Risk Of Chronic Heart Failure Research Articles

The effects of psychiatric disorders on the risk of chronic heart failure: a univariable and multivariable Mendelian randomization study.

Substantial evidence suggests an association between psychiatric disorders and chronic heart failure. However, further investigation is needed to confirm the causal relationship between these psychiatric disorders and chronic heart failure. To address this, we evaluated the potential effects of five psychiatric disorders on chronic heart failure using two-sample Mendelian Randomization (MR). We selected single nucleotide polymorphisms (SNPs) associated with chronic heart failure and five psychiatric disorders (Attention-Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Major Depression, Bipolar Disorder and Schizophrenia (SCZ)). Univariable (UVMR) and multivariable two-sample Mendelian Randomization (MVMR) were employed to assess causality between these conditions. Ever smoked and alcohol consumption were controlled for mediating effects in the multivariable MR. The inverse variance weighting (IVW) and Wald ratio estimator methods served as the primary analytical methods for estimating potential causal effects. MR-Egger and weighted median analyses were also conducted to validate the results. Sensitivity analyses included the funnel plot, leave-one-out, and MR-Egger intercept tests. Additionally, potential mediators were investigated through risk factor analyses. Genetically predicted heart failure was significantly associated with ADHD (odds ratio (OR), 1.12; 95% CI, 1.04-1.20; p = 0.001), ASD (OR, 1.29; 95% CI, 1.07-1.56; p = 0.008), bipolar disorder (OR, 0.89; 95% CI, 0.83-0.96; p = 0.001), major depression (OR, 1.15; 95% CI, 1.03-1.29; p = 0.015), SCZ (OR, 1.04; 95% CI, 1.00-1.07; p = 0.024). Several risk factors for heart failure are implicated in the above cause-and-effect relationship, including ever smoked and alcohol consumption. Our study demonstrated ADHD, ASD, SCZ and major depression may have a causal relationship with an increased risk of heart failure. In contrast, bipolar disorder was associated with a reduced risk of heart failure, which could potentially be mediated by ever smoked and alcohol consumption. Therefore, prevention strategies for heart failure should also incorporate mental health considerations, and vice versa.

Circulating 3-hydroxy butyrate predicts mortality in patients with chronic heart failure with reduced ejection fraction.

In patients with chronic heart failure with reduced ejection fraction (HFrEF), myocardial ketone metabolism is increased and short-term treatment with the ketone body 3-hydroxy butyrate (3-OHB) has beneficial haemodynamic effects. In patients with HFrEF, we investigated whether the level of circulating 3-OHB predicted all-cause mortality and sought to identify correlations between patient characteristics and circulating 3-OHB levels. We conducted a cohort study in 218 patients with HFrEF. Plasma 3-OHB levels were measured using high-performance liquid chromatography tandem mass spectrometry. Data on all-cause mortality were obtained by reviewing the patients' medical records, which are linked to the national 'Central Person Registry' that registers the timing of all deaths in the country. Mean left ventricular ejection fraction was 35±8.6%, mean age was 67±10years, 54% were New York Heart Association II, and 27% had type 2 diabetes mellitus. Median follow-up time was 7.3 (interquartile range 6.3-8.4) years. We observed large variations in 3-OHB levels between patients (median 59μM, range: 14-694μM). Patients with 3-OHB levels above the median displayed a markedly increased risk of death compared with those with low levels {hazard ratio [HR]: 2.1 [95% confidence interval (CI): 1.3-3.5], P=0.003}. In a multivariate analysis, 3-OHB predicted mortality independently of known chronic heart failure risk factors [HR: 1.004 (95% CI: 1.001-1.007), P=0.02] and with a similar statistical strength as N-terminal pro-brain natriuretic peptide (NT-proBNP) [HR: 1.0005 (95% CI: 1.000-1.001), P=0.02]. For every 100μmol increase in plasma 3-OHB, the hazard of death increased by 49%. The following factors significantly predicted 3-OHB levels in the univariate analysis: free fatty acids (FFAs) [β: 238 (95% CI: 185-292), P<0.0001], age [β: 2.43 (95% CI: 1.14-3.72), P<0.0001], plasma insulin {β: -0.28 [95% CI: -0.54-(-0.02)], P=0.036}, body mass index {β: -3.15 [95% CI: -5.26-(-0.05)], P=0.046}, diabetes [β: 44.49 (95% CI: 14.84-74.14), P=0.003], glycosylated haemoglobin [β: 1.92 (95% CI: 0.24-3.59), P=0.025], New York Heart Association class [β: 26.86 (95% CI: 5.99-47.72), P=0.012], and NT-proBNP [β: 0.03 (95% CI: 0.01-0.04), P=0.001]. In a multivariate analysis, only FFAs predicted 3-OHB levels [β: 216 (95% CI: 165-268), P>0.001]. In patients with HFrEF, circulating 3-OHB was a strong predictor of all-cause mortality independently of NT-proBNP. Circulating FFAs were the best predictor of 3-OHB levels.

