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European Journal of Heart Failure 2008 10(8):758-764; doi:10.1016/j.ejheart.2008.06.010
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© 2008 European Society of Cardiology

Venous endothelial function in heart failure: Comparison with healthy controls and effect of clinical compensation

Eneida R. Rabelo, Karen Ruschel, Heitor Moreno, Jr., Marcelo Rubira, Fernanda M. Consolim-Colombo, Maria Cláudia Irigoyen and Luis E. Rohde*

Cardiovascular Division of Hospital de Clínicas de Porto Alegre, The Post-Graduation Programs in Biology?Physiology and Cardiology?Cardiovascular Sciences, Federal University of Rio Grande do Sul Porto Alegre, RS, Brazil The Heart Institute (InCor) São Paulo, SP, Brazil

* Corresponding author. Cardiovascular Division, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Sala 2061, Porto Alegre, RS, 90035-003, Brazil. Tel./fax: +55 51 21018344. E-mail address: lerohde{at}terra.com.br (L.E. Rohde).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Endothelial function has been extensively evaluated at the arterial bed in several cardiovascular scenarios. Venous endothelial dysfunction, however, has not been thoroughly explored particularly in heart failure (HF).

Aims: To characterize venous endothelial function in severe HF.

Methods and results: Venous endothelial function was evaluated by the dorsal hand vein technique using a tripod holding a linear variable differential transformer. Dorsal hand veins were pre-constricted with phenylephrine and dose–response curves were constructed after acetylcholine and sodium nitroprusside administration. Maximum vasodilator response to acetylcholine, a marker of endothelium-dependent venodilation, was significantly lower (47±53% versus 102±54%, respectively, p=0.0004) in HF (n=27) patients compared to healthy controls (n=20). No difference in the endothelium-independent venodilator response was observed (p=0.87). Maximum vasodilator response to acetylcholine was also significantly lower on admission compared to the response immediately before hospital discharge in patients with acute decompensated HF (p<0.01). Improvement in venous endothelial function paralleled weight loss (mean difference of –3.8 kg, p<0.01) and improvement in the 6-minute walk test (mean difference of 107 m, p<0.01). There was no significant change in angiotensin-converting enzyme inhibitor or beta-blocker use during hospital stay.

Conclusions: HF patients experience marked endothelium-dependent venous dysfunction with partial recovery during in-hospital management.

Key Words: Heart failure • Endothelial function • Venous

Received February 7, 2008; Revised May 2, 2008; Accepted June 9, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
A growing body of evidence convincingly demonstrates that endothelial dysfunction plays a critical role in the pathogenesis and progression of heart failure (HF) [1]. Several investigators have shown that decreased endothelial-dependent vasodilation is associated with HF severity, even in elderly patients using modern medical management [2], reflecting impaired functional capacity and a worse prognosis [1-3]. Traditionally, endothelial function has been evaluated at the arterial bed using various invasive and non-invasive methodologies [4-6]. Assessment of venous endothelial function, however, can also be accomplished by a safe, reproducible and minimally invasive method, known as the dorsal hand vein technique [7]. Since more than 70% of total circulating volume lies in the venous vascular bed, it is conceivable that small changes in venous tone may substantially affect filling pressures, making its evaluation an attractive new parameter of vascular homeostasis with potential prognostic and therapeutic implications. Although this methodology has been accurately used in different cardiovascular settings [8-10], a few studies have evaluated venous endothelial function in HF. Data from these reports suggest abnormal venoconstrictive responses to different stimuli (neuropetide Y and endothelin-1) [10,11] and are not consensual about the presence of venous vasodilator dysfunction in HF patients [12,13].

