% of the patients were on SGLT2i, a quarter of which were female. Of those on SGLT2i, 56% were on diuretics, 81% had H2FpEF score &gt; 5, 56% had diabetes, and 19% had a HF hospitalization. SGLT2i was stopped in 1 patient due to cost. Of the (63) 79.8% of patients not on SGLT2I, 65% were on diuretics, 90% had H2FPEF score &gt; 5, 23% had diabetes and 32% had a HF hospitalization. 43% were males, with an average age of 71 for males and 62 for females. Ten patients had documented reasons for not being on SGLT2i including CKD, dialysis, yeast infection and denied insurance coverage. Unadjusted effect measures for HF hospitalization (HR 0.59, RRR 40.9%, OR 0.496; p 0.134). As guidelines are readily investigated and updated by expert consensus groups, evaluating practice patterns is key. Unlike other cardiac medications, SGLT2is are primarily initiated by cardiologists and recognizing barriers can identify generalizability of current guidelines. Our data looked at both objective and clinical endpoints for HFPEF diagnosis. Interestingly, women were less often started on SGLT2i and coverage was not a frequent cause for not using SGLT2i. Our quality metric analysis shows a potential protective effect of HF readmission with SGLT2i use in a highly symptomatic cohort, and suggests future directives need to focus on broadening educational reach among cardiologists.

Abstract 4136009: Adherence and Persistence to Guideline-Directed Medical Therapy in Patients with Heart Failure: A Systematic Review and Meta-Analysis

Introduction: Since individual adherence/persistence studies for heart failure (HF) guideline-directed medical therapy (GDMT) have mainly focused on single classes or had limited sample sizes, providing inconclusive estimates, a comprehensive analysis is needed to understand the magnitude of the problem. Hypothesis: Adherence and persistence to HF GDMT are suboptimal and are associated with increased risks of HF admission and mortality. Aims: To generate estimates of real-world HF medication adherence and persistence and associated clinical outcomes. Methods: We conducted a systematic review and meta-analysis, searching PubMed, EMBASE, and CINAHL for observational studies on adherence and persistence in HF GDMT from inception to 9/25/23. We evaluated bias using the Newcastle-Ottawa Scale. Primary outcomes were adherence and persistence rates using a restricted maximum-likelihood model. Adherence was summarized as the mean proportion of days covered (PDC) and medication possession ratio (MPR), proportion of patients with good adherence (PDC/MPR≥80%), and persistence. Secondary outcomes were all-cause mortality and HF readmission with summary hazard ratios (HRs) and 95% confidence intervals (CI) estimated. Heterogeneity and publication bias were assessed using Cochran’s Q, I squared statistics, funnel plots, and Egger's tests, while subgroup analyses explored variations across studies. Results: The 48 studies included comprised 1,614,985 patients (mean age 71; 57% men). The overall mean PDC/MPR was 76%, with good adherence of 54%, and persistence rates of 60%. Renin-angiotensin-aldosterone system inhibitors had the highest mean PDC/MPR of 78%, good adherence of 56%, and persistence of 64%, while mineralocorticoid receptor antagonists (MRAs) had the lowest at 71%, 47%, and 49% respectively. Nonadherence/nonpersistence to GDMT was associated with a higher rate of mortality (HR 1.27 [95% CI 1.19–1.35]) and HF admission (HR 1.25 [95% CI 1.14-1.37]). Conclusions: Suboptimal adherence/persistence to HF GDMT is common, with only half of patients showing good adherence. Given the association with worse clinical outcomes, clinicians should prioritize identifying barriers to and addressing nonadherence/nonpersistence to HF GDMT, particularly with MRAs.

Abstract 4120515: Impact of 2022 AHA/ACC/HFSA Heart Failure Guideline Value Statement Publication on Medicare Drug Coverage Policies