Abstract 13344: Differential Impact of Self-Care Behaviour on Mortality Between Patients With Stable and Recent Worsening Chronic Heart Failure

Backgrounds: Although self-care is crucial to maintain health and recommended in the guidelines in patients with chronic heart failure (CHF), its prognostic significance is controversial. We hypothesized that self-care is more effective in vulnerable patients with recent hospitalization due to worsening HF (WHF). The aim of this study was to investigate the prognostic significance of self-care behaviour on mortality between patients with stable and recent worsening CHF. Methods: We prospectively examined consecutive 1,873 CHF patients from a Japanese multicenter registry and assessed the European Heart Failure Self-care Behaviour Scale (EHFScBS) at enrollment. The patients were divided into inpatient due to WHF (WHF group) and outpatient stable CHF (stable CHF group). The optimal EHFScBS was defined as more than 70 based on previous reports. The primary outcome was all-cause death. Results: Of studied patients (1,102 male, mean age 72 ± 13 years), 625 (33%) and 1,165 (67%) were classified into WHF and stable CHF groups, respectively. During a median follow-up period of 427 (IQR 273 - 642) days, the primary outcome occurred in 50 patients. In stable CHF group, there was no significant difference on primary outcome between optimal and suboptimal EHFScBS (P = 0.65) (Figure A). On the other hand, patients with suboptimal EHFScBS showed a higher incidence of death than those with optimal score in WHF group (P = 0.01) (Figure B). In WHF group, Cox regressions showed that the EHFScBS score was independently associated with mortality (HR 0.51, 95% CI 0.26-0.99) adjusted for significant covariates including hemoglobin, estimated glomerular filtration rate, serum sodium, log NT-proBNP, and the Meta-Analysis Global Group in Chronic Heart Failure risk score. Conclusions: In patients with recent worsening, not stable CHF, the EHFScBS was associated with subsequent mortality, indicating that the self-care education might be more effective for patients with recent worsening CHF.

Polymorphisms of the NCF4 Gene Increase the Risk of Chronic Heart Failure in Patients with Type 2 Diabetes Mellitus

Polymorphisms of the NCF4 Gene Increase the Risk of Chronic Heart Failure in Patients with Type 2 Diabetes Mellitus

Expression of m6A Regulator Genes can Facilitate the Diagnosis of Chronic Heart Failure.

RNA N6-methyladenosine (m6A) is the most common type of modification in eukaryotic mRNA. The relationship between m6A modification and disease has been studied extensively, but there have been few studies on chronic heart failure (CHF). This study investigated a possible role for m6A in the diagnosis of CHF. Seven candidate m6A regulators (writers: WTAP and ZC3H13; readers: YTHDF3, FMR1, IGFBP1, and ELAVL1; eraser: FTO) were identified using a random forest (RF) model and the GSE5406 dataset from the Gene Expression Omnibus database. A nomogram model was developed to predict the risk of CHF, while consensus clustering methodology assigned CHF samples into two m6A patterns (cluster A and cluster B) according to the 7 candidate m6A regulators. Principal component analysis was used to calculate an m6A score for each sample and to quantify m6A patterns. Decision curve analysis and the nomogram model were used to obtain predictions that may be of clinical use. Patients in cluster B had higher m6A scores than patients in cluster A. Cluster B patients also had higher expression levels (ELs) of IL-4, IL-5, IL-10 and IL-13 than patients in cluster A, whereas cluster A patients had a higher EL for IL-33. The m6A cluster B pattern likely represents the ischemic heart failure (HF) disease group. m6A regulators are important in the pathogenesis of CHF associated with ischemic and idiopathic dilated cardiomyopathy, and may prove useful for the diagnosis and treatment of CHF.

