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Cardiovascular Research 2007 76(3):539-546; doi:10.1016/j.cardiores.2007.07.009
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Copyright © 2007, European Society of Cardiology

Effects of tetrahydrobiopterin on coronary vascular reactivity in atherosclerotic human coronary arteries*

Matthew I. Worthley1, Ronak S. Kanani, Yi-Hui Sun, Yichun Sun, David M. Goodhart, Michael J. Curtis and Todd J. Anderson*

Department of Cardiac Sciences and the Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary AB, Canada

*Corresponding author. Department of Cardiovascular Sciences, Foothills Hospital, 1403 29th Street MW, Calgary, Alberta, Canada, T2N 2T9. Tel.: +1 403 944 1033; fax: +1 403 283 0744. matthew.worthley{at}adelaide.edu.autodd.anderson{at}calgaryhealthregion.ca

Received 21 November 2006; revised 27 June 2007; accepted 10 July 2007


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives Reduced nitric oxide (NO) bioavailability is a key mechanism in the development of endothelial dysfunction. The NO synthase cofactor, tetrahydrobiopterin (BH4), increases NO availability, yet its effect in the human coronary circulation, particularly following PCI, remains uncertain. This study was designed to evaluate the effects of intracoronary BH4 in human coronary arteries with non-critical coronary artery disease or following percutaneous coronary intervention (PCI).

Methods The study group consisted of 57 stable patients, 10 of which were controls. Active drug was administered in 47 patients, with either de novo non-critical coronary disease (non-stent group; n=25) or following PCI (stent group; n=22). Coronary blood flow (CBF) was measured (0.014-inch Doppler flow wire) in each of these groups in response to sequential intracoronary infusions of acetylcholine (Ach, 10–7 & 10–6 M), BH4 (250 µg/min & 500 µg/min) and a co-infusion of BH4 (500 µg/min) and Ach (10–7 & 10–6 M). The primary endpoint evaluated the % change in CBF to Ach compared to co-infusion of Ach and BH4.

Results Mean age was 60±10 years (M 45:F 12). Regarding the primary hypothesis, no difference was observed between Ach response compared to co-infusion of BH4 and Ach in the % change in CBF in either the non-stent group (Ach 97±122%, Ach/BH4 87±95%) or the stent group (Ach 77±105%, Ach/BH4 55±97%).

Conclusions In native non-critical coronary artery disease or following PCI, coronary microvascular endothelial function is not improved by co-administration of Ach and BH4.

KEYWORDS Nitric oxide; Atherosclerosis; Endothelial function; Angioplasty/coronary intervention


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The endothelium is important in maintaining normal vascular tone, structure and function [1]. Once viewed largely as a semi-permeable barrier between the blood and tissues, the vascular endothelium is now known to have a pivotal role in the maintenance of vascular homeostasis including vasomotor effects, platelet function, cell growth and inflammation predominantly through the effects of nitric oxide (NO) [1,2]. A reduction in NO bioavailability and subsequent endothelial dysfunction in the coronary circulation is associated with adverse clinical outcomes [3–7]. Not only is this phenomenon observed in subjects with established coronary artery disease [8], it is further impaired following percutaneous coronary intervention (PCI) [9]. The exact mechanisms behind these observations remain uncertain.

Tetrahydrobiopterin (BH4) is required in the production of NO. It is an essential co-factor, which enables nitric oxide synthase (NOS) to convert L-arginine to L-citrulline and NO. At suboptimal concentrations of BH4, NOS becomes ‘uncoupled’ and acts as an NADPH oxidase, producing superoxide and hydrogen peroxide, which further reduces NO bioavailability [10–13]. Acknowledging the beneficial effects of BH4 administration on peripheral endothelial function in patients with hypercholesterolemia [14], diabetes mellitus [15], essential hypertension [16] and chronic smoking [17] we planned to further evaluate this effect in the coronary circulation.

Scant data exists regarding the effects of BH4 on coronary macrovascular (epicardial coronary vessels) and microvascular (resistance vasculature, <200 µm in diameter) endothelial function. A few small studies have evaluated the effects of BH4 in the coronary circulation with encouraging results [18,19], no data however to date has evaluated the effects of BH4 following coronary stenting. It is in this cohort where the greatest benefit may potentially be obtained, as optimizing coronary endothelial function in the setting of PCI may also have beneficial effects on subsequent acute stent thrombosis and ‘no reflow— phenomenon [20].

