Progression Of Heart Failure Research Articles

Analysis and Prediction of Risk Factors for Heart Failure

Abstract. Heart failure is a grave and progressive illness. It is associated with multiple risk factors such as age and other possible factors. Accurately identifying and quantifying these risk factors is critical to developing personalized prevention and treatment strategies. However, it is difficult for common patients to predict heart failure without the professional diagnosis of doctors, and relying on human resources to predict heart failure is more subjective. This study proposes a method to evaluate and predict the factors related to heart failure based on multiple body indicators by using random forest algorithm. The random forest prediction model was applied to assess the correlation between multiple medical indicators such as creatinine phosphokinase (CPK), serum creatinine (SCR), ejection fraction (EF), age and heart failure. CPK was found to be the most associated with heart failure. In addition, increasing follow-up period can also effectively monitor heart failure progression in patients. In this high dimension prediction problem, the prediction effect of random forest is better, and the overall accuracy is higher. The approach used in this research is important for forecasting the risk of heart failure, enhancing the survival rates of patients, and alleviating the burden on healthcare systems.

Abstract 4115947: Empagliflozin Inhibits the Mobilization of CCR2+ Monocyte-Derived Macrophages by Reducing CCL2 Expression in Fibroblasts and Slows the Progression of Heart Failure After Pressure Overload.

Background: The positive effects of sodium glucose co-transporter-2 (SGLT2) inhibitors on reducing cardiovascular mortality and hospitalizations due to heart failure have been well established. Although numerous theories propose explanations for the cardioprotective actions of SGLT2 inhibitors, these hypotheses primarily rely on initial findings and require further validation. Studies have shown that immune cells, particularly macrophages marked by C-C chemokine receptor type 2 (CCR2), contribute to the progression of heart failure by infiltrating the myocardium and inducing detrimental structural changes following myocardial infarction or pressure overload. Purpose: This study aims to investigate whether SGLT2 inhibitors can mitigate heart damage by inhibiting the migration of CCR2+ monocyte-derived macrophages. Methods: In this experiment, male B6 mice were subjected to transverse aortic constriction (TAC) to induce heart failure. Two weeks post-TAC, with heart function confirmed as equal across all groups by echocardiography, one group began receiving daily oral doses of empagliflozin, while another served as the control. At four weeks post-TAC, cardiac function was reassessed. The animals were then euthanized, and their hearts were analyzed using flow cytometry, staining, and qPCR to evaluate heart failure and the involvement of immune cells. Additionally, isolated cardiac fibroblasts were subjected to cyclic stretching to mimic post-TAC mechanical stress. Results: Treatment with empagliflozin resulted in improved cardiac function and reduced congestion in the heart and lungs, indicating alleviation of heart failure. The treatment notably decreased myocardial fibrosis, evident from Picrosirius-red staining and reduced expression of fibrosis-related mRNA. Importantly, empagliflozin specifically reduced the number of CCR2-positive macrophages in the heart, without affecting other types of immune cells. In cardiac fibroblasts that underwent cyclic stretching, empagliflozin pre-treatment diminished the expression of C-C motif chemokine ligand 2 (CCL2), the ligand for CCR2. Conclusion: Empagliflozin’s ability to suppress CCL2 expression in fibroblasts and curtail the recruitment of CCR2+ macrophages may represent a potential strategy to decelerate heart failure progression. These findings advance our understanding of the cardioprotective mechanisms of SGLT2 inhibitors and propose novel therapeutic avenues for heart failure management.

Abstract 4136813: Redox Serum Proteomics Of Left Ventricular Assist Device Unloaded Human Heart

Heart failure (HF) is a global epidemic claiming millions of lives worldwide. Unloading the heart of end-stage HF patients via left ventricular assist devices (LVADs) is used not only as a bridge to transplantation but also as a bridge to recovery in certain selected patients. To date, assessment of patients’ recovery from HF is based on clinical and symptomatic evaluation. The use of non-invasive biomarkers that monitor the remodeling/reverse remodeling associated with HF progression/recovery is still lacking. In this study we applied mass spectrometry-based quantitative redox proteomics to identify serum biomarkers to monitor both the progression of HF and its recovery after LVAD treatment. A fingerprint of reversed behavior at the protein and at the oxidized Cys peptide level has been discovered when comparing HF and LVAD patients. HDL proteins related to lipid metabolism were decreased in HF samples and increased in LVAD patients. In addition, a number of inflammatory proteins showed a decrease in LVAD samples and an increase in HF samples. In particular APOA4, C7, F2 or SAA2 discriminated between HF and LVAD patients. A pool of peptides containing specific oxidized Cys residues showed an inverse relationship in HF as opposed to LVAD samples. Oxidized Cys-containing peptides derived from Albumin, IGK and IGG1 discriminated HF from LVAD samples. Discriminatory sensitivity and specificity were enhanced by using a combination of the proteins APOA4, C7, F2 and the above-mentioned peptide derived from Albumin. Responders and non-responders could also be separated by proteins such as APOA4, and Cys-oxidized peptides, such as the ones derived from Albumin or IGK mentioned above. This is the first study to apply redox proteomics to explore the protein profile of the LVAD unloaded human heart. These data suggest that HDL plays an important role in LVAD recovery and that a specific group of peptides is associated with the recovery process; the mechanisms involved need further study. Our data could have important implications to the management of patients in the LVAD recovery program and could serve to identify new therapeutic targets.