Background: Patients with heart failure (HF) often have difficulty obtaining life-saving medications due to coverage barriers, such as prior authorizations (PA) and high out of pocket (OOP) costs. To promote better insurance coverage of high value therapies, the AHA/ACC/HFSA added Value Statements to HF guidelines to inform policymakers about medication cost effectiveness. We assessed whether these guidelines influenced Medicare drug coverage policies for two life-saving, costly HF medications: angiotensin receptor neprilysin inhibitors (ARNI – guideline “high value”) and sodium glucose cotransporter 2 inhibitors (SGLT2i – guideline “intermediate value”). Methods: We performed an observational study of Medicare drug plans from 4/2020-4/2023 to assess for changes in ARNI and SGLT2i coverage after Value Statement publication (4/2022), and subsequent Medicare plan online update (10/2022). The primary outcome was any barrier to drug coverage (PA, tier ≥ 3 OOP cost-sharing, step therapy, or no coverage). Analysis utilized interrupted time series and difference-in-difference (DiD) approaches. DiD analyses used direct oral anticoagulants as a control due to similar cost and utilization as ARNI and SGLT2i, but with no Value Statement. Results: Among 7,396 Medicare drug plans, 94.3%-97.4% had coverage barriers to ARNI and 93.2%-96.6% to SGLT2i. The majority of barriers were due to tier ≥ 3 OOP cost-sharing requirements (ARNI: 94.3%-95.8%; SGLT2i: 93.2%-95.6%). Coverage barriers remained stable in 4/2022, and declined slightly in 10/2022 (Figure). In DiD analyses, the presence of a Value Statement was associated with a ~1 percentage point decline in coverage barriers for ARNI and SGLT2i. Conclusion: Coverage barriers to ARNI and SGLT2i were common and did not change much in response to Value Statements in HF Guidelines. Increased consideration for Value Statements by Medicare policy-makers is needed to meaningfully improve access to high value therapies.

Examining the clinical role and educational preparation of heart failure nurses across Europe. A survey of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) and the Association of Cardiovascular Nursing and Allied Professions (ACNAP) of the ESC.

To describe the clinical practice and educational preparation of heart failure (HF) nurses across Europe and determine the key differences between countries. A survey tool was developed, in English, by the Heart Failure Association Patient Care committee of the European Society of Cardiology (ESC). It was translated into eight languages, before electronically disseminated by nurse ambassadors, presidents of HF national societies and through social media. A total of 837 nurses involved in the daily care of patients with HF from 15 countries completed the survey. Most nurses, 78% (n = 395) worked within a hospital outpatient setting, and 51% (n = 431) had access to a specialized HF multidisciplinary team. Nurses performed a range of activities including patient education to promote self-care, virtual and in-person symptom monitoring. A third had more than 5-year experience in cardiac care and 22% (n = 182) prescribed HF medications. There was a significant correlation between HF nurses that prescribed HF medications and access to a specialist multidisciplinary team (p = 0.04). A small number of nurses, mainly from Belgium, supported invasive monitoring (n = 68, 8%) with 14% (n = 120) of mostly Danish nurses supporting exercise programmes. The majority of nurses surveyed were committed to further academic professional development, with 41% (n = 343) having completed a HF course. The role of the HF nurse varies across Europe, however involvement in patient education, symptom monitoring and follow-up remain core to their practice. In specific activities including the prescribing of HF medications and involvement in invasive monitoring, practice has advanced with collaboration in the multidisciplinary team. Consequently, harmonization of education, training and career pathways are required to standardize HF care aligned with expert guidelines across Europe.

Association Between Coexisting Constipation and Heart Failure Readmission in Patients With Heart Failure - A Nationwide Database Study.

Constipation often coexists with heart failure (HF) and can cause increased blood pressure variability, which may increase the risk of repeated HF admissions. However, large-scale contemporary data regarding the prognostic effect of constipation in patients with HF are lacking. We retrospectively identified 556,792 patients admitted for HF for the first time and discharged alive in the fiscal years 2016-2021 using the Japanese Diagnosis Procedure Combination database. Constipation was defined as continued use of laxatives after discharge. We examined the association between constipation and 1-year HF readmission. The prevalence of constipation was 22.0% (n=122,670), which remained stable over the 6 years. Patients with constipation were older (82.7±10.1 vs. 79.3±12.8 years), more often female (53.5% vs. 48.0%), and received medications for HF more frequently at discharge compared with those without constipation. In the multivariable Cox proportional hazards model, constipation was significantly associated with a higher incidence of 1-year HF readmission (24.0% vs. 18.6%; adjusted hazard ratio [HR] 1.08; 95% confidence interval [CI] 1.06-1.10). This result was consistent with the result from the Fine-Gray model accounting for competing risk of death (subdistribution HR 1.08; 95% CI 1.06-1.09). Constipation was associated with a higher risk of HF readmission after the first episode of HF hospitalization. Given the detrimental effect of constipation, further efforts are warranted to decrease constipation-related risk in patients with HF.

