Systems Biology Applied to Heart Failure With Normal Ejection Fraction

Heart failure with normal ejection fraction (HFNEF) is currently the most prevalent clinical phenotype of heart failure. However, the treatments available have shown no reduction in mortality so far. Advances in the omics sciences and techniques of high data processing used in molecular biology have enabled the development of an integrating approach to HFNEF based on systems biology.This study aimed at presenting a systems-biology-based HFNEF model using the bottom-up and top-down approaches.A literature search was conducted for studies published between 1991 and 2013 regarding HFNEF pathophysiology, its biomarkers and systems biology. A conceptual model was developed using bottom-up and top-down approaches of systems biology.The use of systems-biology approaches for HFNEF, a complex clinical syndrome, can be useful to better understand its pathophysiology and to discover new therapeutic targets.     

Atrial Fibrillation in Decompensated Heart Failure: Associated Factors and In-Hospital Outcome

Background

Studies on atrial fibrillation (AF) in decompensated heart failure (DHF) are scarce in Brazil.

Objectives

To determine AF prevalence, its types and associated factors in patients hospitalized due to DHF; to assess their thromboembolic risk profile and anticoagulation rate; and to assess the impact of AF on in-hospital mortality and hospital length of stay.

Methods

Retrospective, observational, cross-sectional study of incident cases including 659 consecutive hospitalizations due to DHF, from 01/01/2006 to 12/31/2011. The thromboembolic risk was assessed by using CHADSVASc score. On univariate analysis, the chi-square, Student t and Mann Whitney tests were used. On multivariate analysis, logistic regression was used.

Results

The prevalence of AF was 40%, and the permanent type predominated (73.5%). On multivariate model, AF associated with advanced age (p < 0.0001), non-ischemic etiology (p = 0.02), right ventricular dysfunction (p = 0.03), lower systolic blood pressure (SBP) (p = 0.02), higher ejection fraction (EF) (p < 0.0001) and enlarged left atrium (LA) (p < 0.0001). The median CHADSVASc score was 4, and 90% of the cases had it ≥ 2. The anticoagulation rate was 52.8% on admission and 66.8% on discharge, being lower for higher scores. The group with AF had higher in-hospital mortality (11.0% versus 8.1%, p = 0.21) and longer hospital length of stay (20.5 ± 16 versus 16.3 ± 12, p = 0.001).

Conclusions

Atrial fibrillation is frequent in DHF, the most prevalent type being permanent AF. Atrial fibrillation is associated with more advanced age, non-ischemic etiology, right ventricular dysfunction, lower SBP, higher EF and enlarged LA. Despite the high thromboembolic risk profile, anticoagulation is underutilized. The presence of AF is associated with longer hospital length of stay and high mortality.     

心率和心率变异性与心力衰竭及预后的相关性

目的　探讨心率及心率变异性与心力衰竭及预后的相关性。方法　入选2010年10月至2012年6月期间就诊宁夏医科大学总医院心内科的慢性充血性心力衰竭患者245例,根据住院期间平均静息心率水平分为3组：A组：50～70次/分;B组：71～90次/分;C组：＞90次/分;共随访1年,完成随访共230例。其中共有97例行动态心电图检查,按患者心功能分级分为Ⅱ级组、Ⅲ级组、Ⅳ级组,同时选择26例正常健康人为对照组。收集上述研究对象的心率变异性时域指标进行对比分析,包括正常RR间期标准差（SDNN）、5　min均值标准差（SDANN）、相邻RR间期相差＞50　ms的个数占总心跳数的百分比（PNN50）、全程相邻RR间期之差的平方根（RMSSD）。结果随着心率水平增加,随访终点射血分数明显降低,再住院率及病死率明显增加（P＜0.01）。不同心率水平心力衰竭患者Cox生存分析显示心率越快,生存率越低。心力衰竭组与对照组相比SDNN、SDANN、PNN50、RMSSD降低（P＜0.01或P＜0.05）,随着心力衰竭程度的加重,SDNN、SDANN、PNN50、RMSSD下降越明显（P＜0.01）。结论　心率越快,心力衰竭预后越差;心力衰竭患者存在心率变异性降低,心率变异性越低,心功能越差。     

Association between Functional Variables and Heart Failure after Myocardial Infarction in Rats

Background

Heart failure prediction after acute myocardial infarction may have important clinical implications.

Objective

To analyze the functional echocardiographic variables associated with heart failure in an infarction model in rats.

Methods

The animals were divided into two groups: control and infarction. Subsequently, the infarcted animals were divided into groups: with and without heart failure. The predictive values were assessed by logistic regression. The cutoff values predictive of heart failure were determined using ROC curves.