Empagliflozin and colchicine in patients with reduced left ventricular ejection fraction following ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: a study protocol for a randomized, double-blinded, three-arm parallel-group, controlled trial

BackgroundPatients with acute myocardial infarction are at greater risk for chronic heart failure and mortality. Currently, there is limited evidence supporting the beneficial effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular outcomes in non-diabetic patients with reduced left ventricular ejection fraction following acute myocardial infarction. Furthermore, the clinical effects of the combination of standard-dose sodium-glucose cotransporter-2 inhibitors with colchicine and high-dose sodium-glucose cotransporter-2 inhibitors in this setting have not been evaluated yet.MethodsA prospective, double-blinded, parallel-group, placebo control randomized trial will be carried out at Shahid Madani Heart Center, the largest teaching referral hospital for cardiovascular diseases, affiliated with Tabriz University of Medical Sciences. A total of 105 patients with reduced left ventricular ejection fraction (≤ 40%) following the first episode of ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention with stent insertion will be randomized 1:1:1 to receive empagliflozin 10 mg daily, a combination of empagliflozin 10 mg daily and colchicine 0.5 mg twice daily, or empagliflozin 25 mg daily for 12 weeks. The primary outcomes are changes in the New York Heart Association functional classification and high-sensitivity C-reactive protein from the randomization through week 4 and week 12.DiscussionThe present study will be the first trial to evaluate the efficacy and safety of early treatment with the combination of standard-dose empagliflozin and colchicine as well as high-dose empagliflozin in non-diabetic patients with reduced left ventricular ejection fraction following ST-elevation myocardial infarction. The results of this research will represent a significant step forward in the treatment of patients with acute myocardial infarction.Trial registrationClinical trial ID: IRCT20111206008307N39. Registration date: 27 October 2022.Graphical

Baroreflex activation therapy in patients with heart failure with reduced ejection fraction: a single-centre experience.

Heart failure with reduced ejection fraction (HFrEF) is associated with excessive sympathetic and impaired parasympathetic activity. The Barostim Neo™ device is used for electronical baroreflex activation therapy (BAT) to counteract autonomic nervous system dysbalance. Randomized trials have shown that BAT improves walking distance and reduces N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels at least in patients with only moderate elevation at baseline. Its impact on the risk of heart failure hospitalization (HFH) and death is not yet established, and experience in clinical routine is limited. We report on patient characteristics and clinical outcome in a retrospective, non-randomized single-centre registry of BAT in HFrEF. Patients in the New York Heart Association (NYHA) Classes III and IV with a left ventricular ejection fraction (LVEF) <35% despite guideline-directed medical therapy were eligible. Symptom burden, echocardiography, and laboratory testing were assessed at baseline and after 12months. Clinical events of HFH and death were recorded at routine clinical follow-up. Data are shown as number (%) or median (inter-quartile range). Between 2014 and 2020, 30 patients were treated with BAT. Median age was 67 (63-77) years, and 27 patients (90%) were male. Most patients (83%) had previous HFH. Device implantation was successful in all patients. At 12months, six patients had died and three were alive but did not attend follow-up. NYHA class was III/IV in 26 (87%)/4 (13%) patients at baseline, improved in 19 patients, and remained unchanged in 5 patients (P<0.001). LVEF improved from 25.5 (20.0-30.5) % at baseline to 30.0 (25.0-36.0) % at 12months (P=0.014). Left ventricular end-diastolic diameter remained unchanged. A numerical decrease in NT-proBNP [3165 (880-8085) vs. 1001 (599-3820) pg/mL] was not significant (P=0.526). Median follow-up for clinical events was 16 (10-33) months. Mortality at 1 (n=6, 20%) and 3years (n=10, 33%) was as expected by the Meta-Analysis Global Group in Chronic Heart Failure risk score. Despite BAT, event rate was high in patients with NYHA Class IV, NT-proBNP levels >1600pg/mL, or estimated glomerular filtration rate (eGFR) <30mL/min at baseline. NYHA class and eGFR were independent predictors of mortality. Patients with HFrEF who are selected for BAT are in a stage of worsening or even advanced heart failure. BAT appears to be safe and improves clinical symptoms and-to a modest degree-left ventricular function. The risk of death remains high in advanced disease stages. Patient selection seems to be crucial, and the impact of BAT in earlier disease stages needs to be established.

Elevated blood acetoacetate levels reduce major adverse cardiac and cerebrovascular events risk in acute myocardial infarction.