Abstract 4135289: Renal Blood Perfusion is Closely Related to Right Ventricular Volume Overload in Congestive Heart Failure

Background: Cardiorenal syndrome (CRS) involves a bidirectional relationship where dysfunction in one organ exacerbates the other. A key factor in this interaction is the impact of right ventricular (RV) volume overload on renal blood flow, which is vital for the progression and management of heart failure (HF). Objective: This study aims to explore and quantify the relationship between right ventricular volume overload, i.e, echocardiographic assessments of right ventricular diameter (RVD), and the time-to-peak (TTP) of renal blood flow in patients with HF measured by 99mTc-DTPA renal scintigraphy. Methods: This single-center study included 304 stable, ambulatory HF patients admitted between October 2017 and August 2022. HF was diagnosed based on the 2016 ESC guidelines. Echocardiographic parameters, including RVD, and TTP of renal blood flow measured by 99mTc-DTPA renal scintigraphy, were collected. Statistical analysis was conducted using SPSS and R software, with Spearman correlation analysis used to assess the relationship between echocardiographic parameters and TTP. Results: The study showed there was a significant correlation between RVD and TTP (rs=0.535, P <0.001), indicating that RV volume overload is closely related to impaired renal perfusion. The median TTP among the study population was 27.25 seconds (IQR: 21-39 seconds). Corrected for body surface area (BSA), RVD was found to be significantly higher in patients with heart failure with reduced ejection fraction (HFrEF) compared to heart failure with preserved ejection fraction (HFpEF) and heart failure with mid-range ejection fraction (HFmrEF) (HFrEF: 20.62 mm/m 2 , HFmrEF: 18.72 mm/m 2 , HFpEF: 18.09 mm/m 2 ; p < 0.001). Furthermore, right atrial diameter (RAD) corrected for BSA (RAD/BSA) demonstrated the strongest correlation with TTP in the HFrEF subgroup (rs=0.602, p<0.001). Conclusions: Our findings highlight the significant impact of right ventricular volume overload on renal perfusion, providing valuable insights into the pathophysiology of CRS. These results suggest that therapeutic strategies aimed at reducing RV overload could enhance renal perfusion and improve overall outcomes in HF patients.

Abstract 4114198: Humanin Level is Inversely Correlated with NT-proBNP Level and Mortality in Heart Failure with Reduced Ejection Fraction

Background: Mitochondrial dysfunction contributes to heart failure (HF) progression via diminished energy supply, release of reactive oxygen species, and increased cell death. However, there has yet to be clinically relevant biomarkers that address mitochondrial-mediated cardiac injury in patients. Humanin (HN) is a mitochondria-derived peptide that protects cells through the interference of apoptosis and reduction of oxidative stress. The objectives of our study were to measure circulating plasma HN levels in patients with HF with reduced ejection fraction and describe the relationship of HN to validated, clinically relevant measures of HF. Methods: We conducted a prospective cohort study. To be included in the study, patients must have: 1) left ventricular ejection fraction <40%, 2) high risk of future clinical instability, 3) medication and device treatment according to guidelines, and 4) stable medical therapy for at least 30 days prior to screening. Plasma HN levels were measured at time of study enrollment by an enzyme-linked immunoassay. Statistical analyses were performed to evaluate the relationships between HN levels and demographic variables, quantitative measures of HF, and clinical outcomes. Results: 54 HF patients were included in the study. Age and sex were not significantly associated with HN level. There was a significant difference in mean HN level by race with highest HN level seen in Caucasians and the lowest HN level seen in Hispanics (1310 pg/ml vs. 630 pg/ml, p=0.012). There was a significant inverse correlation between NT-proBNP level and HN level (r=-0.46, p <0.001). After adjusting for race, higher NT-proBNP level, as both a continuous and categorical variable, was significantly associated with lower HN level. Furthermore, HN level was significantly lower in patients who died within 6 months compared to those who did not (520.7 pg/ml vs. 1146.9 pg/ml, p=0.013). After adjusting for race, lower HN level was significantly associated with increased odds of 6-month mortality (OR=0.784, 95% CI 0.620-0.943, p=0.018). Conclusions: To the best of our knowledge, this is the first study to describe plasma HN levels in HF patients. Its significant correlation with mortality and NT-proBNP level supports a potential role for HN as a novel prognostic biomarker in HF with reduced ejection fraction.

Abstract 4134298: Dipeptidyl Peptidase 4 Promotes Pressure Overload-Induced Heart Failure through enhancing Antigen Presentation

Background: Antigen presentation to CD4+ T cells plays a critical role in heart failure (HF). Dipeptidyl peptidase 4 (DPP4) has been shown to promote the activation of T lymphocytes. This study aims to investigate the role of DPP4 in antigen presentation in pressure overload-induced HF. Methods: To examine the role of DPP4 in antigen presentation during HF, we tested the recruitment and function of dendritic cells (DCs) in transverse aortic constriction (TAC)-induced HF mice. To further investigate, we generated DPP4 knockout mice and induced bone marrow-derived dendritic cells (BMDCs) in vitro. BMDCs were then adoptively transferred into OT-II mice, whose DCs require specific exogenous ovalbumin loading to activate CD4+ T cells. RNA-Seq analysis was performed to elucidate the mechanisms by which DPP4 affects the function of DCs. Results: We observed an increased quantity of DCs in the hearts and mediastinal lymph nodes of TAC mice, accompanied by elevated expression of DPP4. These DCs exhibited enhanced antigen-presenting abilities, resulting in increased activation of CD4+ T cells. DPP4 knockout suppressed DC maturation and attenuated their antigen-presenting capabilities. We found that OT-II mice subjected to TAC showed preserved cardiac function compared to wild-type (WT) mice. However, OT-II mice that received adoptive transfer of DPP4+/+ BMDCs exhibited worse cardiac function compared to those receiving DPP4-/- BMDCs, indicating that DPP4 in DCs contributes to HF progression. RNA-Seq analysis indicated that DPP4 in DCs influenced the T cell receptor signaling pathway and T cell differentiation. Mechanistically, DPP4 was found to inhibit the E3 ubiquitin ligase MARCH1 from binding to MHCII, thereby stabilizing MHCII through preventing its ubiquitin-dependent degradation in DCs. Conclusion: This study elucidates the significance of DPP4 in enhancing antigen presentation during heart failure. We propose that DPP4 represents a potential therapeutic target for heart failure.

