Ischemic Heart Failure Patients Research Articles

Clinical value of a comprehensive clinical- and echocardiography-based risk score on predicting cardiovascular outcomes in ischemic heart failure patients with reduced ejection fraction.

The present study aimed to develop a comprehensive clinical- and echocardiography-based risk score for predicting cardiovascular (CV) adverse outcomes in patients with ischemic heart failure (IHF) and reduced left ventricular ejection fraction (LVEF). This retrospective cohort study included 1341 hospitalized patients with IHF and LVEF < 50% at our hospital from 2009 to 2017. Cox regression models and nomogram were utilized to develop a comprehensive prediction model (C&E risk score) for CV mortality and CV-related events (hospitalization or death). Over a median 26-month follow-up, CV mortality and CV events rates were 17.4% and 40.9%, respectively. The C&E risk score, incorporating both clinical and echocardiographic factors, demonstrated superior predictive performance for CV outcomes compared to models using only clinical or echocardiographic factors. Internal validation confirmed the stable predictive ability of the C&E risk score, with an AUC of 0.740 (95% CI 0.709-0.775, P < 0.001) for CV mortality and an AUC of 0.678 (95% CI 0.642-0.696, P < 0.001) for CV events. Patients were categorized into low-, intermediate-, and high-risk based on the C&E risk score, with progressively increasing CV mortality (5.3% vs. 14.6% vs. 31.9%, P < 0.001) and CV events (28.8% vs. 38.2% vs. 55.0%, P < 0.001). External validation also confirmed the risk score's prognostic efficacy within additional IHF patient datasets. This study establishes and validates the novel C&E risk score as a reliable tool for predicting CV outcomes in IHF patients with reduced LVEF. The risk score holds potential for enhancing risk stratification and guiding clinical decision-making for high-risk patients.

LIPCAR levels in plasma-derived extracellular vesicles is associated with left ventricle remodeling post-myocardial infarction

BackgroundLong Intergenic noncoding RNA predicting CARdiac remodeling (LIPCAR) is a long noncoding RNA identified in plasma of patients after myocardial infarction (MI) to be associated with left ventricle remodeling (LVR). LIPCAR was also shown to be a predictor of early death in heart failure (HF) patients. However, no information regarding the expression of LIPCAR and its function in heart as well as the mechanisms involved in its transport to the circulation is known. The aims of this study are (1) to characterize the transporter of LIPCAR from heart to circulation; (2) to determine whether LIPCAR levels in plasma isolated-extracellular vesicles (EVs) reflect the alteration of its expression in total plasma and could be used as biomarkers of LVR post-MI.MethodsSince expression of LIPCAR is restricted to human species and the limitation of availability of cardiac biopsy samples, serum-free conditioned culture media from HeLa cells were first used to characterize the extracellular transporter of LIPCAR before validation in EVs isolated from human cardiac biopsies (non-failing and ischemic HF patients) and plasma samples (patients who develop or not LVR post-MI). Differential centrifugation at 20,000g and 100,000g were performed to isolate the large (lEVs) and small EVs (sEVs), respectively. Western blot and nanoparticle tracking (NTA) analysis were used to characterize the isolated EVs. qRT-PCR analysis was used to quantify LIPCAR in all samples.ResultsWe showed that LIPCAR is present in both lEVs and sEVs isolated from all samples. The levels of LIPCAR are higher in lEVs compared to sEVs isolated from HeLa conditioned culture media and cardiac biopsies. No difference of LIPCAR expression was observed in tissue or EVs isolated from cardiac biopsies obtained from ischemic HF patients compared to non-failing patients. Interestingly, LIPCAR levels were increased in lEVs and sEVs isolated from MI patients who develop LVR compared to patients who did not develop LVR.ConclusionOur data showed that large EVs are the main extracellular vesicle transporter of LIPCAR from heart into the circulation independently of the status, non-failing or HF, in patients. The levels of LIPCAR in EVs isolated from plasma could be used as biomarkers of LVR in post-MI patients.

Association of D-dimer to albumin ratio with adverse cardiovascular outcomes in ischaemic heart failure patients with diabetes mellitus: a retrospective cohort study

ObjectiveTo determine the association of D-dimer to albumin ratio (DAR) with major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) in ischaemic heart failure patients with diabetes mellitus.DesignA retrospective...

