Persistent Left Superior Vena Cava: Unanticipated Stumbling Block in Cardiac Resynchronization Therapy.

Persistent left superior vena cava (PLSVC) is a relatively rare anatomical anomaly, with a higher prevalence in those with congenital heart defects. While typically asymptomatic, its presence can complicate certain medical procedures, particularly cardiac interventions, such as the implantation of cardiac resynchronization therapy (CRT) devices, due to acute angulation. In this report, we discuss the challenges posed by the unanticipated presence of PLSVC during CRT device implantation and describe the technique used for lead placement using Judkins Right catheter for support, placing coronary wire, and later placing the left ventricle (LV) lead with the help of buddy wire technique, resulting in successful insertion of all three CRT leads despite the anatomical challenges.

Impact of diabetes mellitus on right ventricular dysfunction and ventricular interdependence in hypertensive patients with heart failure with reduced ejection fraction assessed via 3.0 T cardiac MRI.

BACKGROUND: Hypertension (HTN) and diabetes mellitus (DM) are two common comorbidities of heart failure with reduced ejection fraction (HFrEF), each of which can cause right ventricular (RV) dysfunction. The aim of this study was to investigate the impact of DM on RV dysfunction and ventricular interdependence in hypertensive HFrEF patients via cardiac magnetic resonance imaging (MRI) feature tracking. METHODS: This study included 249 patients with HFrEF: 77 HFrEF controls, 97 with hypertensive HFrEF (HTN-HFrEF [DM-]) and 75 with hypertensive HFrEF and comorbid DM (HTN-HFrEF [DM+]). The cardiac MRI-derived biventricular global radial (GRS), circumferential (GCS) and longitudinal (GLS) peak strains were obtained and compared among the groups. Multivariable linear regression and mediation analyses were used to evaluate the effects of DM and left ventricular (LV) strain on RV strain. RESULTS: The biventricular GLS and GLS of segments 8, 9 and 14 of the interventricular septum (IVS) decreased gradually from the HFrEF control group to the HTN-HFrEF (DM-) group to the HTN-HFrEF (DM+) group (all P < 0.05). Patients with DM had even lower biventricular GCS and IVS strains in all directions in specific segments than did those without DM and the HFrEF controls (all P < 0.05). DM was independently associated with impaired RVGLS and RVGCS (both P < 0.05) in hypertensive HFrEF patients. The difference in RVGLS between the hypertensive HFrEF subgroups was partly mediated by LVGLS [ß = 0.80, 95% CI (0.39-1.31)], and that of RVGCS was partly mediated by LVGCS [ß = 0.28, 95% CI (0.01-0.62)]. CONCLUSIONS: In hypertensive HFrEF patients, comorbid DM may have aggravated RV dysfunction and was an independent determinant of impaired RV strain. RV dysfunction might be directly affected by DM and partially mediated by LV strain through unfavorable ventricular independence.

Automated Identification of Heart Failure With Reduced Ejection Fraction Using Deep Learning-Based Natural Language Processing.

BACKGROUND: The lack of automated tools for measuring care quality limits the implementation of a national program to assess guideline-directed care in heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: The authors aimed to automate the identification of patients with HFrEF at hospital discharge, an opportunity to evaluate and improve the quality of care. METHODS: The authors developed a novel deep-learning language model for identifying patients with HFrEF from discharge summaries of hospitalizations with heart failure at Yale New Haven Hospital during 2015 to 2019. HFrEF was defined by left ventricular ejection fraction <40% on antecedent echocardiography. The authors externally validated the model at Northwestern Medicine, community hospitals of Yale, and the MIMIC-III (Medical Information Mart for Intensive Care III) database. RESULTS: A total of 13,251 notes from 5,392 unique individuals (age 73 ± 14 years, 48% women), including 2,487 patients with HFrEF (46.1%), were used for model development (train/held-out: 70%/30%). The model achieved an area under receiver-operating characteristic curve (AUROC) of 0.97 and area under precision recall curve (AUPRC) of 0.97 in detecting HFrEF on the held-out set. The model had high performance in identifying HFrEF with AUROC = 0.94 and AUPRC = 0.91 on 19,242 notes from Northwestern Medicine, AUROC = 0.95 and AUPRC = 0.96 on 139 manually abstracted notes from Yale community hospitals, and AUROC = 0.91 and AUPRC = 0.92 on 146 manually reviewed notes from MIMIC-III. Model-based predictions of HFrEF corresponded to a net reclassification improvement of 60.2 ± 1.9% compared with diagnosis codes (P < 0.001). CONCLUSIONS: The authors developed a language model that identifies HFrEF from clinical notes with high precision and accuracy, representing a key element in automating quality assessment for individuals with HFrEF.