In this study we sought to characterize venous endothelial function in severe HF patients and in a group of healthy volunteers using the dorsal hand vein technique after different pharmacological stimuli. We also investigated whether venous endothelial function improved in hospitalised patients with acute decompensated HF following standard clinical management.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients and subjects
HF patients aged over 18 years, in New York Heart Association (NYHA) functional class III-IV, with left ventricular ejection fraction assessed by two-dimensional echocardiography ≤50% were invited to participate in the study. For the in-hospital sub-group, HF diagnosis was defined by the attending team and confirmed by a cardiologist with expertise in HF, based on Boston's diagnostic criteria [14]. Patients who had suffered an acute myocardial infarction or who had undergone surgical or percutaneous cardiac revascularization in the last 30 days were excluded. Healthy adult volunteers defined by clinical history, complete physical examination and routine laboratory tests were also invited to participate. Subjects with any current known morbid condition (such as diabetes, dyslipidaemia, overweight or obesity), family history of premature heart disease, history of drug abuse, alcoholism or smoking, or those using any chronic medication were also excluded. A structured questionnaire was used to collect demographic, clinical and laboratory data from all patients. The study was reviewed and approved by the ethics committee for research in humans of the Hospital de Clínicas de Porto Alegre and all healthy volunteers and HF patients gave written informed consent prior to enrolment. The investigation conforms to the principles outlined in the Declaration of Helsinki.

2.2. Dorsal hand vein technique
All study subjects underwent a baseline venous endothelial function assessment using the dorsal hand vein technique. In a sub-group of in-hospital patients with acute decompensated HF two evaluations were performed: a baseline (within the first 48 h of hospital admission) and a pre-discharge assessment (24-48 h before hospital discharge).

Venous endothelial studies were undertaken according to previously described protocols [15,16] and patients were instructed to withdraw their usual medications 6 h prior to each evaluation. Each subject was studied in the supine position with one arm placed on a padded support with an upward angle of 30° from the horizontal axis to allow complete emptying of the veins. The dorsal hand vein technique evaluates and quantifies the vascular responsiveness of a pre-constricted dorsal hand vein to acetylcholine and sodium nitroprusside [6]. A suitable vein was chosen on the dorsum of the hand, and a 23-gauge needle was inserted. A tripod holding a linear variable differential transformer (LVDT, Shaevitz Engineering, NJ) was mounted on the back of the hand with the central orifice of the LVDT, containing a movable metal core, at a distance of 10 mm downstream from the tip of the needle (Fig. 1). The output signal of the LVDT, which is linearly proportional to the vertical movement of the core, provides a measure of the vein diameter. All readings were made under a congestive venous pressure of 40 mm Hg by inflating a blood pressure cuff placed on the upper portion of the arm under study.


Figure 01
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  		Fig. 1 Assessment of venous endothelial function using the dorsal hand vein technique. A linear variable differential transformer (LVDT) transducer is firmly attached to the skin and is able to capture the displacement of the metal pin which has one of its extremities positioned on a dorsal hand vein.

 
Normal saline solution was infused for at least 30 min to avoid the effects of the expected initial vasoconstriction due to the needle insertion. Progressive doses of phenylephrine (every 7 min) were administered to induce a pre-constriction state. The infusion rate of phenylephrine that induced 80% venoconstriction was kept constant during the entire study, and this degree of construction was defined as 0% dilatation for the purpose of subsequent calculations. The vasodilator response was calculated as a percentage of the range between 0 and 100% dilation. Endothelium-dependent venodilation was tested by infusing seven increasing doses (0.002-20 nmol/min) of acetylcholine (São Paulo University, Pharmacy Division). Endothelium-independent venodilation was tested by infusing three increasing doses (49-1981 ng/min) of sodium nitroprusside (São Paulo University, Pharmacy Division). Drugs were infused using a Harvard infusion pump (Harvard Apparatus, South Natick, MA) at a flow rate of 0.3 mL/min. Blood pressure and heart rate were monitored in the opposite arm during the experiment. All experiments were performed in a temperature-controlled (~22 °C) laboratory.

The volume of fluid infused during all drug administration was approximately 40 mL per evaluation and each procedure lasted approximately 90-120 min. This protocol has been tested in previous studies, in a large number of healthy volunteers and patients, and is considered extremely safe, producing negligible systemic effects [9,17,18].

2.3. Study logistic
The 6-minute walk test was performed to objectively assess functional capacity at baseline and prior to hospital discharge. A clinical congestion score based on findings from a physical examination and symptoms was also calculated at baseline and prior to hospital discharge [19]. Clinical decisions to use different drug therapies were not influenced by study investigators at any time during the protocol.

