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European Journal of Heart Failure 2004 6(7):901-908; doi:10.1016/j.ejheart.2004.02.008
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© 2004 European Society of Cardiology

Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure

David R. Morgan, Lana J. Dixon, Colm G. Hanratty, Sinead M.T. Hughes, William J. Leahey, Keith P. Rooney, G. Dennis Johnston and Gary E. McVeigh*

Department of Therapeutics and Pharmacology, Whitla Medical Building, Queen's University 97 Lisburn Road, Belfast BT9 7BL, UK

* Corresponding author. Tel.: +44-28-90-335770; Fax: +44-28-90-438346 E-mail address: g.mcveigh{at}qub.ac.uk


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Impaired endothelium-dependent and independent vasodilator responses in chronic heart failure (CHF) have been well described. Previous studies involved younger patients and omitted medications prior to study.

Aims: We explored if new therapeutic interventions would restore vasodilator responses in typical patients with chronic heart failure.

Methods and results: 24 patients and 15 controls were recruited, patients were maintained on their usual medications. Forearm blood flow responses were measured by venous occlusion plethysmography in response to incremental doses of sodium nitroprusside (SNP) (6, 9 and 12 nmol/min), acetylcholine (ACH) (120, 180 and 240 nmol/min), angiotensin II (AII) (1, 10 and 100 nmol/min) and Ng-Nitro-L-arginine methyl ester (L-NAME) (1, 2 and 4 nmol/min) infused into the non-dominant brachial artery. FBF responses to SNP were impaired in patients compared with controls (13.7(9.9,17.4) vs. 24.8(18.6,30.9)) arbitrary units, P<0.001). Similarly FBF responses to ACH were reduced in patients compared with controls (7.5(4.2,10.9) vs. 24.8(16.4,33.2)) arbitrary units, P<0.001. Decreased FBF was noted in response to AII and L-NAME but was significant only for AII and did not differ between groups.

Conclusions: In elderly patients with CHF, endothelium-dependent and independent vasodilator responses were blunted compared with controls. Defects in nitric oxide bioavailability and smooth muscle responsiveness are not reversed by modern medical management of the heart failure syndrome.

Key Words: Heart failure • Endothelium • Nitric oxide • Acetylcholine

Received June 26, 2003; Revised January 28, 2004; Accepted February 5, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Chronic heart failure (CHF) is characterised by systemic vasoconstriction [1] and reduced blood flow in the peripheral circulation [2]. The endothelium plays a pivotal role in regulating blood flow by releasing relaxing and constricting factors under basal conditions and when stimulated by neurotransmitters, hormones, autocoids or physical stimuli. Endothelium-mediated dilation of resistance vessels is blunted in CHF resulting in impaired vasodilator reserve [3,4]. Previous researchers have described impairments in endothelium-mediated vasodilation in patients with CHF, compared to age matched controls [5–7].

In prior studies patients were either not receiving ACE inhibitors or had discontinued ACE inhibitors and other vasoactive medications for at least 24 h prior to study. Experimental evidence has suggested that ACE inhibitors may restore the endothelium-mediated responses in CHF [8] and such an effect has been demonstrated in animal models of CHF [9] as well as in patients with type II diabetes [10] and coronary artery disease [11]. Furthermore, all previous studies were performed before the routine use of beta blockers and the aldosterone antagonist spironolactone.

Competitive inhibitors of endothelial nitric oxide synthase, employed to inhibit basal NO production, have produced variable results in CHF. Ng-mono methyl-L-arginine (L-NMMA), a competitive inhibitor of endothelial nitric oxide (NO) production has been shown to reduce forearm blood flow in normal humans [12]. In patients with CHF, the infusion of, L-NMMA has been associated with increased [3], neutral [13] or impaired vasodilator responses [5].

In CHF baseline production of endothelium-derived NO may be increased [3] but stimulated endothelium-dependent vasodilation is diminished indicating impaired NO release in response to agonists. Alternatively, excess breakdown of NO may occur probably through the interaction of NO with superoxide to produce peroxynitrite that serves to reduce NO bioavailability [13].

