Cardiovascular Diseases Including Heart Failure Research Articles

Abstract 15970: Risk of Heart Failure Preserved Ejection Fraction in Obstructive Sleep Apnea: A Single Center Retrospective Analysis

Background: Inherent characteristics of patients with Obstructive Sleep Apnea (OSA), such as age, obesity, diabetes and hypertension increase the risk for cardiovascular diseases including heart failure (HF). Herein, we sought to elucidate if there is an increased likelihood of having heart failure with preserved ejection fraction (HFpEF) as OSA severity increases. Furthermore, we correlated a validated H2FpEF score system in this cohort with clinical and imaging findings for HFpEF. Results: Out of 585 charts reviewed from patients diagnosed with OSA, a total of 108 patients with a concomitant transthoracic echocardiogram (TTE) and electrocardiogram performed were identified. The median age was 59 years old with 55.6% being males and Hispanic predominance 64.5%. The comorbidities found in our cohort involved hypertension (63.9%), diabetes mellitus (30.6%), coronary artery disease (15.7%), HF (13%), atrial fibrillation (8.3%), and stroke (7.4%). Mean BMI was 32.48 kg/m 2 and average neck size 16.02 inches. TTE findings demonstrated an average ejection fraction of 58±7% and mean pulmonary artery systolic pressure of 24±10 mmHg. OSA severity distribution is shown in Table 1. No significant association was found between grade of severity of OSA with clinical diagnosis of HF, nor with diastolic dysfunction by TTE. The average probability of HFpEF by validated score was 50%, and the distribution of the score was the same across severity of OSA (p=0.260). Pearson’s correlation showed a significant positive relationship between age, BMI and PASP, and H2FpEF score (p<0.01 for all), however, no relation was found when correlating with neck size, apnea-hypopnea index and mean oxygen saturation. Conclusion: Although patients with OSA might have a higher H2FpEF score due to inherent characteristics, the clinical diagnosis of HFpEF in our population was lower than expected by H2FpEF score, in which the degree of severity was not associated with a higher H2FpEF score.

The link between left ventricular extracellular volume determined by T1 myocardial mapping and gut microbiota composition in individuals with heart failure and preserved ejection fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) represents a major challenge in modern cardiology. As described previously, in HFpEF comorbidities promote a systemic inflammatory state, leading to diffuse myocardial fibrosis resulting in myocardial stiffening. Gut dysbiosis which is considered as the novel source of chronic systemic inflammation has been actively investigated as the risk factor for the development and aggravation of cardiovascular diseases including heart failure. Cardiac magnetic resonance T1-mapping is a novel tool, which allows noninvasive quantification of the extracellular space and diffuse myocardial fibrosis. Moreover, the extracellular volume (ECV) fraction can be calculated, providing information on the relative expansion of the extracellular matrix, thus being a noninvasive alternative to myocardial biopsy studies. Purpose The research was aimed at investigating the correlation between the left ventricular ECV and gut microbial genera in patients with HFpEF. Methods 42 patients with confirmed HF-pEF (mediana and interquartile range of age 67 [64; 72] years, 47% men, body mass index <35 kg/m2 with no history of myocardial infarction or diabetes mellitus) were enrolled in the study. The patients underwent transthoracic echocardiography with Doppler study, HF-pEF was confirmed according to the recent ESC guidelines (based on E/e' ratio, N-terminal pro-B type natriuretic peptide >125 pg/ml and symptoms of heart failure). The intestinal microbiome was investigated using high-throughput sequencing of bacterial 16S rRNA gene. As the last step of research T1-myocardial mapping with the modified look-locker inversion-recovery protocol (MOLLI) sequence at 1.5 Tesla was performed to assess left ventricular extracellular volume fraction. Results The mean±std in ECV was 31.02±4.4%. The relative abundance (%) of the most prevalent phyla in gut microbiota was 48±22.5 for Firmicutes, 47.4±22.8 for Bacteroidetes and 1.5 [1.5; 2.5] for Proteobacteria. The analysis showed significant negative correlations between ECV and the following bacterial genera: Faecalibacterium (r=−0.35), Blautia (r=−0.43), Lachnoclostridium (r=−0.32). Moreover ECV positively correlated with Holdemania (r=0.4), Victivallis (r=0.38), Dehalobacterium (r=0.38), Enterococcus (r=0.33) and Catabacter (r=0.32). All correlation values with p<0.05. Conclusion We discovered both negative and positive significant correlations between ECV – the non-invasive marker of myocardial fibrosis and several bacterial genera, which may have negative impact on myocardial remodeling in HF-pEF. Funding Acknowledgement Type of funding source: None

