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Am J Physiol Heart Circ Physiol 290: H1182-H1189, 2006. First published November 4, 2005; doi:10.1152/ajpheart.00280.2005
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Absence of histamine-induced nitric oxide release in the human radial artery: implications for vasospasm of coronary artery bypass vessels

Barbara E. Stähli,1,* Helen Greutert,1,* Shaoping Mei,2 Philipp Graf,2 Karin Frischknecht,1 Mario Stalder,2 Lars Englberger,2 Andreas Künzli,3 Leo Schärer,4 Thomas F. Lüscher,1 Thierry P. Carrel,2 and Felix C. Tanner1

1Cardiovascular Research, Physiology Institute and Center for Integrative Human Physiology, University of Zürich, and Department of Cardiology, Cardiovascular Center, University Hospital, Zürich; 2Cardiovascular Research, Department of Clinical Research, University of Bern and Clinic for Cardiovascular Surgery, University Hospital, Bern; 3Clinic for Cardiovascular Surgery, Cardiovascular Center, University Hospital, Zürich; and 4Dermatology, University Hospital, Zürich, Switzerland

Submitted 22 March 2005 ; accepted in final form 12 October 2005


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Radial artery (RA) bypass grafts can develop severe vasospasm. As histamine is known to induce vasospasm, its effect on RA was assessed compared with the classic bypass vessels internal mammary artery (MA) and saphenous vein (SV). The vessels were examined in organ chambers for isometric tension recording. Histamine induced contractions on baseline; the sensitivity was higher in RA and SV than MA. After precontraction with norepinephrine, histamine did not evoke relaxations of RA but induced relaxations of MA and less of SV at lower concentrations; it induced contractions at higher concentrations, reaching similar levels in all three vessels. Indomethacin did not affect the response of MA and RA but potentiated relaxations and reduced contractions of SV. Endothelium removal, N{omega}-nitro-L-arginine methyl ester (L-NAME), or the H2-receptor blocker cimetidine did not affect the response of RA, but inhibited relaxations and enhanced contractions in MA and inhibited relaxations in SV; in the latter, only L-NAME enhanced contractions. Real-time PCR detected much lower expression of endothelial H2-receptor in RA than MA or SV. Western blots revealed similar endothelial nitric oxide (NO) synthase expression in all three vessels. Relaxations to acetylcholine were identical in RA and MA. Thus histamine releases NO by activating the endothelial H2-receptor, the expression of which is much lower in RA than MA or SV. H2-receptor activation also releases prostaglandins in SV, partially antagonizing NO. The lack of histamine-induced NO production represents a possible mechanism of RA vasospasm.

endothelium-dependent relaxation; heterogeneity; receptor

CORONARY ARTERY DISEASE can be treated by coronary artery bypass grafting (CABG). Internal mammary artery (MA) and saphenous vein (SV) are routinely used conduits; however, long-term patency rates of MA are higher than those of SV (15, 21). The radial artery (RA) has become an alternative arterial graft as its long-term patency is expected to be superior to that of SV as well (1, 2). A problem is, however, that the RA can develop severe vasospasm; a case of ventricular fibrillation due to RA spasm has been reported (10, 20).

Histamine has been implicated in the pathogenesis of vasospasm. Indeed, histamine stores are present in hyperreactive human coronary arteries, and mast cell infiltration has been observed in spastic human coronary arteries as well as in a rabbit vein graft model (6, 9, 17). Consistent with these observations, histamine can induce vasospasm when it is infused into coronary arteries of patients with variant angina (28). Moreover, acute allergic reactions, which are associated with very high histamine plasma levels, can evoke coronary artery spasm, leading to angina pectoris, myocardial infarction, and ventricular fibrillation (3, 19).

The endothelium releases nitric oxide (NO), which evokes relaxation of vascular smooth muscle cells and inhibition of platelet aggregation (36). NO is a crucial protective factor, as vascular smooth muscle cells and platelets are involved in the pathogenesis of both vasospasm and bypass graft disease. Moreover, NO is a major modulator of histamine action. Contractions to the amine can indeed be reduced by concomitant release of NO in several vascular beds (22). As platelets are a source of histamine, inhibition of platelet aggregation by NO has an additional protective effect (25).