Variable responses to endothelium-independent vasoactive compounds have also been reported in CHF. The responses to nitric oxide donors such as glyceryl trinitrate (GTN) and sodium nitroprusside (SNP) have been either attenuated [3,14,15] or unaffected [1,4] in previous studies. The presence of impairments in endothelium-independent vasodilation may be due to impaired smooth muscle responsiveness or structural changes in the arterial wall in CHF [5].

CHF is predominantly a disease of the elderly, only 17% of patients diagnosed with CHF are under 65 years of age [16]. In spite of this the majority of studies of endothelial dysfunction in CHF have studied patients younger than 65 [17]. A strong case has been made for inclusion of patients more representative of those in the community in study protocols [18]. Furthermore, endothelium-dependent vasodilation has been shown to be decreased in healthy older persons in the absence of CHF or other vascular disease [19]. We therefore recruited a group of patients over 65 in order to redress this imbalance in the literature and study a more typical group of heart failure patients. In contrast to previous studies, patients continued treatment on optimal medical therapy for the duration of the study


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
Twenty-four patients (17 male, seven female) mean age 74 years (range 64–85) were recruited from the heart failure and cardiology clinics of the greater Belfast area. The mean duration of symptoms was 23.5 months (range 6–62). All had grade II or III CHF as defined by the New York Heart Association (NYHA) classification. All patients had had documented hospital admission for pulmonary oedema and had a left ventricular ejection factor of <40%. Patients were on maximal tolerated medication for the treatment of heart failure (see Table 1) and had been stable on this therapy for at least 6 weeks prior to study. Patients receiving warfarin were excluded due to the invasive nature of the study as were those with diabetes mellitus (fasting glucose>7.0 mmol/l) or hypertension (BP>160/90) since endothelial dysfunction has been documented in these groups in the absence of CHF.


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  		Table 1 Heart failure therapy prescribed to study patients

 
Fifteen volunteers were recruited from the local community to act as a control group (eight male, seven female) mean age 72 years (range 66–81). Control subjects were screened by history and examination including ECG. Control subjects were excluded from study if they had hypertension, diabetes, vascular disease or were taking any vasoactive medications.

All participants gave written informed consent for all procedures. The investigation conforms with the principles outlined in the Declaration of Helsinki and was approved by the local ethics committee of the Queen's University of Belfast.

2.2. Protocol
Investigations were performed between 09:00 and 10:00 h in a quiet, temperature controlled laboratory with the subjects lying supine. All participants fasted for 14 h prior to study. Alcohol and caffeine were prohibited during this time, and patients were instructed to take their usual medications except loop diuretics, which were withheld on the morning of study to prevent the profound effects of a full bladder on forearm blood flow.

Under local anaesthesia (1% lignocaine) and sterile conditions a 27 gauge heat sterilised steel needle (Cooper's Needle Works, Birmingham, UK) was inserted into the brachial artery of the non-dominant arm and taped to the skin. This needle was sealed to an 18 gauge polyethylene epidural catheter using dental wax, again under sterile conditions.

All subjects were rested for 30 min after catheter placement to establish a stable baseline prior to data collection. NaCl (0.9%) was infused into the brachial artery at 1 ml/min during the control period. Forearm blood flow (FBF) was measured bilaterally by venous occlusion plethysmography. This method assesses variation in limb volume arising from arterial blood flow at the level of the arterial resistance vessels. The forearms were rested comfortably on supports slightly above the level of the heart. Venous occlusion was achieved by a blood pressure cuff applied proximal to the elbow and inflated to 40 mmHg by a rapid cuff inflator. The hands were excluded from the circulation by inflating wrist cuffs to 200 mmHg for 1 min before and during the blood flow measurements. In order to detect variations in limb volume, indium gallium strain gauges were placed around the widest part of the forearm. These strain gauges were coupled to an electronically calibrated plethysmograph (Medasonics model SPG16, CA, USA). The output was transferred to a Macintosh personal computer (Performa 630, Apple Computer Inc. California) with a MacLab analog-to-digital converter and CHART software (v. 3.4.3) (AD Instruments, Sussex, UK). Each forearm blood flow determination comprised five separate measurements performed at 10 s intervals. Drug infusions were performed in the experimental forearm to determine the direct effect of the vasoactive drug, while the forearm flow measurements in the control arm were monitored to ensure that systemic effects did not occur during this period. The mean values of the five consecutive forearm blood flow measurements were taken for statistical evaluation. Forearm blood flow was expressed as millilitre per minute per hundred millilitre forearm volume. Drugs were infused into the study arm using a constant rate infuser (Braun Perfusor pump, Melsungen, Germany).