Guidelines for treating heart failure.

Optimal guideline-directed medical therapy for heart failure with reduced ejection fraction comprises the angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan), an evidence-based beta-blocker (bisoprolol, carvedilol, or sustained-release metoprolol), a mineralocorticoid antagonist (spironolactone or eplerenone), and a sodium-glucose cotransporter-2 inhibitor (dapagliflozin or empagliflozin). Optimal guideline-directed medical therapy for heart failure with preserved ejection fraction comprises a sodium-glucose cotransporter-2 inhibitor with emerging evidence to support the use of a mineralocorticoid antagonist and glucagon-like peptide-1 receptor agonists. This review will summarize the evidence behind the guideline recommendations, the impact of newer trials on management of patients with HF, and strategies for implementation into clinical practice.

Association of depressive symptoms and engagement in physical activity with event-free survival in patients with heart failure.

BACKGROUND: Heart failure (HF) subtype, depressive symptoms, and physical inactivity independently contribute to survival outcomes, but the effect of the interaction of these variables on survival outcomes remains unknown. OBJECTIVES: We aimed to determine whether depressive symptoms and engagement in physical activity differentially interact to predict the combined endpoint of all-cause death or rehospitalization among patients with HF and reduced (HFrEF) or preserved ejection fraction (HFpEF). METHODS: This study was a secondary analysis. The sample was categorized by the presence or absence of depressive symptoms, and engagement or non-engagement in physical activity. Cox proportional hazard modeling was used to predict the combined endpoint of all-cause death or rehospitalization. RESULTS: A total of 1002 patients with HF were included (mean age 64.3 ± 12.7 years; 637 males [64 %]; 844 White [84 %]). Among them, 35.3 % did not engage in physical activity, while 64.7 % engaged in any level of physical activity, and 29.7 % had depressive symptoms. In both subtypes, depressive symptoms were associated with the highest risk of all-cause death or rehospitalization. Among patients with HFrEF, those with depressive symptoms who did not engage in physical activity were associated with a 136 % higher risk of the combined endpoint, while among those with HFpEF, depressive symptoms and engagement in physical activity were associated with a 78 % higher risk. CONCLUSIONS: Depressive symptoms and lack of physical activity predicted the combined endpoint of all-cause death or rehospitalization among patients with HFrEF, while depressive symptoms alone were the strongest predictor among patients with HFpEF.

Cardio-Oncology and Heart Failure: A Scientific Statement from the Heart Failure Society of America.

Heart failure and cancer remain two of the leading causes of morbidity and mortality and the two disease entities are linked in a complex manner. Patients with cancer are at increased risk of cardiovascular complications related to the cancer therapies. The presence of cardiomyopathy or heart failure in a patient with new cancer diagnosis portends a high risk for adverse oncology and cardiovascular outcomes. With the rapid growth of cancer therapies, many of which interfere with cardiovascular homeostasis, heart failure practitioners need to be familiar with prevention, risk stratification, diagnosis, and management strategies in cardio-oncology. This Heart Failure Society of America statement addresses the complexities of heart failure care among patients with active cancer diagnosis and cancer survivors. Risk stratification, monitoring, and management of cardiotoxicity are presented across Stages A through D heart failure, with focused discussion on heart failure preserved ejection fraction and special populations such as survivors of childhood and young adulthood cancers. We provide an overview of the shared risk factors between cancer and heart failure, highlighting heart failure as a form of cardiotoxicity associated with many different cancer therapeutics. Finally, we discuss disparities in the care of patients with cancer and cardiac disease and present a framework for a multidisciplinary team approach and critical collaboration between heart failure, oncology, palliative care, pharmacy, and nursing teams in the management of these complex patients.

