The relationship between heart failure (HF) and immune activation has garnered significant interest. Studies highlight the critical role of inflammation in HF, affecting cardiac structure and function. Despite promising anti-inflammatory therapies, clinical trials have faced challenges, indicating an incomplete understanding of immune mechanisms in HF. Immune cells, which are key cytokine sources, are pivotal in HF progression. In this review, the authors provide a comprehensive overview of the complex role of different types of immune cells and their cell subtypes in HF. In addition, the authors summarize the available targets and animal experimental evidence for targeting immune cells for the treatment of HF. Future research directions will focus on the roles of immune cells and their interrelationships at different stages of HF, aiming to develop more targeted therapeutic strategies that can achieve more precise interventions in the pathological process of HF.

Heart failure is the final outcome of most cardiovascular diseases and shares risk factors with other cardiovascular pathologies. Among these, inflammation plays a central role in disease progression and myocardial remodeling. Over the past 2 decades, numerous studies have explored immune-related mechanisms in cardiovascular disease, highlighting the importance of immune cross-talk between the heart and extra-cardiac organs, including bone marrow, spleen, liver, gut, and adipose tissue. This review examines how immune interactions among these organs contribute to heart failure pathogenesis, with a focus on clonal hematopoiesis, an age-related alteration of hematopoietic stem cells that fosters pathological bone marrow-heart communication. Additionally, we explore recent advances in the understanding of clonal hematopoiesis and its role in heart failure, emphasizing its implications for prognosis and potential therapeutic interventions. By integrating insights from immunology, metabolism, and aging, we provide a comprehensive perspective on the immunologic determinants of heart failure, paving the way for precision medicine approaches aimed at mitigating cardiovascular risk.

Gut dysbiosis is proven to be involved in the pathogenesis and progression of heart failure (HF). Hindering the detrimental effects of gut-heart axis is an emerging trend. Our goal is to investigate the causal relationship between gut microbiota and HF, with the aim of facilitating future exploration of microbiome-targeted approaches to prevent and delay the progression of HF.

Two-sample Mendelian randomization (MR) analysis was applied to investigate the causal association of the gut microbiome with HF among individuals of European ancestry. Genetic variants associated with the 196 bacterial taxa from MiBioGen consortium were used as exposure data, summary statistics for HF derived from Heart Failure Molecular Epidemiology for Therapeutic Targets (HERMES) consortium were used as outcome data. Five MR methods were applied, including inverse variance weighted, maximum likelihood, MR-Egger, weighted median, and weighted mode. Reverse causality of instrumental variables (IVs) was tested by MR Steiger test of directionality. Strength of IVs was evaluated by F-statistics. Cochrane's Q test, MR-Egger regression analysis, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) tests were used to detect heterogeneity and pleiotropy. Leave-one-out method was used for testing the stability of results. Seven microbiomes were found to be associated with HF. Five of them were associated with higher risks of developing HF, these included Order_Selenomonadales (odds ratio [OR] = 1.11, P = 0.024), Family_Peptococcaceae (OR = 1.07, P = 0.045), Genus_Eubacterium eligens group (OR = 1.14, P = 0.022), Genus_Eubacterium oxidoreducens group (OR = 1.12, P = 0.011) and Genus_Flavonifractor (OR = 1.14, P = 0.012). Genus_Anaerostipes and Order_Bacillales were associated with lower risks of HF (OR = 0.90, P = 0.014; OR = 0.95, P = 0.042, respectively). Evidence of pleiotropy or heterogeneity was not observed.

We identified seven intestinal microbiomes that were causally associated with HF at the level of gene prediction. This study will help with the discovery of potential preventive and therapeutic targets for HF.

Hepatorenal dysfunction is prevalent among individuals with heart failure (HF).

This study investigated prognostic value of the modified Model for End-Stage Liver Disease (Model for End-Stage Liver Disease excluding international normalized ratio [MELD-XI] scores and Model for End-Stage Liver Disease with albumin replacing international normalized ratio [MELD-Albumin]) score in patients undergoing cardiac resynchronization therapy (CRT).

We retrospectively evaluated 365 patients (mean age 58.7 ± 11.1 years; 64.9% men) undergoing CRT implantation between 2007 and 2019. Patients were divided into 4 groups based on the modified MELD score quartiles before CRT. The primary endpoint was the combination of all-cause mortality and HF hospitalization, whereas the secondary endpoint was CRT response at 6 months.

During mean follow-up of 3.3 years (interquartile range 1.9-5.2 years), 168 patients reached the primary endpoint. Logistic regression revealed the MELD-Albumin score was independently associated with CRT response, even after adjusting for covariates (odds ratio 1.10; 95% confidence interval [CI] 1.02-1.19; P = .013). Kaplan-Meier analysis revealed that patients with a higher MELD-XI and MELD-Albumin score had a greater risk of adverse outcomes (log-rank test: P < .001). A Cox proportional hazards analysis showed that the modified MELD score remained significantly associated with adverse outcomes after adjusting for clinical and echocardiographic factors (MELD-XI: hazard ratio 1.06, 95% CI 1.02-1.11, P = .006; MELD-Albumin: hazard ratio 1.10, 95% CI 1.05-1.16, P < .001). Furthermore, receiver-operating characteristic analysis indicated that the MELD-Albumin score provided a stronger prognostic value for long-term adverse outcomes in patients undergoing CRT than the MELD-XI score (MELD-Albumin: area under the curve 0.692, 95% CI 0.644-0.742; MELD-XI: area under the curve 0.659, 95% CI 0.608-0.715; P = .008).

The MELD-Albumin score may be useful for stratifying patients at risk for CRT response and adverse outcomes in those undergoing CRT for HF.

The magnitude of cognitive changes after incident heart failure (HF) is unclear. We assessed whether incident HF is associated with changes in cognition after accounting for pre-HF cognitive trajectories and known determinants of cognition.

This pooled cohort study included adults without HF, stroke, or dementia from 6 US population-based studies from 1971 to 2019. Linear mixed-effects models estimated cognitive change with incident HF diagnosis and the rate of cognitive change over the years after HF, controlling for pre-HF cognitive trajectories and participant factors. Outcomes included change in global cognition (primary outcome), executive function, and memory (secondary outcomes). Cognitive outcomes were standardized to a t score metric (mean [SD], 50 [10]); a 1-point difference represented a 0.1-SD difference in cognition.