Causal correlations between inflammatory proteins and heart failure: A two-sample Mendelian randomization analysis.

Inflammation plays a critical role in both the development and progression of heart failure (HF), which is a leading cause of morbidity and mortality worldwide. However, the causality between specific inflammation-related proteins and HF risk remains unclear. This study aims to investigate the genetically supported causality between inflammatory proteins and HF using a two-sample Mendelian randomization (MR) analysis. We utilized genome-wide association study (GWAS) data of 91 inflammation-related proteins as exposures from the SCALLOP Consortium (14,824 participants), alongside outcome GWAS summary statistics from FinnGen (29,218 cases/381,838 controls) and HERMES (47,309 cases/930,014 controls) for HF, to conduct a two-sample MR analysis. For each inflammatory protein, instrumental variables (IVs) were chosen following the three foundational assumptions of the MR analysis, requiring a minimum of three qualifying single nucleotide polymorphisms (SNPs) each with a P<5e-8. Associations between inflammatory proteins and HF were assessed through inverse-variance weighted (IVW), MR-Egger regression, weighted median and weighted mode analysis. The reliability and validity of the results were evaluated by examining heterogeneity, horizontal pleiotropy, leave-one-out analysis, meta-analysis and reverse MR analysis. Heterogeneity refers to the variation in results across different genetic variants. Horizontal pleiotropy occurs when a genetic variant influences multiple traits through different biological pathways. Addressing both heterogeneity and horizontal pleiotropy is crucial for ensuring the reliability and interpretability of MR results. Our analysis identified associations between three inflammatory proteins and HF risk. Matrix metalloproteinase-1 (MMP-1) (OR, 1.09; 95% CI, 1.00-1.18; P=0.04) and TNF-beta (OR, 1.05; 95% CI, 1.01-1.09; P=0.01) were positively associated with HF risk in FinnGen. In contrast, urokinase-type plasminogen activator (uPA) was inversely associated with HF risk in both FinnGen (OR, 0.85; 95% CI, 0.78-0.92; P=3.27e-5) and HERMES (OR, 0.93; 95% CI, 0.87-0.99; P=0.03). No evidence of heterogeneity and horizontal pleiotropy was observed in the MR analysis, indicating the robustness of our findings. A meta-analysis further supported this association, indicating a reduced risk (OR, 0.89; 95% CI, 0.81-0.98; P=0.02). No reverse causality was found between HF and these three inflammatory proteins (P>0.05 for all). This study provides genetically supported evidence of the causal association of specific inflammatory proteins with HF risk. The positive association of MMP-1 and TNF-beta with HF suggests their roles in disease pathogenesis, whereas the inverse association of the uPA indicates its potential protective effect. Our findings highlight the potential of targeting specific inflammatory pathways as a therapeutic strategy for HF.

Exploring the therapeutic mechanisms of heart failure with Chinese herbal medicine: a focus on miRNA-mediated regulation

Heart failure (HF) is a clinical condition caused by abnormalities in the heart’s structure or function, primarily manifested as diminished ability of the heart to pump blood, which leads to compensatory activation of neurohormones and increased left ventricular filling pressure. HF is one of the fastest-growing cardiovascular diseases globally in terms of incidence and mortality, negatively impacting patients’ quality of life and imposing significant medical and economic burdens. Despite advancements in the treatment of HF, hospitalization and mortality remain rates high. In China, Chinese herbal medicine (CHM) has historically played a prominent role in addressing HF, with significant proven efficacy. MicroRNA (miRNA) exerts a pivotal regulatory influence on the maintenance of regular cardiac activity and the progression of HF. MiRNAs, a category of single-stranded RNA molecules, are characterized by their inability to code for proteins. They regulate gene expression by binding to the 3′-untranslated region (3′-UTR) of target mRNAs, thereby influencing the onset and progression of various diseases. Abnormal expression of specific miRNAs is closely associated with HF pathological processes, such as cardiomyocyte apoptosis, myocardial fibrosis, and cardiac hypertrophy. This abnormal expression can influence the pathological progression of HF through the regulation of miRNA expression. This article reviews the regulatory role of miRNAs in HF pathology discusses how CHM compounds and their active ingredients can ameliorate HF pathology through the regulation of miRNA expression. In conclusion, miRNAs represent promising therapeutic targets for HF, and CHM provides a novel strategy for treatment through the regulation of miRNA expression. Future studies must delve deeper into the precise mechanisms by which CHM modulates miRNAs and fully explore its potential for clinical application in HF treatment.