2.4. Statistical analysis
Continuous variables are described as mean±standard deviation and categorical variables are described in absolute numbers and percentages. Differences in the diameter of the dorsal hand vein were calculated by the percentage variation of the established pre-constriction status and vasodilator responses, using the degree of dilation at baseline as reference. The response to maximum dilation to acetylcholine and nitroprusside was used as reference value for the comparison between healthy subjects, patients with decompensated HF (baseline) and compensated HF (pre-discharge). Comparisons were assessed by the Student t test or Wilcoxon test for continuous variables and by the chi-square and Fischer exact tests for categorical variables. Age-adjustment was estimated using general linear models and was compared using analysis of variance. A two-tailed p value <0.05 was considered statistically significant for all analyses. All statistical analyses were performed using the SPSS 14.0 software package.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Clinical and demographic characteristics of the population
Twenty-seven patients with advanced HF and left ventricular systolic dysfunction (left ventricular ejection fraction of 28±9%) predominantly of non-ischaemic aetiology (67%) and in NYHA classes III-IV underwent a baseline venous endothelial study. Three subjects in the control group developed an overconstrictive response after phenylephrine infusion and were excluded from the analysis. The twenty healthy individuals (mean age 55±9 years) who completed the dorsal hand vein protocol comprised the control group. Clinical characteristics of the patients and controls are described in Table 1. Patients and controls were well-matched with respect to age, but there was a higher percentage of males in the control group. HF aetiology was predominantly non-ischaemic, and only one patient had chemotherapy induced left ventricular dysfunction.


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  		Table 1 Clinical and demographic characteristics of controls and HF patients

 
3.2. Baseline venous endothelial assessment
No complications were observed during the dorsal hand vein studies in either the controls or the HF patients. Maximum vasodilator response to acetylcholine, a marker of endothelium-dependent vasodilation, was significantly lower in HF patients compared to controls (47.5±53% versus 102±54%, respectively, p=0.0004, Fig. 2A). The endothelium-independent venodilator response was similar in both groups (155±33% versus 152±54%, respectively; p=0.87, Fig. 2 B). Dose-dependent responses to acetylcholine in controls and HF patients are depicted on Fig. 3. Overall, we observed that the vasodilator differences between patients and controls were more prominent after the third incremental acetylcholine dose.


Figure 02
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  		Fig. 2 Boxplots and individual values depicting the maximum vasodilator response to (A) acetylcholine (ACh) and (B) sodium nitroprusside (SNP) during the dorsal hand vein analysis in controls and heart failure patients.

 


Figure 03
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  		Fig. 3 Dose-response curves after 7 incremental doses of acetylcholine (0.002-20 nmol/min) during the dorsal hand vein analysis for controls and heart failure patients.

 
3.3. Effect of clinical compensation on clinical and haemodynamic variables
Boston criteria score at admission was 10.2±1.1, while estimated glomerular filtration rate was 56.7±22.1 mL/min. Clinical compensation was achieved primarily by the administration of intravenous loop diuretics. The physical examination score before hospital discharge, a marker of clinical congestion, was significantly lower than at baseline (12.1±3 versus 3.4±1; p<0.001). In addition, we also observed a clear improvement in functional assessment, as all patients were in NYHA functional classes III and IV on admission (27% and 73%, respectively), and they were in NYHA classes I and II at hospital discharge (60% and 40%, respectively) (p<0.001). There was a significant improvement in the 6-minute walk test distance, from 145±83 m at baseline to 252±74 m at pre-discharge, representing a relative increase of approximately 75% (p<0.01). As expected, weight loss was also accomplished during clinical stabilization (mean weight reduction of 3.8 kg, p<0.01). These improvements were achieved without significant changes in systolic and diastolic blood pressures, proportional pulse pressure and heart rate (Table 2).