Gender-specific risks for incident cancer in patients with different heart failure phenotypes.

BACKGROUND: There is conflicting evidence regarding whether heart failure (HF) increases the risk of developing cancer. OBJECTIVE: This study aimed to assess the association between HF and incident cancer, considering gender differences and HF phenotypes. METHODS: This retrospective study was conducted on data of adult individuals, free of cancer at baseline, from the First Affiliated Hospital of Wenzhou Medical University between January 2009 and February 2023. The patients with HF were categorized as HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). The primary outcome was incident cancer, including obesity-related, tobacco-related, lung, colorectal and breast cancers. RESULTS: Of 33 033 individuals enrolled, 16 722 were diagnosed with HF, including 10 086 (60.3%) with HFpEF and 6636 (39.7%) with HFrEF. During a median follow-up period of 4.6 years (inter-quartile range: 2.6-7.3), incident cancer was diagnosed in 10.5% (1707 patients) of the non-HF group and 15.1% (2533 individuals) of the HF group. After adjusting for potential confounding factors, patients with HF had a 58% increased risk of cancer than those without HF [adjusted hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.48-1.69, P < 0.001]. This risk was consistent across genders (female: adjusted HR 1.95, 95% CI 1.74-2.18, P < 0.001; male: adjusted HR 1.41, 95% CI 1.30-1.54, P < 0.001) and HF phenotypes (HFpEF: adjusted HR 1.69, 95% CI 1.57-1.81, P < 0.001; HFrEF: adjusted HR 1.32, 95% CI 1.20-1.46, P < 0.001). CONCLUSIONS: Both HFpEF and HFrEF are associated with an increased risk of incident cancer. This correlation maintains its validity across genders.

Endoplasmic reticulum stress and expression of nitric oxide synthases in heart failure with preserved and with reduced ejection fraction - pilot study.

BACKGROUND: Unfolded Protein Response (UPR), endoplasmic reticulum (ER) stress, and inducible nitric oxide synthase (iNOS) overexpression have been found to influence heart failure with preserved ejection fraction (HFpEF) pathogenesis. Their importance in heart failure with reduced ejection fraction (HFrEF) is not entirely established; there is little data involving a detailed comparison between HFpEF and HFrEF from this perspective. This pilot study aimed to compare circulating levels of Glucose-regulated protein 78kDa (GRP78) (ER - stress marker) and all NOS isoforms between both HFpEF and HFrEF and to analyze the correlation between these markers and the clinical characteristics of the patients. METHODS: Forty-two patients with HFpEF and thirty-eight with HFrEF were involved in this study. Clinical characteristics and echocardiographic data were obtained. Basic laboratory tests were performed and ELISA tests for iNOS, endothelial NOS (eNOS), neuronal NOS (nNOS), and GRP78. RESULTS: Patients with HFpEF had lower circulating levels of GRP78 and higher iNOS concentrations when compared to HFrEF patients (P = 0.023, P < 0.0001, accordingly). The subgroup of the HFpEF population with eGFR < 60 mL/min/1.73m2 had higher nNOS and eNOS levels than HFpEF patients with normal GFR (P = 0.049, P = 0.035, respectively). In the HFrEF subgroup, patients with coexistent diabetes mellitus had elevated concentrations of nNOS compared to the subpopulation without diabetes mellitus (P = 0.041). There was a positive correlation between eNOS and nNOS concentrations (ρ = 0.86, P < 0.0001). CONCLUSIONS: In HFpEF, there is a more intensified iNOS overexpression, while in HFrEF, ER stress is more prominent.