Although elevated blood ketone body levels reduce major adverse cardiac and cerebrovascular events (MACCEs) risk in chronic heart failure, their relationship with acute myocardial infarction remains unknown. We investigated this relationship in patients with acute myocardial infarction. This single-institution retrospective observational study analyzed data from 114 patients with acute myocardial infarction at Nihon University Hospital from May 1, 2018, to November 1, 2022. The cut-off value of acetoacetate for the incidence of in-hospital MACCE was determined by drawing a receiver operating characteristic curve (ROC) and defining patients with acetoacetate above and below the optimal cut-off point value as ROC and low-acetoacetate (LA) groups, respectively. Propensity score matching was performed between the LA and high-acetoacetate (HA) groups. Sex, peak creatine kinase, lactate, and blood glucose were defined as confounding factors between in-hospital MACCEs and acetoacetate, and 1:1 propensity score matching between the LA and HA groups was used, resulting in 40 patients from both groups enrolled in the analysis. There was a significantly lower incidence of in-hospital MACCEs in the HA group (LA group: 9 [22%] vs HA group: 1 [3%], P = 0.014). In conclusion, in acute myocardial infarction, elevated blood acetoacetate levels reduce the risk of MACCE.

Cardiovascular outcomes of β-blocker-calcium channel blocker initial dual therapy vs. other initial dual therapies in Chinese patients with hypertension: A real-world retrospective study.

This retrospective study compared cardiovascular (CV) outcomes between initial β-blocker (BB)+calcium channel blocker (CCB) dual therapy ("B+C") and other initial dual therapies in Chinese newly diagnosed hypertensive patients. In this study, all patients in a regional electronic database with newly diagnosed hypertension from January 01, 2012 to December 31, 2016 who received any initial optimal dual therapy recommended by the Chinese hypertension guideline were included. 1:2 propensity score matching (PSM) was used to balance baseline characteristics between patients receiving B+C and patients receiving other initial dual therapies ("Others"). The primary outcome was major adverse cardiovascular events (MACE) that occurred from January 01, 2012 to December 31, 2017, consisting of non-fatal stroke, non-fatal myocardial infarction (MI), non-fatal chronic heart failure (CHF), and all-cause death. Cox proportional hazard models were used to compare these CV outcomes in the 2 matched cohorts. After the PSM, 6227 patients receiving B+C and 12454 patients receiving Others were included. Compared to patients receiving Others, patients receiving B+C had a significantly lower risk of MACE (hazard ratio [HR] 0.85; 95% confidential interval [CI] 0.78-0.92; p<.001), non-fatal stroke (HR 0.89; 95% CI 0.81-0.98; p=.018) and non-fatal CHF (HR 0.74; 95% CI 0.63-0.86; p<.0001). Additionally, differences in risks of non-fatal MI and all-cause death between the 2 treatment cohorts were not statistically significant. In conclusion, BB+CCB initial dual therapy was associated with a lower risk of MACE, stroke, and CHF than other optimal initial dual therapies recommended by the Chinese hypertension guideline in Chinese newly diagnosed hypertensive patients.

A novel method for assessing cardiac function in patients with coronary heart disease based on wrist pulse analysis

BackgroundThe timely assessment of B-type natriuretic peptide (BNP) marking chronic heart failure risk in patients with coronary heart disease (CHD) helps to reduce patients’ mortality.ObjectiveTo evaluate the potential of wrist pulse signals for use in the cardiac monitoring of patients with CHD.MethodsA total of 419 patients with CHD were assigned to Group 1 (BNP < 95 pg/mL, n = 249), 2 (95 < BNP < 221 pg/mL, n = 85), and 3 (BNP > 221 pg/mL, n = 85) according to BNP levels. Wrist pulse signals were measured noninvasively. Both the time-domain method and multiscale entropy (MSE) method were used to extract pulse features. Decision tree (DT) and random forest (RF) algorithms were employed to construct models for classifying three groups, and the models’ performance metrics were compared.ResultsThe pulse features of the three groups differed significantly, suggesting different pathological states of the cardiovascular system in patients with CHD. Moreover, the RF models outperformed the DT models in performance metrics. Furthermore, the optimal RF model was that based on a dataset comprising both time-domain and MSE features, achieving accuracy, average precision, average recall, and average F1-score of 90.900%, 91.048%, 90.900%, and 90.897%, respectively.ConclusionsThe wrist pulse detection technology employed in this study is useful for assessing the cardiac function of patients with CHD.