Neuroimmune cross-talk in heart failure.

Heart failure (HF) is characterized by autonomic nervous system (ANS) imbalance and low-grade chronic inflammation. The bidirectional relationship between the ANS and immune system (IS) is named "neuroimmune cross-talk" (NICT), and is based on common signaling molecules, receptors, and pathways. NICT may be altered in HF, and neuroinflammation seems to be a main driver of HF progression. In HF, heightened sympathetic nerve activity triggers inflammatory cascades that lead to cardiomyocyte death and myocardial interstitial fibrosis. Concurrently, parasympathetic withdrawal may impair the cholinergic anti-inflammatory pathway, with a less effective immune response to infections or inflammatory events. Additionally, microglial activation and inflammatory molecules contribute to autonomic imbalance by acting on central nuclei and peripheral visceral feedbacks, which in turn promote adverse cardiac remodeling, HF decompensation, and potentially life-threatening arrhythmias. Therefore, neuroinflammation has been identified as a potential target for treatment. Pharmacological antagonism of the neurohormonal system remains the cornerstone of chronic HF therapy. While some drugs used in HF management may have additional benefits due to their anti-inflammatory properties, clinical trials targeting inflammation in patients with HF have so far produced inconclusive results. Nevertheless, considering the pathophysiological relevance of NICT, its modulation seems an appealing strategy to optimize HF management. Current research is therefore investigating novel pharmacological targets for anti-inflammatory drugs, and the immunomodulatory properties of denervation approaches and bioelectronic medicine devices targeting NICT and neuroinflammation in HF. A deeper understanding of the complex relationship between the ANS and IS, as outlined in this review, could therefore facilitate the design of future studies aimed at improving outcomes by targeting NICT in patients with HF.

Activation of a GPCR, ORL1 Receptor: A Novel Therapy to Prevent Heart Failure Progression

The number of ischemic heart failure (HF) patients is growing dramatically worldwide. However, there are at present no preventive treatments for HF. Our previous study showed that Gata4 overexpression improved cardiac function after myocardial infarction in rat hearts. We also found that Gata4 overexpression significantly increased the expression of a Pnoc gene, an endogenous ligand for the cell membrane receptor ORL1. We hypothesized that the activation of the ORL1 receptor would suppress HF in a rat ischemic heart model. Adult Sprague Dawley rats (8 weeks old, six males and six females) underwent left anterior descending coronary artery ligation. Three weeks later, normal saline or MCOPPB (ORL1 activator, 2.5 mg/kg/day) intraperitoneal injection was started, and continued 5 days a week for 3 months. Echocardiography was performed six times: pre-operative, 3 days after coronary artery ligation, pre-MCOPPB or saline injection, and 1, 2, and 3 months after saline or MCOPPB injection started. Animals were euthanized after 3 months’ follow-up and the hearts were harvested for histological analysis. The ORL1 activator, MCOPPB, significantly improved cardiac function after myocardial infarction in rats (ejection fraction, MCOPPB vs. saline at euthanasia, 67 ± 3% vs. 43 ± 2%, p &lt; 0.001). MCOPPB also decreased fibrosis and induced angiogenesis. Thus, the ORL1 activator, MCOPPB, may be a novel treatment for preventing HF progression.

Integration of network pharmacology and transcriptomics to explore the mechanism of isoliquiritigenin in treating heart failure induced by myocardial infarction

BackgroundThe inflammatory response and myocardial remodeling play critical roles in the progression of heart failure (HF) following myocardial infarction (MI). Isoliquiritigenin (ISL) possesses anti-inflammatory properties and has been investigated in cardiovascular diseases such as atherosclerosis. However, the effects and mechanism of ISL on MI-induced HF remain unclear. This research aimed to explore the effects and mechanism of ISL in the treatment of HF on the basis of network pharmacology, transcriptomics, and experimental verification. Methods and resultsWe established an MI-induced HF mouse model in which ISL was administered via gavage for 28 days. Ultrasonic cardiogram data were collected from the mice, and pathological staining was conducted. Then, network pharmacology and molecular docking were performed. Transcriptomic analysis was also conducted on mouse myocardial tissue. Ultimately, we integrated transcriptomic data and network pharmacology to reveal the underlying mechanism, with the results verified through in vivo experiments. Our experiments indicated that ISL improved cardiac function, preserved myocardial structure, inhibited collagen fiber accumulation, reduced inflammatory factor secretion, and mitigated myocardial cell apoptosis in mice with MI-induced HF. A combination of transcriptomics and network pharmacology analysis revealed that core targets of ISL related to HF were significantly enriched in the Tumor Necrosis Factor (TNF) signaling pathway. Molecular docking validation demonstrated that ISL shows strong binding to these core targets. Additionally, in vivo experiments verified that ISL protects against HF post-MI by inhibiting the TNF signaling pathway. ConclusionWe clarified the anti-inflammatory and antimyocardial remodeling mechanisms of ISL in the treatment of HF post-MI, which involves the TNF signaling pathway.