Advancing Efficacy Prediction for EHR-based Emulated Trials in Repurposing Heart Failure Therapies.

The High mortality rates associated with heart failure (HF) have propelled the strategy of drug repurposing, which seeks new therapeutic uses for existing, approved drugs to enhance the management of HF symptoms effectively. An emerging trend focuses on utilizing real-world data, like EHR, to mimic randomized controlled trials (RCTs) for evaluating treatment outcomes through what are known as emulated trials (ET). Nonetheless, the intricacies inherent in EHR data-comprising detailed patient histories in databases, the omission of certain biomarkers or specific diagnostic tests, and partial records of symptoms-introduce notable discrepancies between EHR data and the stringent standards of RCTs. This gap poses a substantial challenge in conducting an ET to accurately predict treatment efficacy. The objective of this research is to predict the efficacy of drugs repurposed for HF in randomized trials by leveraging EHR in ET. We proposed an ET framework to predict drug efficacy, integrating target prediction based on biomedical databases with statistical analysis using EHR data. Specifically, we developed a novel target prediction model that learns low-dimensional representations of drug molecules, protein sequences, and diverse biomedical associations from a knowledge graph. Additionally, we crafted strategies to improve the prediction by considering the interactions between HF drugs and biological factors in the context of HF prognostic markers. Our validation of the drug-target prediction model against the BETA benchmark demonstrated superior performance, with an average AUCROC of 97.7%, PRAUC of 97.4%, F1 score of 93.1%, and a General Score of 96.1%, surpassing existing baseline algorithms. Further analysis of our ET framework on identifying 17 repurposed drugs-derived from 266 phase 3 HF RCTs-using data from 59,000 patients at the Mayo Clinic highlighted the framework's remarkable predictive accuracy. This analysis took into account various factors such as biological variables (e.g., gender, age, ethnicity), HF medications (e.g., ACE inhibitors, Beta-blockers, ARBs, Loop Diuretics), types of HF (HFpEF and HFrEF), confounders, and prognostic markers (e.g., NT-proBNP, bUn, creatinine, and hemoglobin). The ET framework significantly improved the accuracy compared to the baseline efficacy analysis that utilized EHR data. Notably, the best results were improved in AUC-ROC from 75.71% to 93.57% and in PRAUC from 78.66% to 90.34%, compared to the baseline models. Our study presents an ET framework that significantly enhances drug efficacy emulation by integrating EHR-based analysis with target prediction. We demonstrated substantial success in predicting the efficacy of 17 HF drugs repurposed for phase 3 RCTs, showcasing the framework's potential in advancing HF treatment strategies.

Mitochondrial Reactive Oxygen Species Dysregulation in Heart Failure with Preserved Ejection Fraction: A Fraction of the Whole.

Heart failure with preserved ejection fraction (HFpEF) is a multifarious syndrome, accounting for over half of heart failure (HF) patients receiving clinical treatment. The prevalence of HFpEF is rapidly increasing in the coming decades as the global population ages. It is becoming clearer that HFpEF has a lot of different causes, which makes it challenging to find effective treatments. Currently, there are no proven treatments for people with deteriorating HF or HFpEF. Although the pathophysiologic foundations of HFpEF are complex, excessive reactive oxygen species (ROS) generation and increased oxidative stress caused by mitochondrial dysfunction seem to play a critical role in the pathogenesis of HFpEF. Emerging evidence from animal models and human myocardial tissues from failed hearts shows that mitochondrial aberrations cause a marked increase in mitochondrial ROS (mtROS) production and oxidative stress. Furthermore, studies have reported that common HF medications like beta blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists indirectly reduce the production of mtROS. Despite the harmful effects of ROS on cardiac remodeling, maintaining mitochondrial homeostasis and cardiac functions requires small amounts of ROS. In this review, we will provide an overview and discussion of the recent findings on mtROS production, its threshold for imbalance, and the subsequent dysfunction that leads to related cardiac and systemic phenotypes in the context of HFpEF. We will also focus on newly discovered cellular and molecular mechanisms underlying ROS dysregulation, current therapeutic options, and future perspectives for treating HFpEF by targeting mtROS and the associated signal molecules.