Abstract P051: Application Of Artificial Intelligence In Transcriptome-based Diagnosis Of Cardiomyopathies

Dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM) are predisposing conditions for increased risk of cardiovascular diseases including heart failure, valve disease and arrhythmias. An accurate diagnostic strategy of differentially classifying different types of cardiomyopathies could contribute to precision medicine in routine clinical care. We hypothesized that artificial intelligence (AI) could be trained with cardiac transcriptomic data for diagnostic classifications of clinical cardiomyopathies. To test this hypothesis, various supervised machine learning (ML) models, such as support vector machine with radial kernel (svmRadial), neural networks with principal component analysis (pcaNNet), decision tree (DT), elastic net (ENet) and random forest (RF), were used to analyze RNA-seq data of human left ventricle tissues collected from 41 DCM patients, 47 ICM patients and 49 non-failure controls (NF). Initial ML classifications achieved an AUC of ~0.96 (ENet, pcaNNet and svmRadial) for NF vs DCM, an AUC of ~0.89 (RF) for NF vs ICM, and an AUC of ~0.90 (svmRadial) for DCM vs ICM. Next, 50 highly contributing genes (HCGs) for classifying NF and DCM, 68 HCGs for classifying NF and ICM, and 59 HCGs for classifying DCM and ICM were selected for re-training ML models. The re-trained models achieved an AUC of ~0.96 (RF) for NF vs DCM, an AUC of ~0.97 (pcaNNet) for NF vs ICM, and an AUC of ~0.94 (RF) for DCM vs ICM. Pathway analyses of the selected HCGs further demonstrated their pathophysiological roles in cardiovascular dysfunctions including cardiomyopathies. Overall, our study demonstrates the promising potential of using AI via ML models as a novel approach to achieve a greater level of precision in diagnosing different types of clinical cardiomyopathies.

Morbidity and mortality in orthostatic hypotension.

This review summarizes the current literature on the epidemiology of orthostatic hypotension (OH) in the elderly and in patients with autonomic impairment also known as neurogenic OH (nOH); these two conditions have distinct pathophysiologies and affect different patient populations. The prevalence of OH in the elderly varies depending on the study population. In community dwellers, OH prevalence is estimated at 16%, whereas in institutionalized patients, it may be as high as 60%. The prevalence of OH increases exponentially with age, particularly in those 75years and older. Multiple epidemiological studies have identified OH as a risk factor for all-cause mortality and cardiovascular disease including heart failure and stroke. Real-world data from administrative databases found polypharmacy, multiple co-morbid conditions, and high health-care utilization as common characteristics in OH patients. A comprehensive evaluation of medications associated with OH is discussed with particular emphasis on the use of anti-hypertensive therapy from two large clinical trials on high-intensive versus standard blood pressure management. Finally, we also review the epidemiology of nOH based on the underlying neurodegenerative disorder (either Parkinson's disease or multiple system atrophy), and the presence of co-morbid conditions such as hypertension and cognitive impairment.

Abstract 295: Genome-wide CRISPR Screen Identifies Keap1-Nrf2 Pathway as a Crucial Regulator for Fibrosis

Cardiac fibrosis is the pathological feature of myocardial remodeling and clinically involved in various cardiovascular diseases including heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation. Accumulating evidence revealed the molecular mechanism behind organ fibrosis, however, no effective anti-fibrotic therapy has been developed. To find novel anti-fibrotic molecular targets, we performed genome-wide CRISPR library screening with focus on myofibroblast activation. Since a feedforward autocrine loop accelerates myofibroblast differentiation, we employed connective tissue growth factor (CTGF), a center of profibrotic secretome, as a target factor for screening assay. We firstly generated a CTGF-GFP knock-in reporter cell in mesenchymal progenitor cells. The reporter cells were transduced with lentivirus CRISPR library and treated with TGF beta, then high and low GFP signal cells were sorted and sequenced. This screening showed that Keap1-NRF2 pathway was one of the top hits and a novel regulator for CTGF expression. Keap1 knockout attenuated TGF beta-mediated CTGF expression and additional NRF2 knockout cancelled it. Keap1-NRF2 pathway also regulated broadly other profibrotic factors, alpha SMA, periostin, and fibronectin. An activator of NRF2, CDDO-Im treatment had similar effect on TGF beta-mediated profibrotic response. CTGF knockout had little effect on these profibrotic factors, indicating that Keap1-NRF2 is better therapeutic target, as compared with CTGF. Keap1-NRF2 originally reported as a transcriptional regulator for antioxidant and detoxification genes. In silico analysis indicates CTFG promoter has NRF2 response element and ChiP-qPCR experiment confirmed that NRF2 directly regulated CTFG transcriptional expression, not indirectly through antioxidant gene expression. In conclusion, genome-wide screening identified Keap1-NRF2 pathway as a crucial regulator for myofibroblast activation and NRF2 activation might be novel therapy for fibrosis-related diseases.