IMPACT OF PRE-EXISTING HYPERTENSION ON THE DEVELOPMENT AND OUTCOMES OF PERIPARTUM CARDIOMYOPATHY

An uncommon but dangerous heart ailment known as peripartum cardiomyopathy (PPCM) may develop in the last month of pregnancy or during the first five months after giving birth. It has been shown that pre-existing hypertension is one risk factor that might make PPCM more severe. The purpose of this research is to assess how pre-existing hypertension affects the course, clinical manifestation, and results of PPCM. Objective: To evaluate the impact that pre-existing hypertension has on the clinical course, echocardiographic results, and maternal outcomes in PPCM maternal cases. Methods: At the DHQ Hospital KDA, Kohat, a retrospective cohort study was carried out between September 2023 and August 2024. There were 56 women with PPCM in total; 28 of them had pre-existing hypertension and the other 28 did not. Data on demographics, clinical conditions, and echocardiograms were gathered. The two groups' maternal outcomes—heart failure progression, recovery of left ventricular function, and problems after childbirth—were compared. SPSS version 26 was used for data analysis, and a p-value of less than 0.05 was deemed statistically significant. Results: Comparing women with pre-existing hypertension to the non-hypertensive group, they showed considerably higher rates of heart failure progression (39% against 21%, p = 0.04) and significantly lower left ventricular ejection fraction (LVEF) at diagnosis (30.1% versus 35.5%, p = 0.01). Women with hypertension were more likely to have persistent LVEF impairment (36% vs 18%, p = 0.03). Additionally, the group with hypertension saw higher readmission rates (25% vs 10.7%, p = 0.02). Conclusion: A substantial risk factor for unfavourable outcomes in PPCM, such as reduced heart function and increased rates of postpartum problems, is pre-existing hypertension. Improving PPCM results for hypertensive women requires closer observation and focused care.

Unravelling cardiomyopathies: a comprehensive analysis of phenotypic diversity, endomyocardial biopsy patterns, and the impact of Gremlin-1 on clinical prognosis

Abstract Background Cardiomyopathies are the main cause of progressive heart failure (HF) and despite outstanding advances of diagnostics and therapies, mortality remains high.1,2 The current phenotype-based classification of non-ischemic cardiomyopathies (NICM) is based on a clinical workflow including endomyocardial biopsy (EMB).3-5 Inflammation and fibrosis are essentially involved in progression of HF and lead to development of adverse cardiovascular (CV) events.6,7 The diagnostic algorithm facilitates risk stratification of HF patients but nonetheless risk factors often remain inapparent prior to disease incidence. Objective In this study we investigate EMB patters in patients with NICM and elucidate alterations associated with phenotypic diversity and progression of HF. Methods We prospectively enrolled patients with HF due to NICM in a large-scale all-comers cohort (n=703). All patients underwent guideline-based phenotypic classification including EMB, and RNA data were acquired alongside histological analyses within the myocardium. We then performed a ten-year follow-up to screen for disease progression. Results A guideline-based classification of patients with NICM resulted in a phenotyping of aetiological risk groups (Figure 1A). We found that characteristic expression of fibroinflammatory mediators within the myocardium occurred in patients with symptomatic NICM (Figure 1B). We found that elevated expression of Gremlin-1 (Grem), a potent downstream profibrotic mediator of TGFß pathway, was associated with pro-fibrotic cardiac remodelling (Figure 1C). Further, Gremlin-1 was associated with a significant decrease of left ventricular functional capacity and inversely correlated with late gadolinium enhancement (LGE) (Figure 1D&amp;E). Moreover, the expression of Gremlin-1 was enriched with pro-fibrotic and inflammatory RNA signalling pathways hinting at underlying pathophysiological cascades (Figure 2A&amp;B). Most strikingly, the expression of Gremlin-1 was independently associated with an increased CV risk during the ten-year follow-up (Figure 2C). Thus, patients with Gremlin-1+ EMB were at elevated risk to suffer from all-cause mortality and number of patients eligible for ICD implantation was critically enhanced in patients with Gremlin-1+ EMB (Figure 2D-F). In addition, the estimation of an elevated CV risk by machine learning including Gremlin-1 improved the ten-year risk stratification among all patients with NICM (Figure 2G). Thus, Gremlin-1 was associated with cardiac remodelling and disease activity in HF patients (Figure 2H). Conclusion Our results unveiled that Gremlin-1 is associated with inflammation and cardiac remodelling in patients with symptomatic cardiomyopathy and patients with Gremlin-1+ EMB are at elevated risk to develop adverse CV events. Thus, the histological evaluation of Gremlin-1 may help to identify pathophysiological cascades and improve early risk discrimination and management of HF patients.Figure 1Figure 2

Discovery of BAY 2413555, First Selective Positive Allosteric Modulator of the M2 Receptor to Restore Cardiac Autonomic Balance.

Autonomic disbalance, i.e., sympathetic overactivation and parasympathetic withdrawal, is a causal driver of disease progression in heart failure. While sympatholytic drugs are established treatments, no drug therapy restoring vagal control of cardiac function is available. We report here the HTS-based discovery of a novel class of 1,8-naphthyridin-4(1H)-one carboxamides acting as positive allosteric modulators (PAMs) of the M2 muscarinic acetylcholine receptor (M2R). M2R is the main postsynaptic myocyte receptor regulating heart rate, electrical conduction, and contractile strength. Extensive optimization of the screening hit in terms of potency, permeation, metabolic stability, and solubility ultimately resulted in the discovery of the first-in-class clinical candidate BAY 2413555 (27). With an overall technical profile compatible with once-daily oral administration in a phase 1 study, no apparent effects on blood pressure, and a mechanism that largely preserves autonomic regulatory capacity, BAY 2413555 could be the tool to finally study the restoration of autonomic balance.