Unveiling the prognostic journey: renal function trajectories in 'de novo' heart failure with reduced ejection fraction - insights from a cohort study and their impact on patient outcomes

Abstract Background HFrEF poses significant clinical challenges globally. Renal dysfunction frequently coexists with HF, exacerbating prognosis. However, the dynamic trajectory of renal function in 'de novo' HFrEF patients and its prognostic implications remain understudied. Methods We conducted a prospective cohort study involving 370 'de novo' HFrEF patients. Renal function was initially assessed upon admission and re-evaluated at the end of the titration period. The CKD-EPI formula was used for renal function assessment. Patients were followed up for a median of 15 months. Statistical analyses were performed to evaluate predictors of adverse outcomes. Results Baseline renal function significantly influenced outcomes, with eGFR &amp;lt; 45 ml/min associated with higher mortality and heart failure readmissions. Among patients with available renal function data at discharge (n=354), 87 (24.6%) had eGFR &amp;lt; 45 ml/min, while 267 (72.2%) ≥ 45 ml/min. Patients with eGFR &amp;lt; 45 ml/min exhibited older age, higher prevalence of comorbidities, lower haemoglobin levels, and higher creatinine and NT-proBNP levels, both at admission and discharge. Furthermore, they were less likely to receive certain heart failure medications at discharge. During follow-up, 46 deaths (13.0%) and 105 events of combined all-cause death and readmission due to heart failure (29.6%) occurred. Patients with eGFR ≥ 45 ml/min exhibited a lower overall mortality (HR: 0.29, p &amp;lt; 0.001) and all-cause death and heart failure readmissions (HR: 0.32, p &amp;lt; 0.001) both in univariate and multivariate analysis (HR: 0.63, p = 0.028 for mortality; HR: 0.53, p = 0.038 for combined endpoint). See Figure 1. Among patients with available renal function data at follow-up (n=304), 240 (78.9%) had eGFR ≥ 45 ml/min (stabilization or improvement), and 64 (21.1%) had eGFR &amp;lt; 45 ml/min (deterioration or previously &amp;lt; 45 ml/min). Patients with eGFR &amp;lt; 45 ml/min at follow-up exhibited older age, lower BMI, higher prevalence of comorbidities, lower haemoglobin levels, and higher NTproBNP levels at admission and discharge. They were also less likely to receive certain crucial heart failure medications at discharge and follow-up (Table 1). During follow-up, 31 deaths (10.1%) and 87 events of combined death and readmission due to heart failure (38.6%) occurred. In univariate analysis, patients with eGFR ≥ 45 ml/min exhibited a lower overall mortality (HR: 0.27, p &amp;lt; 0.001) and admissions (HR: 0.30, p &amp;lt; 0.001), which remained significant in multivariate analysis (HR: 0.43, p = 0.048 for mortality; HR: 46, p = 0.014 for admissions). See Figure 1. Conclusion Our findings underscore the importance of integrated heart-kidney care in 'de novo' HFrEF patients. Continuous monitoring of renal function and interventions to prevent deterioration are crucial for optimizing outcomes. Further research is needed to validate these findings and explore targeted therapeutic strategies for renal protection in HFrEF.