The purpose of the present study was to confirm in an unselected population with de novo non-critical coronary artery disease, randomized to active drug or placebo, the acute effects of intracoronary BH4 on coronary endothelial function. Furthermore, these effects of BH4 were evaluated, for the first time, in patients following coronary stenting, a cohort where the benefits of optimizing coronary endothelial function may be crucial.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Patient selection
Stable patients referred for coronary angiography or angioplasty were eligible for the study. Exclusion criteria were: age <35 or >75 years, recent acute myocardial infarction (<48 h), unstable angina with chest pain in the last 24 h, impaired LV function (ejection fraction <50%), coronary anatomy not amenable to intracoronary study or for which coronary artery bypass grafting (CABG) is indicated, previous CABG, renal insufficiency (creatinine >150 µmol/L), allergy to contrast dye, complications arising from the angiogram or angioplasty, and failure to provide informed consent. Patients receiving glycoprotein IIb/IIIa antagonists were also excluded, as we have previously shown this effects coronary endothelial function [21]. The study artery was either the left anterior descending or a non-dominant left circumflex artery, with the distal vessel free of angiographic coronary disease. Informed consent was obtained and the study was approved by the local institutional ethics review board and conducted according to the Declaration of Helsinki. Patients in both the non-stent and stent group were randomized to active drug (BH4) or placebo in a ratio of approximately 5:1.

  1. a. Non-stent group: This group consisted of patients in whom the ‘study coronary artery— was required to have <30% coronary luminal disease. The majority of these subjects had established atherosclerosis in other vessels.
  2. b. Stent group: This cohort consisted of studies being performed following bare metal stent insertion for a significant (>70%) symptomatic coronary lesion. Minor modification to protocol was made in the Stent group. An extended period of time (15 min rather than 2) was used for the initial saline control infusion to assist with ‘vessel stability— immediately following PCI. To minimize coronary artery spasm to the acetylcholine infusions following stent insertion low dose intravenous nitroglycerin (5 µg/min) was infused for the length of the protocol.
  3. c. Control group: In 10 patients, 5 in the non-stent group and 5 in the stent group, active drug was substituted with normal saline to evaluate the effects of coronary endothelial function over time as well as to maintain blinding. For evaluation of primary and secondary endpoints however, the patients receiving active BH4 acted as their own controls.

2.2 Study protocol
All vasoactive medications were held for 24 h prior to the study. A 7–8 Fr Judkins left guiding catheter was engaged in the ostium of the left main coronary artery. Following angiography in the non-stent group, or stent insertion in the stent group, a 0.014" doppler Flo-wire (Volcano Inc., Mountainview, CA) was placed in the mid portion of the study artery with an infusion catheter placed in the proximal portion of the study artery. The intracoronary (ic) protocol consisted of the following interventions: a) a 5% dextrose control infusion for 2 min (control 1); b) serial 3 min acetylcholine (Ach) (Miochol, Iolab) infusions to achieve final estimated concentrations of 10–7 and 10–6 M (1.6 and 16 µg/min); c) a repeat 5% dextrose control infusion for 5 min (control 2); d) an infusion of BH4 (Clinalfa, Switzerland) at 250 µg/min followed by 500 µg/min for 6 min each e) serial 3 min acetylcholine infusions to achieve final estimated concentrations of 10–7 and 10–6 M (1.6 and 16 µg/min) combined with BH4 (500 µg/min); f) bolus of nitroglycerin (200 µg) and then adenosine (48 µg ic) to assess coronary flow velocity reserve (CFVR). The BH4 was reconstituted in deoxygenated saline and administered at a dose previously shown by our group to be vasoactive [22]. Infusions were via a Harvard pump at 1 ml/min (including co-infusion steps). Data is shown as maximal response to Ach infusion (generally at the 10–6 M dose) for CBF and vessel diameter responses. At the end of each infusion, a coronary angiogram was recorded using 9 ml of non-ionic contrast (Omnipaque, Winthrop Laboratories, NY) injected through a Medrad infusion pump at 5 ml/s. Throughout the study, and at the end of each intervention, the coronary velocity (Flo-wire), the heart rate, blood pressure, an electrocardiogram and the clinical status of the patient was recorded.

To perform a randomized, double blind study the BH4 was mixed by a research nurse not involved in the analysis of the data. This allowed both blinding and a time dependent control for the primary endpoint of acetylcholine-mediated increase in coronary blood flow (CBF). Randomization was performed by random code generation.

