Ischemic Chronic Heart Failure Research Articles

Cardiovascular toxicity of fluoropyrimidines: Experience from a quaternary referral center.

e24028 Background: Fluoropyrimidines, including 5-fluorouracil (5-FU) and capecitabine, are widely used chemotherapeutic agents. Their use has been linked to various forms of cardiovascular (CV) toxicity. We sought to analyze the rate of CV events and associated factors in patients receiving fluoropyrimidines at our institution. Methods: We included all patients who received intravenous 5-FU or oral capecitabine at the Cleveland Clinic since 2000. Diagnosis data was obtained based on ICD-10 Codes. CV events included chest pain/angina, myocardial infarction, chronic ischemic heart disease, arrhythmias, conduction disorders, cardiac arrest, cardiomyopathy, and heart failure. CV events were accounted for if they occurred during treatment or within 30 days following the latest administration of the agent. Logistic regression was performed to identify predictors of CV events. Results: A total of 17,236 patients were included, of which 9,386 (54.5) received 5-FU and 7,850 (45.5) received capecitabine. Median age at treatment was 63. The most frequent malignancies were gastrointestinal (70%) and breast cancer (12.3%). A total of 2,283 patients (13.2%) experienced at least one CV event either during treatment or within 30 days following drug administration. The most frequent CV events were chest pain/angina (35.7% of all events). On multivariable logistic regression, factors associated with increased risk of CV events were black race, smoking history, hypertension, and obesity (Table). A prior history of CV disease was also associated with increased risk of CV events (OR 1.22; 95% CI [1.09 - 1.33]). Finally, intravenous 5-FU was linked to higher odds of CV events compared to oral capecitabine (OR 1.48; 95% CI [1.34 - 1.63]). Conclusions: This large-scale cohort study provides pivotal insights into the cardiovascular risks associated with fluoropyrimidine therapy. Besides traditional risk factors, black patients were more likely to suffer from CV events. Additionally, capecitabine may offer better CV outcomes compared to 5-FU. These findings underscore the need for refined risk assessment and enhanced cardiovascular monitoring in patients treated with fluoropyrimidines. [Table: see text]

Blood Viscosity and its Clinical Implications in Ischemic Stroke and Chronic Heart Failure: Insights from a Case Report

Background Blood viscosity has received increased attention as a potential predictor of ischemic stroke risk, particularly in patients with chronic heart failure (CHF). Despite the importance of this link, there has been a notable paucity of comprehensive research on the subject. Hence, the major goal of this study was to shed light on the potential importance of blood viscosity in individuals with ischemic stroke and CHF. Case Presentation An 85-year-old male was presented to the emergency department after three days of gradually decreasing consciousness. His medical history included hypertension and CHF. His Glasgow Coma Scale (GCS) was determined to be E2M5V3, and he displayed evidence of upper motor neuron facial palsy as well as right hemiparesis. The clinical assessment scores, which included the NIHSS and mRS, were 10 and 4, respectively. MRI imaging confirmed the existence of several acute infarctions. Other diagnostic procedures, including an x-ray, revealed cardiomegaly and echocardiographic findings were compatible with grade I diastolic dysfunction. His blood viscosity was 8.19 cP, which was much higher than normal. The patient was diagnosed with ischemic stroke, CHF, and hyperviscosity based on these findings. Despite a small increase in blood viscosity to 8.16 cP after a six-day treatment session, the patient showed significant clinical improvement. Unfortunately, he was readmitted immediately after being discharged and died three days later. Conclusion This case demonstrates the importance of blood viscosity in the evaluation and prognosis of patients with ischemic stroke and CHF.