Echocardiography-based risk score predicts cardiovascular outcomes in ischemic heart failure patients with reduced ejection fraction

Abstract Background Ischemic heart disease (IHD) is the most common cause of heart failure (HF) and serves as an important prognostic factor across the whole HF spectrum. Prognostic assessment is important for optimal patient care, and a number of prediction models or prognostic scores have been developed in the past years for risk stratification of HF patients. Purpose Present study aimed to develop a comprehensive echocardiography-based score algorism for risk assessment of ischemic heart failure (IHF) patients with reduced left ventricular ejection fraction (&amp;lt;50%). Methods This study included 1355 IHF patients with ejection fraction &amp;lt;50%, the median clinical follow-up was 25 months. Multivariable Cox hazard models were used to assess the associations between echocardiography variables [including 13 standard parameters and global longitudinal strain (GLS)] and major adverse outcomes [including all-cause mortality, cardiovascular (CV) death, and CV related hospitalization]. Results Rates of all-cause mortality, CV mortality, and combined CV events including death and hospitalization, were 29.2%, 18.2%, 41.1%, respectively. Right ventricular mid-cavity diameter (RVD)&amp;gt;38mm, mitral annular plane systolic excursion (MAPSE)&amp;lt;8mm, tricuspid annular plane systolic excursion (TAPSE)&amp;lt;12mm, transmitral early flow velocity to mitral annular velocity ratio (E/E´)&amp;gt;14.5, systolic pulmonary artery pressure (sPAP)&amp;gt;38mmHg, and absolute GLS&amp;lt;8% were identified as independent echocardiographic indexes for worse clinical outcome in the multivariable Cox models. An echocardiography-based risk score (Echo Risk Score, ranged from 0 to 6 points) was established based on these markers and patients were classified into 3 risk groups: a score of 0 to 1 as low-risk, 2 to 3 as intermediate-risk, and 4-6 as high-risk. After adjustment for all clinical covariates, high-risk patients faced 2 to 3-fold increased risk of all-cause mortality (HR 2.42, 95% CI 1.81-3.24), CV mortality (HR 2.75, 95% CI 1.88-4.02), and combined CV events (HR 1.84, 95% CI 1.43-2.36) compared with low-risk patients. Incremental predicting efficacy was evidenced after the addition of Echo Risk Score either to the model including clinical risk factors or to the model including clinical risk factors and N-terminal prohormone of brain natriuretic peptide (all P&amp;lt;0.001, Figure 1). Conclusions This new echocardiography-based risk score is significantly and independently associated with all-cause mortality and CV mortality or hospitalization in ischemic heart failure patients with reduced ejection fraction. Future studies are warranted to validate the predicting efficacy of this echocardiography-based risk score in ischemic heart failure patients with reduced ejection fraction.Figure 1

Monocyte to high-density lipoprotein cholesterol ratio predicts poor outcomes in ischaemic heart failure patients combined with diabetes: a retrospective study

BackgroundThe prevalence of ischaemic heart failure (HF) continues to increase. Diabetes mellitus (DM) concomitant with ischaemic HF increases the risk of major adverse cardiovascular events (MACEs). As a promising predictor for cardiovascular diseases, the predictive value of the monocyte to high-density lipoprotein cholesterol ratio (MHR) for MACE in the ischaemic HF with DM cohort has never been investigated before.ObjectiveWe aimed to investigate the MHR as a predictor for MACE in ischaemic HF patients with DM who underwent percutaneous coronary intervention (PCI).MethodsThis observational study enrolled 1049 patients with ischaemic HF and DM undergoing PCI from June 2017 to June 2019. The baseline data were collected. MACEs, including all-cause mortality, nonfatal myocardial infarction, and any revascularization, were recorded within the 36-month follow-up. The characteristics and incidence of MACE were analysed in four groups stratified by the quartiles of MHR. The hazard ratio for MACE was analysed with Cox regression models. The incidence of MACE in the four groups was evaluated by Kaplan‒Meier survival analysis. Restricted cubic spline analysis was performed to determine the nonlinear correlation between the MHR and MACE.ResultsAfter the 36-month follow-up, 407 patients (38.8%) experienced MACEs. The incidence of MACE was significantly higher among patients in the upper MHR quartile than among those in the lower MHR quartiles (23.4% vs. 36.0% vs. 41.4% and 54.6%; P < 0.001, respectively), which was consistent with the Kaplan‒Meier survival analyses (P < 0.0001). A multivariate Cox regression model showed that the MHR was an independent risk factor for MACE after variables were adjusted (adjusted HR: 2.11; 95% CI 1.47–3.03; P < 0.001). Its predictive effects on MACE showed no interaction with hypercholesterolemia (P > 0.05).ConclusionThe MHR was a significant and independent predictor of MACEs in ischaemic HF patients with DM undergoing PCI.