We included 29 614 adults (mean [SD] age was 61 [10] years, 55% female, 70% White). During a median follow-up of 6.6 (Q1-Q3, 5.0-19.8) years, 1407 (5%) adults received an incident diagnosis of HF. Incident HF diagnosis was associated with initial decreases in global cognition (-1.1 points [95% CI, -1.4 to -0.8]) and executive function (-0.6 points [95% CI, -1.0 to -0.3]). Larger decreases in global cognition after HF were seen with older age, female sex, and White race. Participants with incident HF diagnosis demonstrated faster and long-term declines in global cognition (-0.1 points per year [95% CI, -0.2 to -0.1]) and executive function (-0.2 points per year [95% CI, -0.2 to -0.1]). The change in memory with incident HF diagnosis was not statistically significant but showed a similar trend with an initial decline of -0.5 points (95% CI, -1.4 to +0.3) and a slope of -0.1 points per year (95% CI, -0.3 to 0.0).

In this pooled cohort study, incident HF diagnosis was associated with initial decreases in global cognition and executive function and faster, persistent declines in these domains at follow-up.

To analyse factors associated with cognitive frailty among older chronic heart failure patients in China.

A cross-sectional design.

Between August 2021 and November 2022, a total of 421 chronic heart failure patients (age ≥60 years) were randomly selected from the cardiology department of the affiliated hospital of Zunyi Medical University. The FRAIL scale, Mini-Mental State Examination, 15-item Geriatric Depression Scale, Social Support Rating Scale, Short-form Mini Nutritional Assessment and Pittsburgh Sleep Quality Index were utilized for measurement and evaluation. The demographic and clinical characteristics of patients were collected. To select initial variables, the Least Absolute Shrinkage Selection Operator was applied, and then logistic regression analysis was used to confirm associating factors.

Among 421 elderly people with chronic heart failure, 83 cases (19.7%) showed cognitive frailty. Of 31 variables, seven were selected by Least Absolute Shrinkage Selection Operator regression. Finally, multivariate logistic regression revealed that the age, monthly salary, drinking, NYHA classification, length of hospital stay, depression and malnutrition risk/malnutrition were independently associated with cognitive frailty.

The high proportion of cognitive frailty in older people with chronic heart failure should be concerned. Additionally, in the setting of cognitive frailty, efforts to diagnose it and develop interventions to prevent or reverse cognitive frailty status among older chronic heart failure patients are necessary.

The findings of our study highlight the necessity to evaluate cognitive frailty in older people with chronic heart failure and provide a new perspective and scientific basis for medical staff to develop individualized and specific interventions to prevent or reverse cognitive frailty status.

This study has been reported in compliance with STROBE reporting guidelines for cross-sectional studies.

No Patient or Public Contribution.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a novel target for reducing low-density lipoprotein cholesterol. PCSK9 activates the atherosclerosis process through pro-inflammation signaling. Furthermore, the serum level of PCSK9 is positively correlated with mortality in patients with heart failure (HF). Cardiac fibrosis plays a crucial role in the pathophysiology of HF. In this study, we intended to examine whether PCSK9 can increase fibroblast activities and explore what its underlying mechanisms are. Migration, proliferation analyses, and Western blotting were used on human cardiac fibroblasts with and without PCSK9. Alirocumab (a PCSK9 inhibitor, 10 mg/kg/week intra-peritoneally for 28 consecutive days) was treated in isoproterenol (100 mg/kg, subcutaneous injection)-induced HF rats. PCSK9 (50, 100 ng/mL) increased proliferation, myofibroblast differentiation capability, and collagen type I production. Compared with control cells, PCSK9 (100 ng/mL)-treated cardiac fibroblasts showed higher nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3), interleukin (IL)-1, myofibroblast differentiation, and collagen production capabilities, which were attenuated by MCC950 (an NLRP3 inhibitor, 100 μmol/L). PCSK9 upregulated Myd88 and NF-κB signaling, which were reduced by TAK242 (a toll-like receptor (TLR) 4 inhibitor, 10 μmol/L). Moreover, alirocumab significantly improved left ventricular systolic function and attenuated fibrosis in HF rats. In conclusion, PCSK9 upregulates NLRP3 signaling and the profibrotic activities of cardiac fibroblasts through the activation of TLR4/Myd88/NF-κB signaling.

Vascular aging and its associated diseases represent a principal cause of mortality among the global elderly population, making the mitigation of vascular aging a significant aspiration for humanity. This article explores the intersection of nature and health, focusing on the role of the natural plant, pepper, and its principal bioactive compound, capsaicin, in combating vascular aging. By examining molecular and cellular mechanisms as well as phenotypic alterations in blood vessels, we offer a comprehensive review of the effects of capsaicin and its receptor, transient receptor potential vanilloid 1 (TRPV1), within vascular aging. We propose that capsaicin may serve as the medication with the potential to slow the progress of vascular aging and could constitute a new strategy to treat vascular aging related disease.

Acute cardiogenic pulmonary edema (ACPE) is a common and serious manifestation of heart failure (HF), representing 10-20% of all acute HF admissions. It is associated with elevated in-hospital mortality and high rates of re-hospitalization. MicroRs, like miR-30d, are of particular interest in heart failure due to their regulatory role in gene expression and potential as biomarkers for diagnosing and predicting patient outcomes, especially in high-risk cases such as ACPE. We conducted a cohort study on patients diagnosed with ACPE in the Emergency Department (ED). The circulating levels of miR-30d were analyzed at the time of hospital admission and at one-month follow-up along with other biomarkers. We enrolled 24 ACPE patients and 10 control subjects. Median age was 80.8 years (interquartile range, IQR, 8.2) in ACPE cases, and 78.5 years (IQR 9.8) in controls with a male/female ratio of 2 and 0.66, respectively. In ACPE patients, median cardiac ejection fraction was 42.5%, creatinine 1.63 mg/dL (IQR 1.24), troponin 63.5 ng/dL (58), and NT-proBNP 4243.5 pg/mL (IQR 5846) at ED evaluation. Median concentration of miR30d was 0.81 in controls, and 3.67 and 7.28 in ACPE patients at enrollment time and one month later, respectively. Re-hospitalization occurred in 7 ACPE patients in the following 3 months, and in 9 during the following year. miR-30d had a significant predictive value in assessing the risk of re-hospitalization at both 3 months and 1 year following the initial diagnosis of ACPE, while it did not in assessing the risk of death at 1 year. When compared with the other biomarkers, none of them showed a better accuracy than miR-30d. Our findings suggest that elevated levels of miR-30d are associated with an increased rate of hospital readmission at both 3 months and 1 year after discharge. Larger, multicenter studies will be needed to confirm the validity of circulating miR-30d levels as a potential biomarker useful for risk prediction in ACPE patients and its utility in improving individualized patient care.