Novel Measures of Arterial Hemodynamics and Wave Reflections Associated With Clinical Outcomes in Patients With Heart Failure.

Background Arterial stiffness and earlier wave reflections can increase afterload and impair cardiovascular function. Most prior studies have been performed in patients with preserved left ventricular function. We describe novel measures of pulsatile arterial hemodynamics and their association with clinical outcomes in patients with heart failure with reduced ejection fraction. Methods and Results Participants with heart failure with reduced ejection fraction (n=137, median age 56 years, 49% women, 58% Black) and age-matched healthy controls (n=124) underwent measurements of large artery stiffness and pulsatile arterial hemodynamics. Carotid-femoral pulse wave velocity and augmentation index were assessed using radial applanation tonometry. Pressure-flow analyses derived reflected wave transit time, the systolic pressure-time integral imposed by proximal aortic characteristic impedance, and the pressure-time integral from wave reflection (wasted pressure effort). Cox proportional hazards models defined associations between hemodynamic measures and (1) all-cause death and (2) a combined end point of left ventricular assist device implant, heart transplant, and death, at 2 years adjusted for race, BNP (B-type natriuretic peptide), and the Meta-Analysis Global Group in Chronic Heart Failure Risk Score. Compared with controls, participants with heart failure with reduced ejection fraction exhibited similar carotid-femoral pulse wave velocity (6.8±1.6 versus 7.0±1.6 m/s, P=0.40) but higher augmentation index normalized to a heart rate of 75 bpm (13±2% versus 22±2%, P<0.001). Shorter reflected wave transit time (ie, earlier wave reflection arrival to the proximal aorta) was associated with an increased risk of death (adjusted hazard ratio [aHR] 1.67 [95% CI 1.03-1.63]) and the combined end point of death/left ventricular assist device/heart transplant (aHR, 1.61 [95% CI, 1.06-2.44]) at 2 years. Wasted pressure effort/proximal aortic characteristic impedance, representing the proportion of systolic load from wave reflection versus aortic root characteristic impedance, was univariately associated with death (hazard ratio (HR), 1.44 [95% CI, 1.05-1.97]) and with death/left ventricular assist device/heart transplant on univariate (HR, 1.42 [95% CI, 1.07-1.88]) and multivariable (aHR, 1.40 [95% CI, 1.02-1.93]) analysis. Conclusions Increased left ventricular systolic load from premature wave reflections is associated with adverse clinical outcomes in patients with heart failure with reduced ejection fraction.

Chronic heart failure following hemorrhagic myocardial infarction: mechanism, treatment and outlook.

Myocardial infarction (MI), the blockage of arterial blood supply of the heart, is among the most common causes of death worldwide. Even when patients receive immediate treatment by re-opening blocked arteries, they often develop chronic heart failure (CHF) in the aftermath of MI events. Yet, the factors that contribute to the development of MI-associated CHF are poorly understood. In our recent study (Nat Commun 13:6394), we link intramyocardial hemorrhage, an injury which can occur during reperfusion of areas affected by MI, to an increased risk of CHF. Mechanistically, our data suggest that an iron-induced adverse cascade of events after hemorrhagic MI drives fatty degeneration of infarcted tissue, which ultimately contributes to negative cardiac remodeling. In this Microreview, we discuss the implications of our findings regarding the molecular mechanism, more targeted treatment options as well as perspectives in the clinical care of CHF after hemorrhagic MI.

Differences in red blood cell mass profiles impact intravascular volume and outcome risk in chronic heart failure.

