Effects of Tolvaptan on Systemic and Renal Hemodynamic Function in Dogs with Congestive Heart Failure

Purpose

We investigated the effects of tolvaptan, a vasopressin V₂-receptor antagonist, on diuretic response and systemic and renal hemodynamic characteristics in conscious dogs with congestive heart failure (CHF). We also compared these effects with those of furosemide, a loop diuretic.

Methods

CHF was induced by rapid right-ventricular pacing at 260 beats/min for at least 3 weeks, and maintained with a pacing rate of 220–240 beats/min. CHF dogs were orally given tolvaptan (10 mg/kg), furosemide (10 mg/kg) and vehicle in random order during the stable CHF state. Urine excretion, systemic and renal hemodynamic parameters, and plasma hormone levels were measured over 6-hour periods after drug administration.

Results

Tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Tolvaptan also decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate or renal blood flow. Tolvaptan tended to increase plasma arginine vasopressin concentrations but did not affect plasma renin activity. In contrast, furosemide induced clear saluresis with increased electrolyte excretion, resulting in decreased pulmonary capillary wedge pressure. However, furosemide also decreased serum potassium concentration and increased plasma arginine vasopressin concentrations and plasma renin activity.

Conclusion

Tolvaptan elicited a potent aquaretic response and reduced the cardiac preload without unfavorable effects on systemic or renal hemodynamics, the renin–angiotensin–aldosterone system, or the sympathetic nervous system in CHF dogs. Thus, tolvaptan may offer a novel approach to remove excess water congestion from patients with CHF.

     

Hemodynamic Effect of Propafenone and the Experience in Patients with Congestive Heart Failure

The effects of propafenone on left ventricular function and hemodynamics are presented in this study. In one group of 13 patients who underwent electrophysiological testing and subsequent chronic oral therapy with propafenone, eight had left ventricular ejection fractions determined by nuclear study before and during therapy with the drug. Initial measurements ranged from 22% to 39% (mean 30%), while those on chronic therapy showed no statistical difference and ranged from 22% to 48% (mean 30%). In a separate dose titration study of 14 patients, left ventricular ejection fraction showed a modest but significant decrease (52%± 9% to 48%± 11%; p < 0.05). This change was more marked in patients with an initial low ejection fraction. Propafenone appears to be safe in these patients but should be administered with caution in patients with particularly low ejection fractions.     

西拉普利对充血型心力衰竭的疗效观察

目的：ACE抑制剂已经广泛地用于治疗严重充血性心力衰竭,但是用于治疗轻、中度心力衰竭少见报道。本组观察西拉普利对轻、中度心力衰竭的疗效。方法：68例心力衰竭病人,NYHAⅡ-Ⅲ级,观察治疗前后试验组病人症状、体征和运动试验耐受情况,并同安慰剂组进行对照。结果：试验组运动耐受程度改善27％,而安慰剂组仅为5％（P＜0．001）;试验组心力衰竭和NYHA分级也明显提高,两组血清钾、肌酐和尿酸无显著差异。结论：西拉普利明显改善轻、中度心力衰竭的症状、提高运动耐量,而且耐受良好。     

西拉普利对充血型心力衰竭的疗效观察

目的ACE抑制剂已经广泛地用于治疗严重充血性心力衰竭,但是用于治疗轻、中度心力衰竭少见报道。本组观察西拉普利对轻、中度心力衰竭的疗效。 方法68例心力衰竭病人,NYHAⅡ～Ⅲ级,观察治疗前后试验组病人症状、体征和运动试验耐受情况,并同安慰剂组进行对照。 结果试验组运动耐受程度改善27%,而安慰剂组仅为5%(\%P\%<0.001);试验组心力衰竭和NYHA分级也明显提高,两组血清钾、肌酐和尿酸无显著差异。 结论西拉普利明显改善轻、中度心力衰竭的症状,提高运动耐量,而且耐受良好。     