Abstract 15535: SGK1 is a Key Mediator of Pathological Cardiac Fibrosis

Background: Cardiac fibroblasts initially respond to injury adaptively, proliferating and differentiating into myofibroblasts to maintain cardiac structure and function. However, prolonged cardiac stress leads to pathological cardiac fibrosis, ultimately resulting in heart failure (HF). Thus, there is a major interest in developing therapeutic strategies to constrain fibroblast differentiation and sustained activation. We recently identified the cytosolic protein kinase, serum/glucocorticoid regulated kinase 1 (SGK1), as being largely involved with pathological remodeling in the cardiac myocyte. While there have been reports that SGK1 may also play a role in fibrosis, the mechanistic role for SGK1 in cardiac fibroblasts in response to injury remains unknown. Hypothesis: SGK1 promotes pathological cardiac fibrosis and exacerbates progression to HF. Methods: Transforming growth factor beta, (TGFβ) was used in primary cardiac fibroblasts (CFBs), in vitro , and transverse aortic constriction (TAC) was used as a HF model in mice, in vivo . CFBs were transfected with siRNA to knockdown SGK1, in vitro , and SGK1 floxed mice were injected with a novel AAV9 utilizing a myofibroblast-specific promoter to knockout SGK1 specifically in myofibroblasts (SGK1 mfbKO), in vivo . Results: SGK1 signaling was elevated in cardiac explants obtained from ischemic human HF patients which led us to further evaluate SGK1 activity in CFBs. SGK1 knockdown in CFBs attenuated TGFβ-mediated differentiation and fibrotic signaling. SGK1 mfbKO mice subjected to TAC showed preserved systolic and diastolic cardiac function, measured by echocardiography. At the biochemical level, pathological remodeling and gene markers of fibrosis were attenuated in SGK1 mfbKO mice as determined by qRT-PCR of cardiac extracts. Finally, treatment of CFBs with a small molecule SGK1 inhibitor attenuated differentiation and fibrotic signaling in response to TGFβ treatment. Conclusion: SGK1 knockdown is protective against cardiac fibrosis, attenuating differentiation and fibrotic signaling in CFBs. Further, SGK1 mfbKO protected against pathological cardiac remodeling and functional decline in a mouse model of HF, highlighting the specific pathophysiological contributions of CFBs.

CircRNA-miRNA-mRNA Deregulated Network in Ischemic Heart Failure Patients.

Noncoding RNAs (ncRNAs), which include circular RNAs (circRNAs) and microRNAs (miRNAs), regulate the development of cardiovascular diseases (CVD). Notably, circRNAs can interact with miRNAs, influencing their specific mRNA targets' levels and shaping a competing endogenous RNAs (ceRNA) network. However, these interactions and their respective functions remain largely unexplored in ischemic heart failure (IHF). This study is aimed at identifying circRNA-centered ceRNA networks in non-end-stage IHF. Approximately 662 circRNA-miRNA-mRNA interactions were identified in the heart by combining state-of-the-art bioinformatics tools with experimental data. Importantly, KEGG terms of the enriched mRNA indicated CVD-related signaling pathways. A specific network centered on circBPTF was validated experimentally. The levels of let-7a-5p, miR-18a-3p, miR-146b-5p, and miR-196b-5p were enriched in circBPTF pull-down experiments, and circBPTF silencing inhibited the expression of HDAC9 and LRRC17, which are targets of miR-196b-5p. Furthermore, as suggested by the enriched pathway terms of the circBPTF ceRNA network, circBPTF inhibition elicited endothelial cell cycle arrest. circBPTF expression increased in endothelial cells exposed to hypoxia, and its upregulation was confirmed in cardiac samples of 36 end-stage IHF patients compared to healthy controls. In conclusion, circRNAs act as miRNA sponges, regulating the functions of multiple mRNA targets, thus providing a novel vision of HF pathogenesis and laying the theoretical foundation for further experimental studies.

Impact of temporal and spatial resolution on atrial feature tracking cardiovascular magnetic resonance imaging

BackgroundMyocardial deformation assessment by cardiovascular magnetic resonance-feature tracking (CMR-FT) has incremental prognostic value over volumetric analyses. Recently, atrial functional analyses have come to the fore. However, to date recommendations for optimal resolution parameters for accurate atrial functional analyses are still lacking. MethodsCMR-FT was performed in 12 healthy volunteers and 9 ischemic heart failure (HF) patients. Cine sequences were acquired using different temporal (20, 30, 40 and 50 frames/cardiac cycle) and spatial resolution parameters (high 1.5 × 1.5 mm in plane and 5 mm slice thickness, standard 1.8 × 1.8 × 8 mm and low 3.0 × 3.0 × 10 mm). Inter- and intra-observer reproducibility were calculated. ResultsIncreasing temporal resolution is associated with higher absolute strain and strain rate (SR) values. Significant changes in strain assessment for left atrial (LA) total strain occurred between 20 and 30 frames/cycle amounting to 2,5–4,4% in absolute changes depending on spatial resolution settings. From 30 frames/cycle onward, absolute strain values remained unchanged. Significant changes of LA strain rate assessment were observed up to the highest temporal resolution of 50 frames/cycle. Effects of spatial resolution on strain assessment were smaller. For LA total strain a general trend emerged for a mild decrease in strain values obtained comparing the lowest to the highest spatial resolution at temporal resolutions of 20, 40 and 50 frames/cycle (p = 0.006–0.046) but not at 30 frames/cycle (p = 0.140). ConclusionTemporal and to a smaller extent spatial resolution affect atrial functional assessment. Consistent strain assessment requires a standard spatial resolution and a temporal resolution of 30 frames/cycle, whilst SR assessment requires even higher settings of at least 50 frames/cycle.