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  		Table 2 Clinical characteristics at baseline and after clinical compensation

 
On admission, all patients were on diuretics, and most were taking digoxin and angiotensin-converting enzyme (ACE) inhibitors, whereas only 50% used spironolactone. During the stabilization phase, most patients received intravenous diuretic therapy. At hospital discharge, there were no remarkable changes in most other medications. In particular, there was no increase in the percentage of patients receiving medications that are known to interfere with arterial endothelial function, such as ACE inhibitors and beta-blockers.

3.4. Effect of clinical compensation on venous endothelial function
Baseline and pre-discharge venous endothelial assessments were performed approximately 8 days apart (median, ranging from 6 to 41 days). After clinical compensation, maximum vasodilator response to acetylcholine in the dorsal hand vein was significantly higher compared to the response on admission (86±52% versus 40±28%, respectively, p<0.01, Fig. 4). We also observed a moderate negative, but non-significant association between improvement in the endothelial-dependent venous dilation and weight reduction during clinical compensation (r=0.44; p=0.10). The endothelium-independent vasodilatation response elicited by sodium nitroprusside was unchanged between the analyzed periods.


Figure 04
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  		Fig. 4 Maximum vasodilator response to acetylcholine administration during the dorsal hand vein analysis, before and after clinical compensation.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
A growing body of evidence suggests that the vascular endothelium plays a major role in HF pathogenesis, clinical presentation and prognosis [1-3,20-22]. Endothelial dysfunction implies an altered vasodilator response to physiological stimuli, an event that is frequently associated with reduced cardiac output, impaired peripheral perfusion and poor functional performance [23,24]. In this study, we have demonstrated features of venous endothelial dysfunction in patients with advanced HF. We also observed that patients hospitalised with acute decompensated HF show a remarkable improvement in venous endothelial function after clinical compensation. This improvement occurs simultaneously with the resolution of signs of clinical congestion, and does not seem to be directly mediated by drugs that are known to be beneficial to arterial endothelial function.

Since its first description in 1947 by Shaevitz, the dorsal hand vein technique has undergone a number of technical adaptations and improvements [25]. Following the first report using this technique [7], several investigators have used it to evaluate venous compliance following local, systemic, subcutaneous or oral administration of different drugs. The dorsal hand vein technique provides the opportunity to study the venous endothelium using a simple, safe and minimally invasive approach. In addition, drugs are infused at very low concentrations, avoiding virtually all systemic effects. Venous endothelial dysfunction has been described in a variety of cardiovascular disorders, including systemic hypertension, dyslipidaemia and diabetes [8,26-28]. Surprisingly, a few reports have evaluated endothelium-dependent and endothelium-independent responses in the setting of HF. Two recent studies, however, have explored different stimuli in an attempt to unravel altered venous responses in HF patients [10-11]. Feng et al. observed an increased venoconstrictor response to infusions of neuropeptide Y in a subset of HF patients with moderate to severe left ventricular dysfunction [10]. This unanticipated result was contrary to the authors' expectation, as downregulation mechanisms were expected to decrease neuropeptide Y responsiveness in severe HF. Conversely, Love et al. demonstrated that venoconstriction after endothelin-1 infusion was blunted in a small group of HF patients compared to controls [11]. The mechanisms responsible for these paradoxical findings remain to be elucidated, but suggest that regulation of venous tone is a complex process that involves different stimuli and regulators with specific selectivity and heterogeneous responses. In fact, a recent report suggests a major role of prostaglandin-mediated modulation of vascular tone in veins in both HF patients and controls [13]. In our study, the maximal vasodilator effect elicited by acetylcholine was significantly lower in HF patients compared to healthy controls, suggesting a blunted endothelium-dependent response. No significant differences were observed in endothelium-independent venodilation following sodium nitroprusside infusion. In contrast to these findings, a previous study that used radionuclide forearm venous plethysmography, did not observe venous dysfunction in the capacitance veins of HF patients. In this study, Nightingale and co-workers demonstrated that changes in venous tone induced by basal and carbachol-stimulated nitric oxide release were remarkably similar between healthy controls and HF patients. This discrepancy might be at least partially explained by specific differences between capacitance and conduit veins. It is important to point out that the majority of blood volume resides in capacitance veins, and, theoretically, venous endothelial dysfunction of capacitance veins may be more important in heart failure pathophysiology. Importantly, however, pre-discharge data from our HF patients demonstrated a near-normalization of venous endothelial function. This finding may indicate that stable compensated heart failure patients, such as those studied by Nightingale et al., might in fact have a near-normal venous endothelial function. Also, although it is intuitive to assume that nitric oxide may play an essential role in the regulation of venous tone, as it is well recognized for the arterial vasculature, it is possible that other as yet unknown molecular pathways may be involved [12].