2.3 Quantitative coronary angiography and coronary blood flow
Details of our methods have been previously published [23]. In brief, an automated edge-detection program is used to measure the diameter of the vessel (CMS software, Medis Corp, Leiden). A 5 mm segment of the coronary artery that encompassed a region 5 mm distal to the Doppler tip (proximal) and a further 10 mm segment of the distal vessel (distal) were analyzed by quantitative coronary angiography (QCA). The coronary velocity measurements were analyzed by a technician blinded to the results of the QCA. The coronary flow is then calculated as the following: CBF=({theta} D2/4) (APV/2) (0.6) where CBF=flow (ml/min); D=vessel diameter (mm) by QCA; APV=average peak velocity (cm/s), 0.6 is the conversion factor. This system and formulation have been previously validated [24]. Coronary flow velocity reserve (CFVR) is evaluated as a ratio of APV (post adenosine)/APV (baseline).

2.4 Data analysis and statistics
Statistically these two studies were run in parallel with the focus to analyze the data separately, therefore in the non-stent and stent group the primary and secondary endpoints were as follows. i) Primary endpoint: The percent change in CBF to maximal acetylcholine response compared to percentage change in CBF of co-infusion of maximal acetylcholine response plus BH4. ii) Secondary endpoints: The effect of BH4 on basal CBF and coronary diameter. The data is presented as mean±standard deviation for continuous variables and number and percent for categorical variables. Statistical significance was defined as a two-sided p<0.05. The primary and secondary endpoints were analyzed by two way repeated measures ANOVA. The p values shown in tables, directly compares the infusion protocol with associated control infusion, i.e. for the initial Ach infusions this is control 1, for all other infusions, control 2 is used. Results remain unchanged whether the second control ‘baseline’ is taken before or after the first BH4 (250 µg/min) infusion. Statistical analyses were performed using SPSS version 13.0 (SPSS Inc. Chicago, Il) statistical software. The determination of sample size for this study has been based on BH4 studies from the peripheral circulation. These studies [14,15] have demonstrated improvement with BH4 in 12–20 patients. The increase in CBF to acetylcholine was expected to be 70±48%. A relative improvement of 50% has been observed in previous studies. Assuming an {alpha}=0.05 and β=0.20 (80% power) and a SD equal to the treatment effect the sample size will be 10 subjects per study. To ensure adequate power we aimed to study 20–25 patients with BH4 and 5 with saline placebo.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Patient characteristics
The baseline clinical characteristics of patients receiving active drug are shown in Table 1. As the primary objective of this study was not to compare these two groups, no statistical analysis has been performed to evaluate any potential differences between these two groups. No change was seen over time in CBF or vessel diameter in the saline control group and hence further data regarding this group is not shown. In addition the demographics of the control subjects were not different than their respective active treatment cohorts. No difference was seen between BH4 and placebo groups in either the non-stent or stent arm regarding medications known to impact on oxidative stress such as aspirin [25], heparin [26] and/or clopidogrel [27].


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  		Table 1 Patient demographics

 
3.2 Stenting outcome
In the stent group, all patients successfully had a bare metal stent inserted. The culprit artery was the left anterior descending artery in 14 cases, 8 the left circumflex. The angiographic stenosis prior to intervention was 83±8% with a residual stenosis of 8±3 % post procedure. Two stents were required in 2 procedures resulting in a total mean stent length for the cohort of 16±4 mm. No significant periprocedural events were seen with the post procedure creatine kinase level (taken on the following day) 80±62 IU/L.

3.3 Effects on vessel diameter
The effects of Ach, BH4 and combination of Ach and BH4 on vessel diameter are shown for both the non-stent and stent group in Tables 2 and 3Go respectively. In these tables p values represent a single factor ANOVA comparing effect with the most immediate comparable control value. Regarding a secondary hypothesis, BH4 in isolation was not associated with any macrovascular effect. Acetylcholine was associated with a vasoconstrictor effect whether given alone or in combination with BH4. Of note however, a trend was seen in the stent group when comparing the vascular effects of Ach with those of the combination of Ach and BH4, with the % change in the proximal vessel constricting more with the combined infusion (p=0.07).