Obesity Paradox in Heart Failure Revisited: Etiology as Effect Modifier

The prognostic value of overweight/obesity in heart failure (HF) may vary according to HF etiologies. We aim to determine whether body mass index has differential impacts on survival among hospitalized HF patients with varying etiologies. Consecutive hospitalized HF patients between December 2006 and December 2017 were included. Multivariable analyses, including Cox proportional hazard models and restricted cubic splines, were used to investigate the impact of body mass index on mortality by HF etiology. Among the 3,836 patients included (mean age 57.1years, 28.4% women), 1,475 (38.5%) were identified as having ischemic etiology. Of the remaining 2,361 patients with non-ischemic etiologies, dilated cardiomyopathy (DCM) accounted for 45.6% (n=1,077). The rest of the patients were uniformly classified as having non-ischemic-non-DCM HF. The unadjusted data demonstrated an adiposity-related survival paradox in HF across all etiologies. However, the paradox holds only among non-ischemic-non-DCM HF patients after multivariate adjustment, wherein overweight patients exhibit the lowest mortality compared with their normal-weight counterparts (adjusted hazard ratio [aHR] 0.69, 95% confidence interval [CI] 0.52 to 0.91), with a nadir in mortality risk at 28.18kg/m2. Similar survival benefits of overweight were not demonstrated in ischemic or DCM HF patients (ischemic etiology: aHR 1.07, 95% CI 0.84 to 1.36; DCM etiology: aHR 0.97, 95% CI 0.74 to 1.28). In conclusion, being overweight or obese does not confer better survival in HF patients of ischemic or DCM etiology, and the prognostic benefit of being overweight is maintained only in non-ischemic-non-DCM HF patients. Pathophysiologic interpretations are warranted, and whether patients of certain etiologies would benefit from weight reduction needs to be explored.

Correlation between Heart Rate Recovery &amp; Global Longitudinal Strain in Heart Failure Patients Subjected to Cardiac Rehabilitation

Abstract Background Cardiac rehabilitation is a medically supervised program designed to improve cardiovascular outcomes after MI, heart failure, angioplasty, or heart surgery. It is a complex intervention that involves a variety of therapies, including supervised exercise training, health education and risk factor modification, behavior change, social and psychological support. Objective To study the correlation between heart rate recovery &amp; global longitudinal strain in heart failure patients subjected to cardiac rehabilitation. Patients and Methods This study was conducted in the cardiac rehabilitation (CR) unit in the cardiology department of Ain Shams University hospital between December 2019 and December 2020 to investigate the correlation between heart rate recovery &amp; global longitudinal strain in heart failure patients subjected to cardiac rehabilitation. Results Our study is the first study that investigated the correlation between HRR and GLS in ischemic heart failure patients subjected to cardiac rehabilitation. Conclusion Exercise-based cardiac rehabilitation leads to improvement in the functional capacity of ischemic heart failure patients as reflected by the improvement in HRR and also leads to IMPROVEMENT in LV functions as reflected by the improvement in GLS. Moreover, METs and HR reserve was improved significantly with CR.

Prognostic value of mitral regurgitation in patients with heart failure undergoing cardiac resynchronization therapy