Despite previous histopathologic evidence for its presence, the role of myocardial inflammation in the development and progression of cardiac transthyretin amyloidosis (ATTR-CA) remains insufficiently understood. Thus, this study sought to characterize the prevalence and potential prognostic implications of myocardial inflammation in ATTR-CA.

A retrospective observational study including patients with ATTR-CA diagnosed by endomyocardial biopsy was conducted. Myocardial inflammation was diagnosed through a review of routine endomyocardial biopsy reports. Baseline characteristics were compared using the Mann-Whitney U test and the Pearson χ2 test. Clinical outcomes were monitored via follow-up visits or telephone calls. Primary outcomes were all-cause death and a composite end point of all-cause death or heart failure hospitalization. Kaplan-Meier analyses, as well as univariable and age- and sex-adjusted multivariable Cox regression analyses, were used to assess differences in overall and composite end point-free survival between patients with ATTR-CA with and without myocardial inflammation.

A total of 103 patients with ATTR-CA (100 wild type; 3 variant) were enrolled. Median follow-up was 18.2 (8.0-31.1) months. Myocardial inflammation was prevalent in 32% (n=33/103) of patients with ATTR-CA. Among evaluable patients with myocardial inflammation, 96% (n=26/27) and 31% (n=9/29) had elevated CD68 (clusters of differentiation 68)-positive macrophage and CD3 (clusters of differentiation 3)-positive T-cell counts, respectively. Overall survival (P=0.017) and composite end point-free survival (P=0.014) were significantly impaired in patients with ATTR-CA with myocardial inflammation (n=33) compared with those without (n=70). Statistical significance for both associations was sustained after adjustment for age and sex, yielding adjusted hazard ratios of 4.72 (95% CI, 1.33-16.71; P=0.016) and 2.30 (95% CI, 1.04-5.11; P=0.041) for all-cause death and the composite end point, respectively.

Our findings affirm previous evidence that myocardial inflammation is present in approximately one-third of all patients with ATTR-CA. Moreover, we provide first data indicating that myocardial inflammation may be associated with a higher risk of death and heart failure hospitalizations in ATTR-CA.

Current diagnostic biomarkers for acute myocardial infarction (AMI), such as troponins, often lack specificity, leading to false positives under non-cardiac conditions. Recent studies have implicated circadian rhythm and immune infiltration in the pathogenesis of AMI. This study hypothesizes that analyzing the interplay between circadian rhythm-related gene expression and immune infiltration identify highly specific diagnostic biomarkers for AMI. Our results demonstrated differential expression of 15 circadian rhythm-related genes (CRGs) between AMI patients and healthy individuals, with five key genes-JUN, NAMPT, S100A8, SERPINA1, and VCAN identified as key contributors to this process. Functional enrichment analyses suggest these genes significantly influence cytokine and chemokine production in immune responses. Immune infiltration assessments using ssGSEA indicated elevated levels of neutrophils, macrophages, and eosinophils in AMI patients. Additionally, we identified potential therapeutic implications with 13 pivotal miRNAs and 10 candidate drugs targeting these genes. The Benjamini-Hochberg method was employed to adjust for multiple testing, and the results retained statistical significance. RT-qPCR analysis further confirmed the upregulation of these five genes under hypoxic conditions, compared to controls. Collectively, our findings highlight the critical role of CRGs in AMI, providing a foundation for improved diagnostic approaches and novel therapeutic targets.

Bromodomain and extraterminal domain (BET) proteins, including BRD4, bind acetylated chromatin and coactivate gene transcription. A BET inhibitor, JQ1, prevents and reverses pathological cardiac remodeling in preclinical models of heart failure. However, the underlying cellular mechanisms by which JQ1 improves cardiac structure and function remain poorly defined. Here, we demonstrate that BRD4 knockdown reduced expression of genes encoding CC chemokines in cardiac fibroblasts, suggesting a role for this epigenetic reader in controlling fibroblast-immune cell cross talk. Consistent with this, JQ1 dramatically suppressed recruitment of monocytes to the heart in response to stress. Normal mouse hearts were found to have approximately equivalent numbers of major histocompatibility complex (MHC-II)high and MHC-IIlow resident macrophages, whereas MHC-IIlow macrophages predominated following JQ1 treatment. Single-cell RNA-seq data confirmed that JQ1 treatment or BRD4 knockout in CX3CR1+ cells reduced MHC-II gene expression in cardiac macrophages, and studies with cultured macrophages further illustrated a cell autonomous role for BET proteins in controlling the MHC-II axis. Bulk RNA-seq analysis demonstrated that JQ1 blocked pro-inflammatory macrophage gene expression through a mechanism that likely involves repression of NF-κB signaling. JQ1 treatment reduced cardiac infarct size in mice subjected to ischemia/reperfusion. Our findings illustrate that BET inhibition affords a powerful pharmacological approach to manipulate monocyte-derived and resident macrophages in the heart. Such an approach has the potential to enhance the reparative phenotype of macrophages to promote wound healing and limit infarct expansion following myocardial ischemia.NEW & NOTEWORTHY BRD4 inhibition blocks stress-induced recruitment of pro-inflammatory monocytes to the heart. BRD4 inhibition reprograms resident cardiac macrophages toward a reparative phenotype marked by reduced NF-κB signaling and diminished MHC-II expression. BRD4 inhibition reduces infarct size in an acute model of ischemia/reperfusion injury in mice.

Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) inhibitors play a pivotal role in treating various tumors; however, the clinical characteristics and molecular mechanisms of their associated heart failure (HF) remain incompletely understood.

We investigated the epidemiological characteristics of VEGF or VEGFR inhibitors [VEGF(R)i]-related heart failure (VirHF) using the global pharmacovigilance database Vigibase. The phenotypic features and molecular mechanisms of VirHF were characterized using VEGF(R)i-treated mouse models through a combination of echocardiography, histopathological analysis, and transcriptome sequencing. Furthermore, we performed a retrospective analysis of cardiac function parameters in patients undergoing VEGF(R)i treatment at local hospitals.

In the analysis of 1871 VirHF cases, elderly patients (≥ 65 years) and female subjects demonstrated an elevated risk of occurrence. Experimental studies in mice revealed that both acute and chronic VEGF(R)i administration resulted in reduced left ventricular EF, cardiomyocyte hypertrophy, and myocardial fibrosis. Transcriptomic analysis identified significant dysregulation of multiple key signaling pathways, including DNA repair (R = 0.46), mitochondrial ATP synthesis (R = 0.39), glycogen metabolism regulation (R = 0.45), and proteasome-mediated protein degradation (R = 0.45). Moreover, significant upregulation was observed in inflammatory pathways, specifically those involving IL-1, IL-6, TNF-α, and IRF3/IRF7-mediated immune responses. Clinical cohort analyses demonstrated significant elevations in both cardiac injury biomarkers (NT-proBNP, CK-MB, cTnT) and inflammatory mediators (CRP) following VEGF(R)i administration.

Our findings present the first comprehensive characterization of VirHF clinical features and elucidate its underlying molecular mechanisms, thereby providing a theoretical framework for optimizing the clinical safety of VEGF(R)i therapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many malignant tumors. However, ICI-induced hyper-immune activation causes cardiotoxicity. Traditional treatments such as glucocorticoids and immunosuppressants have limited effectiveness and may even accelerate tumor growth. This study aimed to identify approaches that effectively reduce cardiotoxicity and simultaneously preserve or enhance the antitumor immunity of ICI therapy.

ICI injection in melanoma-bearing C57BL/6J female mice was used to simulate cardiotoxicity in patients with tumor undergoing immune therapy. MCC950 was used to block nod-like receptor protein 3 (NLRP3) inflammasome activity. Echocardiography, immunofluorescence, flow cytometry, and reverse transcription quantitative polymerase chain reaction were used to assess cardiac function, immune cell populations, and inflammatory factor levels. Bulk and single-cell RNA sequencing was used to detect the changes in cardiac transcriptome and immunological network.

NLRP3 inhibition reduced inflammatory response and improved cardiac function. Notably, NLRP3 inhibition also resulted in a pronounced suppression of tumor growth. Single-cell RNA sequencing elucidated that MCC950 treatment reduced the cardiac infiltration of pathogenic macrophages, cytotoxic T cells, activated T cells, and their production of inflammatory cytokines, while enhancing the presence of reparative macrophages and naive T cells. In addition, MCC950 attenuated cardiotoxicity induced by dual programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) immunotherapy and promoted tumor regression, and showed efficacy in treating established cardiotoxicity.

Our findings provide a promising clinical approach for preventing and treating cardiotoxicity induced by ICIs, dissociating the antitumor efficacy of ICI-based therapies from their cardiotoxic side effects.

Right ventricular (RV) function determines outcomes in RV pressure loading. A better understanding of the time-course and regional distribution of RV remodeling may help optimize targets and timing for therapeutic intervention. We sought to characterize RV remodeling between zero and 6 wk after the initiation of RV pressure loading. Thirty-six rats were randomized to either sham surgery or to pulmonary artery banding (PAB). After echocardiography and conductance catheter studies, groups of rats were euthanized at 1 wk, 3 wk, and 6 wk after sham surgery, or induction of RV pressure loading, for RV histological, RNA, and molecular analysis. A vigorous inflammatory response characterized by increased RV inflammatory cytokines, chemokines, and macrophage markers was observed at 1 wk following PAB. Metabolic changes, transforming growth factor-β (TGF-β)1 canonical signaling, collagenous fibrosis deposition, and apoptosis were already significantly increased by 1 wk after PAB. Genes marking fibroblast activation were upregulated at 1 wk but not at 6 wk post-PAB surgery. Mitochondrial dysfunction was evidenced by increased pyruvate dehydrogenase kinase (PDK) activity and decreased pyruvate dehydrogenase (PDH) phosphorylation significantly at 6-wk post-PAB. These processes preceded the development of overt myocardial hypertrophy and impaired echo parameters of systolic and diastolic function that occurred significantly from 3 wk after PAB. RV myocardial inflammation, metabolic shift, metabolic gene transcription, and profibrotic signaling occur early after initiation of pressure loading when RV pressures are only moderately elevated, before the development of overt myocardial hypertrophy and dysfunction, suggesting that adaptive hypertrophy and maladaptive remodeling occur simultaneously. These results suggest that therapeutic intervention to reduce adverse RV remodeling may be needed earlier and at lower thresholds than currently used.NEW & NOTEWORTHY Exploring the dynamics of right ventricular remodeling: unveiling the intricate interplay between inflammation, metabolic shifts, and fibrotic signaling in response to pressure loading. Through a comprehensive study spanning from initiation to 6 wk post-pressure loading, our research sheds light on the early onset of crucial molecular processes preceding overt hypertrophy and dysfunction. These findings challenge conventional intervention timing, advocating for early, targeted therapeutic strategies to mitigate adverse remodeling in right ventricular pressure loading.