Characterization and progression of heart failure with preserved ejection fraction in SDT fatty rats

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a complex clinical phenotype associated with the presence of multiple comorbidities including diabetes, obesity, and metabolic syndrome. A major challenge in the search of new therapies for HFpEF is the development of relevant animal models. The Spontaneously Diabetic Torii (SDT) fatty rat is a well-established type2 diabetic model with multiple diabetes-related comorbidities such as nephropathy, neuropathy, and retinopathy. However, the onset and spontaneous progression of cardiac dysfunction is not yet reported in this model. Purpose To validate the SDT fatty rat as a type2 diabetes related HFpEF model, we assessed the natural evolution, i.e., without any diet or surgical intervention, of cardiac function in SDT fatty at different ages starting at 7-week of age. Methods The cardiovascular phenotyping of male SDT fatty rats was assessed by echocardiography at 7, 12 and 17-week of age and invasive left intraventricular and blood pressure measurements at 17-week of age. Vascular function of isolated thoracic aortas was also evaluated at 17-week of age. Renal function was investigated by measuring the Glomerular Filtration Rate (GFR) and urine parameters at 7, 12 and 17-week of age. A group of Sprague Dawley (SD) rats was included as a negative control. Results Compared to SD rats, echocardiography in SDT fatty showed cardiac remodeling starting at 7 weeks and persistent with age. Systolic function and ejection fraction were preserved, while diastolic function was impaired as early as 7-week of age and worsened with time. E/A was comparable in SDT fatty and SD rats at 7-week of age and then increased with age to reach 1.8±0.1 vs 1.2±0.05 in SD (p&amp;lt;0.001) at 17 weeks, while E’/A’ was already inverted at 7 weeks (0.9± 0.02 vs 1.3±0.03 in SD, p&amp;lt;0.001), and lasted with age which is a sign of relaxation default and suggestive of a restrictive filling pattern. E/E’ was significantly higher at 7-week of age (16.1± 0.9 vs 12.1±0.6 in SD, p&amp;lt;0.01) and further increased at 17 weeks (23.1± 0.8 vs 12.1±0.8 in SD, p&amp;lt;0.001) indicating higher filling pressure. Intraventricular and arterial pressure were also increased (p&amp;lt;0.05). As well, SDT fatty rats showed altered endothelium vasodilating properties. As expected, SDT fatty rats were hyperglycemic and showed renal impairment expressed by higher proteinuria, urine albumin/creatinine ratio, KIM-1 and cystatin-C levels and a hyperfiltration state (80% higher GFR, p&amp;lt;0.05). Conclusions The present data demonstrate that the SDT fatty rats developed diastolic dysfunction characterized by a restrictive profile combining compliance and relaxation impairments as well as higher filling pressure along with hypertension. This type2 diabetic model seems as a very promising model to translate the hypertension/kidney dysfunction and cardiometabolic clinical HFpEF phenogroups and is consequently a relevant model to evaluate drugs targeting HFpEF.

Epicardial adipose tissue volume and density are associated with heart failure with improved ejection fraction

Abstract Background Heart failure (HF) with improved ejection fraction (EF, HFimpEF) gains increasing attention as a distinct HF subtype, characterized by left ventricular reverse remodeling and myocardial recovery. Multiple cardiometabolic factors are implicated in this process. Epicardial adipose tissue (EAT), emerging as an endocrine and paracrine organ, contributes to the onset and progression of HF. However, the relation between EAT and the incidence of HFimpEF is still unclear. Methods A total of 203 hospitalized HF patients with reduced EF (HFrEF, EF≤ 40%) who underwent coronary CT angiography (CCTA) during index hospitalization were consecutively enrolled between November 2011 and December 2022. Routine follow-up and repeat echocardiograms were performed. The incidence of HFimpEF was defined as (1) an absolute EF improvement ≥10% and (2) a second EF &amp;gt; 40% (at least 3 months apart). EAT volume and density were semiautomatically quantified on non-enhanced series of CCTA scans. Results During a median follow-up of 8.6 (4.9~13.3) months, 104 (51.2%) patients developed HFimpEF. Compared with HFrEF patients, HFimpEF patients had lower EAT volume (126.03 ± 57.71 cm3 vs 182.74 ± 82.99 cm3 , P&amp;lt; 0.001) and higher EAT density (-74.92 ± 6.84 HU vs -78.76 ± 6.28 HU, P&amp;lt; 0.001) both in ischemic and non-ischemic HF patients. EAT density was inversely correlated with EAT volume (r= -0.33, P&amp;lt; 0.001). Multivariate analysis showed lower EAT volume (OR: 0.881 [95% CI 0.821~0.939]) and higher density (OR: 2.354 [95% CI 1.314~4.415]) were both independently associated with the incidence of HFimpEF, after adjusting for conventional risk factors, pharmacological therapies and baseline anthropometric parameters including body mass index. Subgroup analysis revealed that the association between EAT properties and HFimpEF was not modified by HF etiology. Conclusions This study reveals that lower EAT volume and higher EAT density are associated with development of HFimpEF. Therapies targeted at reducing EAT quantity and improving its quality might provide favorable effects on myocardial recovery in HF patients.