Abstract Funding Acknowledgements Type of funding sources: None. Background Cardiac resynchronization therapy (CRT) is a well-established treatment for specific groups of heart failure (HF) patients. CRT improves outcomes in ischemic and non-ischemic HF patients, depending on different predictors. Mitral regurgitation (MR) is a common echocardiographic finding with uncertain reported impact on prognosis. Purpose We sought to investigate clinical outcomes in HF patient undergoing CRT according to MR severity, for both ischemic and non-ischemic HF etiology. A transthoracic echocardiogram was performed before and 1-year after device-based therapy to all patients (in doubtful cases, a cardiac magnetic resonance imaging was also performed to evaluate the mitral regurgitant volume). Methods Single-center retrospective study of consecutive patients submitted to CRT implantation. Patients were stratified attending to MR at baseline and after CRT, as having significant (moderate and severe MR) or non-significant MR. The primary endpoint was a composite of major adverse cardiac events (MACE), including HF hospitalization or all-cause mortality. Sustained ventricular arrhythmic events were the secondary endpoint. Results 117 HF patients (mean age 71.1 ± 10.6 years, males 67.5%) were enrolled, 31.6% had an ischemic HF etiology and 23.9% were included in the baseline significant MR (SMR) group. Regarding baseline characteristics, 40.2% had atrial fibrillation (AF), 23.9% obstructive pulmonary disease (COPD) and 9% peripheral artery disease (PAD). Patients in SMR group had more dyslipidemia (p = 0.026) and lower left ventricular ejection fraction (median 25% vs 32%, p = 0.001). At 1-year of follow-up, 11.1% had significant MR, most (61.5%) with the same MR baseline degree and presented with higher NYHA class (p = 0.032). During the follow-up, 15.4% reached the primary endpoint while 8.5% the secondary endpoint. Ischemic etiology (p = 0.204, p = 0.191) and the severity of baseline MR (p = 0.106, p = 0.213) did not predict any of the endpoints. On the contrary, male gender (p = 0.033), alcohol consumption (p = 0.003), PAD (p = 0.004) and COPD (p = 0.005) were independent predictors for MACE endpoint at a multivariable analysis. For the secondary endpoint, PAD (p = 0.020) and AF (p = 0.001) were both significant predictors. Significant MR after CRT implantation was an independent strong predictor only for MACE outcome (HR 4.37, p = 0.014). Conclusions Baseline significant MR was not associated with clinical outcomes after CRT implantation. However, MR at follow-up was a strong determinant of higher mortality and HF hospitalizations in more symptomatic patients, regardless of HF etiology.

Prognostic impacts of geriatric nutritional risk index in patients with ischemic heart failure after percutaneous coronary intervention

Malnutrition has been proven to be associated with increased risk of poor prognosis in a series of diseases. This study explored the association between poor nutritional status and prognosis in patients with ischemic heart failure (IHF) undergoing percutaneous coronary intervention (PCI). The study enrolled 1745 patients with IHF undergoing PCI. The mean follow-up time was 28.7 months. Nutritional status was assessed by geriatric nutritional risk index (GNRI). All patients were divided into four groups according to GNRI quartiles (median and interquartile range: 103.8, 99.9-107.7). The primary endpoint was major adverse cardiovascular events (MACE), and the secondary endpoints were each component of the primary endpoint as follows: all-cause mortality, non-fatal myocardial infarction (MI), and any revascularization. The Kaplan-Meier survival analyses were performed to evaluate the incidence of the endpoints among 4 groups. The multivariate Cox proportional hazards analysis confirmed the independent effect of GNRI on the primary endpoint and secondary endpoints. The restricted cubic spline (RCS) was performed to evaluate the non-linear association of GNRI with MACE. The negative correlation of the GNRI with MACE (Log-rank P<0.001), all-cause mortality (Log-rank P<0.001) and any revascularization (Log-rank P<0.001) was confirmed through the Kaplan-Meier curves. Multivariate analysis showed that the decreased GNRI was independently related to increased risk of MACE (Quartile 1 versus Quartile 4: HR, 95% CI: 2.66, 2.01-3.51, P<0.001), all-cause mortality (Quartile 1 versus Quartile 4: HR, 95% CI: 2.33, 1.54-3.50, P<0.001) and any revascularization (Quartile 1 versus Quartile 4: HR, 95% CI: 3.42, 2.22-5.27, P<0.001). In addition, the non-linear association of GNRI with MACE was shown through RCS and the risk of MACE decreased as the GNRI increased in general (Non-linear P<0.001). Decreased GNRI was an independent risk factor of MACE in IHF patients undergoing PCI.

Diabetes mellitus status modifies the association between N-terminal B-type natriuretic peptide and all-cause mortality risk in ischemic heart failure: a prospective cohort study

BackgroundN-terminal B-type natriuretic peptide (NT-proBNP) discriminates mortality risk in diabetes mellitus (DM) and in heart failure (HF) populations. Whether DM status modifies the association between NT-proBNP and all-cause mortality risk in ischemic HF is unknown.MethodsThis was a single-center, prospective cohort study conducted with 2287 ischemic HF patients. Subjects were divided into with DM group and without DM group. Multivariate Cox proportional-hazards models were conducted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). The product of DM status and NT-proBNP were used to assess the interaction. Propensity score matching analysis was used to verify the robustness of the results.ResultsOf 2287 ischemic HF participants, 1172 (51.2%) had DM. After a median follow-up of 3.19 years (7287 person-years), 479 (20.9%) of the participants died. After adjusting for the covariates, continuous NT-proBNP was more prominently associated with risk of mortality in HF patients with DM (HR: 1.65, 95% CI: 1.43–1.91) than those without (HR: 1.28, 95% CI: 1.09–1.50). A significant interaction of DM status and NT-proBNP was observed (P-interaction = 0.016). The relationships were consistent when NT-proBNP was considered as a categorical variable and in the propensity matching analysis.ConclusionsDM status modified the association between NT-proBNP and all-cause mortality in ischemic HF patients, suggesting that NT-proBNP was more prominently associated with risk of mortality in patients with DM than those without. Future studies to clarify the mechanisms underlying these observations are needed.