2.3. Drug infusions
All drugs were prepared in 0.9% saline on the day of the study. Sodium Nitroprusside (SNP) (F H Faulding and Co. Limited, Australia) was infused in incremental doses (6, 9 and 12 nmol/min) for 3 min each to assess endothelium-independent vasodilation, with FBF measured in the last minute of each infusion. After a washout period of 30 min during which 0.9% saline was infused basal FBF was again measured. Angiotensin II (Clinalfa AG, Switzerland) was infused in incremental doses (1, 10 and 100 nmol/min) for 5 min each to assess endothelium-independent vasoconstriction. After a further 30 min washout period and basal FBF measurement acetylcholine (ACH) (Clinalfa AG, Switzerland) was infused in incremental doses (120, 180 and 240 nmol/min) for 3 min each to assess endothelium-dependent vasodilation. After a final 30 min washout period and basal FBF Ng-nitro-L-arginine methyl ester (L-NAME) (Clinalfa AG, Switzerland) was infused in incremental doses (1, 2 and 4 nmol/min) for 4 min each to assess the decrease in blood flow produced by antagonising endogenous NO production.

2.4. Statistical analysis
The responses to the vasoactive substances were expressed as the measure of area under the curve (AUC) of change in FBF from baseline, expressed as arbitrary units. This technique which includes all responses has previously been employed by our group [20] is recommended as a useful method for measuring responses over a series of time points [21].

In addition we calculated maximal endothelium-independent vasodilation (MEIDV) defined as the FBF response during 12 nmol/min SNP minus resting FBF divided by resting FBF, and the maximal endothelium-dependent vasodilation (MEDV) defined as FBF response during 240 nmol/min ACH minus resting FBF divided by resting FBF. The endothelial function index (EFI) was then calculated as MEDV/MEIDV ratio. This ratio reflects the contribution of the endothelium to the vasodilator responses [22].

The haemodynamic and biochemical characteristics of the patient and control groups were compared by use of independent samples t-test. Data are expressed as mean plus 95% Confidence Intervals unless otherwise stated. Differences were considered significant at a value of P<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The baseline characteristics of the normal control subjects and CHF patients were similar. There were no differences in age or body mass index. Patients had significantly lower total cholesterol, LDL and HDL cholesterol levels than controls (see Table 2). Mean left ventricular ejection fraction was 34% (range 20–40%), and cardiothoracic ratio on chest radiograph was greater than 0.5 in all patients. The aetiology of heart failure was ischaemic in 17, hypertensive in five, valvular heart disease in one (mitral regurgitation) and idiopathic dilated cardiomyopathy in one. All patients were in sinus rhythm except four who were in paced rhythm (one single chamber pacemaker, one AV sequential pacemaker and two biventricular pacemakers).


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  		Table 2 Patient characteristics

 
Baseline FBF was similar between patients and controls (2.01 (95% CI 1.67–2.35) vs. 1.84 (95% CI 1.37–2.30)) respectively (P=0.56). After each of the washout periods, there were no differences in baseline FBF between patients and controls. Forearm blood flow in the control arm did not change in response to infusion of any study drug thus confirming that the drug effects were confined to the experimental forearm (data not shown), which is in keeping with previous studies [5,6,20].

Sodium nitroprusside was associated with increased FBF in both groups (Fig. 1) and there was a significant smaller AUC in the patients compared with the control group (13.7 (95% CI 9.9–17.4) vs. 24.8 (95% CI 18.6–30.9) arbitrary units, P<0.001, Table 3, Fig. 2).


Figure 1
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  		Fig. 1 Forearm blood flow in patients and controls in response to sodium nitroprusside and acetylcholine. Data are mean and 95% confidence limits.

 


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  		Table 3 Basal forearm blood flow and the area under the curve for change in forearm blood flow following infusion of vasoactive substances

 


Figure 2
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  		Fig. 2 Area under curve (AUC) for patients vs. controls following acetylcholine (b) and sodium nitroprusside (a). Data are mean and 95% confidence limits. *P<0.05.