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  		Table 2 Effects of study drug infusions on vessel diameter in non-stent group

 

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  		Table 3 Effects of study drug infusions on vessel diameter in stent group

 
3.4 Effects on coronary blood flow
The effects on coronary blood flow of Ach, BH4 and combination of Ach and BH4 are shown for both the non-stent and stent group in Tables 4 and 5Go respectively. A representation of exact results of Ach 10–7 and 10–6 doses is also shown in Fig. 1. As expected, significant changes in blood flow were observed when intracoronary Ach was administered. This effect was not altered by a combined BH4, Ach infusion. Regarding our primary hypothesis, no significant effect was observed on % change in CBF when comparing maximal Ach response compared to the maximal response of the co-infusion of BH4 and Ach (no-stent group p=.84; stent group p=.39). Likewise, regarding our secondary hypothesis evaluating effects of isolated BH4 intracoronary infusion, not significant effect was seen. No significant changes in heart rate or blood pressure were seen across the infusion protocols.


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  		Table 4 Effects of study drug infusions on coronary blood flow in non-stent group

 

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  		Table 5 Effects of study drug infusions on coronary blood flow in stent group

 

Figure 1
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  		Fig. 1 Effects of sequential intracoronary infusions.

 
3.5 Comparison between non-stent and stent group
While not a pre-defined focus of our study it is enticing to evaluate potential differences between these two groups. The vessels tended to be smaller in the stent group compared to non-stent group which may have reflected associated atherosclerotic disease. The resting flow in the stent group was significantly less (p=0.01) than that observed in the non-stent cohort (23±10 ml/min compared to 37±24 ml/min). This observation does not relate to a significant attenuation in microvascular dynamic function as no difference was observed in Ach response or in CFVR between these 2 groups.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This present study was unable to demonstrate a beneficial effect of acute tetrahydrobiopterin replacement in human coronary microvascular function in patients with non-critical coronary artery disease or following PCI.

Tetrahydrobiopterin is an important co-factor in the formation of NOS. Without this co-factor NOS becomes ‘un-coupled— and can generate reactive oxygen species rather than NO, further reducing NO bioavailability [10–13]. While tetrahydrobiopterin has had beneficial effects in human studies evaluating peripheral measures of endothelial function [14–17], only a few studies to date have evaluated its effects in the human coronary macro and microvascular circulation. Setoguchi et al. [19] demonstrated an improvement in acetylcholine-mediated coronary blood flow in 15 patients without angiographic evidence of coronary disease when evaluating a co-infusion of Ach and BH4. There was an eightfold increase in the concentration of BH4 used in this study compared to our study. This cohort of patients, as predefined, had no coronary disease and minimal risk factors when compared to our cohort of patients. This study however, divided patients into ‘normal’ or ‘diminished’ coronary endothelial function and only evaluated effects in the later group. Maier and co-workers [18] evaluated in the human coronary circulation the effects of a co-infusion of BH4 and Ach. This study was closer aligned to ours in regards to the dose of BH4 used. Once again however, this study pre-selected patients with severe coronary endothelial dysfunction as vasodilator response to Ach was excluded from the analysis, hence not surprisingly coronary blood flow responses to Ach were markedly suppressed in this study when compared to the responses seen in our cohort. Finally Fukuda et al. [28], likewise showed in patients with impaired microvascular coronary endothelial function, that co-infusion of Ach and BH4 improved coronary blood flow compared to Ach alone. This mainly reflected the fact that hypercholesterolemic patients, a cohort known to have significant coronary endothelial dysfunction [29,30], were evaluated. All three of these in vivo human coronary studies pre-selected patients with ‘diminished’ microvascular coronary endothelial dysfunction when evaluating the effects of dual intracoronary infusion of Ach and BH4. As no control groups were evaluated with comparative macro or microvascular endothelial function, the data from these studies potentially may have suffered from ‘regression to the mean— and hence interpreting their findings should be done with caution.