不同部位组合起搏对充血性心力衰竭患者急性血流动力学影响的研究

观察右房左室起搏对充血性心力衰竭 (CHF)患者急性血流动力学的影响。 8例心功能II～IV级CHF患者 ,分别置入右房、右室和左室电极 (经冠状静脉窦 ) ,行不同部位组合起搏的急性血流动力学研究 ,其中 6例获得成功。使用Bitronic公司生产的双腔起搏分析仪 (ERA30 0 )分别行单纯右室心尖部 (RVA)、右房右室 (RA +RV)、右房左室 (RA +LV)、右房双室 (RA +BiV)起搏 ,同时用二维超声心动图测定上述四种起搏状况下的血流动力学参数 ,并进行比较。结果 :右房左室起搏和右房双室起搏血流动力学参数两者间无显著差异 ,但比单纯右室心尖部起搏和右房右室起搏有所改善。结论 :右房左室起搏似可使更多的CHF患者在得益于起搏治疗的同时明显降低医疗费用。     

Hemodynamic Effects at Rest and during Exercise in Long-term Treatment with Prazosin in Chronic Congestive Heart Failure

ABSTRACT. The long-term effects of prazosin in chronic congestive heart failure were studied in 10 patients (New York Heart Association class III-IV) in a double-blind cross-over study. Patients with systolic blood pressure > 120 mmHg and left ventricular filling pressure > 15 mmHg were included. Prazosin lowered the arteriovenous oxygen difference both at rest and during exercise (p < 0.05), increased cardiac index (p < 0.01) and reduced right atrial pressure and systemic vascular resistance (p < 0.05) during exercise. Left ventricular filling pressure was also reduced, but not significantly, during exercise. Our data show that prazosin has beneficial long-term effects during exercise in patients with chronic congestive heart failure.     

Effects of Bed Rest and Prazosin in Congestive Heart Failure

ABSTRACT. Twelve patients with congestive heart failure were monitored with invasive and noninvasive techniques to evaluate the effect of vasodilator treatment. During the 18 hours of strict bed rest before administration of prazosin, the hemodynamics improved substantially while only small and transient hemodynamic changes were observed after introduction of prazosin. At 6 weeks' control the effect of vasodilator treatment with prazosin, 3 mg × 4, was lost. The beneficial results often credited to vasodilators in studies on congestive heart failure might in part be due to the concomitant bed rest introduced during the monitoring of the patients.     

Functional Effects of Endogenous Bradykinin in Congestive Heart Failure

Objectives. The purpose of this study was to determine the level and functional effects of endogenous bradykinin in congestive heart failure (CHF).

Background. There is experimental evidence that bradykinin is increased in several cardiac disease states. However, it is unknown whether plasma levels of bradykinin are elevated in CHF. Further, the cardiac and vascular responses to bradykinin in CHF are unclear.

Methods. The circulating levels of bradykinin and the effects of endogenous bradykinin were assessed in eight instrumented, conscious dogs both before and after pacing-induced CHF.

Results. Before CHF, the plasma bradykinin level was 53.1 ± 12.4 pg/ml. Blocking endogenous bradykinin with HOE-140 (0.3 mg/kg), a specific bradykinin B₂-receptor antagonist, produced no significant alterations in heart rate, left ventricular (LV) end-systolic pressure (P_es), total systemic resistance (TSR), the time constant of LV relaxation (tau) or the maximal rate of LV filling (dV/dt_max). However, coronary blood flow was significantly reduced (p < 0.05). LV contractile performance measured by the slopes of pressure–volume relations was unaffected. After induction of CHF, the plasma bradykinin level increased to 234.2 ± 19.4 pg/ml (p < 0.05). Blocking endogenous bradykinin with HOE-140 reduced coronary blood flow and produced significant increases in P_es and TSR, prolonged tau, decreased dV/dt_max and elevated minimal LV pressure and mean left atrial pressure. Furthermore, the slopes of pressure–volume relations (p < 0.05) were decreased, indicating depressed contractility with HOE-140 after CHF.