Patient characteristics and incidence of cardiac amyloidosis: an observational study in the UK clinical setting using electronic health records

Abstract Background Cardiac amyloidosis (CA) is associated with a high mortality rate due to sudden or progressive heart failure. It is often misdiagnosed due to non-specific symptoms, and its true incidence and prevalence in the United Kingdom (UK) remain uncertain. Purpose To describe patient characteristics and incidence of CA in the UK clinical setting using electronic health records. Methods In this retrospective observational study, anonymised, linked primary and secondary care data (Clinical Practice Research Datalink, CPRD and Hospital Episode Statistics, HES) were used to describe individuals diagnosed with CA. The CPRD database contains de-identified patient data sourced from a sample of general practitioner (GP) practices in the UK. Patients aged 18 years and older with a recorded Read or SNOMED-CT diagnosis code for CA or record of treatment with tafamidis (a licensed but not reimbursed treatment for transthyretin amyloid cardiomyopathy, ATTR-CM in the UK) in the period between January 2004 to December 2021 were included. The index date was defined as the earliest recorded date of CA diagnosis or tafamidis treatment. Demographic and clinical data were summarised using descriptive statistics. Incidence rates were reported per 100,000 person-years (PY). Results There were a total of 3,788 patients with CA (mean age: 67 years; 61% males) of which only 277 were coded as having wild-type transthyretin (ATTRwt) CA in mostly older patients (mean age: 79 years). The low patient counts of ATTRwt amyloidosis could be attributed to the lack of specificity in CA types and the low utilisation of ATTR amyloidosis codes. Heart Failure, essential hypertension and dyspnoea were the most common clinical presentations recorded in the 12 months to first diagnosis code or tafamidis prescription for CA (Table). The incidence of CA varied from 0.75 in 2004 to a peak of 1.96 in 2021, per 100,000 PY; a 2.9-fold increase in newly coded diagnoses in CA. There was a slight decline in the rates in 2020 and 2021 (Figure). Incidence rates in males and females increased over the 17-year period, with males consistently having higher rates than females. The incidence rate in females started from a lower base at 0.62/100,000 PY in 2004, increased by a factor of 1.9 to 1.1/100,000 PY, whereas in males it started at 0.88/100,000 PY and rose by a factor of 2.9 to 2.5 /100,000 PY. Incidence rates in subgroup populations have also been analysed. Conclusions In the UK clinical setting, the incidence rate of newly coded CA increased overall between 2004 and 2021, as well as in both male and female subgroups. The data suggest CA is becoming more common, or that awareness has improved, and there is now an urgent need for enhanced methods of detection, characterisation, and the need for thorough data capture to shape future pathway advancements.

High incidence of malignant arrhythmias and heart failure in patients with RBM20-associated cardiomyopathy: a multicenter cohort study and review of the literature

Abstract Background Patients with RBM20 cardiomyopathy commonly experience malignant arrhythmias, sudden cardiac death (SCD), and progressive heart failure (HF). Objective The aim of this study is to investigate genotype-phenotype correlations, clinical outcomes and causes of death in patients with RBM20-associated cardiomyopathy in a multicenter cohort, combined with an overview of the current literature. Methods This international, multicenter cohort included all patients with cardiomyopathy who had a pathogenic (P) or likely pathogenic (LP) RBM20 variant. For survival and regression analysis, we matched a control group based on sex, age, and presence of left ventricular dysfunction. Additionally, we conducted a literature search on studies investigating RBM20-associated cardiomyopathy. Results Sixty-two patients (45% male) were included in the study, with a mean age of 42 ± 15 years at presentation. Of the LP/P RBM20 variants identified, 9 were novel. Eleven variants were truncating, while the remaining variants consisted of missense and splice-site variants. Patients with a truncating variant who developed HF were on average older at the time of diagnosis compared to patients with missense variants (mean age 62 ± 9 vs. 45 ± 14; p=0.01). After a median follow-up duration of 5.0 [1.0 – 10.5] years, 21 (34%) patients reached the composite endpoint of ventricular arrhythmias (VA), implantable cardioverter-defibrillator therapy, heart transplantation (HTx), left ventricular assist device (LVAD) implantation, or cardiovascular death. Of these, 19 (31%) patients experienced malignant VA (mean age 45 ± 15 years, 63% males). Males were at higher risk for the composite endpoint (log-rank p= 0.02), particularly for VA (log-rank p=0.007). The literature review analyzed 34 studies with a total of 678 patients, of whom 53% were male. In these studies, 123 (24%) patients experienced a VA, 58 (12%) underwent HTx or were treated with LVAD, and 52 (11%) died. Conclusion In this multicenter study the patients carrying a LP/P variant in RBM20 variants had a severe phenotype, with a high incidence of VA, particularly in males. Additionally, this study presents 9 novel DNA variants, of which 8 were truncating, and were mainly observed in older individuals. Finally, we report a lower mortality rate compared to the literature, possibly due to a higher number of heart transplantations performed in our patient cohort.Survival composite endpoint for sex

Outcomes in patients with light chain cardiac amyloidosis undergoing heart transplantation: a single centre UK study

