Decreased renal sympathetic activity in response to cardiac unloading with nitroglycerin in patients with heart failure

AIMS: To examine changes in renal sympathetic outflow in response to cardiac unloading with nitroglycerin (GTN) in patients with chronic heart failure (CHF) and healthy subjects (HS). METHODS AND RESULTS: Renal (RNAsp) and total body (TBNAsp) noradrenaline (NA) spillover were measured with radiotracer methods in 16 patients with CHF (50+/-3 years, LVEF 20+/-1%) and nine HS (57+/-2 years) during right heart and renal vein catheterisation. Low dose GTN decreased mean pulmonary artery pressure (PAm: CHF -7+/-2 mm Hg, HS -4+/-1 mm Hg, p<0.05 vs. baseline) but not mean arterial pressure (MAP: CHF -2+/-1 mm Hg, HS -2+/-1 mm Hg) and did not affect RNAsp in any of the study groups. High dose GTN lowered MAP (CHF -12+/-1 mm Hg, HS -12+/-2 mm Hg, p<0.05 vs. baseline) and PAm (CHF -13+/-2 mm Hg, HS -5+/-1 mm Hg, p<0.05 vs. baseline) and was accompanied by a significant reduction in RNAsp only in CHF (1.3+/-0.1 nmol/min baseline to 0.9+/-0.2 nmol/min, p<0.05), whereas RNAsp in HS remained unchanged. CONCLUSIONS: In spite of a reduction in both arterial pressure and cardiac filling pressures, renal sympathetic activity decreased in CHF and did not increase in HS. These findings suggest that the altered loading conditions resulting from high-dose GTN infusion have renal sympathoinhibitory effects.     

Muscle sympathetic nerve activity and ventilation during exercise in subjects with and without chronic heart failure

BACKGROUND:

Changes within skeletal muscle, including augmentation of its capacity to elicit reflex increases in both efferent muscle sympathetic nerve activity (MSNA) and ventilation during work, contribute significantly to exercise intolerance in heart failure (HF). Previously, we demonstrated that peak oxygen uptake (pVO₂) in HF relates inversely to MSNA at rest and during exercise.

OBJECTIVE:

To test the hypothesis that there is an independent positive relationship between resting MSNA and the ratio of ventilation to carbon dioxide output during exercise (VE/VCO₂) that is augmented in HF.

METHODS:

MSNA at rest and VE/VCO₂ during stationary cycling were measured in 30 patients (27 men) with HF (mean ± SD ejection fraction 20±6%) and in 31 age-matched controls (29 men).

RESULTS:

MSNA was higher in HF patients than in controls (51.5±14.3 bursts/min versus 33.0±11.1 bursts/min; P<0.0001). The VE/VCO₂ slope was also higher in HF patients than in controls (33.7±5.7 versus 26.0±3.5; P<0.0001), whereas pVO₂ was lower in HF patients than in controls (18.6±6.6 versus 31.4±8.4 mL/kg/min; P<0.0001). There were significant relationships between MSNA and VE/VCO₂ in both HF (r=0.50; P=0.005) and control subjects (r=0.36; P=0.046). The slope of this regression equation was steeper in HF (0.20 versus 0.11 × MSNA; P=0.001). An analysis of covariance for main effects, including age and pVO₂, identified a significant independent relationship between MSNA burst frequency and VE/VCO₂ (P=0.013) that differed between HF and controls (P<0.01).

CONCLUSIONS:

The magnitude of resting sympathetic activity correlates positively with the VE/VCO₂ slope. Augmentation of this relationship in HF patients is consistent with the concept that enhanced mechanoreceptor reflex activity exaggerates their ventilatory response to exercise.     

去肾交感神经术对治疗慢性心力衰竭的作用

慢性心力衰竭(简称心衰)为各种心脏疾病的严重和终末阶段,是危害人类健康的最主要疾患之一。交感神经系统的激活对心肌病理性重构和心竭发生发展起着至关重要的作用,交感神经系统激活所致的去甲肾上腺素释放与心衰的发病率和死亡率密切相关,影响心衰的预后。近年研究证实,去肾交感神经术能够特异性地阻断肾脏传入和传出交感神经活动从而降低全身交感神经活性和减少去甲肾上腺素溢出,它不仅能够降低血压,还能减轻心肌肥厚,改善心功能等,从而为心衰的非药物治疗提供了一种新的方式。     

Renal denervation and heart failure

Renal denervation has been developed in order to lower systolic blood pressure in resistant hypertension by a reduction in renal afferent and efferent sympathetic nerve activity. In heart failure sympathetic activation, in particular, renal norepinephrine release is closely associated with morbidity and mortality. Initial studies have shown that renal denervation is able to reduce not only blood pressure but also heart rate, and is associated with a reduction in myocardial hypertrophy, improved glucose tolerance, and ameliorated microalbuminuria. Since some experimental and observational data suggest an antiarrhythmic effect, it is possible that renal denervation might also play a therapeutic role in arrhythmias often occurring in chronic heart failure. The first proof‐of‐concept studies are planned to evaluate the clinical effect of this pathophysiologically plausible method, which might be able to change clinical practice.     