Recent research has suggested imbalances in gut microbiota composition as contributors to cardiac aging. An individual's physical condition, along with lifestyle-associated factors, including diet and medication, are significant determinants of gut microbiota composition. This review discusses evidence of bidirectional associations between aging and gut microbiota, identifying gut microbiota-derived metabolites as potential regulators of cardiac aging. It summarizes the effects of gut microbiota on cardiac aging diseases, including cardiac hypertrophy and fibrosis, heart failure, and atrial fibrillation. Furthermore, this review discusses the potential anti-aging effects of modifying gut microbiota composition through dietary and pharmacological interventions. Lastly, it underscores critical knowledge gaps and outlines future research directions. Given the current limited understanding of the direct relationship between gut microbiota and cardiac aging, there is an urgent need for preclinical and clinical investigations into the mechanistic interactions between gut microbiota and cardiac aging. Such endeavors hold promise for shedding light on the pathophysiology of cardiac aging and uncovering new therapeutic targets for cardiac aging diseases.

The most common form of heart failure is heart failure with preserved ejection fraction (HFpEF). While heterogeneous in origin, the most common form of HFpEF is the cardiometabolic manifestation. Obesity and aging promote systemic inflammation that appears integral to cardiometabolic HFpEF pathophysiology. Accumulation of immune cells within the heart, fueled by an altered metabolome, contribute to cardiac inflammation and fibrosis. In spite of this, broad anti-inflammatory therapy has not shown significant benefit in patient outcomes. Thus, understanding of the nuances to metabolic and age-related inflammation during HFpEF is paramount for more targeted interventions. Here, we review clinical evidence of inflammation in the context of HFpEF and summarize our mechanistic understanding of immunometabolic inflammation, highlighting pathways of therapeutic potential along the way.

Hyperuricemia (HU) is associated with an increased risk of incident heart failure (HF) and adverse HF outcomes. Patients with diabetes mellitus (DM) have a greater prevalence of HU.

We evaluated the prognostic impact of HU in patients with HF according to the coexistence of DM.

A retrospective cohort study of ambulatory patients with HF with left ventricular systolic dysfunction (LVSD) was conducted from January 2012 to May 2018. The end point was all-cause mortality; follow-up was until January 2021. A Cox regression analysis was used to assess the prognostic impact of elevated uric acid (UA) levels. The cut-off for HU was 8.2 mg/dL. A multivariate model was built accounting for confounders. The analysis was stratified according to DM, and interaction between DM and UA levels was tested.

We studied 538 patients, of whom 66% were males. Of the patients, 45% had ischemic HF, 41% had DM, and 11% were receiving urate-lowering therapies. The median (interquartile range (IQR)) admission UA was 5.5 (5.8-9.2) mg/dL, and 40% had UA > 8.2 mg/dL. During a median 46-month follow-up, 48.5% of patients died. Patients with UA > 8.2 mg/dL had a multivariate-adjusted hazard ratio (HR) (95% confidence interval (CI)) of all-cause mortality of 1.75 (1.20-2.55; p=0.003). The interaction between DM and UA levels was significant (p=0.04). The independent association of hyperuricemia with mortality persisted only in non-DM patients (HR: 1.70, 95% CI: 1.16-2.51; p=0.007). In those with DM, hyperuricemia portended no survival disadvantage.

DM appears to influence the prognostic impact of HU in chronic HF. The risk of all-cause mortality in hyperuricemic HF patients without DM increases by 70% when compared with those with normal UA levels.

The systemic inflammatory response index (SIRI) is a recently developed composite index that assesses the entire extent of inflammation in the body, closely linked to heart failure (HF). This study aimed to evaluate the potential association between SIRI and HF.

The cross-sectional study utilized data from the National Health and Nutrition Examination Survey (NHANES) database from 2001 to 2018. SIRI is calculated based on the counts of monocytes, neutrophils, and lymphocytes. A weighted multiple-variable linear regression model examined the correlation between SIRI and HF. Using restrained cubic splines explored the nonlinear relationship between the two, and the robustness of the results was verified by subgroup analysis and interaction tests.

Our study included 30,294 participants, 814 of whom were diagnosed with HF and 29,480 with non-HF. The multiple linear regression analysis showed that SIRI was positively correlated with HF (OR = 1.66; 95 % CI, 1.21, 2.29) and that there was no nonlinear relationship between the two. This relationship persisted in subgroup analyses.

The results indicate a linear positive correlation between SIRI and HF. Further extensive prospective studies are needed to validate these findings.

Inflammation and metabolic disturbances are key culprits in the pathogenesis of obesity-associated cardiomyopathy. The NLRP3 (nucleotide-binding oligomerization domain-like receptor 3) inflammasome mediates the release of the proinflammatory cytokines IL-1β (interleukin-1β) and IL-18 by activating caspase-1, which is strongly implicated in metabolic disturbances. We here sought to determine whether NLRP3 inflammasome inhibition could ameliorate obesity cardiomyopathy and if so, to further explore its underlying mechanisms.

Male mice were fed a high-fat diet for 24 weeks to induce obesity cardiomyopathy. MCC950 was used to inhibit NLRP3 inflammasome activation. Recombinant adeno-associated virus serotype 9 encoding TXNIP (thioredoxin-interacting protein) under cTnT (cardiac troponin T) promoter and the mitochondrial-targeted antioxidant MitoTEMPO were injected into obese mice to investigate the specific mechanism. To mimic obesity cardiomyopathy in vitro, neonatal rat ventricular myocytes transfected with the small interfering RNA against TXNIP were incubated with 400 μmol palmitic acid for 24 hours. NLRP3 inflammasome was significantly increased in obese hearts. NLRP3 inflammasome inhibition by NLRP3 deletion or MCC950 prevented obesity-induced cardiac systolic and diastolic dysfunction, myocardial hypertrophy and fibrosis, and excessive lipid accumulation in male mice. Conversely, TXNIP overexpression worsened obesity-associated cardiomyopathy. Similarly, MCC950 treatment or TXNIP knockdown reduced palmitic acid-induced NLRP3 inflammasome activation and lipid storage. Mechanistically, abnormal NF-κB (nuclear factor kappa B) pathway activation, increased mitochondrial reactive oxygen species, and elevated TXNIP levels led to excessive NLRP3 inflammasome activation.

Our study confirms that aberrant NLRP3 inflammasome activation in cardiomyocytes worsens obesity-associated cardiomyopathy and implicates inhibition of NLRP3 inflammasome as a potent therapeutic approach for obesity cardiomyopathy.