Abstract Background Light chain cardiac amyloidosis (AL-CA) results in restrictive cardiomyopathy associated with progressive heart failure and poor survival. Traditionally, outcomes following heart transplantation in patients with AL-CA have been worse than in other heart failure cohorts and consequently, many centres do not offer this population transplantation. Purpose and Methods This was a retrospective observational study of 18 patients with AL-CA (age 52.7years +/- 8.3, male 66%) referred to our centre in the UK for assessment for heart transplantation from 2008 to 2023. Seven patients (39%) were listed for transplant, and all received orthotopic heart transplantation (OHT). This study compared pre-transplantation characteristics in those offered cardiac transplantation with those not transplanted. We also examined post-transplantation outcomes in this group (n=7) compared with the overall heart transplantation population (n=95) at our centre. Results Patients with AL-CA who were not offered transplantation (n=11) were older (mean age 54.3 vs 50.3 years), were more likely male (72% vs 57%) but had similar baseline renal function to those transplanted (median eGFR 60.4 vs 54.2ml/min). Reasons against offering OHT included extensive multisystem or renal amyloid deposition (n=4), insufficient haematological response (n=2), heart failure not advanced enough for OHT (n=1) and malignancy (n=1). Pre-transplant right heart catheterisation of patients undergoing OHT demonstrated a mean transpulmonary gradient of 7.8mmHg (+/- 1.9) and cardiac output of 2.94/min (+/- 0.3). Five patients (71%) had a complete and two (29%) a partial haematological response to clonally directed chemotherapy. Three patients were bridged to transplant with biventricular assist devices for 9, 10 and 51 days, respectively. Five patients developed episodes of histologically confirmed rejection of grade 2R that resolved with medical management. One patient experienced first degree atrioventricular block and had a pulseless electrical activity arrest 19 days after transplantation before being fitted with a permanent pacemaker. Two patients went on to receive autologous stem cell transplantation. Patients with AL-CA undergoing OHT had a lower mortality rate compared with non-transplanted patients over a median follow up of 9 months (HR 0.3, 95%CI 0.07-1.3, p = 0.10). Two patients with AL-CA died at 42 days and 7.7 years after OHT. Five patients (71%) are alive under follow up at 4, 7.5, 9, 10 months and 7.7 years post OHT. There was no difference in survival between patients who underwent heart transplantation for AL-CA and patients who underwent heart transplantation for all other indications (HR 1.94, 95%CI 0.3 – 12, p=0.45). Conclusions In selected patients with AL-CA, OHT offers favourable outcomes. After clonally directed therapy to control the underlying plasma cell dyscrasia, heart transplantation should be considered in the absence of widespread systemic disease.

Cardiopulmonary exercise testing predicts risk of progressive heart failure and long term mortality in ambulatory patients awaiting isolated heart transplant

Abstract Introduction Cardiopulmonary exercise testing (CPET) parameters such as peak VO2 ≤ 14ml/kg/min, percentage predicted peak VO2 (ppVO2) ≤ 50% and ventilation equivalent of carbon dioxide (Ve/VCO2) &amp;gt;35 l/min/l/min are recommended thresholds to list for isolated heart transplant. There is minimal data on clinical events after listing to guide clinical management or priority in organ allocation. Purpose To assess the effect of peak VO2, ppVO2, Ve/VCO2 on clinical events after listing for isolated heart transplant. Methods In a single centre retrospective study, we identified patients who were status 6 or status 2 prior to 2018 at time of listing for isolated heart transplant between 2007 and 2021. Clinical data were collected by chart review. Primary outcome of progressive heart failure was defined as death or upgrade in transplant priority status (new inotropes or mechanical circulatory support). Comparison was made between peak VO2 strata (&amp;gt; 14 vs ≤ 14 ml/kg/min), ppVO2 strata (&amp;gt; 50% vs 40-50% vs &amp;lt;40%) and Ve/VCO2 strata (&amp;lt;35 vs &amp;gt;35 l/min/l/min). Secondary outcome was time dependent survival after listing for heart transplant. Results We identified 141 patients of which 133 underwent CPET and follow up was available for 130 who were included in the analysis. Median age was 53 years (interquartile range 41-59 years), 29.1% of patients were female. Median peak VO2 was 14.0 ml/kg/min (11.2-15.7), ppVO2 was 44% (36-52), Ve/VCO2 slope was 34.0 (31.0-37.0) and RER was 1.1 (1.1-1.2). 87 patients had progressive heart failure consisting of 34 deaths and 83 patients having upgrade in priority status. There was a significant difference in risk of progressive heart failure comparing peak VO2 strata (Figure 1) (freedom from event at one year 71.4% with peak VO2 &amp;gt; 14 vs 46.5% with peak VO2 ≤ 14, p=0.00061) and ppVO2 strata (Figure 2) (freedom from event at one year 75.0% with ppVO2 &amp;gt;50% vs 61.2% with ppVO2 40-50% vs 42.6% with ppVO2 &amp;lt;40%, p=0.0015). There was no significant difference with Ve/VCO2 strata (freedom from event at one year 59.8% with Ve/VCO2 &amp;lt;34 vs 54.9% with Ve/VCO2 &amp;gt;34, p=0.52). There were 34 deaths before transplant and 23 deaths after transplant. 87 patients underwent transplant. In a time dependent survival analysis, age, gender and ppVO2&amp;lt;50% (HR 1.65 (0.87-3.12)) were not significant predictors of mortality. Both early transplant (defined as &amp;lt; 1 year after listing, HR 0.14 (0.06-0.34) and late transplant (defined as &amp;gt; 1 year after listing, HR 0.16 (0.08-0.32)) were significant predictors of lower mortality whilst Ve/VCO2&amp;gt;35 (HR 2.09 (1.19-3.68)) was a significant predictor of higher mortality. Conclusions Peak VO2 and ppVO2 stratify risk of progressive heart failure in ambulatory patients awaiting isolated heart transplant. However, Ve/VCO2 is a predictor of significantly higher mortality. These findings should affect clinical management and transplant priority status; and influence revision of future guidelines.Freedom from event by peak VO2 strataFreedom from event by ppVO2 strata