Ischaemic Cardiomyopathy Secondary to Asymptomatic Coronary Artery Disease: A Case Report.

Ischaemic cardiomyopathy (ICM) represents a common complication of coronary artery disease (CAD). Ischaemia causes ventricular remodelling, leading to an irreversible loss of myocardial tissue and adequate contractility, primarily affecting the left ventricular ejection fraction (LVEF). We present the case of a 46-year-old male known as hypertensive presented to the hospital with a five-week history of progressive exertional dyspnoea, bilateral lower limb oedema subsequently involving his scrotum and penis. He reported reduced oral intake and occasional palpitations but denied chest pain, cough, fever, or haemoptysis. He had no personal history of cardiac disease, recent travels, or recreational drug use. Notably, he consumed approximately 12 units of alcohol weekly and was a non-smoker. On admission, he was treated for new-onset heart failure, and initial investigations showed acute kidney injury, raised troponin, and brain natriuretic peptide (BNP), and chest X-ray showed an enlarged heart size (cardiothoracic ratio (CTR), 0.56) with moderate right pleural effusion. Echocardiography revealed a severely dilated left ventricle with severely impaired systolic function (LVEF 16%), bi-atrial dilatation, borderline dilated right ventricle with impaired systolic function, and moderate tricuspid regurgitation. Cardiac MRI showed that the left ventricle was severely dilated with severely impaired systolic function with nonviable mid to apical inferior and inferoseptal transmural post-ischaemic scar with associated hypokinesia. Ischaemic cardiomyopathy may vary from asymptomatic to severely symptomatic, commonly when symptomatic patients will present with anginal chest pain and dyspnoea on exertion. In contrast, asymptomatic patients can sometimes have up to 80% of transient ischaemic events with no chest pain or associated symptoms. This case underscores the importance of considering asymptomatic coronary artery disease in clinical practice and highlights the need for novel interventions and markers for early ischemia detection.

The Impact of Sacubitril/Valsartan on Heart Failure Patient with Reduced Left Ventricular Ejection Fraction: Single Center Retrospective Study in Saudi Arabia.

Background: Sacubitril/valsartan (S/V) is used in managing heart failure with reduced ejection fraction (HFrEF), reducing morbidity and mortality while improving symptoms and prognosis. This study aims to evaluate the effectiveness of S/V in patients with reduced left ventricular ejection fraction (LVEF) and its safety. Methods:  This retrospective cohort study included adult patients aged ≥18 years diagnosed with HFrEF, receiving S/V, and followed up at a tertiary hospital in Riyadh. Primary outcomes included improvements in LVEF on echocardiography and the number of hospitalizations due to acute decompensated heart failure (ADHF). Secondary outcomes assessed the safety profile of S/V. Multinomial logistic regression analysis was performed with statistical significance set at P < 0.05. . Results: The study included 107 patients: 80 with LVEF < 30% and 27 with LVEF 30-40%. Six-month follow-up, LVEF improvement was categorized into three groups: no improvement, LVEF increased by 1 to <10 points, and LVEF increased by ≥10 points. The LVEF was similar across groups (P = 0.59). Although hospitalizations due to ADHF were not significantly different between groups, they numerically decreased after initiating S/V (P = 0.1). S/V was generally well tolerated. Conclusion: This study suggests no significant benefit from S/V regarding LVEF improvement. It is recommended that heart failure clinics assess and titrate S/V to the maximum tolerated dose.

Imaging Advances in Heart Failure.

This paper delves into the significance of imaging in the diagnosis, aetiology and therapeutic guidance of heart failure, aiming to facilitate early referral and improve patient outcomes. Imaging plays a crucial role not only in assessing left ventricular ejection fraction, but also in characterising the underlying cardiac abnormalities and reaching a specific diagnosis. By providing valuable data on cardiac structure, function and haemodynamics, imaging helps diagnose the condition, evaluate haemodynamic status and, consequently, identify the underlying pathophysiological phenotype, as well as stratifying the risk for outcomes. In this article, we provide a comprehensive exploration of these aspects.