Plasma Galectin-3 and H-FABP correlate with poor physical performance in patients with congestive heart failure.

Heart failure (HF) is often associated with compromised physical capacity in patients. However, it is unclear if established HF markers correlate with the physical performance of patients with congestive HF (CHF). We assessed the left ventricular end-systolic dimension (LVESD) and ejection fraction (LVEF) and, physical performance parameters, including short physical performance battery (SPPB), gait speed (GS), and handgrip strength (HGS) in 80 patients with CHF along with 59 healthy controls. Furthermore, levels of plasma HF markers galectin-3 and heart-specific fatty acid binding protein (H-FABP) were measured in relation to the severity of HF and physical performance. Irrespective of etiology, significantly greater LVESD and lower LVEF were observed in HF patients versus controls. As expected, the levels of HF markers galectin-3 and H-FABP were upregulated in the CHF patients which were accompanied by significantly elevated levels of plasma zonulin and inflammatory marker C-reactive protein (CRP). The SPPB scores, GS, and HGS were significantly lower in the ischemic and non-ischemic HF patients than controls. The level of galectin-3 was inversely correlated with SPPB scores (r2 = 0.089, P = 0.01) and HGS (r2 = 0.078, P = 0.01). Similarly, H-FABP levels were also inversely correlated with SPPB scores (r2 = 0.06, P = 0.03) and HGS (r2 = 0.109, P = 0.004) in the patients with CHF. Taken together, CHF adversely affects physical performance, and galectin-3 and H-FABP may serve as biomarkers of physical disability in patients with CHF. The robust correlations of galectin-3 and H-FABP with the physical performance parameters and CRP in CHF patients suggest that the poor physical performance may partly be caused due to systemic inflammation.

Ciclopirox Inhibition of eIF5A Hypusination Attenuates Fibroblast Activation and Cardiac Fibrosis.

Cardiac fibrosis is a primary contributor to heart failure (HF), and is considered to be a targetable process for HF therapy. Cardiac fibroblast (CF) activation accompanied by excessive extracellular matrix (ECM) production is central to the initiation and maintenance of fibrotic scarring in cardiac fibrosis. However, therapeutic compounds targeting CF activation remain limited in treating cardiac fibrosis. Eukaryotic translation initiation factor 5A (eIF5A), upon being hypusinated, is essential for the translation elongation of proline-codon rich mRNAs. In this study, we found that increased hypusinated eIF5A protein levels were associated with cardiac fibrosis and heart dysfunction in myocardial infarction (MI) mouse models. Ciclopirox (CPX), an FDA-approved antifungal drug, inhibits the deoxyhypusine hydroxylase (DOHH) enzyme required for eIF5A hypusination. Results from preventive and reversal mouse models suggest that CPX treatment significantly reduced MI-driven cardiac fibrosis and improved cardiac function. In vitro studies of isolated mouse primary CFs revealed that inhibition of eIF5A hypusination using CPX significantly abolished TGFβ induced CF proliferation, activation, and collagen expression. Proteomic analysis from mouse CFs reveals that CPX downregulates the expression of proline-rich proteins that are enriched in extracellular matrix and cell adhesion pathways. Our findings are relevant to human heart disease, as increased hypusinated eIF5A levels were observed in heart samples of ischemic heart failure patients compared to healthy subjects. Together, these results suggest that CPX can be repurposed to treat cardiac fibrosis and ischemic heart failure.

Baroreflex sensitivity but not microvolt T-wave alternans can predict major adverse cardiac events in ischemic heart failure.