СРЕДНЕСРОЧНЫЕ ЭФФЕКТЫ УСИЛЕННОЙ НАРУЖНОЙ КОНТРПУЛЬСАЦИИ НА МАРКЕРЫ ГЛИКЕМИЧЕСКОГО КОНТРОЛЯ У ПАЦИЕНТОВ С ХРОНИЧЕСКОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТЬЮ ИШЕМИЧЕСКОГО ГЕНЕЗА

Aim. To study the effects of complex therapy with the addition of enhanced external counterpulsation (EECP) on exercise tolerance, echocardiographic parameters, markers of glycemic control and clinical outcomes in patients with ischemic chronic heart failure (CHF) with concomitant type 2 diabetes mellitus (DM). Material and methods. Patients with ischemic CHF II-III functional class with type 2 DM were randomized into group 1 (n=20) – optimal medical therapy (OMT) and EECP (35 hours, 2 courses per year), group 2 (n=21) – OMT and EECP (35 hours, 1 course per year), control group (n=20) – OMT and placebo-counterpulsation (35 hours, 1 course per year). The primary endpoint was achieving an HbA1c level of ≤7%. Secondary endpoints included the development of a combined endpoint (CEP: cases of adverse outcomes, hospitalizations for CHF, new onsets of atrial fibrillation, decreased renal function), as well as an increase after 12 months in the distance covered in 6-minue walk test (6MWT) by 20% or more from the baseline. Results. After 12 months, the proportion of patients achieving an HbA1c level of ≤7% in group 1 increased by 30%, in group 2 – by 14.3%, and remained the same in the control group (p=0.005). The proportion of patients with an increase in distance traveled according to 6MWT data >20% after 12 months in the 1st, 2nd and control groups was 100%, 76.2% and 15.0%, respectively (p<0.001). The development of CEP was observed in 3 (15.0%) patients of the 1st group, 7 (33.3%) – of the 2nd group and 12 (60.0%) – of the control group (including 1 case of death), p =0.003. Conclusion. Over a 12-month study period in patients with ischemic heart failure and type 2 diabetes, the addition of EECP to OMT after 12 months demonstrated an improvement in the clinical status of patients, which was accompanied by a decrease in levels of markers of glycemic control and the incidence of adverse outcomes compared with the placebo counterpulsation group.

ДОЛГОСРОЧНЫЕ СОСУДИСТЫЕ ЭФФЕКТЫ УСИЛЕННОЙ НАРУЖНОЙ КОНТРПУЛЬСАЦИИ У ПАЦИЕНТОВ С ИШЕМИЧЕСКОЙ БОЛЕЗНЬЮ СЕРДЦА, ОСЛОЖНЕННОЙ СЕРДЕЧНОЙ НЕДОСТАТОЧНОСТЬЮ

Aim. To study the long-term effect of complex therapy with the addition of enhanced external counterpulsation (EECP) on the structural and functional parameters of the cardiovascular system in patients with ischemic chronic heart failure (CHF). Material and methods. Patients with ischemic CHF NYHA class II-III (n=59; median age 64.8 [57.6; 71.2] years; 81.4% men), receiving EECP in addition to optimal medical treatment (35-hour course every 6 months; compression pressure 220-280 mmHg) had an assessment of exercise tolerance (distance in the 6-minute walk test; 6MWT), structural and functional state of large vessels and microvasculature (computer video capillaroscopy of the periungual bed, photoplethysmography, applanation tonometry), assessment of echocardiographic parameters (volume dimensions, systolic and diastolic functions of the left ventricle) at baseline, after 12, 24 and 36 months. The follow-up period was 36 months. Results. Significant stable positive dynamics of tolerance to physical activity (the distance in the 6MHT increased by 59.4%) was found. Functional parameters of the heart (LVEF from 40.6 [34.6; 43.2] to 49.2 [43.0; 52.7] %, p=0.003; NT-proBNP from 246 [167; 341] to 120 [93; 148] pg/ml), large (occlusion index by phase shift) and small (occlusion index by amplitude, percentage of perfused capillaries, percentage of capillary restoration) vessels significantly improved already in the first year of observation, while structural parameters (volume dimensions; indexed LV myocardial mass from 94.3 [79.4; 97.4] to 121 [109; 134] g/m2, p=0.010; radial augmentation index, stiffness index, occlusion index) began to change significantly by 2-3-years. Conclusion. A stable positive effect of EECP treatment in patients with ischemic heart failure on the structural and functional parameters of the heart and blood vessels has been demonstrated. At the same time, the rate of improvement in functional indicators was much faster than that of structural parameters.