Results

Six months after surgery, 88 infarcted animals and 43 control animals were included in the study. Myocardial infarction increased left cavity diameters and the mass and wall thickness of the left ventricle. Additionally, myocardial infarction resulted in systolic and diastolic dysfunction, characterized by lower area variation fraction values, posterior wall shortening velocity, E-wave deceleration time, associated with higher values of E / A ratio and isovolumic relaxation time adjusted by heart rate. Among the infarcted animals, 54 (61%) developed heart failure. Rats with heart failure have higher left cavity mass index and diameter, associated with worsening of functional variables. The area variation fraction, the E/A ratio, E-wave deceleration time and isovolumic relaxation time adjusted by heart rate were functional variables predictors of heart failure. The cutoff values of functional variables associated with heart failure were: area variation fraction < 31.18%; E / A > 3.077; E-wave deceleration time < 42.11 and isovolumic relaxation time adjusted by heart rate < 69.08.

Conclusion

In rats followed for 6 months after myocardial infarction, the area variation fraction, E/A ratio, E-wave deceleration time and isovolumic relaxation time adjusted by heart rate are predictors of heart failure onset.     

Effects of Exercise Training on Heart Rate Variability in Chagas Heart Disease

Background:

Heart rate variability (HRV) is a marker of autonomic dysfunction severity. The effects of physical training on HRV indexes in Chagas heart disease (CHD) are not well established.

Objective:

To evaluate the changes in HRV indexes in response to physical training in CHD.

Methods:

Patients with CHD and left ventricular (LV) dysfunction, physically inactive, were randomized either to the intervention (IG, N = 18) or control group (CG, N = 19). The IG participated in a 12-week exercise program consisting of 3 sessions/week.

Results:

Mean age was 49.5 ± 8 years, 59% males, mean LVEF was 36.3 ± 7.8%. Baseline HRV indexes were similar between groups. From baseline to follow-up, total power (TP): 1653 (IQ 625 - 3418) to 2794 (1617 - 4452) ms, p = 0.02) and very low frequency power: 586 (290 - 1565) to 815 (610 - 1425) ms, p = 0.047) increased in the IG, but not in the CG. The delta (post - pre) HRV indexes were similar: SDNN 11.5 ± 30.0 vs. 3.7 ± 25.1 ms. p = 0.10; rMSSD 2 (6 - 17) vs. 1 (21 - 9) ms. p = 0.43; TP 943 (731 - 3130) vs. 1780 (921 - 2743) Hz. p = 0.46; low frequency power (LFP) 1.0 (150 - 197) vs. 60 (111 - 146) Hz. p = 0.85; except for high frequency power, which tended to increase in the IG: 42 (133 - 92) vs. 79 (61 - 328) Hz. p = 0.08).

Conclusion:

In the studied population, the variation of HRV indexes was similar between the active and inactive groups. Clinical improvement with physical activity seems to be independent from autonomic dysfunction markers in CHD.     

肾上腺髓质素与神经肽Y在慢性心率增快心力衰竭患者中的变化及临床意义

目的　观察存在慢性心率增快的慢性心力衰竭患者血浆肾上腺髓质素（ADM）、神经肽Y（NPY）水平变化及临床意义,进一步探讨其在慢性心率增快中的作用。方法　将2011～2012年收住我院的慢性心力衰竭患者,根据患者入院时24　h动态心电图结果分为慢性心率增快组：80例,平均心率≥80次/分;非慢性心率增快组：80例,平均心率＜80次/分。使用酶联免疫吸附法测定两组慢性心力衰竭患者的血浆ADM、NPY、脑钠肽水平,用超声心动图测量左心房内径、左心室舒张末内径、左心室射血分数、左心室短轴缩短率。结果　慢性心率增快组慢性心力衰竭患者的血浆ADM、NPY水平均高于非慢性心率增快组（P<0.05）,随NYHA分级逐级增高,差异有统计学意义（P<0.01）。单因素分析显示ADM、NPY水平与左心房内径呈正相关（P<0.001）,与左心室射血分数、左心室短轴缩短率呈负相关（P<0.001）。结论　ADM、NPY可能参与了慢性心力衰竭中慢性心率增快的病理生理过程,是心力衰竭恶化的危险因素。     