Survival outcomes in post-menopausal patients with underlying cardiovascular disease receiving endocrine therapy for the treatment of breast cancer.

e12549 Background: Breast cancer remains the number one threat to women’s health while cardiovascular disease (CVD) continues to be the leading cause of mortality in women worldwide. Adjuvant therapy with endocrine therapies (selective estrogen receptor modulators (SERM), estrogen receptor blockers (ERB), and aromatase inhibitors (AI) although known to reduce the recurrence of breast cancer in hormone receptor positive breast cancer patients, raise a concern for increased risk of cardiovascular disease. Our study aims to examine breast cancer survival outcomes on patients receiving endocrine therapy who have pre-existing CVD including heart failure. Methods: An institutional database of 478 patients with histologically confirmed hormone receptor positive breast cancer diagnosed between 01/01/2014 to 12/31/2017 was reviewed after IRB approval. Preexisting CVD included coronary artery disease (CAD), history of myocardial infarction (MI), and prior diagnosis of heart failure (HF). Patients were divided in groups depending on treatment with endocrine therapy and underlying CVD. Statistical analysis was performed with SAS v9.4. software. Survival curves were estimated using Kaplan-Meier methodology and analyzed with a log rank test. Predictors of survival were assessed with Cox proportional hazards regression analyses. All significance was assumed at the p < 0.05 level. Results: Of 478 patients who met the inclusion criteria, 336 (70%) patients were postmenopausal. Out of those 336 patients, 62.2 % (n = 209) received at least one of the endocrine therapies consisting of AI, SERM or an ERB. Of these patients, 2.9 % (n = 6), 9.6% (n = 20) and 5.7% (n = 12) had a significant medical history of underlying MI, HF and CAD, respectively. Survival analysis was performed on 80% (n = 168) patients of the 209 patients with 2.3% (n = 4), 8.9% (n = 15) and 5.2% (n = 11) with underlying MI, HF and CAD respectively. There was no statistically significant difference in survival in these postmenopausal women who received endocrine therapy despite preexisting cardiovascular disease (HR 3; 95% CI, 0.5-16, p > 0.05). Conclusions: A commonly known toxicity related to the adjuvant therapy including endocrine therapy of breast cancer is cardiac toxicity. Patients with history of CVD might be at the highest risk for such toxicity. Our finding is reassuring that endocrine therapy in patients with preexisting CVD including heart failure did not result in reduced survival for our patient cohort.

Mitochondrial protection by simvastatin against angiotensin II-mediated heart failure.

Background and PurposeMitochondrial dysfunction plays a role in the progression of cardiovascular diseases including heart failure. 3‐Hydroxy‐3‐methylglutaryl‐CoA reductase inhibitors (statins), which inhibit ROS synthesis, show cardioprotective effects in chronic heart failure. However, the beneficial role of statins in mitochondrial protection in heart failure remains unclear.Experimental ApproachRats were treated with angiotensin II (1.5 mg·kg−1·day−1) or co‐administered simvastatin (oral, 10 mg·kg−1) for 14 days; and then administration was stopped for the following 14 days. Cardiac structure/function was examined by wheat germ agglutinin staining and echocardiography. Mitochondrial morphology and the numbers of lipid droplets, lysosomes, autophagosomes, and mitophagosomes were determined by transmission electron microscopy. Human cardiomyocytes were stimulated, and intracellular ROS and mitochondrial membrane potential (ΔΨ m) changes were measured by flow cytometry and JC‐1 staining, respectively. Autophagy and mitophagy‐related and mitochondria‐regulated apoptotic proteins were identified by immunohistochemistry and western blotting.Key ResultsSimvastatin significantly reduced ROS production and attenuated the disruption of ΔΨ m. Simvastatin induced the accumulation of lipid droplets to provide energy for maintaining mitochondrial function, promoted autophagy and mitophagy, and inhibited mitochondria‐mediated apoptosis. These findings suggest that mitochondrial protection mediated by simvastatin plays a therapeutic role in heart failure prevention by modulating antioxidant status and promoting energy supplies for autophagy and mitophagy to inhibit mitochondrial damage and cardiomyocyte apoptosis.Conclusion and ImplicationsMitochondria play a key role in mediating heart failure progression. Simvastatin attenuated heart failure, induced by angiotensin II, via mitochondrial protection and might provide a new therapy to prevent heart failure.