Network and Experimental Pharmacology on Mechanism of Yixintai Regulates the TMAO/PKC/NF-κB Signaling Pathway in Treating Heart Failure.

This study aims to explore the mechanism of action of Yixintai in treating chronic ischemic heart failure by combining bioinformatics and experimental validation. Five potential drugs for treating heart failure were obtained from Yixintai (YXT) through early mass spectrometry detection. The targets of YXT for treating heart failure were obtained by a search of online databases. Gene ontology (GO) functional enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were conducted on the common targets using the DAVID database. A rat heart failure model was established by ligating the anterior descending branch of the left coronary artery. A small animal color Doppler ultrasound imaging system detected cardiac function indicators. Hematoxylin-eosin (HE), Masson's, and electron microscopy were used to observe the pathological morphology of the myocardium in rats with heart failure. The network pharmacology analysis results were validated by ELISA, qPCR, and Western blotting. A total of 107 effective targets were obtained by combining compound targets and eliminating duplicate values. PPI analysis showed that inflammation-related proteins (TNF and IL1B) were key targets for treating heart failure, and KEGG enrichment suggested that NF-κB signaling pathway was a key pathway for YXT treatment of heart failure. Animal model validation results indicated the following: YXT can significantly reduce the content of intestinal microbiota metabolites such as trimethylamine oxide (TMAO) and improve heart failure by improving the EF and FS values of heart ultrasound in rats and reducing the levels of serum NT-proBNP, ANP, and BNP to improve heart failure. Together, YXT can inhibit cardiac muscle hypertrophy and fibrosis in rats and improve myocardial ultrastructure and serum IL-1β, IL-6, and TNF-α levels. These effects are achieved by inhibiting the expressions of NF-κB and PKC. YXT regulates the TMAO/PKC/NF-κB signaling pathway in heart failure.

Ischemic heart disease-related mortality in Brazil, 2006 to 2020. A study of multiple causes of death

ContextBoth the aging of the population and the increase in noncommunicable diseases may influence the progression and outcomes culminating in death, changing the evolution of ischemic heart diseases (IHDs) and their associated causes. Using the multiple causes of death method could help understand the magnitude of these relationships and enable better targeting of investments in health.ObjectivesTo evaluate the mortality from IHD in Brazil between 2006 and 2020 using the method of multiple causes and identify differences in the distribution pattern of IHD mortality by sex and geographic region.MethodsBased on information extracted from death certificates (DCs) obtained from the database of the Department of Informatics of the Unified Health System (DATASUS), we used the multiple causes method to analyze the causes of death associated with IHD when IHD was defined as the underlying cause of death (UC) and the causes of death listed as the UC when IHD was recorded in any other lines of the DC, from 2006 to 2020, in Brazil. Subsequently, the proportion of these causes of death and differences between sexes and geographic regions were evaluated, with statistical relevance analyzed using the chi-square test, and the dependence between factors illustrated using stacked bar charts and small-world network graphs.ResultsWhen IHD was listed as the UC of death, the most frequent associated causes of death were, in descending order of frequency, acute myocardial infarction (AMI), arterial hypertension (AH), chronic ischemic heart disease (CHID), heart failure (HF), and diabetes mellitus (DM). When IHD was mentioned in any line of the DC, the most frequent UCs of death were AMI followed by DM, CIHD, chronic obstructive pulmonary disease (COPD), stroke, dyslipidemia, and, in the year 2020, COVID-19. The most frequent cause of death in women were DM as the UC and associated cause of death, AH as the UC, and CIHD and Alzheimer's disease as associated causes of death, while the most frequent causes of death in men were substance dependence as the UC and associated cause of death, and cancer as an associated cause of death. The most frequent causes of death were DM and stroke in the North and Northeast, dyslipidemia and obesity in the Midwest, Alzheimer's disease in the South and Southeast, and atherosclerotic heart disease (AHD) and COPD in the South.ConclusionsSeveral diseases – including AMI, AH, CIHD, HF, and DM – were the most frequent associated causes of death when IHD was recorded as the UC. In contrast, AMI, DM, CIHD, COPD, and stroke were the most frequent UCs when IHD was listed as an associated cause of death. The degree of these associations varied between sexes and geographic regions.