This study was performed to examine 1) whether histamine induces endothelium-dependent relaxations of RA, 2) whether there are differences in RA compared with MA or SV, and 3) whether the pattern of these differences is consistent with the propensity to vasospasm.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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Materials. Vessel segments were collected from patients undergoing CABG, which was approved by the institutional Committee on Human Research. Written informed consent was obtained from every patient. All vessels were isolated from their original location; hence, arterialization of veins can be excluded. Cardiovascular risk factors and current drug treatment of the patients from whom the vessels were collected are summarized in Table 1. No significant difference between MA, RA, and SV was observed for any risk factor or drug treatment. Norepinephrine, acetylcholine, bradykinin, histamine, cimetidine, indomethacin, and N{omega}-nitro-L-arginine methyl ester (L-NAME) were from Sigma Chemical (St. Louis, MO). Concentrations are indicated as final molar concentration in the organ chambers. All drugs were prepared daily and dissolved in distilled water except for indomethacin, which was dissolved in 28 mmol/l Na2CO3.


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  		Table 1. Cardiovascular risk factor and drug treatment of patients from whom vessels were collected

 
Organ chambers. Vessel segments were placed in sterile PBS (4°) immediately after excision. Surrounding adventitial tissue was carefully removed under the dissection microscope to avoid any effect of adrenergic innervation in the organ chamber experiments. Then vessels were cut into 3-mm-rings and suspended in organ chambers for isometric tension recording (System 700 MO, Danish Myo Technology A/S, Aarhus, Denmark) as described previously (33). Rings were progressively stretched until a maximal contraction to 100 mmol/l KCl was achieved. The presence of the endothelium was tested in norepinephrine-precontracted rings by addition of 10–5 mol/l acetylcholine for MA or RA and 10–5 mol/l bradykinin for SV; rings exhibiting more than 50% relaxation were considered to possess a functional endothelial layer (33). For some experiments, the endothelium was removed by gently rubbing the intimal surface with a cotton swab as described (33). Endothelial denudation was confirmed in norepinephrine-precontracted rings by the absence of a relaxation to 10–5 mol/l acetylcholine for MA or RA and 10–5 mol/l bradykinin for SV (33). The effect of L-NAME, indomethacin, pyrilamine, and cimetidine was also examined in vessels precontracted with norepinephrine.

Real-time PCR. The adventitia was carefully removed from all the vessels. For RNA isolation, 30 mg of tissue were snap-frozen and pulverized. Total RNA was extracted by the RNeasy Mini RNA Kit (Quiagen, Basel, Switzerland). RNA yield and purity were determined by spectrophotometer (Spectronic 601, Milton Roy, Ivyland, PA). The reverse transcription reaction followed a standard protocol using 0.2 µg total cellular RNA; the reaction mixture was incubated at 37° for 90 min and then stored at –20° until use. Primers and TaqMan probes for H2-receptor and CD31 were designed using Primer Express (Applied Biosystems, Rotkreuz, Switzerland) and obtained from Microsynth (Balgach, Switzerland). Sequences of primers and probes are described in Table 2. 6-Carboxy-fluorescein (FAM) was used as reporter and 6-carboxy-tetramethyl-rhodamine (TAMRA) as quencher. The two-step RT-PCR amplification was performed using the TaqMan Universal PCR Master Mix (Applied Biosystems), primers (300 nmol/l each), probes (200 nmol/l each), and RNA (20, 40, or 80 ng). The reaction mixture was preheated at 50° for 2 min and then kept at 95° for 10 min (activation), followed by 40 cycles at 95° for 15 s (denaturation) and 60° for 1 min (annealing and extension). The fluorescence signal was monitored real-time using the laser detector of the ABI Prism 7700 Sequence Detection System (Applied Biosystems) (4). Expression of 18S-rRNA was used as internal control (5). As the presence of some remaining adventitial tissue could not be excluded, the CT value (PCR cycle number at the threshold value) of each vessel was subtracted from the CT value of vascular smooth muscle cells; the latter was obtained by performing the real-time PCR analysis with isolated vascular smooth muscle cells from five patients for each type of vessel. The identity of all these cells was confirmed as vascular smooth muscle cells by immunofluorescent staining for smooth muscle {alpha}-actin. This difference between the CT value of a vessel and the CT value of the corresponding vascular smooth muscle cells is defined as the {Delta}CT value.