Long-term follow-up of the TRED-HF trial

Abstract Background The TRED-HF trial (1) found that 44% of patients with recovered dilated cardiomyopathy (DCM) relapsed in the short term after withdrawal of medical therapy. The longer-term risk of relapse is uncertain. Purpose This follow-up aims to investigate the longer-term risk of relapse in patients with recovered DCM and any possible predictive factors. Methods TRED-HF trial participants were followed until May 2023. The primary outcome was DCM relapse defined as &amp;gt;10% reduction in left ventricular (LV) ejection fraction to &amp;lt;50%, doubling in N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) to &amp;gt;400ng/L, or clinical recurrence of heart failure (HF). Therapy intensity for HF was calculated using QUAD scores. The incidence of relapse was calculated using Kaplan-Meier estimates. Predictors of relapse were investigated using Cox proportional hazard modelling. Results For all fifty-one patients, median follow-up from enrolment was 6 (IQR: 6-7) years. Overall, thirty-three patients (65%) relapsed with an estimated 5-year relapse rate of 61% (95% CI 45-73). Twenty patients relapsed during the randomised trial, nine of whom had a recurrent relapse during follow-up (Figure 1). Thirteen patients relapsed for the first time after completion of the trial; of those, one patient did not have therapy withdrawn during the trial, 8 had restarted low intensity HF therapy and 4 patients stayed on no therapy. Five patients stayed off HF therapy and did not relapse. The overall mean intensity of HF therapy was lower after the trial compared to enrolment (mean difference in QUAD score -6 [-8 to -4]; p&amp;lt;0.001). A mean reduction in medication intensity was also seen at the point of relapse during the trial and during follow-up (Figure 2). Of relapses during follow-up, seven had identifiable triggers (arrhythmia (n=4), pregnancy (n=1), hypertension (n=1), infection (n=1)). Patients taking more HF medications at baseline or with higher baseline NT-pro-BNP were more likely to relapse. Corrected atrial fibrillation was associated with reduced future risk of relapse. Conclusions In patients with recovered DCM, the risk of relapse after therapy withdrawal increased with longer follow-up. Lower doses of HF medications and recurrent external triggers contributed to relapse. Few patients who stopped medications had sustained remission. Recovery of DCM after correction of AF was associated with a low risk of relapse provided atrial fibrillation did not recur.

Up-titration of Guideline Directed Medical Therapy (GDMT) and the occurrence of side effects in Heart Failure with reduced Ejection Fraction (HFrEF)

Abstract Background The ESC Guidelines recommend early, full-dose use of heart failure (HF) medications to enhance survival, but real-world application often faces delays and inconsistencies. Clinicians often fear side effects during up-titration to the recommended target dose (TD), i.e. hypotension, bradycardia, renal impairment, and hyperkalemia (HK). The dependency of side effects during dose escalation from the severity of HF remains unclear. Purpose This study aimed to evaluate the relationship between the occurrence of side effects during up-titration of HF medication and HF severity reflected by N-terminal pro B-type natriuretic peptide (NT-proBNP). Methods 425 patients with HFrEF and a complete data set of patient characteristics, medications and laboratory values at baseline (BL), 2 months (2M), and 6 months (6M) were included from our outpatient HF unit's prospective registry. Significant side effects were defined as: systolic blood pressure (SBP) &amp;lt;90mmHg, heart rate (HR) &amp;lt;50 beats per minute (bpm), potassium (K) &amp;gt;5.0mmol/l or K &amp;gt;5,5mmol/l and estimated glomerular filtration rate (eGFR) &amp;lt;30ml/min/1.73m2. Patients were categorized into three risk groups based on their NT-proBNP levels, i.e. low-risk with NT-proBNP &amp;lt;1000pg/ml, medium-risk with NT-proBNP 1000-2000pg/ml or high-risk with NT-proBNP &amp;gt;2000pg/ml. The occurrence of side effects was recorded and the development compared among the HF risk groups. Results Figure 1 shows up-titration of HF medication. Mean daily dosages of betablockers (BB), mineralocorticoid receptor antagonists (MRA) and renin-angiotensin-system inhibitors (RASi) increased significantly during follow-up (BL vs 2M and BL vs 6M, p&amp;lt;0.001 for all). The majority of patients received ≥50% of the recommended TDs at 6M (89% for BB, 83% for MRA, 88% for RASi and 91% for total mean TDs ≥50%), and the achieved daily dosages at 6M were largely comparable across the HF risk groups at 6M, except for RASi (p=0.030). Figure 2 depicts the side effects. Side effects developed almost exclusively at short-term within 2M except for lower SBP (Figure 2A). Newly developed side effects occurring after up-titration (2B) were even more rare and predominantly occurred within the highest NT-proBNP group. The occurrence of hypotension and bradycardia was infrequent and comparable within the HF risk groups. Renal dysfunction (at 6M p=0,041) and HK occurred predominantly in higher risk patients (HK at 2M p=0,001 and at 6M p&amp;lt;0,001). Conclusions Up-titration of HF medications is highly feasible, particularly in low- and medium-risk patients. Despite rare side effects such as hyperkalemia and renal impairment, up-titration remains unimpeded, especially in patients with NT-proBNP levels below 2000pg/ml. These findings emphasize the safety of up-titration in HF.