Testosterone Level Does Not Affect the Risk of Admission or Length of Hospital Stay in Patients with Heart Failure — A National Health and Nutrition Examination Survey-Based Study

Introduction There is some evidence concerning the role of testosterone in cardiovascular diseases including heart failure. Some evidence favors reduced risk of cardiovascular events with higher levels while others have found no association. Hypothesis We hypothesized that lower testosterone level is associated with a lower hospital stay and admission rates in those with heart failure. Methods We used the NHANES database to identify males with a reported diagnosis of heart failure. The outcomes were inpatient admission in the past year and the number of days spent in the hospital in the past year. Results We identified 284 males with a reported a diagnosis of heart failure in 2011-2016 NHANES, mean age was 66.5 years, and there was no statistically significant difference in age between the group with serum testosterone less than 250 ng/ml and the group with serum testosterone more than 250 ng/ml(p=0.21). In the monovariate analysis, the group with lower testosterone levels are less likely to be admitted when compared to the group with higher testosterone, but this association was not statistically significant (25.6% vs. 40.0%,P=0.05). After multivariate analysis using logistic regression adjusting for comorbid conditions, the odds of being admitted is less in those with normal testosterone, but this was not statistically significant (OR 0.54, 95CI 0.25-1.57,p=0.11). In the linear regression model, we didn't find any significant effect of serum testosterone in the overall number of days spent in the hospital. Conclusions There was no evidence of an association between testosterone and increased admission and also no evidence of an association between serum testosterone and the overall length of stay. Some studies have shown possible benefits of testosterone supplementation in heart failure, but our study revealed that there is likely no effect on the risk of admission or length of stay.

ELEVATION OF DIASTOLIC BLOOD PRESSURE AND REDUCTION OF VASCULAR CONTRACTION IN MAGNESIUM DEFICIENT RAT MODEL

Objective:Magnesium (Mg) deficiency has been reported to be associated with the development of various cardiovascular diseases including heart failure and hypertension, however, vascular responses in Mg deficient state have not been fully evaluated. The purpose of the present study is to examine the

AORTIC STIFFNESS IS NOT ONLY ASSOCIATED WITH STRUCTURAL BUT ALSO WITH FUNCTIONAL PARAMETERS OF MICROCIRCULATION

Objective: The aim of the study was to test the hypothesis if arterial stiffness is linked to reduction of retinal capillary blood flow and development of retinal microvascular remodelling. Design and method: The study group comprised of 88 patients with essential hypertension (n = 88, 54.3 ± 8.3 years, 44.3% were female) and 32 healthy controls. Inclusion criteria were: essential hypertension, age of 40–70 years old. Exclusion criteria were: secondary hypertension, any cardiovascular disease including heart failure, coronary artery disease, arrhythmia, moderate or severe valve disease, history of stroke or transient ischemic attack, chronic kidney disease with eGFR < 60 mml/min/1.73 m2, diabetes mellitus, eye disease, pregnancy. Retinal microcirculation was evaluated by scanning laser Doppler flowmetry. Macrovascular changes were assessed on the basis of measurement of arterial stiffness (by carotid-femoral pulse wave velocity, central pulse pressure, augmentation pressure and augmentation index) and intima media thickness of common carotid artery. Diastolic dysfunction and left ventricular hypertrophy were analysed by echocardiography. Results: Pulse wave velocity was inversely correlated with mean retinal capillary blood flow in a group of hypertensive patients (R = −0.32, p < 0.01). This relationship remained significant in multivariate regression analysis even after adjustment for age, systolic blood pressure and waist to hip ratio (β = −40.275, p < 0.001). Central pulse pressure was positively correlated with retinal wall thickness (R = 0.44, p < 0.05), wall cross sectional area (R = 0.44, p < 0.05) and wall to lumen ratio (R = 0.43, p < 0.05). Brachial pulse pressure was positively correlated with wall thickness (R = 0.43, p < 0.05), wall cross sectional area (R = 0.41, p < 0.05) and wall to lumen ratio (R = 0.47, p < 0.05). In contrast, the relationship between augmentation pressure or augmentation index and structural indicators of retinal remodelling was not observed. Conclusions: In conclusion, the study provides an evidence that microcirculation is coupled with macrocirculation not only in terms of structural but also functional parameters. Pulse wave velocity was independently associated with retinal capilary flow. Central and brachial pulse pressure were significantly related to retinal wall thickness, wall cross sectional area and wall to lumen ratio.