充血性心力衰竭病人昼夜心脏自主神经功能与平均心率的研究

目的:了解充血性心力衰竭病人心脏自主神经活性和平均心率的昼夜改变.方法:对59例充血性心力衰竭病人(心力衰竭组)和40例健康者(对照组)经Holter记录进行24 h长程心功率谱分析和平均心率计算.结果:心力衰竭组清醒期或睡眠期LFnu均明显升高而HFnu明显降低(P＜0.01或P＜0.05),LF/HF均大于对照组(P＜0.05),同时心力衰竭组夜间平均心率明显高于对照组(P＜0.01).结论:心力衰竭病人昼夜交感神经活性均升高,同时伴迷走神经活性减退,这种改变与心力衰竭病人夜间平均心率明显高于对照组可能有内在联系.     

慢性心力衰竭患者肾功能恶化的危险因素分析

目的 研究慢性心力衰竭(心衰)患者肾功能恶化的危险因素及其对预后的影响.方法 采用病例对照研究方法,分析与肾功能恶化发生有统计学关联的独立危险因素,同时观察肾功能恶化对预后的影响.结果 住院心衰患者肾功能恶化发生率31%,入院肌酐水平及心功能分级与肾功能恶化的发生独立相关,OR值分别为2.248(95%CI1.088～4.647,P=0.029)和2.485(95%CI1.385～4.459.P＝0.002).发生肾功能恶化的患者住院期间病死率明显高于对照组(16.7%比2.1%,P=0.000),调整混杂因素后,肾功能恶化是死亡的独立危险因素,OR值3.824(95%CI2.452～5.137.P＜0.015).结论 肾功能恶化在住院心衰患者中发生率较高,与住院期间病死率明显相关.入院肌酐水平偏高及心功能差为发生肾功能恶化的独立危险因素.

Abstract：

Objective To investigate the risk factors of worsening renal function (WRF) in patients with chronic heart failure ( CHF) and WRF influence on prognosis. Methods A case-control study were undertaken to analyze independent risk factor statistically related to incidence of WRF, and to assess the influence of WRF on prognosis. Results The independent predictors of WRF were creatinine level at admission (OR 2.248,95% CI 1.088-4.647, P = 0.029) and NYHA class on admission ( OR 2.485, 95% CI 1.3854. 459, P = 0.002). The mortality of patient with WRF was obviously higher than that of control group during hospitalization( OR 3. 824,95% CI 2. 452-5. 637 ,P ＜0.015). Conclusions WRF is a common complication among patients hospitalized for CHF, and is obviously associated with mortality during hospitalization. Higher creatinine level and weak heart function are independent risk factors for incidence of WRF of patients with CHF.     

Targeting the autonomic nervous system: Measuring autonomic function and novel devices for heart failure management

Neurohumoral activation, in which enhanced activity of the autonomic nervous system (ANS) is a key component, plays a pivotal role in heart failure. The neurohumoral system affects several organs and currently our knowledge of the molecular and systemic pathways involved in the neurohumoral activation is incomplete. All the methods of assessing the degree of activation of the autonomic system have limitations and they are not interchangeable. The methods considered include noradrenaline spillover, microneurography, radiotracer imaging and analysis of heart rate and blood pressure (heart rate variability, baroreceptor sensitivity, heart rate turbulence).     

托伐普坦对老年慢性心力衰竭合并轻中度肾功能不全伴低钠血症患者的疗效及安全性

目的:评估传统利尿剂及托伐普坦对老年慢性心力衰竭(心衰)合并轻中度肾功能不全伴低钠血症患者的疗效与安全性,为老年心衰患者的治疗提供临床依据。方法:随机对照临床试验,将老年心衰合并轻中度肾功能不全伴低钠血症患者88例随机分为对照组46例和试验组42例,两组均停用口服袢利尿剂,对照组46例在心衰常规治疗的基础上加用呋塞米4...     