The severity of chronic heart failure and the parameters of daily blood pressure profile in patients with coronary heart disease

Aim: Although the prevalence of coronary heart disease (CHD) and hypertension which are the most common causes of the development and progression of chronic heart failure (CHF) is high, 24-hour ambulatory blood pressure (BP) monitoring (ABPM) in patients with CHF is not mandatory to be performed. The growing number of evidence suggests that excessive decrease in BP which clearly reflects increased BP variability (BPV) affects the survival of patients with heart failure (HF). The objective of the study was to investigate the relationship between the parameters specific to CHF severity and features of daily BP profiles in patients with ischemic CHF and hypertension. Methods: Ninety patients with functional class II–IV of CHF and CHD (the main group) and 50 non-CHF patients with hypertension (the comparative group) were examined. The transthoracic echocardiography (TTE) [atrial end-systolic dimension (ESD), ventricular end-diastolic dimension (EDD), left ventricular mass index (LVMI), and left ventricular ejection fraction (LVEF)] and 24-hour ABPM (BPV parameters and proportions of hypotensive episodes) were performed. The relationships between the abovementioned parameters were evaluated using the univariate correlation analysis and stepwise multiple linear regression. Results: Higher functional class of CHF is found to be associated with a higher incidence of daytime systolic BP (SBP) decline and nighttime SBP and diastolic BP (DBP) variability while higher LVEF is related to the hypotensive episodes regardless of CHF. Conclusions: It appears that the larger trials involving CHF patients with reduced LVEF should be conducted to clarify the obtained results.

Neutrophils are indispensable for adverse cardiac remodeling in heart failure

Persistent immune activation contributes significantly to left ventricular (LV) dysfunction and adverse remodeling in heart failure (HF). In contrast to their well-known essential role in acute myocardial infarction (MI) as first responders that clear dead cells and facilitate subsequent reparative macrophage polarization, the role of neutrophils in the pathobiology of chronic ischemic HF is poorly defined. To determine the importance of neutrophils in the progression of ischemic cardiomyopathy, we measured their production, levels, and activation in a mouse model of chronic HF 8 weeks after permanent coronary artery ligation and large MI. In HF mice, neutrophils were more abundant both locally in failing myocardium (more in the border zone) and systemically in the blood, spleen, and bone marrow, together with increased BM granulopoiesis. There were heightened stimuli for neutrophil recruitment and trafficking in HF, with increased myocardial expression of the neutrophil chemoattract chemokines CXCL1 and CXCL5, and increased neutrophil chemotactic factors in the circulation. HF neutrophil NETotic activity was increased in vitro with coordinate increases in circulating neutrophil extracellular traps (NETs) in vivo. Neutrophil depletion with either antibody-based or genetic approaches abrogated the progression of LV remodeling and fibrosis at both intermediate and late stages of HF. Moreover, analogous to murine HF, the plasma milieu in human acute decompensated HF strongly promoted neutrophil trafficking. Collectively, these results support a key tissue-injurious role for neutrophils and their associated cytotoxic products in ischemic cardiomyopathy and suggest that neutrophils are potential targets for therapeutic immunomodulation in this disease.

Associations between air pollution and the risk of first admission and multiple readmissions for cardiovascular diseases

ObjectivesWe aimed to investigate the associations between air pollutants and the risk of admission and multiple readmission events for cardiovascular disease (CVD).MethodsA total of 285 009 participants free of CVD...

Gene therapy encoding cell cycle factors to treat chronic ischemic heart failure in rats.