Use and associations with mortality/morbidity of guideline-directed medical therapy use in heart failure with improved ejection fraction: a PS-matched analysis from the swedish heart failure registry

Abstract Background Guideline-directed medical therapy reduces mortality/morbidity in heart failure (HF) with reduced ejection fraction (EF). However, evidence about its use and prognostic role once EF has improved is limited. Purpose To assess use and associations with mortality/morbidity of renin-angiotensin system inhibitors (RASi), angiotensin-receptor neprilysin inhibitors (ARNi), beta-blockers (BBL), and mineralocorticoid receptor antagonists (MRA) in patients with HF and improved EF (HFimpEF). Methods We analyzed patients with HFimpEF, defined as a first recorded EF &amp;lt;40% and a subsequent EF ≥40%, registered in the Swedish HF registry between 2004 and 2021. Index date was the SwedeHF registration reporting the second (i.e. improved) EF assessment. To reduce the bias related to the initial recommendation for MRA limited to more severe HF (NYHA III-IV), the assessment of MRA was restricted to patients with index date 2016 or later, when Swedish guidelines on HF included a recommendation for MRA in patients with NYHA class II–IV. The association between treatment use and the composite outcome cardiovascular mortality (CVM)/HF hospitalization (HHF) (with censoring &amp;gt;3 years) was assessed by Cox proportional hazard models in a 2:1 propensity score-matched cohort. Propensity scores for treatment use were calculated by a logistic regression model including 38 variables, achieving a standardized mean difference &amp;lt;0.1 for all evaluated variables. Since matching reduces the sample size and may limit generalizability, a Cox proportional hazard model was fitted in the overall cohort adjusting, rather than matching, for the propensity score (Overall HR). Results Of 4700 patients with HFimpEF (mean age 68±12 yrs, 70% male), 94%, 95%, and 50% received RASi/ARNi, BBL, and MRA, respectively. Regardless of the specific treatment, non-users had lower BMI, education level and use of other HF medications, but older age, higher EF at improvement, higher NT-proBNP, and more likely peripheral artery disease, anemia, and valvular disease. In the matched cohorts, RASi/ARNi use was associated with a statistically significant lower risk of CVM/HHF [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.53–0.95] (Figure). There was no statistically significant association between CVM/HHF and beta-blockers (HR 0.75, (95% CI 0.53-1.08), and MRA (HR 1.16, 95% CI 0.90-1.49). These results were consistent after adjustment for the propensity score in the overall cohort (Figure). Conclusion In patients with HFimpEF use of GDMT was high. Treatment with RASi/ARNi was associated with lower morbidity and mortality, whereas no statistically significant association was observed with beta-blockers which might be explained by limited statistical power.Composite outcome.

Long-term outcomes in women with a history of peripartum cardiomyopathy

Abstract Background Peripartum cardiomyopathy (PPCM) remains an important cause of cardiac-related maternal morbidity and mortality in previously healthy young women. Data on the long-term clinical course of PPCM are sparse. In this study, we report the long-term outcomes in patients with PPCM. Methods and Results Long-term follow-up (median 9.6, min 5, and max 24 years) was available in 72 women with PPCM followed in a cardio-obstetrics clinic. Five-year follow-up data were available for 19 PPCM patients, 10-year follow-up data for 24 PPCM patients, and more than 15 years of follow-up data for 24 PPCM patients. Seven patients were lost to cardiac follow-up but are known to be alive. The mean age at diagnosis was 35 ± 7 years, and 85% were Caucasian. The mean parity was 2.2 ± 1.3, and gravidity was 2.7 ± 1.7. Twin pregnancies were reported in 13% of cases. Pre-eclampsia was present in 25% of the patients and the development of hypertension in the long-term was documented in 18%. The mean LVEF was 34.5 ± 9.9% at diagnosis. One-year LVEF data were available in 72 patients: 54 patients (75%) experienced LV recovery (LVEF≥ 50%). After 1 year, the mean LVEF was 53.4± 8.2%. Among patients remained with LV&amp;lt;50% at one year (n=10) no LV function recovery was reported at long-term follow-up. At a median follow-up of 9.6 years (n=66) mean LVEF was 52.1±10.4%, nine patients had a reduction in LVEF (&amp;lt;50%) function in the long-term follow-up with a mean LVEF of 46.1± 2.1%. Out of 72 PPCM patients, 3 patients developed arrhythmia, in one woman coronary artery disease occurred and 7 underwent pacemaker implantation. Almost half of patients (n=65) remained with long term treatment of b-blockers, 38% received medications for hypertension or heart failure. No cases of myocardial infarctions, cardiovascular death, or heart transplantations were reported. Two women died during follow-up: one with normal LVEF died from breast cancer, and another patient with reduced LVEF and severe diabetes. The cause of her death remained unclear. During follow-up, 30 women had ≥ 1 subsequent pregnancy (SSP), and there was no reduction in their mean LVEF before SSP 57.0 ± 5.4% and at long-term follow-up was 59.6± 1.3% (p=ns). Conclusion Our study demonstrates favorable long-term outcomes with high and stable recovery rates with low mortality rates, and no impact of subsequent pregnancies on the clinical course of the condition. Nevertheless, persisting or new diagnosis of hypertension and use of cardiovascular medications were noted in the long term follow up.