Conclusions. Before CHF, endogenous bradykinin results in coronary dilation but has no effect on systemic arterial vasodilation or cardiac performance. After CHF, endogenous bradykinin is significantly increased and, acting through B₂-receptors, produces coronary and arterial vasodilation and improves LV relaxation and contractile performance. Thus, endogenous bradykinin may play an important role in preserving cardiovascular function in CHF.     

Effects of Calcium Antagonist Felodipine on Renal Sympathetic Nerve Activity in Rats with Congestive Heart Failure

In order to assess the effects of dihydropyridine calcium antagonist on sympathetic nerve activity (SNA) in experimental chronic heart failure (CHF), felodipine was given to rats with CHF induced by coronary artery ligation. Anesthetized CHF (n = 7) and sham-operated (n = 9) rats were injected with a bolus dose of felodipine (20 μg/kg) and then infused with felodipine (30 μg/kg/h) for 3 hours. Control CHF rats (n = 8) were given vehicle in the same way. After felodipine treatment, mean blood pressure (MBP) rapidly decreased to 75–85 mmHg, and there was a reflex tachycardia and reflex activation of renal SNA. The heart rate (HR) had returned to baseline level after 3 hours of continuous felodipine infusion, and the SNA returned to baseline level after 2 hours of infusion. At the end of the experiment, renal SNA was 65.4 ± 11.5% of the baseline level in CHF rats receiving felodipine (P < 0.05) and 94.1 ± 22.8% in CHF rats receiving vehicle (P > 0.05), but there was no statistical difference between the two groups. Arterial baroreceptor sensitivity (assessed by phenylephrine infusion), which was impaired in CHF rats (−2.7 ± 0.2 SNA%/mmHg in all CHF rats together vs. −3.6 ± 0.4 in sham-operated rats, P < 0.5) did not differ significantly from that in sham-operated rats during felodipine infusion (−3.2 ± 0.4 in felodipine-treated CHF rats vs. −3.7 ± 0.6 in sham-operated rats) but deteriorated without felodipine treatment (−2.1 ± 0.3 in CHF rats receiving vehicle, P < 0.05). The biphasic renal SNA response during felodipine infusion suggests that felodipine does not cause persistent sympathetic activation and relatively improves baroreceptor sensitivity in CHF rats. This revised version was published online in July 2006 with corrections to the Cover Date.     

Endothelial Dysfunction in Congestive Heart Failure: Effects of Carvedilol

In this review, we have examined the role of oxidative stress and apoptosis in the continuum of molecular changes that accompanies congestive heart failure. Cytokine activation and tumor necrosis factor-, in particular, may play a role in this continuum, favouring both oxidative stress and apoptosis. Carvedilol, a non selective - and -blocker, exerts an anti-apoptotic effect on both the myocytes and the endothelial cells as a consequence of its antioxidant activity. The ability of carvedilol to inhibit apoptosis may have important clinical relevance in congestive heart failure. It is also important to emphasise that, in congestive heart failure, apoptosis occurs, not only in the heart, but also in the periphery. An increased rate of endothelial apoptosis may explain the occurrence of endothelial dysfunction in congestive heart failure.     