高血压与肾交感神经活性的关系再评价

<正>高血压是一种常见的慢性疾病,常并发多种疾病而严重影响患者的生活质量,且增加心血管疾病患者的死亡风险,顽固性高血压的治疗至今仍是一个难题[1]。我们就高血压与肾交感神经活性的关系及治疗新技术做一综述。1高血压与肾交感神经的关系交感神经过度兴奋常常导致血压上升,而高血压患者也往往合并交感神经活性增加,尤其是肾交感神经活性增加。     

氯沙坦对慢性心力衰竭病人心肾功能的影响

目的 探讨氯沙坦对慢性心力衰竭病人心肾功能的影响。方法 慢性心力衰竭病人65例,常规治疗组35例,氯沙坦组30例,连续治疗8周。治疗前、后,抽静脉血、留尿,采用免疫比浊法测定血清胱抑素C和尿微量白蛋白水平,酶联免疫分析法测定尿水通道蛋白-2浓度,超声心动图检测病人心脏收缩功能。结果 与常规治疗组比较,氯沙坦组病人左心室舒张末期内径显著下降,而左心室射血分数、左心室短轴缩短率显著升高;血清胱抑素C、尿微量白蛋白、水通道蛋白-2较常规治疗组显著下降。结论 氯沙坦可改善慢性心力衰竭病人的心功能和肾功能。     

Adrenal G protein-coupled receptor kinase-2 in regulation of sympathetic nervous system activity in heart failure

Heart failure (HF), the number one cause of death in the western world, is caused by the insufficient performance of the heart leading to tissue underperfusion in response to an injury or insult. It comprises complex interactions between important neurohormonal mechanisms that try but ultimately fail to sustain cardiac output. The most prominent such mechanism is the sympathetic (adrenergic) nervous system (SNS), whose activity and outflow are greatly elevated in HF. SNS hyperactivity confers significant toxicity to the failing heart and markedly increases HF morbidity and mortality via excessive activation of adrenergic receptors, which are G protein-coupled receptors. Thus, ligand binding induces their coupling to heterotrimeric G proteins that transduce intracellular signals. G protein signaling is turned-off by the agonist-bound receptor phosphorylation courtesy of G protein-coupled receptor kinases (GRKs), followed by βarrestin binding, which prevents the GRK-phosphorylated receptor from further interaction with the G proteins and simultaneously leads it inside the cell (receptor sequestration). Recent evidence indicates that adrenal GRK2 and βarrestins can regulate adrenal catecholamine secretion, thereby modulating SNS activity in HF. The present review gives an account of all these studies on adrenal GRKs and βarrestins in HF and discusses the exciting new therapeutic possibilities for chronic HF offered by targeting these proteins pharmacologically.     

卡维地洛治疗充血性心力衰竭的临床研究

目的:探讨卡维地洛对充血性心力衰竭(CHF)患者心功能的影响。方法:45例CHF患者被随机分成2组.对照组(B组)用利尿剂、强心甙、硝酸酯类等药进行治疗,治疗组(A组)在B组治疗基础上加用卡维地洛,起始剂量3.125mg,2次/d,每2周加量1倍,至最大剂量25mg,2次/d。结果:治疗16周后,两组的心功能分级均有明显改善.与对照组比较,治疗组LVEF增加更加显著(P<0.05)。结论:卡维地洛对CHF有较好的疗效。     

Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure.

AIMS: To investigate whether strong cardiac sympathetic activity contributes primarily to sudden death or to worsening heart failure, and to determine the relationship of the size of cardiac noradrenaline stores to the mode of death. METHODS AND RESULTS: The study population comprised 116 patients with congestive heart failure (ejection fraction 19+/-7%) and a mean follow-up of 18+/-19 months. Cardiac sympathetic nervous function was measured using coronary sinus blood sampling and noradrenaline isotope dilution methodology. Cardiac sympathetic activity was estimated from cardiac noradrenaline spillover, and noradrenaline stores from the overflow of the tritiated noradrenaline metabolite [(3)H]dihydroxyphenylglycol, which is produced by monoamine oxidase inside nerve endings. Small cardiac noradrenaline stores (below median) predicted death from worsening heart failure (hazard ratio=4.18, P<0.05), particularly if cardiac noradrenaline spillover was elevated (hazard ratio=2.36 per tertile, P<0.01), indicating progression of disease associated with defective sympathetic innervation. In contrast, large stores (hazard ratio=2.81, P<0.05), especially if coupled with increased noradrenaline spillover (hazard ratio=1.64 per tertile, P<0.05), were related to sudden death. CONCLUSION: High cardiac sympathetic activity is a risk factor for sudden death, particularly in the presence of intact cardiac sympathetic innervation. Conversely, progression of myocardial disease and heart failure is closely associated with depletion of sympathetic nerves in the heart, especially if rates of noradrenaline release paradoxically remain high.     