Cardiac sympathetic innervation, assessed with 123I-MIBG SPECT, predicts left ventricular function improvement in patients with newly diagnosed dilated cardiomyopathy

Abstract Introduction Beta-blockers (BB) are commonly prescribed medications for heart failure (HF) due to their ability to counteract the increased sympathetic nervous system (SNS) activity seen in HF, resulting in downregulation and desensitization of β-receptors. In patients with dilated cardiomyopathy (DCM), the introduction of BB therapy can lead to left ventricular ejection fraction (LVEF) improvement in 30-50% of cases. Single-photon emission computed tomography (SPECT) with 123I-meta-iodobenzylguanidine (MIBG) is a useful tool for assessing cardiac SNS activity. Healthy individuals typically exhibit high SPECT-MIBG uptake and low washout rate (WR) due to normal β-receptor levels and low norepinephrine (NE) levels, respectively (Fig 1A). While better SPECT-MIBG results have been associated with LVEF improvement in the general HF population, less data is available for DCM patients. Purpose This study aimed to evaluate the predictive value of MIBG-SPECT for LVEF improvement in newly diagnosed DCM patients. Methods Twenty-one DCM patients (mean age 47 ± 10 years, 90% male, baseline LVEF 29.5 ± 8.7%, left ventricular end-diastolic volume (LVEDV) 114 ± 36 ml/m2) with stable HF symptoms (NYHA class 1.8 ± 0.6) and newly diagnosed DCM underwent baseline MIBG-SPECT and echocardiography. HF therapy was initiated and up-titrated, and echocardiography was repeated at 6 months. Semi-quantitative parameters from MIBG-SPECT, including the MIBG uptake ratio from the heart and mediastinum (H/M) at 15 minutes (-15) and 4 hours (-4), as well as the WR [WR = (H/M-15 - H/M-4) / H/M-15], were evaluated. Patients were stratified based on median WR - 8.79 (IQR 5.17-12.90). Results After 6-months of HF therapy up-titration, 18 patients improved LVEF, and the mean LVEF increase was 7.7 ± 10.4%. Although, patients with WR &amp;gt; median did not differ in terms of baseline LVEF (30.2 ± 7.0 vs. 27.7 ± 9.6, p=0.52), they had worse LVEF at 6 months (32.0 ± 11.0 vs. 40.6 ± 9.2%, p=0.04). Moreover, WR at baseline strongly correlated with 6-month LVEF (R=-0.51, p=0.01) and was a significant predictor of 6-month LVEF (β=-0.55 ± 0.19, p=0.009). Moreover, WR could successfully predict LVEF improvement ≥ 10% (OR 1.27 [95%CI 1.01-1.61], p=0.03; AUC 0.82 [95%CI 0.63-0.99], p&amp;lt;0.001) with a cut-off point of 8.0 (sensitivity 88%, specificity 77%) (Fig 1B). Conclusion Most DCM patients demonstrated LVEF improvement during 6 months of HF therapy up-titration. Baseline WR from MIBG-SPECT was found to be a reliable predictor of significant LVEF improvement in this patient population.Fig1.A-SPECT-MIBG results. B-ROC curve.