LUMEN NARROWING OF RETINAL ARTERIOLES IS A VALUABLE BIOMARKER OF CARDIAC DAMAGE

Objective: The aim of the study was to establish the relationship between structural and functional abnormalities of retinal microcirculation and cardiac damage defined as the presence of left ventricle hypertrophy and/or diastolic dysfunction. Design and method: The study consisted of 88 patients with essential hypertension (54.3 ± 8.3 years, 44.3% were female) and 32 healthy subjects. Inclusion criteria were: essential hypertension, age of 40–70 years old. Exclusion criteria were: secondary hypertension, any cardiovascular disease including heart failure, coronary artery disease, arrhythmia, moderate or severe valve disease, history of stroke or transient ischemic attack, chronic kidney disease with eGFR < 60 mml/min/1.73 m2, diabetes mellitus, eye disease, pregnancy. Scanning laser Doppler flowmetry was used to evaluate retinal structure and function. Diastolic dysfunction and left ventricle hypertrophy were analysed by echocardiography. The group was divided into two subgroups: 1. hypertensives without cardiac damage (n = 55); 2. hypertensives with cardiac damage (n = 33). Cardiac damage was defined as the presence of left ventricle hypertrophy and/or diastolic dysfunction. Results: Among all retinal parameters lumen diameter was significantly smaller in patients with cardiac damage versus healthy subjects (77 vs. 83 μm, p < 0.05). Lumen diameter revealed a significant decreasing trend across the groups of controls, patients without cardiac damage and patients with concomitant cardiac damage (84 vs. 81 vs. 77 μm, p trend <0.01). Moreover, in correlation analysis lumen diameter was inversely related to intraventricular septum diameter (r = −0.25 p < 0.05), left ventricular mass (r = −0.23, p < 0.05) and left atrial volume (r = −0.22 p < 0.05). These associations remained significant even after adjustment for age, sex and mean blood pressure in multivariate analysis: intraventricular septum diameter (β = −1.1 p < 0.05), left ventricular mass (β = −0.4, p < 0.05) and left atrial volume (β = −0.05 p < 0.05). The association of lumen diameter with diastolic dysfunction indices apart left atrial volume was not observed. Conclusions: Retinal examination performed by mean of scanning laser Doppler flowmetry is of great value in detecting patients with cardiac damage. Lumen narrowing of retinal arterioles was independently associated with intraventricular septum diameter, left ventricular mass and left atrial volume.

The gut microbiome and heart failure.

The human gut is populated by a complex community of microbiota that coexists with the host to maintain homeostasis. Accumulating evidence shows that changes in the composition and diversity of gut microbiota, known as dysbiosis, is associated with cardiovascular diseases, such as atherosclerosis, hypertension, and heart failure. Although recent advances in biochemical and molecular analyses have contributed to the detection, identification, and characterization of a variety of gut microbiota genomes and their associated metabolites, the exact mechanisms of action remain unclear. As the prevalence of cardiovascular disease continues to rise, investigating the gut microbiome as a potential strategy for clinical intervention is highly warranted. In this review, we discuss correlations between the gut microbiome and heart failure, as well as the effects of altering the microbiome as a potential therapeutic target in cardiovascular diseases including heart failure.

Cardiac Specific Knockout of p53 Decreases ER Stress-Induced Mitochondrial Damage.