To identify different red blood cell mass (RBCM) profiles, separate from haemoglobin concentrations, and their impact on blood volume expansion and clinical outcomes in chronic heart failure. RBCM was measured at hospital discharge using standardized nuclear medicine indicator-dilution methodology in patients following diuretic treatment for clinical congestion. Individual RBCM phenotypes were prospectively identified and analysed for heart failure-related mortality or first rehospitalization over 1year. Of 132 patients, 42 (32%) demonstrated normal RBCM, 36 (27%) RBCM deficit (true anaemia), and 54 (41%) RBCM excess (erythrocythemia). Dilutional 'anaemia' defined by haemoglobin <12g/dL with normal or an excess in RBCM with plasma volume expansion was identified in 37 (28%) patients. There were 61 composite outcome events, which included 38 deaths (29% of cohort) occurring over the 1year follow-up period [14/36 (39%) in RBCM deficit, 12/42 (29%) in normal RBCM, and 12/54 (22%) in RBCM excess subgroups]. By Kaplan-Meier and multivariate analyses, RBCM excess was independently associated with the best event-free survival while RBCM deficit (true anaemia) the poorest outcomes; both compared with normal RBCM (P<0.001). Dilutional 'anaemia' demonstrated a lower risk compared with true anaemia (P=0.03). Markedly different RBCM profiles are identifiable among comparably compensated heart failure patients, and this variability carries significant implications for post-hospital outcomes. Novel to this analysis and in contrast to RBCM deficit is the independent association of RBCM excess with better event-free survival compared with normal RBCM. The distinction of RBCM profiles to guide risk stratification and individualized patient management strategies warrants further study.

Clinical and laboratory indicators in predicting the risk of chronic heart failure in COVID-19 survivors

Clinical and laboratory indicators in predicting the risk of chronic heart failure in COVID-19 survivors

Validation of the Meta-Analysis Global Group in Chronic Heart Failure risk score for the prediction of 1-year mortality in a Chinese cohort.

The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score was developed in 2013 to predict survival in heart failure (HF) patients. However, it has yet to be validated in a Chinese population. Our study aimed to investigate the ability of the score to predict 1-year mortality in a Chinese population. Consecutive patients with HF were retrospectively selected from the inpatient electronic medical records of the cardiology department in a regional hospital in China. A total integer score was calculated for each enrolled patient based on the value of each risk factor in the MAGGIC scoring system. Each enrolled patient was followed for at least 1 year. The observational endpoint of this study was all-cause mortality. The predictive ability of the MAGGIC score was assessed by comparing observed and predicted mortality within 1 year. Between January 2018 and December 2020, a total of 635 patients were included in the study: 57 (9.0%) of whom died within 1 year after discharge. The average age of all patients was 74.6 ± 11.2 years, 264 of them (41.6%) were male, and the average left ventricular ejection fraction was 50.7% ± 13.2%. The area under the receiver operating characteristic curve was 0.840 (95% confidence interval: 0.779, 0.901), which indicated a fair discriminatory ability of the score. The Hosmer-Lemeshow test result ( χ2  = 12.902, degree of freedom = 8, P   =  0.115) indicated that the MAGGIC score had good calibration. The decision curve analysis showed that the MAGGIC score yielded a good clinical net benefit and net reduction in interventions. This validation of the MAGGIC score showed that it has a good ability to predict 1-year mortality in Chinese patients with HF after discharge. Due to regional and inter-hospital differences, external validation studies need to be further confirmed in other centers.

Gelatin coating enhances therapeutic cell adhesion to the infarcted myocardium via ECM binding.

Acute myocardial infarction (AMI) results in weakening of the heart muscle and an increased risk for chronic heart failure. Therapeutic stem cells have been shown to reduce inflammatory signaling and scar tissue expansion, despite most of these studies being limited by poor retention of cells. Gelatin methacrylate (GelMA) coatings have been shown to increase the retention of these therapeutic cells near the infarct. In this work, we evaluate two different potential binding partners for GelMA-coated bone marrow cells (BMCs) and myocardial tissue: the extracellular matrix (ECM) and interstitial non-cardiomyocytes. While cells containing β1 integrins mediate cell-ECM adhesion in vivo, these cells do not promote binding to our collagen-degraded, GelMA coating. Specifically, microscopic imagining shows that even with high integrin expression, GelMA-coated BMCs do not bind to cells within the myocardium. Alternatively, BMC incubation with decellularized heart tissue results in higher adhesion of coated cells versus uncoated cells supporting our GelMA-ECM binding mode. To further evaluate the ECM binding mode, cells were incubated on slides modified with one of three different major heart ECM components: collagen, laminin, or fibronectin. While all three components promoted higher adhesion than unmodified glass, collagen-coated slides resulted in a significantly higher adhesion of GelMA-coated BMCs over laminin and fibronectin. Incubation with unmodified BMCs confirmed that without a GelMA coating minimal adhesion of BMCs occurred. We conclude that GelMA cellular coatings significantly increase the binding of cells to collagen within the ECM. Our results provide progress towards a biocompatible and easily translatable method to enhance the retention of transplanted cells in human studies.