Gene therapies to induce cardiomyocyte (CM) cell cycle re-entry have shown a potential to treat subacute ischaemic heart failure (IHF) but have not been tested in the more relevant setting of chronic IHF. Our group recently showed that polycistronic non-integrating lentivirus encoding Cdk1/CyclinB1 and Cdk4/CyclinD1 (TNNT2-4Fpolycistronic-NIL) is effective in inducing CM cell cycle re-entry and ameliorating subacute IHF models and preventing the subsequent IHF-induced congestions in the liver, kidneys, and lungs in rats and pigs. Here, we aim to test the long-term efficacy of TNNT2-4Fpolycistronic-NIL in a rat model of chronic IHF, a setting that differs pathophysiologically from subacute IHF and has greater clinical relevance. Rats were subjected to a 2-h coronary occlusion followed by reperfusion; 4 weeks later, rats were injected intramyocardially with either TNNT2-4Fpolycistronic-NIL or LacZ-NIL. Four months post-viral injection, TNNT2-4Fpolycistronic-NIL-treated rats showed a significant reduction in scar size and a significant improvement in left ventricular (LV) systolic cardiac function but not in the LV dilatation associated with chronic IHF. A mitosis reporter system developed in our lab showed significant induction of CM mitotic activity in TNNT2-4Fpolycistronic-NIL-treated rats. This study demonstrates, for the first time, that TNNT2-4Fpolycistronic-NIL gene therapy induces CM cell cycle re-entry in chronic IHF and improves LV function, and that this salubrious effect is sustained for at least 4 months. Given the high prevalence of chronic IHF, these results have significant clinical implications for developing a novel treatment for this deadly disease.

Clinical efficacy and safety of adjunctive treatment of chronic ischemic heart failure with Qishen Yiqi dropping pills: a systematic review and meta-analysis.

Our study was to evaluate the effect of Qishen Yiqi Dropping Pills(QSYQ) on the prognosis of chronic ischemic heart failure(CIHF) and its safety. Databases including CNKI, Wanfang, VIP, CBM, PubMed, Web of Science, The Cochrane Library and EMbase were searched from their inception to April 2023 to screen relevant randomized controlled trials (RCTs). Primary indicators included readmission rates, rates of major adverse cardiovascular events (MACE), and all-cause mortality rates. The quality of the literature was assessed according to the Cochrane Reviewers' Handbook 5.0 and the Modified Jadad Scale (with a score of 4-7 rated as high quality). Meta-analysis was performed using the meta-package created by R software version 4.2.3, continuous data were compared using SMDs, and dichotomous and ordered data were compared using ORs; and the I2 test was used to assess the heterogeneity. Fifty-nine studies out of 1,745 publications were finally included, totalling 6,248 patients. Most studies were poorly designed and had some publication bias, with only 26 high-quality papers (Jadad score ≥4). Meta-analysis showed that the combined application of QSYQ was able to reduce the readmission rate [OR = 0.42, 95% CI (0.33, 0.53), P < 0.001], all-cause mortality rate [OR = 0.43, 95% CI (0.27, 0.68), P < 0.001], and the incidence of MACE [OR = 0.42, 95% CI (0.31, 0.56), P < 0.001]. Also, the treatment method can improve clinical effectiveness [OR = 2.25, 95% CI (1.97, 2.58), P < 0.001], increase 6-min walking distance (6MWD) [SMD = 1.87, 95% CI (1.33, 2.41), P < 0.0001] and left ventricular ejection fraction (LVEF) [SMD = 1.08, 95% CI (0.83, 1.33), P < 0.0001], and decrease the Minnesota Living with Heart Failure Questionnaire (MLHFQ) scores [SMD = -2.03, 95% CI (-3.0, -1.07), P < 0.0001], BNP levels [SMD = -2.07, 95% CI (-2.81, -1.33), P < 0.0001] and NT-ProBNP levels [SMD = -2.77, 95% CI (-4.90, -0.63), P < 0.05]. A total of 21 studies (n = 2,742) evaluated their adverse effects, of which 13 studies reported no adverse effects and 8 studies reported minor adverse effects. Our results suggest that the combined application of QSYQ can further improve patients' cardiac function and exercise tolerance, improve their quality of life, and ultimately improve patients' prognosis with a favorable safety profile. Nonetheless, limited by the quality and high heterogeneity of the literature, we must be conservative and cautious about the present results. PROSPERO (CRD42023449251).