冠心病慢性充血性心功能衰竭患者心率变异性及其昼夜节律变化

目的探讨冠心病慢性充血性心功能衰竭患者心率变异性及其昼夜节律的变化,以及自主神经功能损害与心功能的关系.方法用24 h动态心电图分析52例冠心病慢性充血性心功能衰竭患者(心功能衰竭组),33例冠心病心功能代偿期患者(心功能代偿组),23例健康体检者(对照组)的心率变异性时域指标和频域指标.比较三组间心率变异性时域指标的变化和慢性充血性心功能衰竭患者心率变异性昼夜频域指标变化;分析此类患者心率变异性时域指标变化与美国纽约心脏协会心功能分级的关系.结果冠心病心功能代偿组24 h心率变异性时域指标窦性心律R-R间期标准差、5 min窦性R-R间期平均值标准差和5 min窦性R-R标准差平均值较对照组显著下降(P<0.05),相邻R-R间期之差的均方根值、相邻R-R间期差值>50 ms的个数除以整R-R间期的个数的百分比和三角指数与对照组无显著差别(P>0.05);冠心病慢性充血性心功能衰竭组的各时域指标均显著低于对照组(均P<0.01),也低于心功能代偿组(均P<0.05),且昼夜频域指标变化无差异;将冠心病慢性充血性心功能衰竭组分为心功能Ⅱ级组(n=32)和心功能≥Ⅲ级(n=20)两个亚组,结果发现心功能≥Ⅲ级组心率变异性各时域指标明显低于心功能Ⅱ级组(P<0.05).结论冠心病患者可能在心功能代偿期自主神经平衡就已受到损害,当出现慢性充血性心功能衰竭时交感活性增强,迷走张力进一步下降,自主神经调节昼夜节律功能丧失,心率变异性指标的下降与心功能损害程度相关,因此心率变异性指标可作为评价慢性充血性心功能衰竭预后指标之一.     

Meta-Analysis of Ultrafiltration versus Diuretics Treatment Option for Overload Volume Reduction in Patients with Acute Decompensated Heart Failure

Introduction

Although diuretics are mainly used for the treatment of acute decompensated heart failure (ADHF), inadequate responses and complications have led to the use of extracorporeal ultrafiltration (UF) as an alternative strategy for reducing volume overloads in patients with ADHF.

Objective

The aim of our study is to perform meta-analysis of the results obtained from studies on extracorporeal venous ultrafiltration and compare them with those of standard diuretic treatment for overload volume reduction in acute decompensated heart failure.

Methods

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases were systematically searched using a pre‑specified criterion. Pooled estimates of outcomes after 48 h (weight change, serum creatinine level, and all-cause mortality) were computed using random effect models. Pooled weighted mean differences were calculated for weight loss and change in creatinine level, whereas a pooled risk ratio was used for the analysis of binary all-cause mortality outcome.

Results

A total of nine studies, involving 613 patients, met the eligibility criteria. The mean weight loss in patients who underwent UF therapy was 1.78 kg [95% Confidence Interval (CI): −2.65 to −0.91 kg; p < 0.001) more than those who received standard diuretic therapy. The post-intervention creatinine level, however, was not significantly different (mean change = −0.25 mg/dL; 95% CI: −0.56 to 0.06 mg/dL; p = 0.112). The risk of all-cause mortality persisted in patients treated with UF compared with patients treated with standard diuretics (Pooled RR = 1.00; 95% CI: 0.64–1.56; p = 0.993).

Conclusion

Compared with standard diuretic therapy, UF treatment for overload volume reduction in individuals suffering from ADHF, resulted in significant reduction of body weight within 48 h. However, no significant decrease of serum creatinine level or reduction of all-cause mortality was observed.     

Reverse Cardiac Remodeling: A Marker of Better Prognosis in Heart Failure

In heart failure syndrome, myocardial dysfunction causes an increase in neurohormonalactivity, which is an adaptive and compensatory mechanism in response to thereduction in cardiac output. Neurohormonal activity is initially stimulated in anattempt to maintain compensation; however, when it remains increased, it contributesto the intensification of clinical manifestations and myocardial damage. Cardiacremodeling comprises changes in ventricular volume as well as the thickness and shapeof the myocardial wall. With optimized treatment, such remodeling can be reversed,causing gradual improvement in cardiac function and consequently improvedprognosis.     

Temporal Variation in the Prognosis and Treatment of Advanced Heart Failure - Before and After 2000

Background

The treatment of heart failure has evolved in recent decades suggesting that survival is increasing.

Objective

To verify whether there has been improvement in the survival of patients with advanced heart failure.

Methods

We retrospectively compared the treatment and follow-up data from two cohorts of patients with systolic heart failure admitted for compensation up to 2000 (n = 353) and after 2000 (n = 279). We analyzed in-hospital death, re-hospitalization and death in 1 year of follow-up. We used Mann-Whitney U test and chi-square test for comparison between groups. The predictors of mortality were identified by regression analysis through Cox proportional hazards model and survival analysis by the Kaplan-Meier survival analysis.