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  		Table 2. Primers for real-time PCR analysis of histamine H2-receptor expression

 
Western blots. Vessel segments were cleaned of loose connective tissue and lysed in buffer as described previously (34). Cellular debris was removed by centrifugation at 16,000 g for 10 min, and protein concentration was determined by the Bio-Rad assay (Bio-Rad Laboratories, Munich, Germany). One hundred micrograms of protein were loaded per lane, resolved by SDS-PAGE under reducing conditions, blotted on Immobilon-P transfer membranes (Millipore, Bedford, MA), and incubated with antibodies against endothelial NO synthase (eNOS) (Santa Cruz Biotechnology; no. 654; 1:1,000), CD31 (R&D Systems; no. BBA7; 1:500), or {alpha}-tubulin (Sigma; no. T5168; 1:20,000). Proteins were detected with a horseradish peroxidase-coupled secondary antibody (ECL, Amersham, Buckinghamshire, UK) (34).

Data analysis. Concentration-response curves were analyzed using GraphPad Prism software (GraphPad Software, San Diego, CA). Results are reported as means ± SE with n designating the number of patients. Statistical analysis was performed with unpaired Student's t-test or ANOVA as appropriate. Patient characteristics were compared in between the different groups by the {chi}2-test. A P value <0.05 indicates a significant difference.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
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Response to histamine. In vessels without precontraction, histamine induced contractions, the sensitivity of which was higher in RA and SV than MA [n = 7, P = not significant (NS) for RA vs. SV; P < 0.005 for MA vs. RA; and P < 0.05 for MA vs. SV; Fig. 1]. In the presence of 3 x 10–4 mol/l L-NAME, the increase in sensitivity to histamine was less pronounced in RA and SV than MA (n = 6–7, P = NS vs. control for all vessels; Fig. 1). The numerical data of the responses to histamine are summarized in Table 3.


Figure 1
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  		Fig. 1. Effect of N{omega}-nitro-L-arginine methyl ester (L-NAME) on the response to histamine of human coronary artery bypass vessels without precontraction.

 

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  		Table 3. Responses to histamine in internal mammary artery, radial artery, and saphenous vein

 
After precontraction with norepinephrine, histamine did not evoke relaxations of RA but induced relaxations of MA and less of SV at lower concentrations (n = 6–8; Fig. 2; Table 3). Histamine caused contractions at higher concentrations, reaching similar levels in all three vessels (P = NS). The competitive antagonist of NO formation, L-NAME (3 x 10–4 mol/l), did not affect the response of RA (n = 5, P = NS; Fig. 2; Table 3). In contrast, L-NAME blunted relaxations in MA (n = 7–8, P < 0.0001); moreover, it increased sensitivity and enhanced maximal contractions (P < 0.005; Fig. 2; Table 3). Similarly, L-NAME blunted relaxations and unmasked contractions in SV (n = 6–8, P < 0.01); moreover, it enhanced maximal contractions (P < 0.01; Fig. 2; Table 3).


Figure 2
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  		Fig. 2. Effect of L-NAME and endothelial removal on the response to histamine of human radial artery (RA), internal mammary artery (MA), and saphenous vein (SV) precontracted with norepinephrine.

 
Mechanical denudation of the endothelium did not affect the response of precontracted RA to histamine (n = 5, P = NS; Fig. 2; Table 3). In contrast, removal of the endothelium abrogated relaxations of MA and increased sensitivity as well as maximal contractions to histamine (n = 5–8, P < 0.005; Fig. 2; Table 3). Similarly, SV without endothelium exhibited blunted relaxations, while maximal contractions to histamine were only slightly enhanced (n = 6, P = NS; Fig. 2; Table 3). In all three vessels, maximal contractions to histamine in the presence of L-NAME did not differ significantly from those without endothelium (P = NS; Fig. 2; Table 3). In RA and SV, the sensitivity to histamine was comparable in L-NAME-treated vessels and those without endothelium (P = NS; Fig. 2; Table 3); in MA, L-NAME increased the sensitivity to the amine to a lower extent than endothelial denudation (P < 0.05; Fig. 2; Table 3).