This study aims to identify m6A methylation-related and immune cell-related key genes with diagnostic potential for heart failure (HF) by leveraging various bioinformatics techniques.

The GSE116250 and GSE141910 datasets were sourced from the Gene Expression Omnibus (GEO) database. Correlation analysis was conducted between differentially expressed genes (DEGs) in HF and control groups, alongside differential m6A regulatory factors, to identify m6A-related DEGs (m6A-DEGs). Subsequently, candidate genes were narrowed down by intersecting key module genes derived from weighted gene co-expression network analysis (WGCNA) with m6A-DEGs. Key genes were then identified through the Least Absolute Shrinkage and Selection Operator (LASSO) analysis. Correlation analyses between key genes and differentially expressed immune cells were performed, followed by the validation of key gene expression levels in public datasets. To ensure clinical applicability, five pairs of blood samples were collected for quantitative real-time fluorescence PCR (qRT-PCR) validation.

A total of 93 m6A-DEGs were identified (|COR| > 0.6, P < 0.05), and five key genes (LACTB2, NAMPT, SCAMP5, HBA1, and PRKAR2A) were selected for further analysis. Correlation analysis revealed that differential immune cells were negatively associated with the expression of LACTB2, NAMPT, and PRKAR2A (P < 0.05), while positively correlated with SCAMP5 and HBA1 (P < 0.05). Subsequent expression validation confirmed significant differences in key gene expression between the HF and control groups, with consistent expression trends observed across both training and validation sets. The expression trends of LACTB2, PRKAR2A, and HBA1 in blood samples from the qRT-PCR assay aligned with the results derived from public databases.

This study successfully identified five m6A methylation-related key genes with diagnostic significance, providing a theoretical foundation for further exploration of m6A methylation's molecular mechanisms in HF.

Inflammation has emerged as a potential key pathophysiological mechanism in heart failure (HF) in general and acute HF (AHF) specifically, with inflammatory biomarkers shown to be highly predictive of adverse outcomes in these patients. The CORTAHF study builds on both these data and the fact that steroid burst therapy has been shown to be effective in the treatment of respiratory diseases and COVID-19. Our hypothesis is that in patients with AHF and elevated C-reactive protein (CRP) levels without symptoms or signs of infection, a 7-day course of steroid therapy will lead to reduced inflammation and short-term improvement in quality of life and a reduced risk of worsening HF (WHF) events.

The study, which is currently ongoing, will include 100 patients with AHF ages 18-85, regardless of ejection fraction, screened within 12 h of presentation. Patients will be included who have NT-proBNP > 1500 pg/mL and CRP > 20 mg/L at screening. Exclusion criteria include haemodynamic instability and symptoms and signs of infection. After signed consent, eligible patients will be randomized according to a central randomization scheme stratified by centre 1:1 to either treatment once daily for 7 days with 40 mg prednisone orally or to standard care. Patients will be assessed at study day 2, day 4 or at discharge if earlier, and at days 7 and 31 at the hospital; and at day 91 through a telephone follow-up. The primary endpoint is the change in CRP level from baseline to day 7, estimated from a mixed model for repeated measures (MMRM) including all measured timepoints, in patients without a major protocol violation. Secondary endpoints include the time to the first event of WHF adverse event, readmission for HF, or death through day 91; and changes to day 7 in EQ-5D visual analogue scale score and utility index. Additional clinical and laboratory measures will be assessed.

The results of the study will add to the knowledge of the role of inflammation in AHF and potentially inform the design of larger studies with possibly longer duration of anti-inflammatory therapies in AHF.

Increased TNF-α levels following acute myocardial infarction (AMI) contribute to impaired recovery of myocardial function. Interaction of inactive rhomboid protein 2 (iRhom2) with TNF-α converting enzyme (TACE) is required for TNF-α shedding from immune cells. We hypothesized that iRhom2 expression increases in circulating monocytes following AMI. Transcript levels of iRhom2, TACE and TNF-α were evaluated by quantitative real-time PCR in isolated monocytes of 50 AMI patients at admission (d1) and 3 days (d3) after. We observed a significant increase in levels of iRhom2 mRNA expression in monocytes between d1-3, while TNF-α and TACE mRNA expression remained unchanged. At d3, iRhom2 mRNA expression positively correlated with levels of intermediate monocytes or serum TNF-α, and negatively with LV systolic function. iRhom2 may contribute to regulation of post-infarction inflammation and is associated with LV dysfunction following AMI. iRhom2 modulation should be evaluated as a potential therapeutic strategy to attenuate cardiac remodeling following AMI.

Heart failure (HF) and inflammation have a bidirectional relation leading to activation and adaptation of multiple cellular lines, including leucocyte subtypes and platelets. We aimed to assess and compare the predictive value of the neutrophil-lymphocyte (NLR), monocyte-lymphocyte (MLR) and platelet-lymphocyte (PLR) ratios for all-cause long-term mortality in HF.

This is an observational retrospective cohort study that included patients from the HI-HF cohort that survived the initial hospitalization. Vital status and survival time were assessed in June 2020.

We analyzed 1018 HF patients with a mean age of 72.32 ± 10.29 years and 53.54 % women. All-cause long-term mortality was 38.21 % after a median follow-up time of 68 [38 - 82] months. NLR (AUC 0.667, 95 %CI 0.637 - 0.697), MLR (AUC 0.670, 95 %CI 0.640 - 0.700) and PLR (AUC 0.606, 95 %CI 0.574 - 0.636) were predictors of all-cause mortality. In multivariable Cox proportional hazards analysis, NLR≥3.56 was the only hematological index independent predictor of fatality (HR 1.36, 95 %CI 1.05 - 1.76).

Of the three hematological indices, NLR was the only independent predictor of all-cause long-term mortality of HF patients. We suggest NLR≥3.56 as an auxiliary prognostic biomarker for the evaluation of HF patients.

Background/Objectives: Chronic heart failure (CHF) is characterized by complex pathophysiology, leading to increased hospitalizations and mortality. Inflammatory biomarkers such as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) provide valuable diagnostic insights.