Results

The patients admitted until 2000 were younger, had lower left ventricular impairment and received a lower proportion of beta-blockers at discharge. The survival of patients hospitalized before 2000 was lower than those hospitalized after 2000 (40.1% vs. 67.4%; p<0.001). The independent predictors of mortality in the regression analysis were: Chagas disease (hazard ratio: 1.9; 95% confidence interval: 1.3-3.0), angiotensin-converting-enzyme inhibitors (hazard ratio: 0.6; 95% confidence interval: 0.4-0.9), beta-blockers (hazard ratio: 0.3; 95% confidence interval: 0.2-0.5), creatinine ≥ 1.4 mg/dL (hazard ratio: 2.0; 95% confidence interval: 1.3-3.0), serum sodium ≤ 135 mEq/L (hazard ratio: 1.8; 95% confidence interval: 1.2-2.7).

Conclusions

Patients with advanced heart failure showed a significant improvement in survival and reduction in re-hospitalizations. The neurohormonal blockade, with angiotensin-converting-enzyme inhibitors and beta-blockers, had an important role in increasing survival of these patients with advanced heart failure.     

Resting Heart Rate Does Not Reflect the Degree of Beta‐Blockade in Subjects with Heart Failure on Chronic Beta‐Blocker Therapy

We investigated the relationship between resting heart rate (HR) and two measures of beta‐1 receptor sensitivity/blockade: (1) the percentage of maximal predicted heart rate reached during exercise (%MPHR), and (2) the HR increase per unit of circulating norepinephrine (NE) or the chronotropic responsiveness index (CRI) in 28 patients with systolic CHF on chronic beta‐blocker therapy. Our results show that resting HR is not associated with HR response during exercise nor with beta‐1 receptor sensitivity to circulating NE.     

Cardiac Remodeling: Concepts,Clinical Impact,Pathophysiological Mechanisms and Pharmacologic Treatment

Cardiac remodeling is defined as a group of molecular, cellular and interstitialchanges that manifest clinically as changes in size, mass, geometry and function ofthe heart after injury. The process results in poor prognosis because of itsassociation with ventricular dysfunction and malignant arrhythmias. Here, we discussthe concepts and clinical implications of cardiac remodeling, and thepathophysiological role of different factors, including cell death, energymetabolism, oxidative stress, inflammation, collagen, contractile proteins, calciumtransport, geometry and neurohormonal activation. Finally, the article describes thepharmacological treatment of cardiac remodeling, which can be divided into threedifferent stages of strategies: consolidated, promising and potential strategies.     

Relationship between Fibrosis and Ventricular Arrhythmias in Chagas Heart Disease Without Ventricular Dysfunction

Background

Patients with Chagas disease and segmental wall motion abnormality (SWMA) have worse prognosis independent of left ventricular ejection fraction (LVEF). Cardiac magnetic resonance (CMR) is currently the best method to detect SWMA and to assess fibrosis.

Objective

To quantify fibrosis by using late gadolinium enhancement CMR in patients with Chagas disease and preserved or minimally impaired ventricular function (> 45%), and to detect patterns of dependence between fibrosis, SWMA and LVEF in the presence of ventricular arrhythmia.

Methods

Electrocardiogram, treadmill exercise test, Holter and CMR were carried out in 61 patients, who were divided into three groups as follows: (1) normal electrocardiogram and CMR without SWMA; (2) abnormal electrocardiogram and CMR without SWMA; (3) CMR with SWMA independently of electrocardiogram.

Results

The number of patients with ventricular arrhythmia in relation to the total of patients, the percentage of fibrosis, and the LVEF were, respectively: Group 1, 4/26, 0.74% and 74.34%; Group 2, 4/16, 3.96% and 68.5%; and Group 3, 11/19, 14.07% and 55.59%. Ventricular arrhythmia was found in 31.1% of the patients. Those with and without ventricular arrhythmia had mean LVEF of 59.87% and 70.18%, respectively, and fibrosis percentage of 11.03% and 3.01%, respectively. Of the variables SWMA, groups, age, LVEF and fibrosis, only the latter was significant for the presence of ventricular arrhythmia, with a cutoff point of 11.78% for fibrosis mass (p < 0.001).

Conclusion

Even in patients with Chagas disease and preserved or minimally impaired ventricular function, electrical instability can be present. Regarding the presence of ventricular arrhythmia, fibrosis is the most important variable, its amount being proportional to the complexity of the groups.     

比索洛尔对慢性心力衰竭室性心律失常和心率变异性的影响

目的 :观察比索洛尔对慢性心力衰竭患者的室性心律失常和心率变异性的影响。方法 :86例慢性心力衰竭 (CHF)患者在常规抗心衰药物治疗的基础上 ,随机分成两组 ,比索洛尔组每日口服比索洛尔 1.2 5～ 10mg ,对照组口服安慰剂 ,疗程 12个月 ,观察治疗前后心率、室性心律失常和心率变异性的变化。结果 :比索洛尔组室性心律失常明显减少 ,心率变异性参数显著改善。结论 :长期使用比索洛尔可降低CHF恶性室性心律失常的发生 ,改善心率变异性