Potential diagnostic value of circulating miRNAs in HFrEF and bioinformatics analysis.

Background: Few studies have compared the performances of those reported miRNAs as biomarkers for heart failure with reduced EF (HFrEF) in a population at high risk. The purpose of this study is to investigate comprehensively the performance of those miRNAs as biomarkers for HFrEF. Methods: By using bioinformatics methods, we also examined these miRNAs' target genes and possible signal transduction pathways. We collected serum samples from patients with HFrEF at Zhongshan Hospital. Receiver operating characteristic (ROC) curves were used to evaluate the accuracy of those miRNAs as biomarkers for HFrEF. miRWALK2.0, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed to predict the target genes and pathways of selected miRNAs. Results: The study included 48 participants, of whom 30 had HFrEF and 18 had hypertension with normal left ventricular ejection fraction (LVEF). MiR-378, miR-195-5p were significantly decreased meanwhile ten miRNAs were remarkably elevated (miR-21-3p, miR-21-5p, miR-106-5p, miR-23a-3p, miR-208a-3p, miR-1-3p, miR-126-5p, miR-133a-3p, miR-133b, miR-223-3p) in the serum of the HFrEF group. Conclusion: The combination of miR 133a-3p, miR 378, miR 1-3p, miR 106b-5p, and miR 133b has excellent diagnostic performance for HFrEF, and there is a throng of mechanisms and pathways by which regulation of these miRNAs may affect the risk of HFrEF.

Looking for the ideal medication for heart failure with reduced ejection fraction: a narrative review.

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.

Progression from cardiomyopathy to heart failure with reduced ejection fraction: A CORIN deficient course.

Cardiomyopathies, encompassing hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), constitute a diverse spectrum of heart muscle diseases that often culminating in heart failure (HF). The inherent molecular heterogeneity of these conditions has implications for prognosis and therapeutic strategies. Publicly available microarray and RNA sequencing (RNA-seq) data sets of HCM (n = 106 from GSE36961) and DCM (n = 18 from GSE135055 and 166 from GSE141910) patients were employed for our analysis. The Non-negative Matrix Factorization (NMF) algorithm was applied to explore the molecular stratification within HCM and DCM, and enrichment analysis was performed to delineate their biological characteristics. By integrating bulk and single-nucleus RNA-seq (snRNA-seq) data, we identified a potential biomarker for HCM progression and cardiac fibrosis, which was subsequently validated using mendelian randomization and in vitro. Our application of NMF identified two distinct molecular clusters. Particularly, a profibrotic, heart failure with reduced ejection fraction (HFrEF)-resembling Cluster 1 emerged, characterized by diminished expression of CORIN and a high degree of fibroblast activation. This cluster also exhibited lower left ventricular ejection fraction (LVEF) and worse prognostic outcomes, establishing the significance of this molecular subclassification. We further found that overexpression of CORIN could mitigate TGFß1-induced expression of col1a1 and α-SMA in neonatal rat cardiac fibroblasts. Our results indicated the heterogeneity of HCM population, and further evidenced the participation of corin in the progression of HCM, DCM and HFrEF. Nevertheless, our study is constrained by the lack of corresponding clinical data and experimental validation of the identified subtypes. Therefore, further studies are warranted to elucidate the downstream pathways of corin and to validate these findings in independent patient cohorts.

Translating the 2021 ESC heart failure guideline recommendations in daily practice: Results from a heart failure survey. A scientific statement of the ESC Council for Cardiology Practice and the Heart Failure Association of the ESC.