This study evaluates the prognostic relationship between NLR, PLR, and, in a specific subcohort, N-terminal pro B-type natriuretic peptide (NT-proBNP), alongside length of stay (LOS) and 90-day readmission rates in CHF patients, irrespective of heart failure phenotype. A retrospective analysis of 427 CHF admissions (males = 57.84%) was conducted.

The mean age of the entire population was 68.48 ± 11.53 years. The average LOS was 8.33 ± 5.26 days, with a readmission rate of 73 visits (17.09%) for 56 patients. The NLR (3.79 ± 3.32) showed a low but positive correlation with the LOS (r = 0.222, p < 0.001). Conversely, the PLR (144.84 ± 83.08) did not demonstrate a significant association with the LOS. The NLR presented a low negative correlation for days until the next admission (r = -0.023, p = 0.048). In a prespecified subanalysis of 323 admissions, the NT-proBNP exhibited a low positive Pearson correlation with the NLR (r = 0.241, p < 0.001) and PLR (r = 0.151, p = 0.006).

The impact of the NLR across heart failure phenotypes may suggest the role of systemic inflammation in understanding and managing CHF.

Doxorubicin (DOX) is an effective chemotherapeutic drug, but its use can lead to cardiomyopathy, which is the leading cause of mortality among cancer patients. Macrophages play a role in DOX-induced cardiomyopathy (DCM), but the mechanisms undlerlying this relationship remain unclear. This study aimed to investigate how IKKα regulates macrophage activation and contributes to DCM in a mouse model. Specifically, the role of macrophage IKKα was evaluated in macrophage-specific IKKα knockout mice that received DOX injections. The findings revealed increased expression of IKKα in heart tissues after DOX administration. In mice lacking macrophage IKKα, myocardial injury, ventricular remodeling, inflammation, and proinflammatory macrophage activation worsened in response to DOX administration. Bone marrow transplant studies confirmed that IKKα deficiency exacerbated cardiac dysfunction. Macrophage IKKα knockout also led to mitochondrial damage and metabolic dysfunction in macrophages, thereby resulting in increased cardiomyocyte injury and oxidative stress. Single-cell sequencing analysis revealed that IKKα directly binds to STAT3, leading to the activation of STAT3 phosphorylation at S727. Interestingly, the inhibition of STAT3-S727 phosphorylation suppressed both DCM and cardiomyocyte injury. In conclusion, the IKKα-STAT3-S727 signaling pathway was found to play a crucial role in DOX-induced cardiomyopathy. Targeting this pathway could be a promising therapeutic strategy for treating DOX-related heart failure.

The phosphodiesterases type 5 (PDE5) are catalytic enzymes converting the second messenger cyclic guanosine monophosphate (cGMP) to 5' GMP. While intracellular cGMP reduction is associated with several detrimental effects, cGMP stabilization associates with numerous benefits. The PDE5 specific inhibitors, PDE5i, found their explosive fortune as first-line treatment for erectile dysfunction (ED), due to their powerful vasoactive properties. The favorable effect for ED emerged as side-effect when PDE5i were originally proposed for coronary artery disease (CAD). From that point on, the use of PDE5i captured the attention of researchers, clinicians, and companies. Indeed, PDE5-induced intracellular cGMP stabilization offers a range of therapeutic opportunities associated not only with vasoactive effects, but also with immune regulatory/anti-inflammatory actions. Chronic inflammation is acknowledged as the common link underlying most non-communicable diseases, including metabolic and cardiac diseases, autoimmune and neurodegenerative disorders, cancer. In this scenario, the clinical exploitation of PDE5i is undeniably beyond ED, representing a potential therapeutic tool in several human diseases. This review aims to overview the biological actions exerted by PDE5i, focusing on their ability as modulators of inflammation-related human diseases, with particular attention to inflammatory-related disorders, like cardiac diseases and cancer.

Chronic primary mitral regurgitation (MR) is caused by the defect in >1 component of the mitral valve, potentially leading to left ventricular hypertrophy (LVH). The relationship between LVH subtypes and the insufficiency grading of chronic MR remains unclear. Thus, we aimed to investigate this association and explore the impact of unhealthy habits on LVH development in patients with chronic primary MR through a cross-sectional study.

Cardiac magnetic resonance (CMR) data was retrospectively collected from 3T magnetic resonance imaging (MRI) scanners in 71 patients with chronic primary MR (range, 20-84 years, 52% men). Considered patients (with mild-to-severe MR) were enrolled between March 2015 and September 2022 from the Cardiovascular Imaging Registry of Calgary (CIROC) database. Left ventricle (LV) function was assessed using cvi42 v5.11.5. Patients were categorized into 'mild-to-severe' MR using regurgitation fraction (RF), according to the current imaging guidelines. LVH subtypes were determined using mass-to-volume (M/V) calculations. IBM SPSS was used to run all the statistical analyses. This study employed normality checks by using the Shapiro-Wilk test; one-way analysis of variance (ANOVA) and Kruskal-Wallis tests with post-hoc pairwise comparisons; Chi-squared tests, Fisher's Exact test, crosstabulation analysis, and multinomial logistic regression to examine relationships between MR severity, LVH types, and impact of lifestyle factors, significance at P<0.05.

Eccentric LVH was significantly associated with increased severity of MR, while concentric remodeling (CR) was linked to decreased MR severity (χ2=13.276, P=0.03, stratified by sex χ2=7.729, P=0.005). Sex differences emerged in the overall study population. Eccentric LVH was dominantly higher than CR in both males and females (females: 57.7% vs. 42.3%, P=0.05, males: 82.8% vs. 17.2%, P=0.26). No differences were observed between age groups ('Young-Middle' = under 60 years, and 'Middle-Old' = over 60 years). Still, there were notable differences in LVH prevalence within the 'Young-Middle' age group for mild-moderate (P=0.01) and moderate-severe MR (P=0.02). Eccentric LVH was associated with higher body mass index (BMI), smoking, and frequent alcohol consumption [odds ratio (OR) 1.02, 95% confidence interval (CI): 0.56-1.26; OR 1.65, 95% CI: 1.31-6.52; OR 1.15, 95% CI: 0.26-1.34], while CR was solely associated with increased BMI (smokers OR =1.84, 95% CI: 1.25-3.91 and alcohol consumers OR =1.32, 95% CI: 0.86-2.48). Nicotine and caffeine consumption did not appear to be a risk factor for LVH (nicotine: eccentric, OR =0.99, 95% CI: 0.65-1.86; CR, OR =0.97, 95% CI: 0.69-2.39 and caffeine: eccentric, OR =0.69, 95% CI: 0.48-1.61; CR, OR =0.97, 95% CI: 0.78-4.01).