VDD起搏对缓慢性心律失常心力衰竭的血液动力学影响

为了评估ＶＤＤ起搏对缓慢性心律失常心力衰竭的血液动力学影响，对２１例心功能Ⅲ～Ⅳ级的缓慢性心律失常病人安置ＶＤＤ起搏器，并用Ｓｗａｎ－Ｇａｎｚ导管监测起搏前和起搏后３０ｍｉｎ、２４ｈ、４８ｈ、７２ｈ的心输出量（ＣＯ）、心脏指数（ＣＩ）、右房压（ＲＡＰ）、平均肺动脉压（ＭＰＡＰ）和肺毛细血管楔嵌压（ＰＣＷＰ），并记录各时期的心房率（ＡＲ）和心室率（ＶＲ）。结果：ＶＲ在术后即时及各时期显著升高（Ｐ均＜０．０５），ＣＯ、ＣＩ在起搏后３０ｍｉｎ即显著升高〔分别为４．１８±０．８１Ｌ／ｍｉｎｖｓ２．８１±０．９３Ｌ／ｍｉｎ、２．３６±０．６６Ｌ／（ｍｉｎｍ２）ｖｓ１．１８±０．６３Ｌ／（ｍｉｎｍ２），Ｐ均＜０．０５〕，起搏４８ｈ达高峰；ＲＡＰ、ＭＰＡＰ、ＰＣＷＰ在起搏后３０ｍｉｎ无显著改变（Ｐ＞０．０５），但２４ｈ开始显著性下降（分别为１．２８±０．４１ｋＰａｖｓ１．４１±０．３４ｋＰａ、２．６０±０．５１ｋＰａｖｓ３．４０±０．５６ｋＰａ、３．１０±０．５６ｋＰａｖｓ３．５４±０．６８ｋＰａ，Ｐ均＜０．０５），７２ｈ后进一步降低。结果提示ＶＤＤ起搏治疗能显著改善缓慢性心律失常心力衰竭的血液动力学，可作为治疗缓慢性心?     

Effects of Carvedilol on Heart Rate Dynamics in Patients with Congestive Heart Failure

Background: Patients with congestive heart failure (CHF) have alterations in the traditional and nonlinear indices of heart rate (HR) dynamics, which have been associated with an increased risk of mortality. This study was designed to test the effects of carvedilol, a nonselective beta‐blocker with alpha‐1 blocking properties, on HR dynamics in patients with CHF. Methods: We studied 15 patients with CHF secondary to ischemic or idiopathic cardiomyopathy who met the following inclusion criteria: NYHA functional class II‐III, optimal conventional medical therapy, normal sinus rhythm, left ventricular ejection fraction (LVEF) of < 40%, and resting systolic blood pressure greater than 100 mmHg. The 6‐minute corridor walk test, estimation of LVEF, and 24‐hour Holter recording were performed at baseline and after 12 weeks of therapy with carvedilol. Traditional time and frequency domain measures and short‐term fractal scaling exponent of HR dynamics were analyzed. Results: After 12 weeks of therapy with carvedilol, the mean LVEF improved significantly (from 0.27 ± 0.08 to 0.38 ± 0.08, P < 0.001). The average HR decreased significantly (from 86 ± 11 to 70 ± 8 beats/min, P < 0.001). The mean distance traveled in the 6‐minute walk test increased significantly (from 177 ± 44 to 273 ± 55 m, P < 0.01). The frequency‐domain indices (HF and LF), the time domain indices (rMSSD and PNN5), and the short‐term fractal scaling exponent increased significantly. The scaling exponent increased particularly among the patients with the lowest initial values (< 1.0), and the change in the fractal scaling exponent correlated with the change in ejection fraction (r = 0.63, P < 0.01). Conclusion: Carvedilol improves time and frequency domain indices of HR variability and corrects the altered scaling properties of HR dynamics in patients with CHF. It also improves LVEF and functional capacity. These specific changes in HR behavior caused by carvedilol treatment may reflect the normalization of impaired cardiovascular neural regulation of patients with CHF. A.N.E. 2002;7(2):133–138     

Hemodynamic Effects of Bosentan in Patients with Chronic Heart Failure

A role of the potent and long-acting vasoconstrictor peptide endothelin-1 and the pathophysiology of chronic human heart failure has been postulated based upon indirect evidence such as elevated plasma endothelin-1 levels and their with the degree of hemodynamic impairment. The advent of specific of endothelin-1 receptor antagonists has provided the opportunity not only to directly evaluate its pathophysiological role but also to assess its potential role as a new approach to heart failure therapy. This brief review summarizes the evidence linking endothelin-1 to the pathophysiology of chronic heart failure and the clinical results obtained in patients during acute, intravenous and more prolonged, oral administration with bosentan, a mixed ET_A/ET_B-receptor antagonist. Bosentan acutely and during short-term oral therapy markedly improved hemodynamics in patients in addition to standard heart failure therapy, including an ACE-inhibitor. These effects were associated with a reduced responsiveness of the renin-angiotensin system to diuretic therapy and reduced basal plasma aldosterone levels. Although the hemodynamic and neurohumoral profile of short-term bosentan therapy looks promising for the treatment of patients with chronic heart failure appropriate trials will have to be performed to document clinical benefit during long-term therapy. Finally, the question remains open whether mixed endothelin-1 receptor antagonists like bosentan will have similar effects as compared to antagonists which block the ET_A receptor only.     