 
Following infusion of acetylcholine there was a marked difference in FBF in the patients compared to the control group (Fig. 1) which was found to be highly significant when the AUC between both groups was compared (7.5 (95% CI 4.2–10.9) vs. 24.8 (95% CI 16.4–33.2) arbitrary units, P<0.001, Table 3, Fig. 2).

Following infusion of angiotensin there was reduction in FBF compared to baseline in both groups. When the AUC was compared there was a trend to greater reduction in patients than controls (–2.0 (95% CI –3.1––1.0) vs. –0.7 (95% CI –1.7–0.3) arbitrary units, P=0.06, Table 3). Infusion of L-NAME resulted in no significant differences in FBF between patients and control subjects, AUC –0.5 (95% CI –1.5–0.4) vs. 0.8 (95% CI –0.5–2.2) P=0.09 (Table 3).

Maximal endothelium-independent vasodilation (MEIDV) was not significantly reduced in patients as compared to controls ((2.02 (95% CI 1.34–2.71) vs. 2.92 (95% CI 2.34–3.49) P=0.06, Fig. 3) although the response to SNP 12 nmol/min was different ((6.32 (95% CI 5.26–7.38) ml 100 ml–1 min–1 vs. 9.09 (95% CI 7.42–10.77) ml 100 ml–1 min–1, P<0.05). MEDV was significantly reduced in patients as compared to controls (0.57 (95% CI 0.12–1.03) vs. 1.27 (95% CI 0.62–1.92), P<0.05, Fig. 3), as was EFI (0.91 (95% CI 0.4–1.42) vs. 2.39 (95% CI 1.47–3.30) P<0.05, Fig. 3).


Figure 3
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  		Fig. 3 (a) Maximal endothelium independent vasodilation (MEIDV), (b) maximal endothelium dependent vasodilation (MEDV) and (c) endothelial function index (EFI) in patients and controls. Data are mean and 95% confidence limits. *P<0.05.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Previous studies have shown impaired endothelium-dependent vasodilation in patients with CHF and a majority have shown impairment in endothelium-independent vasodilation. This is the first study to show impaired endothelium-dependent and -independent vasodilation to ACH and SNP respectively, persist in typical elderly patients with CHF on optimal modern medical therapy. The vasoconstrictor response to angiotensin II was not different between patients and controls. At the doses employed in this study, L-NAME produced no statistically significant changes in forearm blood flow in patients or controls.

Abnormalities in endothelial function have been a consistent finding in studies involving both coronary and peripheral arteries in patients with CHF [6,7]. It has been suggested that the impaired vascular responses are due to several coexistent abnormalities of arterial function including impaired endothelium-derived release of nitric oxide [9]. ACE inhibitors (which all our patients were receiving) have the potential to reverse impairments in endothelium-dependent vasodilation in patients with CHF [8,23] as in other disease states [10,11]. ACE inhibitors decrease the breakdown of bradykinin, which stimulates the release of both nitric oxide and vasodilating prostaglandins. HMG CoA reductase inhibitors (statins) have also been shown to improve endothelial function as assessed by forearm blood flow techniques in renal transplant patients [24] and patients with diabetes [25,26]. Additive effects from the combination of statins and ACE Inhibitors have also been shown [27]. Low dose (50 mg) spironolactone has been shown to improve endothelial vasodilator function and increase vasoconstrictor effects of L-NMMA in CHF [28]. Carvedilol has been demonstrated to improve endothelial dependent vasodilation as assessed by flow mediated dilatation in younger patients with coronary artery disease, though these patients still showed a degree of impairment when compared to control subjects [29]. Although the acute effects of beta blockers include peripheral vasoconstriction there is little data on the effects of their long term use on endothelium-dependent or -independent vasodilation. It is also unclear if the potential vasodilator actions of carvedilol result in any differential effects as compared to other beta blockers used in CHF. Aspirin has been shown to inhibit arachidonic acid mediated vasodilation in CHF and as such could reduce vasodilator responses or attenuate the increase in vasodilation seem in CHF after ACE inhibitor treatment [30]. There is, however, also evidence of aspirin producing beneficial effects on endothelium-dependent but not endothelium-independent vasodilation [31]. Since our patients were not studied before and after starting vasoactive medications it is not possible to demonstrate any altered response to vasoactive medications. However, despite administration of agents known to favourably influence vasodilator responses [13], defects in endothelium-dependent vasodilation persist in patients with CHF.