In MA and RA, the cyclooxygenase inhibitor indomethacin (10–5 mol/l) did not affect the response to histamine (n = 9, P = NS; Fig. 3). In SV, however, it potentiated relaxations to histamine (n = 9–12, P < 0.05, Fig. 3; Table 3) and reduced contractions to the amine (P = 0.10; Fig. 3; Table 3). In the presence of indomethacin, relaxations to histamine did not differ anymore between MA and SV (maximal relaxation: P < 0.05 for MA vs. SV without indomethacin, P = NS for MA vs. SV with indomethacin).


Figure 3
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  		Fig. 3. Effect of the cyclooxygenase inhibitor indomethacin on the response to histamine of human radial artery, internal mammary artery, and saphenous vein precontracted with norepinephrine.

 
Histamine H1-receptor. The histamine H1-receptor blocker pyrilamine (10–6 mol/l) blunted contractions of all three vessels. Maximal contraction of RA was 79.10 ± 13.82% under control conditions compared with 17.56 ± 8.91% in the presence of pyrilamine (n = 5; P < 0.01; Fig. 4; Table 3). A weak relaxation occurring at high histamine concentrations (3 x 10–6 mol/l to 1 x 10–4 mol/l) was unmasked in the presence of pyrilamine; this effect was maximal at 10–4 mol/l, reaching 9.43 ± 2.41%. Maximal contraction of MA was 106.25 ± 18.95% under control conditions compared with –34.36 ± 5.10% in the presence of pyrilamine (n = 5; P < 0.0001; Fig. 4; Table 3). Maximal contraction of SV was 69.62 ± 21.67% under control conditions compared with –29.60 ± 9.25% in the presence of pyrilamine (n = 5; P < 0.005; Fig. 4).


Figure 4
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  		Fig. 4. Effect of the H1-receptor blocker pyrilamine on the response to histamine of human radial artery, internal mammary artery, and saphenous vein precontracted with norepinephrine.

 
Histamine H2-receptor. The histamine H2-receptor blocker cimetidine (10–6 mol/l) did not affect the response of RA (P = NS; Fig. 5; Table 3). In contrast, cimetidine blunted relaxations in MA (n = 7–8, P = 0.0005); moreover, it increased sensitivity (P < 0.005) and enhanced maximal contractions (P < 0.001; Fig. 5). In SV, cimetidine inhibited relaxations (maximal relaxation: –12.99 ± 3.57% without cimetidine, 0.06 ± 0.67% with cimetidine, n = 5–8, P < 0.05); unlike L-NAME, however, it did not significantly alter contractions (P = NS; Fig. 5; Table 3). Addition of cimetidine did not alter vascular tone by itself in any of the vessels examined (P = NS; data not shown).


Figure 5
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  		Fig. 5. Effect of the H2-receptor blocker cimetidine on the response to histamine of human radial artery, internal mammary artery, and saphenous vein precontracted with norepinephrine.

 
Histamine H2-receptor expression was assessed by real-time PCR. For each vessel, the presence of the endothelium was confirmed by performing a relaxation to acetylcholine (10–5 mol/l) for MA and RA or to bradykinin (10–5 mol/l) for SV (data now shown). Removal of the endothelium was confirmed by the absence of a real-time PCR signal for CD31 (data not shown). The {Delta}CT signal of vessels with endothelium was subtracted from that of vessels without. The real-time PCR analysis revealed that endothelial H2-receptor expression in RA was low ({Delta}CT: 0.62 ± 0.76), while expression was readily detected in MA ({Delta}CT: 6.27 ± 1.00) and SV ({Delta}CT: 7.75 ± 1.92; P < 0.05 for RA vs. MA, P < 0.01 for RA vs. SV, P = NS for MA vs. SV; n = 6–7; Fig. 6).


Figure 6
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  		Fig. 6. Real-time PCR analysis of histamine H2-receptor expression in human radial artery, internal mammary artery, and saphenous vein. Vessels with endothelium were compared with those without. CT, cycle number at the threshold value; {Delta}CT, CTvessel – CTvascular smooth muscle. A: mean values and SEs from all experiments. B: representative original recordings of vessels with endothelium. Dashed line represents the threshold. {Delta}Rn, emission intensity of reporter dye/emission intensity of reference dye.