AIMS: Real-world data show that guidelines are insufficiently implemented, and particularly guideline-directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines. METHODS AND RESULTS: A 22-question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non-cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin-converting enzyme inhibitors/angiotensin receptor-neprilysin inhibitor (ACEi/ARNi) (91.2%), beta-blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1-3 months by 52%, 3-6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time-to-initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach. CONCLUSION: Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care.

Rapidly Progressive High-Grade Leiomyosarcoma in an Elderly Patient.

An 84-year-old female with a history of hypertension, diabetes, and hypothyroidism initially presented in November 2023, with a rapidly enlarging (19.5 cm) left proximal thigh mass. Biopsy diagnosed high-grade leiomyosarcoma, which doubled in size within two weeks, confirming aggressive biology. In January 2024, the patient, who had been ambulating independently one year prior to her diagnosis, underwent radical resection and femoral neurolysis, and initiated radiotherapy, without receiving neoadjuvant chemotherapy due to cachexia. Three months postoperatively, in April 2024, the patient presented with acute respiratory distress, requiring 4L oxygen, and bilateral lower extremity edema. Imaging revealed numerous bilateral pulmonary metastases and an acute pulmonary embolism in the right inferior segment branch. She was admitted with decompensated heart failure, an ejection fraction of 30-45%, and extensive metastatic leiomyosarcoma. Despite anticoagulation, her status rapidly declined.  This case highlights the challenges of rapidly progressive sarcomas characterized by fulminant growth and early metastatic spread. Earlier treatment with neoadjuvant chemotherapy prior to surgery may have improved outcomes but was precluded by the patient's frailty. After a multidisciplinary discussion, the decision was made to transition to hospice care. This case also underscores the potential for rapid clinical deterioration with metastatic leiomyosarcoma. It highlights the challenges of managing complications from aggressive malignancies, especially in frail patients, where treatment-related toxicities may outweigh the benefits. Careful patient selection for cancer-directed therapies via multidisciplinary input is imperative.

Patiromer for Heart Failure Medication Optimization in Patients With Current or Past Hyperkalemia: DIAMOND Subanalysis.

BACKGROUND: For heart failure with reduced ejection fraction (HFrEF), suboptimal use of renin-angiotensin-aldosterone system inhibitors (RAASis), including mineralocorticoid receptor antagonists (MRAs), due to hyperkalemia, may be improved by potassium binders. OBJECTIVES: This prespecified analysis of the phase 3 DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) trial assessed the effect of patiromer in patients with HFrEF and either current or past hyperkalemia. METHODS: Patients with HFrEF and current or past (within 1 year before enrollment) hyperkalemia (serum potassium [sK+] >5.0 mmol/L) entered a single-blind, run-in phase to optimize RAASis while receiving patiromer. They were subsequently randomized, double-blind, to continue patiromer or change to placebo. RESULTS: Of the 1,038 patients who completed run-in, 354 (83.9%) of 422 with current hyperkalemia and 524 (85.1%) of 616 with past hyperkalemia achieved RAASi optimization and were randomized to treatment. During the double-blind phase, patiromer lowered sK+ levels compared with placebo in both the current and past hyperkalemia subgroups: difference in adjusted mean change from baseline: -0.12 (95% CI: -0.17 to -0.07) and -0.08 (95% CI: -0.12 to -0.05), respectively; Pinteraction = 0.166. Patiromer was more effective than placebo in maintaining MRA at target dose in patients with current vs past hyperkalemia (HR: 0.45 [95% CI: 0.26-0.76] vs HR: 0.85 [95% CI: 0.54-1.32]; Pinteraction = 0.031). Adverse events were similar between subgroups. CONCLUSIONS: The use of patiromer facilitates achieving target doses of RAASis in patients with HFrEF with either current or past hyperkalemia. For those with current hyperkalemia before RAASi optimization, use of patiromer may be more beneficial in helping to maintain sK+ control and achieve MRA target dose. (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure [DIAMOND]; NCT03888066).