Abstract 11803: Applicability of the New Proposed Criteria for Iron Deficiency in Japanese Patients With Heart Failure

Backgrounds: Iron deficiency (ID) is a common comorbidity in patients with heart failure (HF). A recent study from a large single-center chronic HF cohort including predominantly white British population showed that ID defined by current guideline criteria was not associated with poor outcome, and a new ID criteria targeting for HF population was proposed. However, its external applicability is unclear. Methods: We prospectively examined consecutive 711 chronic HF patients and measured serum iron, transferrin saturation (TSAT) and serum ferritin from a Japanese multicenter registry. The proposed ID criteria were TSAT &lt;20% and serum iron ≤13 mmol/L and the guideline ID criteria were serum ferritin &lt;100 ng/mL or, when ferritin was 100-299 ng/mL, TSAT &lt;20%. The primary outcome was all-cause death. Results: Of studied patients (433 male, mean age 71 ± 13 years, mean left ventricular ejection fraction 47 ± 16%), 198 (28%) and 416 (59%) met the proposed and guideline ID criteria, respectively. During a median follow-up period of 441 (IQR 306-564) days, the primary outcome occurred in 50 patients. There was no significant difference on primary outcome between the patients with and without guideline ID criteria ( P = 0.24) ( Figure A ), while patients with serum iron ≤10 mmol/L showed a higher mortality than those without ( P = 0.004) ( Figure B ). In multivariable Cox regressions, the proposed ID criteria, but not guideline ID criteria, were independently associated with higher mortality (HR 1.92, 95% CI 1.06-3.47; and HR 1.42; 95% CI 0.79-1.24, respectively) adjusted for significant covariates including age, hemoglobin, estimated glomerular filtration rate and log NT-proBNP, and the Meta-Analysis Global Group in Chronic Heart Failure risk score. Conclusions: As defined by the proposed criteria, but not the guideline criteria, ID was associated with higher mortality in patients with chronic HF, suggesting that the proposed ID criteria might be applicable to Japanese population.

Should HFrEF patients with NYHA class II expect benefit from CCM therapy? Results from the MAINTAINED observational study.

Cardiac contractility modulation (CCM) is an FDA-approved device therapy for patients with refractory systolic heart failure and normal QRS width. Randomized trials demonstrated benefits of CCM primarily for patients with severe heart failure (> NYHA class II). To better understand individualized indication in clinical practice, we compared the effect of CCM in patients with baseline NYHA class II vs. NYHA classIII or ambulatory IV over the 5-year period in our large clinical registry (MAINTAINED Observational Study). Changes in NYHA class, left ventricular ejection fraction (LVEF), tricuspid annular plane systolic excursion (TAPSE), NT-proBNP level, and KDIGO chronic kidney diseasestage were compared as functional parameters. In addition, mortality within 3years was compared with the prediction of the Meta-Analysis Global Group in Chronic heart failure risk score. A total of 172 patients were included in the analyses (10% with NYHA class II). Only patients with NYHA class III/IV showed a significant improvement in NYHA class over 5years of CCM (II: 0.1 ± 0.6; p = 0.96 vs. III/IV: -0.6 ± 0.6; p < 0.0001). In both groups, LVEF improved significantly (II: 4.7 ± 8.3; p = 0.0072 vs. III/IV: 7.0 ± 10.7%; p < 0.0001), while TAPSE improved significantly only in NYHA class III/IV patients (II: 2.2 ± 1.6; p = 0.20 vs. III/IV: 1.8 ± 5.2mm; p = 0.0397). LVEF improvement was comparable in both groups over 5years of CCM (p = 0.83). NYHA class II patients had significantly lower NT-proBNP levels at baseline (858 [175/6887] vs. 2632 [17/28830] ng/L; p = 0.0044), which was offset under therapy (399 [323/1497] vs. 901 [13/18155] ng/L; p = 0.61). Actual 3-year mortality was 17 and 26% vs. a predicted mortality of 31 and 42%, respectively (p = 0.0038 for NYHAclass III/IVpatients). NYHA classIII/IV patients experienced more direct and extensive functional improvements with CCM and a survival benefit compared with the predicted risk. However, our data suggest that NYHA classII patients may also benefit from the sustained positive effects of LVEF improvement.

The Relationship Between the Blood-Brain-Barrier and the Central Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter-2 Inhibitors.