Major adverse cardiovascular events (MACE) constitutes the main cause of morbidity and mortality in ischemic heart failure (HF) patients. The prognostic value of the autonomic nervous system parameters and microvolt T-wave alternans (MTWA) in this issue has not been identified to date. The aim herein, was to assess the usefulness of the abovementioned parameters in the prediction of MACE in HF patients with left ventricular systolic dysfunction of ischemic origin. Baroreflex sensitivity (BRS), heart rate variability (HRV), MTWA and other well-known clinical parameters were analyzed in 188 ischemic HF outpatients with left ventricular ejection fraction (LVEF) ≤ 50%. During 34 (14-71) months of follow-up, 56 (30%) endpoints were noted. Univariate Cox analyses revealed BRS (but not HRV), MTWA, age, New York Heart Association functional class III, LVEF, implantable cardioverter-defibrillator presence, use of diuretics and antiarrhythmic drugs, diabetes, and kidney insufficiency were defined as significant predictors of MACE. Pre-specified cut-off values for MACE occurrence for the aforementioned continuous parameters (age, LVEF, and BRS) were: ≥ 72 years, ≤ 33%, and ≤ 3 ms/mmHg, respectively. In a multivariate Cox analysis only BRS (HR 2.97, 95% CI 1.35-6.36, p < 0.006), and LVEF (HR 1.98, 95% CI 0.61-4.52, p < 0.038) maintained statistical significance in the prediction of MACE. Baroreflex sensitivity and LVEF are independent of other well-known clinical parameters in the prediction of MACE in patients with HF of ischemic origin and LVEF up to 50%. BRS ≤ 3 ms/mmHg and LVEF ≤ 33% identified individuals with the highest probability of MACE during the follow-up period.

Prognostic Significance of Statins in Ischemic and Non-ischemic Heart Failure Patients with Reduced Ejection Fraction in Real Life.

Although the positive effects of statin therapy in cardiovascular diseases are known, current heart failure guidelines do not recommend statins. The aim of this study was to investigate the effect of statin on all-cause mortality in patients with ischemic or non-ischemic heart failure with low ejection fraction using real-life data. In this study, 1144 patients with heart failure with low ejection fraction were included retrospectively. In the study cohort, 55.4% were ischemic heart failure patients and 42.4% of the patients were on statin therapy. The rate of patients using statins was 60.5% in the ischemic group and 20.2% in the non-ischemic group (P <.001). During the median 35-month follow-up, 337 deaths were observed. Mortality rates were similar in ischemic and non-ischemic groups (31.3% vs 26.9%, P =.092). When the statin usage status of the patients was examined, ischemic heart failure, all survivors, and survivors with ischemic heart failure were using statins at a higher rate (P <.001). In the Kaplan-Meier analysis of all patients, the mortality rate was 22.7% in statin users, while the mortality rate was significantly higher in those who did not use statins, 34.4% (P <001). All-cause mortality was significantly higher in patients with ischemic heart failure not using statins than in patients using statins (P <.001) but not in non-ischemic heart failure (P =.07). Using statin was an independent predictor of all-cause mortality in all patients (hazard ratio: 0.661, 95% CI: 0.518-0.843, P =.001) and ischemic heart failure patients (hazard ratio: 0.618, 95% CI: 0.456-0.838, P =.002). Since statin use reduces all-cause mortality in patients with ischemic heart failure, it may be recommended to continue statin therapy.

Plasma zonulin correlates with cardiac dysfunction and poor physical performance in patients with chronic heart failure

AimsAn aberrant intestinal permeability is often associated with systemic inflammation and cardiovascular diseases accompanied by compromised physical performance. However, the link between these complications is poorly defined. Here we investigated the potential association of zonulin, a regulator of intestinal permeability, with ischemic and non-ischemic heart failure (HF) and, associated physical disability. Main methodsThe investigation including echocardiography, short physical performance battery (SPPB) and measurement of plasma zonulin and c-reactive protein (CRP), was performed in 59 HF patients and an equal number of healthy controls. Key findingsAs expected, the left ventricular end-systolic dimension (LVESD) was significantly higher, which was accompanied by a significantly lower LV ejection fraction (EF) in the HF patients compared to controls. The levels of plasma zonulin and CRP was profoundly elevated in both ischemic (P < 0.0001) and non-ischemic (P < 0.01) HF patients. Interestingly, LVESD positively (r2 = 0.156, P = 0.001) and LVEF negatively (r2 = 0.186, P = 0.0006) correlated with the level of zonulin in HF patients. The SPPB scores for balance, chair sit-to-stand (STS), gait speed (GS), and hand grip strength (HGS) were consistently compromised in HF patients. Moreover, LVESD was negatively (r2 = 0.118, P = 0.007), and there was trend of positive correlation of LVEF (r2 = 0.05, P = 0.08) with the SPPB scores for balance. Consistently, zonulin levels was negatively correlated with SPPB scores for balance (r2 = 0.176, P = 0.0009), STS (r2 = 0.120, P = 0.001) and HGS (r2 = 0.085, P = 0.02). SignificanceChronic cardiac complications induce the level of plasma zonulin, which predicts the cardiac remodeling and dysfunction and physical performance in patients with chronic HF.