Endoplasmic reticulum (ER) stress contributes to cardiovascular disease including heart failure. Interactions between the ER and mitochondria during ER stress can impair the mitochondrial respiratory chain and increase cell injury. p53 is a tumor suppressor protein that regulates apoptosis. p53 contributes to the regulation of mitochondrial and ER interactions, especially during the progression of ER stress. The knockout (KO) of p53 leads to decreased injury in hearts following ischemia-reperfusion. We asked if KO of p53 can protect mitochondria during the induction of ER stress and decrease cell injury. Floxed p53 mice were crossed with mice carrying an α-myosin heavy chain cre to generate cardiac specific p53 KO mice. Thapsigargin (THAP) was used to induce ER stress in wild type (WT) and p53 KO mice. Mice were euthanized after 48 h THAP treatment. Cardiac mitochondria were isolated for functional measurement. TUNEL staining was used to assess myocyte death. In WT mice, THAP treatment decreased the rate of oxidative phosphorylation using pyruvate + malate as complex I substrates compared to vehicle-treated control. Complex I activity was also decreased in the THAP-treated WT mice. The rate of oxidative phosphorylation and complex I activity were not altered in THAP-treated p53 KO mice. The content of pyruvate dehydrogenase (PDH) α1 subunit was decreased in THAP-treated WT mice but not in p53 KO mice. ER stress led to a release of cytochrome c and apoptosis inducing factor from mitochondria into cytosol in WT but not in KO mice. Knockout of p53 also preserved mitochondrial bcl-2 content in THAP-treated mice. In WT mice, THAP treatment markedly increased cell death compared to vehicle treated hearts. In contrast, cell injury was decreased in THAP-treated p53 KO mice compared to corresponding wild type. Thus, KO of p53 decreased cell injury by protecting mitochondria during the ER stress.

Correlation between Pentraxin-3 and Left Ventricular Diastolic Dysfunction in Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is one of independent dangerous factors for cardiovascular disease including heart failure. Recent studies demonstrated that left ventricular diastolic dysfunction (LVDD) and pentraxin-3 (PTX-3) are early signs for development of heart failure. The objective of our study was to estimate the relation between OSA severity and LVDD and PTX-3.

The effects of xanthine oxidase inhibitor in patients with chronic heart failure complicated with hyperuricemia: a prospective randomized controlled clinical trial of topiroxostat vs allopurinol\u2014study protocol

BackgroundHyperuricemia has a close relationship with cardiovascular diseases including heart failure. However, it is controversial whether xanthine oxidase inhibition has benefits for patients with chronic heart failure. We designed the Effect of Xanthine Oxidase Inhibitor in Chronic Heart Failure Patients Complicated with Hyperuricemia study (Excited-UA study) to compare the beneficial effects between a novel xanthine oxidoreductase inhibitor, topiroxostat, and a conventional agent, allopurinol, in patients with chronic heart failure and hyperuricemia. We focus on serum N-terminal pro-brain natriuretic peptide (NT-proBNP) level, echocardiography-based cardiac function, vascular endothelial function, renal function, inflammation, and oxidative stress.MethodsThe excited-UA is a prospective, randomized, open-label, blinded-endpoint clinical trial designed to prove our hypothesis that topiroxostat is more effective than allopurinol in patients with chronic heart failure and hyperuricemia. A total of 140 patients with chronic heart failure and hyperuricemia (plasma brain natriuretic peptide level ≥ 40 pg/mL and serum uric acid level ≥ 7.0 mg/dL) are randomly assigned (ratio 1:1) into either the topiroxostat group (40–160 mg/day) or allopurinol group (100–300 mg/day), to achieve the target uric acid level of 6.0 mg/dL. According to the protocol, all patients are followed up annually for 24 weeks. The primary endpoint is percent change in serum NT-proBNP level at 24 weeks from baseline.ConclusionsThe Excited-UA study would provide novel evidence for the clinical relevancy of xanthine oxidoreductase inhibitor treatment in patients with chronic heart failure and hyperuricemia.

Clinical Characteristics and Mid-Term Outcomes of Non-Elderly Obese Patients with Acute Decompensated Heart Failure in Japan.