Biologically derived epicardial patch induces macrophage mediated pathophysiologic repair in chronically infarcted swine hearts

There are nearly 65 million people with chronic heart failure (CHF) globally, with no treatment directed at the pathologic cause of the disease, the loss of functioning cardiomyocytes. We have an allogeneic cardiac patch comprised of cardiomyocytes and human fibroblasts on a bioresorbable matrix. This patch increases blood flow to the damaged heart and improves left ventricular (LV) function in an immune competent rat model of ischemic CHF. After 6 months of treatment in an immune competent Yucatan mini swine ischemic CHF model, this patch restores LV contractility without constrictive physiology, partially reversing maladaptive LV and right ventricular remodeling, increases exercise tolerance, without inducing any cardiac arrhythmias or a change in myocardial oxygen consumption. Digital spatial profiling in mice with patch placement 3 weeks after a myocardial infarction shows that the patch induces a CD45pos immune cell response that results in an infiltration of dendritic cells and macrophages with high expression of macrophages polarization to the anti-inflammatory reparative M2 phenotype. Leveraging the host native immune system allows for the potential use of immunomodulatory therapies for treatment of chronic inflammatory diseases not limited to ischemic CHF.

Abstract 17096: Immune Modulation to Treat Ischemic Heart Failure

Introduction: Clinical use of induced pluripotent derived cardiomyocytes (iPSC-CMs) has been slow because their mechanism is not well defined. Our lab developed a cardiac patch composed of iPSC-CMs and human neonatal dermal fibroblast (NDF) seeded on a bioresorbable matrix. Implantation on the epicardium of the infarcted heart in immune competent animal models of ischemic CHF (mice, rats, swine) repaired the damaged heart, improved cardiac function/structure with increased viable myocardium, increased myocardial blood flow, improved left ventricular (LV) contractility, and reversal of maladaptive LV remodeling. Preliminary analysis indicates that the patch created a novel host derived immune response not observed in untreated animals. Hypothesis: The iPSC-CMs and NDFs coordinate an immunomodulatory response that results in reduction of inflammatory cytokine producing M1 macrophages with concomitant polarization to the M2 state. Methods: Spatial transcriptomics and histological analysis was utilized for investigation of patch driven immunomodulatory responses in WT BL6 mice. All animals underwent two procedures; 1) Infarct via left coronary ligation 2) Left lateral sternotomy with patch placement (N=5) (no patch for controls, N=3) 3 weeks post MI. Patch secretions underwent quantitative mass spectroscopy to identify drivers of immunomodulation. Results: Histology demonstrated reduction of left chamber dimension and presence of viable cardiomyocytes in the LV wall. IF demonstrated a novel immune response in the treated group absent in the controls. This response is isolated to the epicardial infarct-patch interface. Cellular deconvolution of the infarct region revealed macrophages and dendritic cells compose this response. Macrophage phenotype was assessed via expression of classical M1(CD68, NOS2, AXL) as well as M2 markers (RETNLA, MRC1, ADGRE1) which were found to be significantly elevated in treated groups. Proteomic analysis of the patch secretome indicates the patch has a role in coordinating this response by upregulation of Il-4/Il-13 signaling and wound healing that stimulates enrichment of pathways associated with reorganization of the ECM.

Right ventricular free wall and four-chamber longitudinal strain in relation to incident heart failure in the general population.