Diabetes and obesity are growing problems worldwide and are associated with a range of acute and chronic complications, including acute myocardial infarction (AMI) and stroke. Novel anti-diabetic medications designed to treat T2DM, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is), exert beneficial effects on metabolism and the cardiovascular system. However, the underlying mechanisms are poorly understood. GLP-1RAs induce anorexic effects by inhibiting the central regulation of food intake to reduce body weight. Central/peripheral administration of GLP-1RAs inhibits food intake, accompanied by an increase in c-Fos expression in neurons within the paraventricular nucleus (PVN), amygdala, the nucleus of the solitary tract (NTS), area postrema (AP), lateral parabrachial nucleus (LPB) and arcuate nucleus (ARC), induced by the activation of GLP-1 receptors in the central nervous system (CNS). Therefore, GLP-1RAs need to pass through the blood-brain barrier to exert their pharmacological effects. In addition, studies revealed that SGLT-2is could reduce the risk of chronic heart failure in people with type 2 diabetes. SGLT-2 is extensively expressed throughout the CNS, and c-Fos expression was also observed within 2 hours of administration of SGLT-2is in mice. Recent clinical studies reported that SGLT-2is improved hypertension and atrial fibrillation by modulating the “overstimulated” renin-angiotensin-aldosterone system (RAAS) and suppressing the sympathetic nervous system (SNS) by directly/indirectly acting on the rostral ventrolateral medulla. Despite extensive research into the central mechanism of GLP-1RAs and SGLT-2is, the penetration of the blood-brain barrier (BBB) remains controversial. This review discusses the interaction between GLP-1RAs and SGLT-2is and the BBB to induce pharmacological effects via the CNS.

Vericiguat and NT-proBNP in patients with heart failure with reduced ejection fraction: analyses from the VICTORIA trial.

Treatment response to vericiguat, based on baseline N-terminal pro-brain natriuretic peptide (NT-proBNP) subgroups specified in the protocol, was evaluated in the heart failure (HF) VICTORIA trial population by post hoc analysis of combined lower three quartiles [Q1-Q3] vs. the upper quartile [Q4]. VICTORIA participants with available baseline NT-proBNP levels (n=4805; 95.1% of total) were included. Compared with patients in Q1-Q3 (NT-proBNP: Q1, ≤1556pg/mL; Q2, >1556-2816pg/mL; and Q3, >2816-5314pg/mL), patients in Q4 (NT-proBNP: >5314pg/mL) were older (69.2±12.0 vs. 66.6±12.1years), had lower mean ejection fraction (27.2±8.3% vs. 29.5±8.2%; P<0.0001), and were more likely to be in New York Heart Association (NYHA) Class III (51.8 vs. 35.6%) or IV (2.4 vs. 1.0%). Compared with Q1-Q3, patients in Q4 had higher mean Meta-Analysis Global Group in Chronic Heart Failure risk score (27.3±6.6 vs. 23.5±6.4; P<0.0001), had lower mean estimated glomerular filtration rate (eGFR; 51.5±25.5 vs. 65.0±26.8mL/min/1.73m2 ; P<0.0001) and haemoglobin (12.8±2.0 vs. 13.6±1.9g/dL; P<0.0001), and more had atrial fibrillation (48.7% vs. 43.1%; P=0.0007) and were randomized while hospitalized for HF (14.8 vs. 9.9%; P<0.0001). Target dose was achieved in 72.3 and 63.7% of patients in Q1-Q3 and Q4, respectively (P<0.0001). Primary outcome (composite of time to cardiovascular death or first HF hospitalization) rates were 24.5 and 31.7 per 100 patient-years for vericiguat and placebo in Q1-Q3 [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.69-0.88, P<0.001] and 73.6 and 63.6 in Q4 (HR 1.15; 95% CI 0.99-1.34, P=0.070). Serious adverse events were more frequent in NT-proBNP Q4 (total population) compared with Q1-Q3 (38.3 vs. 32.3%; P=0.0001), driven mainly by the placebo group. Adverse events leading to death were more frequent in Q4 than Q1-Q3 (5.8 vs. 2.4%; P<0.0001). Plasma NT-proBNP may help identify patients with worsening HF with reduced ejection fraction, in whom the beneficial effects of vericiguat may be highest. Patients with highest NT-proBNP values are probably too far advanced, suffering more co-morbidities, or still clinically unstable after decompensation to derive benefit from vericiguat.