Low clinical utility of global longitudinal strain in a real-world breast cancer population

Abstract Background The 2022 European Society of Cardiology (ESC) Cardio-Oncology guidelines recommend the use of global longitudinal strain (GLS) to detect mild asymptomatic cancer therapy related cardiac dysfunction (ma-CTRCD). However, it remains unknown how to best manage these patients in order to prevent clinically significant CTRCD. Purpose To assess the course and outcomes of breast cancer patients meeting criteria for ma-CTRCD. Methods Echocardiograms and medical records were assessed for breast cancer patients receiving trastuzumab or an anthracycline, who underwent serial echocardiographic monitoring, including routine GLS. CTRCD was defined as an absolute decline in LVEF of &amp;gt;10% to &amp;lt;50%. ma-CTRCD was defined as a relative decline in average GLS of &amp;gt;15%, in the absence of significant LVEF decline. Normal was defined as no significant change in LVEF or GLS during cancer therapy. Clinical and echocardiographic course post ma-CTRCD detection was assessed. Baseline risk factors were compared between the three groups. Results 878 echocardiograms from 258 patients were analysed. GLS analysis was available in 76% of echocardiograms. CTRCD occurred in 23 (9%) and ma-CTRCD in 63 (24%). Only eight ma-CTRCD patients had management altered (cancer therapy withheld/ceased in three and heart failure medication commenced in six). Only two ma-CTRCD patients subsequently developed CTRCD, and GLS improved in 74%. Compared to the normal group (172, 67%), at baseline the ma-CTRCD group had higher average GLS (-21.8 vs -19.4, p&amp;lt;0.0001) and less borderline/abnormal average GLS (4% vs 36%, p&amp;lt;0.004). Conclusion Isolated declines in GLS are common and may have low clinical utility in preventing CTRCD. The findings support ESC guideline recommendations that cancer therapy should not be withheld in these patients. Those with higher baseline GLS may be more prone to clinically insignificant declines in GLS during cancer therapy.

Discordance between symptomatic response and changes in cardiac structure and function one year after transcatheter aortic valve implantation

Abstract Background Symptomatic improvement is one of the main goals of transcatheter aortic valve implantation (TAVI) in patients with severe symptomatic aortic stenosis. We hypothesized that the degree of symptomatic response after TAVI is associated with improvement in cardiac structure and function after TAVI. Purpose We aimed to evaluate 1) the change in symptomatic burden measured by New York Heart Association (NYHA) and Canadian Cardiovascular Society (CCS) functional class after TAVI, 2) the change in echocardiographic structural and functional parameters after TAVI, and 3) the association of symptomatic response with echocardiographic response as well as long-term survival. Methods In patients undergoing TAVI, we assessed New York Heart Association (NYHA) and Canadian Cardiovascular Society (CCS) functional class at 12 months. Symptomatic response was defined as NYHA/CCS class I or ≥ 1 improvement in NYHA/CCS class compared to baseline at 12 months. Echocardiographic images at baseline and 6-18 months post-TAVI were analysed using an automated, validated, deep-learning workflow. Logistic regression was used to assess association between change in echocardiographic parameters and symptomatic change at 12 months. The association of symptomatic response and echocardiographic changes in the first 12 months after TAVI with survival beyond 12 months, was evaluated by landmark analysis using Kaplan-Meier analysis. Results Among 868 TAVI patients (median age 80 years, 53% female), the majority (74%) had NYHA/CCS class III at baseline and 77% of patients experienced improvement in symptoms at 12 months post-TAVI (Figure 1). Patients without an improvement in symptoms more often had COPD, atrial fibrillation and more heart failure medications compared to responders. Left ventricular systolic function did not show improvement compared to baseline, whereas a modest improvement in left atrial volume index, left ventricular mass index, E/A ratio, E/e’ ratio, mean e’ and tricuspid regurgitation peak jet velocity was observed. Symptomatic response was not associated with echocardiographic response. Beyond 12 months, patients with symptomatic improvement had lower mortality than those without symptomatic improvement (1.5 vs. 2.4 per 10 patient years; p = .001), whereas changes in echocardiographic parameters were not associated with subsequent mortality (Figure 2). Conclusion Patients undergoing TAVI for symptomatic severe aortic stenosis, showed substantial symptomatic improvement at one year after the procedure, whereas only a modest improvement in echocardiographic parameters was observed. Improvement in symptoms was not associated with improvement in echocardiographic measures of cardiac structure and function. Symptomatic improvement, but not improvement in cardiac structure and function at 12 months, was a strong predictor of subsequent survival.Change in NYHA/CCS class after TAVISymptoms and echo versus mortality