Effects of Captopril on Peripheral Hemodynamics in Severe Congestive Heart Failure

The effects of captopril on the forearm hemodynamics in patients with severe congestive heart failure were studied, using strain-gauge plethysmography. To determine whether prostaglandins are involved in the captopril actions, indomethacin, an inhibitor of prostaglandin synthesis, was administered. In 8 patients, captopril (25 mg) decreased mean blood pressure (P < 0.01) and venous pressure (P < 0.05); forearm blood flow (P < 0.05) and maximum venous volume (P < 0.05) were increased; forearm vascular resistance (P < 0.05) and forearm venous tone (P < 0.05) were decreased. Venous distensibility was improved with captopril (P < 0.05). All the hemodynamic changes were attenuated by indomethacin (50mg). Captopril increased circulating bradykinin (P < 0.05), prostaglandin E₂ (P < 0.05) and 6-keto-prostaglandin F_1α (P < 0.05). Indomethacin did not affect bradykinin level but blocked the increase in prostaglandins. These data suggest that captopril dilates both arterial and venous vessels not only by blocking the renin-angiotensin system but by increasing local or circulating vasodilator prostaglandins.     

Hemodynamic Effect and Safety of Intermittent Sequential Pneumatic Compression Leg Sleeves in Patients With Congestive Heart Failure

BackgroundPneumatic leg sleeves are widely used after prolonged operations for prevention of venous stasis. In healthy volunteers they increase cardiac function. We evaluated the hemodynamic effects and safety of intermittent sequential pneumatic compression (ISPC) leg sleeves in patients with chronic congestive heart failure (CHF).Methods and ResultsWe studied 19 patients with systolic left ventricular dysfunction and CHF. ISPC leg sleeves, each with 10 air cells, were operated by a computerized compressor, exerting 2 cycles/min. Hemodynamic and echocardiographic parameters were measured before, during, and after ISPC activation. The baseline mean left ventricular ejection fraction was 29 ± 9.2%, median 32%, range 10%–40%. Cardiac output (from 4.26 to 4.83 L/min; P = .008) and stroke volume (from 56.1 to 63.5 mL; P = .029) increased significantly after ISPC activation, without a reciprocal increase in heart rate, and declined after sleeve deactivation. Systemic vascular resistance (SVR) decreased significantly (from 1,520 to 1,216 dyne-s/cm⁵; P = .0005), and remained lower than the baseline level throughout the study. There was no detrimental effect on diastolic function and no adverse clinical events, despite increased pulmonary venous return.ConclusionsISPC leg sleeves in patients with chronic CHF do not exacerbate symptoms and transiently improve cardiac output through an increase in stroke volume and a reduction in SVR.     

硝普钠与乌拉地尔治疗顽固性心力衰竭的临床观察

目的观察硝普钠与乌拉地尔治疗顽固性心力衰竭的疗效。方法对42例顽固性心力衰竭患者在综合治疗的基础上应用硝普钠与乌拉地尔治疗顽固性心衰,疗程7-10d。结果乌拉地尔组总有效率(90．9％)显著高于硝普钠组(80％);两组治疗前后的心功能状况左心室射血分数(LVEF)、左心室短轴缩短率(FS)、舒张早期最大充盈速度(E)与舒张晚期最大充盈速度(A)的比值(E／A)、每搏输出量(SV)、心输出量(CO)心脏指数(CI)、及心率、呼吸频率均可得到明显的改善。但乌拉地尔可以更明显地改善心功能。结论在综合治疗的基础上应用乌拉地尔治疗顽固性心力衰竭可以更明显地改善顽固性心力衰竭心功能,且具有更高的临床有效率而无明显的毒副作用。