Studies that have assessed endothelium-independent vasodilation in patients with CHF have produced variable results. Some workers [3,14] have shown preserved responses to nitric oxide donors, whilst others have shown impaired responses [5,7,32]. All previous studies have omitted ACE inhibitors and other vasoactive medications for at least 24 h prior to study. Our data support and extend previous findings of impaired endothelium-independent vasodilation in patients with CHF, by demonstrating persistent defects in smooth muscle responsiveness in spite of maximal medical therapy. The persistence of abnormalities of endothelium-independent vasodilation may relate to a combination of impaired smooth muscle responsiveness to NO [15], impairment of NO diffusion to the smooth muscle [5] or structural alterations in arterial compliance associated with CHF [33,34]. Alterations in arterial wall properties have been documented in CHF [35] as well as other vascular diseases [36].

We demonstrated a non-significant impairment in maximal endothelium-independent vasodilation (MEIDV) along with significant impairments in maximal endothelium-dependent vasodilation (MEDV) and endothelial function index (EFI) in patients as compared to control subjects. Endothelial function index is suggested as a marker for the contribution of the endothelium to vasodilation. The relatively greater impairment in MEDV than MEIDV and the impairment in EFI along with the greater impairment in AUC for ACH (30% of control response) as compared to SNP (50% of control response) may suggest that defects in endothelium-dependent rather than endothelium-independent responses are more predominant in these patients.

In keeping with typical population data on the aetiology of CHF, the majority of our patients had CHF secondary to atherosclerotic ischaemic heart disease. Since impaired endothelium-dependent vasodilation has been demonstrated in patients with atherosclerosis in the absence of CHF [29,37] it is possible that the impairment in endothelium-dependent vasodilation are partially explicable on the basis of atherosclerosis. Previous studies assessing CHF in the absence of atherosclerosis have, however, also shown impaired endothelium-dependent vasodilation [4,14,38].

We found a non-significant trend for decreased responsiveness to exogenous angiotensin II in patients as compared to controls. This observation is in agreement with a previous study using identical doses of angiotensin II which showed no differences in vasoconstriction in patients as compared to controls, although these patients had received no vasoactive medications for one week prior to study [39]. Basal NO production has been variously described as increased, decreased and unchanged in patients with CHF. Endothelium-dependent vasoconstrictors have had variable effects in patients with CHF. Kubo et al. [13] found no difference in vasoconstrictor effect between patients with CHF and controls given intra arterial L-NMMA, concluded that the nitric oxide pathway in forearm resistance vessels is not impaired under basal conditions. In contrast others have found exaggerated [3,4] and impaired responses to L-NMMA [5,13,40]. It has been suggested that patients treated with ACE inhibitors have preserved basal NO activity whilst those not treated with ACE inhibitors do not [40]. We found no differences in response to an arginine analogue (L-NAME) between control subjects and patients. However, it is important to appreciate that changes in FBF in response to vasoconstrictors especially when assessed from low baseline blood flow values as in this study may be difficult to detect. Therefore the failure to document a significant effect of L-NAME on FBF between patients and controls, which has also been noted previously [41] should be interpreted with caution.

A potential confounding factor in our study is the significantly lower blood pressure and heart rate in the patients as compared to the control group. Although some of the differences could be suggested to be due to the lower vasomotor tone in patients as compared to controls such differences are inevitable in patients with treated CHF and are in part due to the effects of the medications previously shown to improve vasodilator status [13].

Our results demonstrate impairment in endothelium-dependent and independent vasodilation in patients with CHF. To our knowledge, this is the first study to assess responses in elderly patients maintained on optimal modern medical therapy. The results show that in patients with CHF abnormalities persist in both endothelial and smooth muscle function despite maximal tolerated therapy to treat the syndrome.


   Acknowledgements
 
This work was supported by a grant from PPP Healthcare Trust.


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

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