Obesity is a well-known risk factor for cardiovascular diseases including heart failure (HF). However, some literatures suggested better clinical outcomes in obese patients with HF. Since higher body mass index (BMI) levels of HF patients were significantly associated with younger age, the impact of obesity on clinical outcomes in non-elderly HF patients should be elucidated.Consecutive 155 non-elderly acute decompensated HF patients (< 60-year-old) who admitted to our institution between 2009 and 2013 were included. Those patients were divided into the two groups according to the BMI: the obesity group (BMI ≥ 25 kg/m2, n = 81) and the non-obesity group (BMI < 25 kg/m2, n = 74). The primary composite outcome of this study was defined as re-admission due to HF and all-cause death.The primary composite outcome was less frequently observed in the obesity group as compared with the non-obesity group (Hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.26-0.95, P = 0.03). Re-admission due to HF was significantly less in the obesity group than in the non-obesity group (HR 0.44, 95% CI 0.23-0.86, P = 0.02), whereas all-cause death was not significantly different between the groups (P = 0.44).The mid-term outcomes in non-elderly HF patients with obesity were better as compared with non-elderly HF patients without obesity, which supports obesity paradox in this specific population.

ER stress induces cardiac dysfunction through cardiomyocytes architectural modifications and alteration of mitochondrial function

Endoplasmic reticulum (ER) stress has recently emerged as an important mechanism involved in the pathogenesis of cardiovascular diseases including heart failure. However, the molecular mechanisms by which ER stress leads to cardiac dysfunction remain poorly understood. In the present study, we evaluated the early cardiac effects of ER stress induced by tunicamycin (TN) in mice. Electrocardiographic analysis indicated that TN-induced ER stress led to a significant impairment of the cardiac function. Electron microscopic observations revealed that ultrastructural changes of cardiomyocytes in response to ER stress manifested extensively at the level of the sarco-endoplasmic reticulum membranes. Smooth tubules of sarcoplasmic reticulum in connection with short sections of rough endoplasmic reticulum were observed. The presence of rough instead of smooth reticulum was increased at the interfibrillar space, at the level of dyads and in the vicinity of mitochondria. At a functional level, ER stress resulted in a substantial decrease in mitochondrial biogenesis as demonstrated by the decrease of the expression of PGC-1α and of its targets NRF1, Tfam, CS and COXIV. ER stress also led to an impairment of mitochondrial oxidative phosphorylation and to a metabolic remodeling characterized by a shift from fatty acid to glycolytic substrate consumption. Our findings show that ER stress induces cytoarchitectural and metabolic alterations in cardiomyocytes and provide evidences that ER stress could represent a primary mechanism that contributes to the impairment of energy metabolism reported in most cardiac diseases.

Neonatal Rat Cardiomyocytes Isolation, Culture, and Determination of MicroRNAs' Effects in Proliferation.

Cardiomyocytes loss is a major contributor for many cardiovascular diseases including heart failure and myocardial infarction. Although extremely limited, adult cardiomyocytes are able to proliferate. Understanding the molecular mechanisms controlling cardiomyocytes proliferation is extremely important for enhancing cardiomyocyte proliferation to promote cardiac regeneration and repair. MicroRNAs (miRNAs, miRs) are powerful controllers of many essential biological processes including cell proliferation. Here, we described in detail a protocol for isolation and culture of neonatal rat cardiomyocytes and the determination of miRNAs' effects in proliferation based on two well-established methods including EdU and Ki67 immunofluorescent stainings.

Red blood cell distribution width and myocardial scar burden in coronary artery disease

IntroductionRed blood cell distribution width (RDW) is a novel independent marker of cardiovascular disease including heart failure, coronary artery disease and myocardial ischaemia. The aim of the study was to...

Mitochondrial Mechanosensor Microdomains in Cardiovascular Disorders.

The cardiomyocytes populating the 'working myocardium' are highly organized and such organization ranges from macroscale (e.g. the geometrical rod shape) to microscale (dyad/t-tubules) domains. This meticulous level of organization is imperative for assuring the normal and physiological pump-function of the heart. In the pathological cardiac tissue, the domains-related architecture is partially lost, resulting in morphological, electrical and metabolic remodeling and promoting cardiovascular diseases including heart failure and arrhythmias. Indeed, arrhythmogenesis during heart failure is a major clinical problem. Arrhythmias have been extensively studied from an electrical etiology, but only recently, physiologists and scientists have focused their attention on cellular and subcellular mechanosensors. We and others have investigated whether the nanoscale mechanosensitive properties of cardiomyocytes from failing hearts have a bearing upon the initiation of abnormal electrical activity. This chapter highlights the recent findings in the field, especially the role of mitochondria function and alignment in failing cardiomyocytes interrogated via nanomechanical stimuli.