Pulse pressure and all-cause mortality in ischaemic heart failure patients: a prospective cohort study

Background Whether the association between pulse pressure (PP) and mortality varies with systolic blood pressure (SBP) in ischaemic heart failure (HF) with left ventricular systolic dysfunction (LVSD) is unknown. Objective To evaluate the association between PP and all-cause mortality in ischaemic HF patients with SBP status at admission. Patients and methods This prospective cohort study included 1581 ischaemic HF patients with LVSD. A total of 23.3% (n = 368) and 22.2% (n = 351) of the participants had SBP <110 mmHg and SBP >140 mmHg, respectively, with more than 80% of participants being male. Restricted cubic spline was performed to determine whether a nonlinear relationship existed between PP and all-cause mortality risk. A multivariable Cox proportional hazards model was used to assess the association between PP and all-cause mortality. Results After a median of follow-up of 3.0 years, 257 events (16.4%) were observed in the cohort. There was a J-shaped relationship between PP and all-cause mortality (P value for nonlinearity = 0.020), with a risk nadir of approximately 46–49 mmHg. All-cause mortality risk varied with SBP status. Higher PP was associated with worse prognosis when the SBP was ≥110 mmHg, whereas the relationship did not reach statistical significance when the SBP was <110 mmHg. Conclusion A J-shaped relationship between PP and all-cause mortality was observed in ischaemic HF patients with LVSD, and higher PP was associated with worse prognosis only in those with SBP ≥110 mmHg. Further studies are needed to corroborate these findings. KEY MESSAGES A J-shaped relationship between pulse pressure and all-cause mortality was observed in ischaemic heart failure patients with left ventricular systolic dysfunction, with a risk nadir of approximately 46–49 mmHg. All-cause mortality risk varied with systolic blood pressure status, and higher pulse pressure was associated with worse prognosis when systolic blood pressure was above 110 mmHg.

Cd4+ T cell phenotypes, autoantibodies and transcriptional signatures overlap between myocarditis, ischemic and nonischemic heart failure, suggesting shared inflammatory pathogenic mechanisms

Abstract Background Myocarditis may progress to heart failure (HF) often as a result of viral myocardial infection where cardiomyocyte damage exposes sequestered self-antigens including cardiac myosin (CM) leading to autoimmunity. CM acts as an adjuvant via activation of Toll-like receptor (TLR)2 and TLR8, and is a potent autoantigen promoting HF in myocarditis through elevated IL-6, IL-17A and Th17 differentiation concomitant with autoantibody responses against CM. Since cardiomyocyte damage also occurs in ischemic and nonischemic cardiomyopathies, we investigated the hypothesis that ischemic and nonischemic HF would have similar inflammatory phenotypes. Purpose We defined CD4+ T helper cell phenotypes, autoantibodies, and peripheral blood transcriptome of the inflammatory phenotypes in myocarditis, compared to ischemic, and nonischemic HF. The identification of immune phenotypes in myocarditis and HF are important for consideration of inflammatory interventions and immunotherapies in myocarditis and HF. Methods Peripheral blood was collected from myocarditis patients within 6 months of disease onset, and from clinically stable, chronic HF patients. CD4+ T helper cells (Th1, Th2, and Th17) were evaluated by flow cytometry after density gradient separation, and human CM autoantibody titers were determined by ELISA. Whole blood RNA sequencing, Ingenuity Pathway Analysis (IPA), as well as multi-contrast pathway enrichment were performed. Results (Fig. 1A) Significantly elevated human CM autoantibodies were observed in myocarditis, ischemic and nonischemic HF patients, and correlated with nonrecovered patients and poor outcomes. (Fig. 1B) Myocarditis and nonischemic HF patients had significantly elevated Th17 and Th2 frequencies. Ischemic HF patients had a trend toward elevated Th 17 and Th 2 CD4+ T cell frequencies. None of the cohorts demonstrated an elevation in Th1 (not shown) (Fig 2A), IPA canonical pathway enrichment for all cohorts together showed elevated pathways concordant with our proposed pathogenic mechanisms in myocarditis and HF, including TLR and inflammasome signaling and IL17A and IL13 pathways (Fig. 2B). Myocarditis and nonischemic HF shared more inflammatory pathway enrichment in common than ischemic HF (Fig. 2C) Multi contrast pathway enrichment demonstrated that males in each cohort shared TLR and IL1b signaling that was not observed in females. Conclusion Nonischemic HF patients have overlapping immunological features with myocarditis including elevated anti-CM autoantibodies, as well as Th17, and Th2 frequencies. Ischemic HF demonstrated elevated CM autoantibodies and fewer inflammatory genes and pathways. The transcriptome supported the immune phenotypes in myocarditis and heart failure suggesting pathogenic autoimmune and inflammatory mechanisms shared in myocarditis and ischemic HF. The results have implications for immunomodulatory therapies in myocarditis and HF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health