This study reveals sex-based associations between LVH subtypes and severity of chronic primary MR. Lifestyle factors such as cigarette smoking, alcohol consumption, and elevated BMI influence LVH risk, while nicotine and caffeine consumption exhibit minimal effects.

The role of immune system components in the development of myocardial remodeling in chronic kidney disease (CKD) and kidney transplantation remains an open question. Our aim was to investigate the associations between immune cell subpopulations in the circulation of CKD patients and kidney transplant recipients (KTRs) with subclinical indices of myocardial performance. We enrolled 44 CKD patients and 38 KTRs without established cardiovascular disease. A selected panel of immune cells was measured by flow cytometry. Classical and novel strain-related indices of ventricular function were measured by speckle-tracking echocardiography at baseline and following dipyridamole infusion. In CKD patients, the left ventricular (LV) relative wall thickness correlated with the CD14++CD16- monocytes (β = 0.447, p = 0.004), while the CD14++CD16+ monocytes were independent correlates of the global radial strain (β = 0.351, p = 0.04). In KTRs, dipyridamole induced changes in global longitudinal strain correlated with CD14++CD16+ monocytes (β = 0.423, p = 0.009) and CD4+ T-cells (β = 0.403, p = 0.01). LV twist and untwist were independently correlated with the CD8+ T-cells (β = 0.405, p = 0.02 and β = -0.367, p = 0.03, respectively) in CKD patients, whereas the CD14++CD16+ monocytes were independent correlates of LV twist and untwist in KTRs (β = 0.405, p = 0.02 and β = -0.367, p = 0.03, respectively). Immune cell subsets independently correlate with left ventricular strain and torsion-related indices in CKD patients and KTRs without established CVD.

Non-ischemic dilated cardiomyopathy (NIDCM) is a form of heart failure with a poor prognosis and unclear optimal management. The aim of the study was to systematically review the literature and assess the efficacy and safety of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors in the management of chronic heart failure secondary to NIDCM and explore their putative mechanisms of action.

Studies from 1990 to 2023 were reviewed using PubMed and EMBASE, focusing on their effects on left ventricular ejection fraction (LVEF) in NIDCM patients, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Beta-blockers showed a significant beneficial effect on LVEF improvement in NIDCM, with an overall effect size of Cohen's d = 1.30, 95% confidence interval (CI) (0.76, 1.84), high heterogeneity (Tau2 = 0.90; Chi2 = 162.05, df = 13, P < 0.00001; I2 = 92%), and a significant overall effect (Z = 4.72, P < 0.00001). ACE inhibitors also showed a beneficial role, but with less heterogeneity (Tau2 = 0.02; Chi2 = 1.09, df = 1, P = 0.30; I2 = 8%) and a nonsignificant overall effect (Z = 1.36, P = 0.17), 95% CI (-0.24, 1.31).

The study highlights the efficacy of carvedilol in improving LVEF in NIDCM patients over ACE inhibitors, recommends beta-blockers as first-line therapy, and advocates further research on ACE inhibitors.

Doxorubicin (DOX) is a commonly used drug in chemotherapy for cancer treatment. However, it can cause the threatening side effect of cardiotoxicity. This study investigates whether the hydro-alcoholic leaves of Moringa oleifera have any protective potential against DOX-induced cardiotoxicity. The phytochemical analysis showed that the plant extracts contained bioactive compounds with antioxidant activities. The DOX-treated group confirmed a significant increment in cardiac troponin I (cTnI) and proinflammatory cytokine interleukin-6 (IL-6) levels, which indicates damage to the cardiomyocytes and also inflammation. However, treatment with the M. oleifera extracts significantly inhibited DOX-induced cardiomyocyte damage, as indicated by the significantly low cTnI release. Furthermore, treatment with M. oleifera extracts further increased antioxidant activities, thereby decreasing oxidative stress and lipid peroxidation. Moreover, DOX was found to increase the IL-6 level, and treatment with M. oleifera extracts had a significant impact on the inhibition of IL-6 levels. These results indicate that the M. oleifera extracts have a cardioprotective effect and can play a role as an adjunct drug in mitigating DOX-induced cardiotoxicity, thus providing new prospects for the improvement of safety and efficacy in the treatment of cancer.

Farnesoid X receptor (FXR) plays critical regulatory roles in cardiovascular physiology/pathology. However, the role of FXR agonist obeticholic acid (OCA) in sepsis-associated myocardial injury and underlying mechanisms remain unclear. C57BL/6J mice are treated with OCA before lipopolysaccharide (LPS) administration. The histopathology of the heart and assessment of FXR expression and mitochondria function are performed. To explore the underlying mechanisms, H9c2 cells, and primary cardiomyocytes are pre-treated with OCA before LPS treatment, and extracellular signal-regulated protein kinase (ERK) inhibitor PD98059 is used. LPS-induced myocardial injury in mice is significantly improved by OCA pretreatment. Mechanistically, OCA pretreatment decreased reactive oxygen species (ROS) levels and blocked the loss of mitochondrial membrane potential (ΔΨm) in cardiomyocytes. The expression of glutathione peroxidase 1 (GPX1), superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2), and nuclear factor erythroid 2-related factor 2 (NRF-2) increased in the case of OCA pretreatment. In addition, OCA improved mitochondria respiratory chain with increasing Complex I expression and decreasing cytochrome C (Cyt-C) diffusion. Moreover, OCA pretreatment inhibited LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway. FXR agonist OCA inhibits LPS-induced mitochondria dysfunction via suppressing ERK1/2-DRP signaling pathway to protect mice against LPS-induced myocardial injury.