There are a few studies evaluating endothelial function in acute decompensated HF. Patel et al. [29] compared flow-mediated vasodilatation induced by reactive hyperaemia in patients with severe HF after administration of dobutamine and in a control group. The percentage increase in brachial artery diameter was significantly higher in patients who received dobutamine, an effect that lasted for 2 weeks after drug discontinuation. These findings suggest that clinical compensation, mediated by an adrenergic agonist, may be associated with beneficial effects on the vascular endothelium. Our findings indicate that clinical compensation (without additional use of dobutamine, ACE inhibitors or beta-blockers) is associated with a remarkable improvement of the endothelium-dependent venodilation response in hospitalised patients with severe HF. In this scenario, it is reasonable to speculate that the congestive state itself may play an essential role in venous endothelial dysfunction.

Blood vessels, either arterial or venous, are constantly submitted to mechanical forces, including cyclic deformations inherent to the pulsatile nature of the blood flow, in addition to shear stress and to the stress secondary to pressure waves (normal stress). These deformation forces are accompanied by phenotypic modulation of endothelial cells, which contain several receptors, mainly in their cytoskeleton, able to capture and respond to these stimuli [30]. Multiple and complex transduction pathways can take part in processes that convert mechanical signals to biochemical substances, including ionic channels activated by stretch, paracrine growth factors, G proteins, kinases, integrins and products from phospholipid metabolism. In this context, the molecular mechanisms that can explain the improvement in venodilation after improvement of the congestive state are still unknown, but may involve cellular mechanotransduction processes. Dancu et al., for example, demonstrated that shear stress and circumferential deformation of endothelial cells attenuate the gene expression of endothelial nitric oxide synthase and induce endothelin-1 production [31]. Thus, the haemodynamic status seems to interact with biological processes that potentially maintain the characteristic vasoconstriction in HF. Reversion of the congestive state is likely to have a regulatory effect on the production of vasoactive substances by different cell types, including the endothelial tissue, with potential effects on venous and arterial tone.

Some methodological aspects of our protocol deserve consideration. Our control group was not perfectly matched by gender, and this represents one limitation of our analysis. However, as we had more women in the control group, this would potentially cause no change in the mean vasodilation response or even increase it (as pre-menopausal women exhibit improved endothelial function compared to men), which consequently could increase the difference in venodilation between groups. In patients in whom an ACE inhibitor was introduced during the hospital stay, the magnitude of improvement in venous endothelial function was not superior to that in patients who maintained ACE inhibitor use. However, we acknowledge that we were not adequately powered to perform a sub-group analysis.

In conclusion, the assessment of endothelium-dependent vasomotor function is an important tool to evaluate the functional integrity of the vascular endothelium. A recent report suggested that venous abnormalities and dynamic vasodilator function may play an important role in the complex pathophysiology of patients with HF and preserved systolic function [32]. Our data support the concept that impaired endothelium-dependent vasodilation occurs throughout the vascular system in HF, and is not restricted to the arterial system. In addition, we have demonstrated that improvement of the congestive status itself is associated with a better profile of venous endothelial function. In the context of acute decompensated HF, new prospective studies are required to evaluate whether the endothelial phenotype - either venous or arterial - can help in prognostic analysis, to determine which patients are more likely to have a new decompensation and, therefore, provide a new therapeutic target.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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M. Klosinska, T. Rudzinski, P. Grzelak, L. Stefanczyk, J. Drozdz, and M. Krzeminska-Pakula
Endothelium-dependent and -independent vasodilation is more attenuated in ischaemic than in non-ischaemic heart failure
Eur J Heart Fail, August 1, 2009; 11(8): 765 - 770.
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