In our cohort, patients were not divided into modest and severe endothelial dysfunction and furthermore randomized control patients were also evaluated. No significant effect on coronary endothelial function was observed when comparing dual Ach and BH4 infusions with Ach alone. The explanation of these findings may be multifactorial, particularly in the post stent group. It is possible that our results were effected by including patients with ‘preserved’ endothelial function, as previous studies have shown minimal impact of BH4 in this cohort [17–19,28]. It has been well established that one of the effects of ischemia/reperfusion injury is impairment of endothelial function [31,32]. In the setting of PCI this endothelial dysfunction has been linked to diverse adverse findings such as no-reflow [33] as well as in-stent restenosis [34]. While BH4 was previously shown to improve endothelial dysfunction following ischemia/reperfusion in vitro, this had not been previously assessed in humans. Acknowledging our negative findings, exogenously administered BH4 may still impact on coronary endothelial function, however possibly at higher doses. Despite previous positive results evaluating BH4 in humans, in vitro cell culture systems support relatively minimal cellular uptake of BH4 compared to its precursor, sepiapterin [35]. Furthermore, evidence now supports that BH4 itself can be oxidized with the potential production of detrimental byproducts. Vascular disease and its associated risk factors are associated with an increase in oxidative stress and thus the appropriate substrate for the oxidation of BH4 to BH2 [36]. The likely culprit for oxidation of BH4 is peroxynitrite with both in vitro [37] and in vivo [38] evidence indicating that peroxynitrite can oxidize BH4 within minutes, at physiologically relevant concentrations and lead directly to NOS uncoupling and endothelial dysfunction. Oxidation may not only directly reduce BH4 bioavailability but the oxidation itself produces BH2, which may compete with BH4 for binding to NOS [39]. In addition, as a cofactor for aromatic amino acid hydroxylases, BH4 may also stimulate biosynthesis of catecholamines [40]. These above listed mechanisms, may in part explain some of the vasoconstrictive effects seen with the BH4/Ach combination infusion in our stent group.

While the major vasoactive mediator of this endothelial dysfunction has been assumed to be NO, our data would support that other factors may also play an important role. Studies to date support the fact that potassium channels may play an important role in microvascular dysfunction. The potassium channel opener nicorandil has been shown to be more effective than isosorbide dinitrate in restoring coronary flow following primary angioplasty [41]. Furthermore, endothelin-1 may be actively involved as endothelin receptor antagonists have been shown to be beneficial in reducing no-reflow following left anterior descending artery occlusion in anesthetized dogs [42]. It is also possible that the microvascular dysfunction seen post stenting is related to basal as opposed to stimulated function. Indeed our data would support this observation, as a significant reduction was observed in resting basal coronary basal flow rate in the stent group compared to the non-stent group. This may be explained by distal showering of atherothrombotic debris during PCI.

4.1 Limitations
Our study has limitations mainly related to a lack of mechanistic understanding of these findings. It is possible that the effects of BH4 are not apparent at rest [43]. While coronary CFVR did not differ between control and active study patients, it may have been interesting to evaluate CFVR at baseline as well as following co-infusion of Ach and BH4. Acetylcholine while evaluating endothelial function, does not exclusively test eNOS activity and hence results may have been impacted by Ach mediated effects on prostacyclin [44] and endothelial derived hyperpolarizing factor [45]. Biopterin levels may have enabled us to better understand the in-vivo levels of this drug throughout the protocol as well as whether the benefit is only seen in patients with an initial biopterin deficiency. While notoriously variable, a measure of redox stress as well as nitrotyrosine the ‘footprint’ of peroxynitrite, would enable us a better understanding of the potential oxidation of BH4 and subsequent culprits. Furthermore while other studies have shown benefits with BH4 infusions, with concerns regarding cellular uptake and potential oxidation, we may have been better served by considering sepiapterin in evaluating potential coronary dynamic effects of this substance. Finally it is possible that, in the stent group, the low dose intravenous nitroglycerin infusion may have obscured any subtle changes in this group. This infusion was commenced regarding a potential increase in paradoxical vasoconstriction associated with Ach following stenting. This finding may have been overcome by administering a purely vasodilating endothelial dependent substance such as substance P.

4.2 Conclusions
In this study in humans with native non-critical coronary artery disease or following PCI, demonstrable coronary microvascular endothelial function was not improved by co-administration of Ach and BH4.


   Acknowledgements
 
We are grateful to the staff of the Foothills Interventional Cardiology Research group and the Foothills Medical Centre Cardiovascular Laboratory for their assistance, without whom this study would not have been possible. Dr. Subodh Verma is acknowledged as a co-author for assistance with studies evaluating vasoactive effectiveness of BH4 dose.


   Notes
 
1 Current address: Cardiovascular Investigation Unit, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia, 5000. Tel.: +61 8 8222 5608; fax: +61 8 8222 2454. Back

* Dr. Matthew Worthley was supported by a Royal Australasian College of Physician traveling fellowship. Dr. Anderson is a Senior Scholar of the Alberta Heritage Foundation for Medical Research (Edmonton, AB). The study was funded by the Heart and Stroke Foundation of Alberta (TJA). Back


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

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