Right ventricular free wall (RVFWLS) and four-chamber longitudinal strain (RV4CLS) are associated with adverse events in various patient populations including patients with heart failure (HF). We sought to investigate the prognostic value of RVFWLS and RV4CLS for the development of incident HF in participants from the general population. Participants from the 5th Copenhagen City Heart Study (2011-2015) without known chronic ischaemic heart disease or HF at baseline were included. RVFWLS and RV4CLS were obtained using two-dimensional speckle-tracking echocardiography from the right ventricular (RV)-focused apical four-chamber view. The primary endpoint was incident HF. Among 2740 participants (mean age 54 ± 17 years, 42% male), 43 (1.6%) developed HF during a median follow-up of 5.5 years (IQR 4.5-6.3). Both RVFWLS and RV4CLS were associated with an increased risk of incident HF during follow-up independent of age, sex, hypertension, diabetes, body mass index and tricuspid annular plane systolic excursion (TAPSE), (HR 1.06, 95%CI 1.00-1.11, P = 0.034, per 1% absolute decrease and HR 1.14, 95%CI 1.05-1.23, P = 0.001, per 1% absolute decrease, respectively). Left ventricular ejection fraction (LVEF) modified the association between RV4CLS and incident HF (P for interaction = 0.016) such that RV4CLS was only of prognostic importance among those with LVEF < 55% (HR 1.21, 95%CI 1.11-1.33, P < 0.001 vs. HR 0.94, 95%CI 0.80-1.10, P = 0.43 in patients with LVEF ≥ 55%). In participants from the general population, both RVFWLS and RV4CLS were associated with a greater risk of incident HF independent of important baseline characteristics and TAPSE, and LVEF modified the relationship between RV4CLS and incident HF.

Longitudinal associations of cardiovascular health and vascular events with incident dementia

IntroductionEvidence supporting cardiovascular diseases could increase the risk of dementia remains fragmented. A comprehensive study to illuminate the distinctive associations across different dementia types is still lacking. This study is...

Too Loud to Handle? Transportation Noise and Cardiovascular Disease.

The World Health Organization reported that more than 1.6 million healthy life-years are lost yearly from traffic-related noise in western Europe. In addition, the number of studies on health side effects in response to traffic noise is steadily growing, mainly cardiovascular disease, such as acute and chronic ischemic heart disease, heart failure, arrhythmia, and stroke. Pathophysiologically nighttime noise has been shown to cause sleep disturbances, including too short sleep periods and frequent interruption of sleep leading to an increase in the levels of circulating stress hormones and subsequently to a significant increase in the production of reactive oxygen species (oxidative stress) and inflammation in the vasculature and the brain. The consequence is arterial hypertension and vascular (endothelial) dysfunction, which might increase the risk of cardiovascular disease. With the present review, we give an overview of the "so-called" nonauditory cardiovascular health effects of noise, which have been proposed to be responsible for the future development of cardiovascular disease. We present epidemiological evidence but also evidence provided by translational human and experimental noise studies. Finally, we discuss manoeuvres to mitigate noise effectively.

Current Role of Myocardial Viability Imaging Using Positron Emission Tomography in Patients with Chronic Ischemic Heart Failure and Left Ventricular Dysfunction

Current Role of Myocardial Viability Imaging Using Positron Emission Tomography in Patients with Chronic Ischemic Heart Failure and Left Ventricular Dysfunction

Abstract P3084: Neutrophil Expansion And Netosis Are Essential For Adverse Left Ventricular Remodeling And Dysfunction In Chronic Ischemic Heart Failure

Chronic inflammation contributes significantly to disease progression in heart failure (HF) with the expansion and adverse activation of macrophages, dendritic cells, and T cells in the failing heart. Neutrophils play a well-known role in the initial acute immune response to myocardial infarction (MI), however, whether and how they contribute to inflammation and adverse LV function and remodeling in chronic ischemic HF is unknown. We tested the hypothesis that activated neutrophils are required for tissue remodeling and disease progression in HF in mice studied 4 and 8 weeks after MI during established ischemic HF (vs sham). CD11b + Ly6G + neutrophils were expanded in peripheral blood (PB), heart, spleen and bone marrow 8 w post-MI. Neutrophils in the failing heart were localized to the MI border zone and augmented in remote zone myocardium by immunofluorescent staining. CXCL1 and CXCL5 expression was increased in the failing heart, consistent with chemotactic signals for myocardial neutrophil recruitment. Plasma from HF mice elicited greater chemotaxis in naïve neutrophils (vs naïve plasma) by time-lapse video microscopy. Further, PB neutrophils from HF mice exhibited significantly increased neutrophil extracellular trap (NET) production, with concomitant increase in plasma NETs (histone-DNA complexes) in HF mice. The direct pathological impact of NETs was demonstrated by intramyocardial injection of isolated NETs into naïve hearts mimicking HF with decreased EF, LV dilation, and fibrosis. Finally, the in vivo role of neutrophils in chronic HF (4 and 8 w post-MI) was determined via depletion studies using genetic (Ly6G-diptheria toxin receptor mice) and antibody (1A8) based approaches. Neutrophil depletion significantly improved LV EF and reduced end systolic and diastolic volumes. 1A8 treated HF mice also exhibited reduced remote zone fibrosis. The necessity of NETosis in HF development was confirmed using neutrophil and myeloid – specific PAD4 deletion where the decline in LV EF and increase in volumes in HF were attenuated. In conclusion , neutrophil expansion and NETosis are important contributors to chronic inflammation in HF and play an obligatory role in the development of LV dysfunction and remodeling in ischemic cardiomyopathy.