Comparison of mouse models of heart failure with reduced ejection fraction.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of death worldwide; thus, therapeutic improvements are needed. In vivo preclinical models are essential to identify molecular drug targets for future therapies. Transverse aortic constriction (TAC) is a well-established model of HFrEF; however, highly experienced personnel are needed for the surgery, and several weeks of follow-up are necessary to develop HFrEF. To this end, we aimed (i) to develop an easy-to-perform mouse model of HFrEF by treating Balb/c mice with angiotensin-II (Ang-II) for 2 weeks by minipump and (ii) to compare its cardiac phenotype and transcriptome to the well-established TAC model of HFrEF in C57BL/6J mice. METHODS: Mortality and gross pathological data, cardiac structural and functional characteristics assessed by echocardiography and immunohistochemistry and differential gene expression obtained by RNA-sequencing and gene-ontology analyses were used to characterize and compare the two models. To achieve statistical comparability between the two models, changes in treatment groups related to the corresponding control were compared (ΔTAC vs. ΔAng-II). RESULTS: Compared with the well-established TAC model, chronic Ang-II treatment of Balb/c mice shares similarities in cardiac systolic functional decline (left ventricular ejection fraction: -57.25 ± 7.17% vs. -43.68 ± 5.31% in ΔTAC vs. ΔAng-II; P = 0.1794) but shows a lesser degree of left ventricular dilation (left ventricular end-systolic volume: 190.81 ± 44.13 vs. 57.37 ± 10.18 mL in ΔTAC vs. ΔAng-II; P = 0.0252) and hypertrophy (cell surface area: 58.44 ± 6.1 vs. 10.24 ± 2.87 µm2 in ΔTAC vs. ΔAng-II; P < 0.001); nevertheless, transcriptomic changes in the two HFrEF models show strong correlation (Spearman's r = 0.727; P < 0.001). In return, Ang-II treatment in Balb/c mice needs significantly less procedural time [38 min, interquartile range (IQR): 31-46 min in TAC vs. 6 min, IQR: 6-7 min in Ang-II; P < 0.001] and surgical expertise, is less of an object for peri-procedural mortality (15.8% in TAC vs. 0% in Ang-II; P = 0.105) and needs significantly shorter follow-up for developing HFrEF. CONCLUSIONS: Here, we demonstrate for the first time that chronic Ang-II treatment of Balb/c mice is also a relevant, reliable but significantly easier-to-perform preclinical model to identify novel pathomechanisms and targets in future HFrEF research.

A prospective randomized controlled study of multi-intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure and reduced ejection fraction (PRIME-HFrEF) trial: Rationale and design.

Background and objective: The use of mesenchymal stem cells for heart failure treatment has gained increasing interest. However, most studies have relied on a single injection approach, with no research yet confirming the effects of multiple administrations. The present trial aims to investigate the safety and efficacy of multi-intravenous infusion of umbilical cord-mesenchymal stem cells (UC-MSCs) in patients with heart failure and reduced ejection fraction (HFrEF). Methods: The PRIME-HFrEF trial is a single-center, prospective, randomized, triple-blinded, placebo-controlled trial of multi-intravenous infusion of UC-MSCs in HFrEF patients. A total of 40 patients meeting the inclusion criteria for HFrEF were enrolled and randomized 1:1 to the MSC group or the placebo group. Patients enrolled will receive intravenous injections of either UC-MSCs or placebo every 6 weeks for three times. Both groups will be followed up for 12 months. The primary safety endpoint is the incidence of serious adverse events. The primary efficacy endpoint is a change in left ventricular ejection fraction (LVEF) measured by left ventricular opacification (LVO) with contrast echocardiography and magnetic resonance imaging (MRI) at 12 months. The secondary endpoints include a composite of the incidence of death and re-hospitalization caused by heart failure at the 12th month, serum NT-proBNP, growth stimulation expressed gene 2 (ST2), and a change of right ventricular structure and function. Conclusions: The PRIME-HFrEF study is designed to shed new light on multiple UC-MSC administration regimens for heart failure treatment.