老年人慢性心力衰竭早期肾功能损害的临床观察

目的探讨老年人慢性心力衰竭(CHF)患者早期肾功能损害及其与心功能的关系。方法测定40例60～80岁的CHF患者、40例同年龄的心功能代偿的心脏病患者及40例同年龄的健康对照者的常规尿蛋白(UP)、血清/尿肌酐(S/UCr)、尿素氮(BUN)、尿微量白蛋白(UMA)、尿β_2-微球蛋白(Uβ_2-MG)水平。并与左心室射血分数(LVEF)进行相关分折。结果老年CHF患者UMA水平较健康对照组和心功能代偿的心脏病组明显升高[分别为(8．69±10．23)、(1．72±1．25)和(2．30+2．08)mg/mmol UCr],差异有统计学意义(均为P＜0．01);与LVEF呈显著负相关(r= -0．36,P＜0．01);Uβ_2-MG 3组分别为(0．143±0．223)mg/mmol UCr、(0．135±0．215)mg/mmol UCr和(0．146±0．249)mg/mmol UCr,差异无统计学意义(均为P＞0．05)。结论老年CHF患者存在以肾小球滤过功能受损为特征的早期肾功能异常;CHF程度越重,肾小球滤过功能损害越明显。     

Orthostatic function after renal sympathetic denervation in patients with resistant hypertension

Introduction

Catheter-based renal denervation (RDN) reduces local and whole-body sympathetic activity and blood pressure (BP) in patients with resistant hypertension. However, safety concerns exist concerning the development of orthostatic dysfunction after RDN.

Methods and results

In 36 patients (65 ± 7.6 years, 75% male) with resistant hypertension (office BP 162 ± 24/91 ± 14 mm Hg) treated with 4.8 ± 1.7 antihypertensive drugs, tilt table testing (TTT) was performed before and three months after RDN. Response to RDN was defined as a reduction in office systolic BP (SBP) ≥ 10 mm Hg three months after RDN. Responders (n = 26; 72.2%) and non-responders (n = 10; 27.8%) were evaluated separately. After RDN, office SBP and diastolic BP (DBP) were reduced by 29 ± 6.2/14 ± 3.6 mm Hg (p < 0.0001; p = 0.0002) only in responders. During TTT, SBP and DBP in supine position were only reduced in responders. Resting heart rate (HR) decreased in responders but not in non-responders by 5.9 ± 1.7 beats/min (p = 0.0016). Mean and minimal SBP were not altered during passive tilting. In the responder group, ?SBP was reduced in the initial phase of tilting. The adaptive increase of HR was preserved in both groups after RDN, while only in responders mean and minimal HR were reduced after passive tilting. Following drug provocation, mean and minimal SBP during all phases of passive tilting remained unchanged. ?SBP, ?HR and total number of (pre-)syncopes were neither influenced by RDN nor differing between responders and non-responders.

Conclusions

In patients with resistant hypertension, RDN reduced office BP, supine BP and HR during TTT without causing orthostatic dysfunction or (pre-)syncopes three months after treatment.     

心力衰竭时中枢盐皮质激素受体通过促炎因子发挥交感兴奋作用

目的探讨RU28318阻断中枢盐皮质激素受体（MR）的作用,验证慢性充血性心力衰竭时,中枢内MR的交感兴奋作用是通过提高外周血促炎因子（PIC）实现的。方法采用结扎冠状动脉左前降支致心肌梗死的方法制备心衰大鼠模型,假手术对照只穿线不结扎。大鼠分两部分处理：一部分给药组大鼠6周内每天口服MR阻滞剂奥孕酸钾（RU28318）,每天30mg／kg,溶于饮用水中,对照组给普通饮用水;另一部分使用抗PIG药物己酮可可碱（pentoxifylline,fyIx）,每天30mg／kg,溶人饮用水中,以确定单纯促炎因子减少能否足以引起RU28318所致的结果。6周后,保证各组至少有12只动物存活。测定各组大鼠血流动力学指标,评价左心功能;电生理记录肾交感神经放电（RSNA）;ELISA技术测定血浆去甲肾上腺素（NE）,PIC包括肿瘤坏死因子-α（TNF-α）、白介素-α（IL-1α）含量,以及脑组织TNF—d和脑脊液中前列腺素E2（PGE2）水平。通过免疫组织化学染色和Westernblot评价环氧酶-2（cox-2）的表达。结果对心衰大鼠外周使用抑制PIC合成的药物PTX产生的各项结果和用RU28318处理的心衰大鼠很相似：治疗后的心衰大鼠右室体重比（RV／BW）降低,左室舒张末压（LVEDP）、肺体重比（1ung／BW）下降,说明右室重构和肺淤血都有所减轻;但心功能没有明显改善（左室最大上升／下降速率LV＋dp／dtmax变化没有统计学意义）;血浆PIC中TNF—d、IL-1和IL-6水平均降低;肾交感神经放电减弱,同时血中NE减少;下丘脑室旁核（PVN）COX-2染色减弱,蛋白含量降低;同时脑脊液中PGE2减少。结论慢性心衰时,利用RU28318阻断MR产生的交感活动抑制是通过降低血中促弗I天l千耗椎阳的．