Abstract P3068: Hematopoietic Loss Of Y-chromosome In Circulating Monocytes Derived From Heart Failure Patients Associates With Cardiac Fibrotic Signaling

Background: Hematopoietic mosaic loss of Y chromosome (LOY) correlates with age and associates with increased cardiovascular disease incidence. Moreover, new murine studies propose that LOY could promote cardiac fibrosis by stimulating cardiac infiltration and activation of circulating macrophages. Yet, specific profiles of hematopoietic LOY cells in patients with heart failure (HF) are missing. Methods and Results: To decipher the genetic profile of human circulating immune cells and assess the effects of LOY, we performed single-cell RNA-sequencing (scRNA-seq) with immune cells of 10 male patients having chronic ischemic HF (mean age 67.3 years, ejection fraction 34.4%). We bioinformatically sorted immune cells by presence or absence of Y-chromosome-associated genes. Relative distribution of LOY was assessed, with monocytes having the greatest absolute count of LOY cells with no significant change in distribution among cell types. Given the abundance of monocytic LOY cells, we examined LOY monocytic cells transcriptional profiles (29810 Y-carrier monocytes, 2205 LOY monocytes) in an unbiased manner. Using a patient-specific, paired analysis, LOY monocytes showed significantly diminished expression of TGF-ß inhibiting genes (SMAD7, TGIF2) in LOY cells versus Y-carrier cells. Opposingly, from 193 upregulated genes, LOY cells showed elevated markers associated with monocyte/macrophage-mediated tissue damage and pro-fibrotic cardiac remodelling (S100A8, CLEC4D, TLR2). Gene ontology terms derived from upregulated genes in LOY cells further supported a mechanistic link to cardiac fibrosis by calling terms associated with TLR signaling, which are known to enhance cardiac fibrosis. Conclusion: This is the first study to study the genetic signature of LOY monocytes in HF patients. Our results considerably extend very recent experimental results in mice that LOY sensitizes macrophages to enhanced signaling associated with cardiac fibrosis. Reduced TGF-ß inhibitory molecule expression and enhanced TLR signaling may contribute to the aggravation of heart failure by LOY in patients with HF.

Circulating H-FABP as a biomarker of frailty in patients with chronic heart failure.

Increased vulnerability to physiologic stressors, termed frailty, is a common occurrence in patients with chronic heart failure (CHF). However, the definite biomarkers to assess frailty in CHF patients are not known. Here, we assessed the frailty phenotype and its potential association with heart failure (HF) markers in CHF patients. We categorized controls (n = 59) and CHF patients (n = 80), the participants, into robust, pre-frail, and frail based on the cardiovascular health study (CHS) frailty index. The plasma levels of HF markers, including tumorigenicity 2 (s-ST2), galectin-3, and heart-type fatty acid binding protein (H-FABP), were measured and correlated with frailty phenotype and cardiac function. The levels of plasma s-ST2, galectin-3, and H-FABP were profoundly elevated in CHF patients. Conversely, the frailty index scores were significantly lower in ischemic and non-ischemic CHF patients versus controls. Of the assessed HF markers, only H-FABP was positively correlated (r2 = 0.07, P = 0.02) with the frailty score in CHF patients. Collectively, these observations suggest that circulating H-FABP may serve as a biomarker of frailty in CHF patients.