 
Endothelial NO synthase. Expression of endothelial NO synthase (eNOS) was determined by Western blot analysis. As the thickness of the tunica media differs in the three vessels, expression of the endothelial marker CD31 was assessed as well, which permitted one to relate the signal for eNOS to that for CD31. The blots demonstrated that eNOS was expressed at a similar level in RA compared with MA and SV (Fig. 7). Consistent with this observation, endothelium-dependent relaxations to acetylcholine, which are mediated by NO, were comparable in RA and MA. Indeed, neither the maximal relaxation to acetylcholine nor the EC50 of the response differed between the two vessels (P = NS; Fig. 8).


Figure 7
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  		Fig. 7. Western blot analysis of endothelial nitric oxide synthase (eNOS) in human radial artery, internal mammary artery, and saphenous vein (SV). To correct for differences in protein from endothelium vs. tunica media, the eNOS signal was related to that for CD31. A: mean values and SEs of densitometric analysis from all experiments. B: representative original blots. {alpha}Tub, {alpha}-tubulin.

 

Figure 8
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  		Fig. 8. Endothelium-dependent relaxations to acetylcholine in human radial artery and internal mammary artery precontracted with norepinephrine (NE).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
This study demonstrates that histamine induces only contractions in the RA, while it evokes relaxations at lower concentrations and contractions at higher concentrations in MA and SV. The contractions are mediated by the H1-receptor in all three vessels. The relaxations in MA and SV appear to be caused by NO release due to activation of the endothelial H2-receptor; the lower relaxations in SV than MA are related to concomitant release of vasoconstrictive prostaglandins, leading to partial counteraction of relaxations in the vein. The absence of significant relaxations in RA is related to the lack of NO production due to minimal endothelial expression of the histamine H2-receptor in this vessel compared with MA and SV, while expression of the NO-generating enzyme eNOS is similar in all three vessels (Fig. 9).


Figure 9
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  		Fig. 9. Schematic representation of the response to histamine in human coronary artery bypass vessels: internal mammary artery, radial artery, and saphenous vein. H1, histamine H1-receptor; H2, histamine H2-receptor; PG, prostaglandins.

 
Although the same histamine concentrations were used in all three vessels, no relaxation to histamine was observed in RA. This response was surprising because acetylcholine elicited potent endothelium-dependent relaxations of this vessel; indeed, relaxations reached a similar level in RA and MA. Consistent with this finding, expression of eNOS in RA and MA was similar as well. In line with our observations, a previous study revealed similar endothelium-dependent relaxations to acetylcholine in RA and MA; furthermore, these relaxations were shown to be mediated by NO (13, 14). Thus the NO pathway per se cannot account for the absence of endothelium-dependent relaxations of RA in response to histamine; the pathway rather does not seem to be activated in this vessel.

The different release of NO in RA vs. MA or SV on stimulation with histamine may be due to a difference at the receptor level. Histamine-induced relaxations in MA and SV were blunted by L-NAME as well as by removal of the endothelium, confirming that the relaxations are mediated by endothelium-derived NO. The relaxations were also blocked by cimetidine, which revealed that the release of NO is mediated by activation of the endothelial H2-receptor. Indeed, the effect of L-NAME vs. cimetidine on the response to histamine was absolutely identical. Consistent with these observations, the H2-receptor mediates vasodilation in rabbit renal arteries as well as in the canine and human coronary circulation (8, 26, 40). Moreover, cimetidine augments the histamine-induced vasoconstriction at sites of coronary artery spasm in a pig model, and it can induce coronary artery spasm in patients with vasospastic angina (30–32). Therefore, endothelial expression of the H2-receptor was assessed by real-time PCR. Similar expression of the H2-receptor on the endothelium of MA and SV was confirmed, while RNA expression of this receptor was barely detectable in RA. These data demonstrate that the H2-receptor is expressed on the endothelium of MA and SV, while expression is minimal, if present at all, on the endothelium of RA. Although the RNA level does not always correlate well with the protein level, mRNA expression of the endothelial H2-receptor was barely detectable in the RA, and a significant protein expression of this receptor would not be expected under these circumstances. Moreover, posttranscriptional regulation of H2-receptor expression has not been observed so far. Because pharmacological blockade of this receptor is sufficient to induce vasospasm in patients with variant angina, its absence in RA may indeed be important for the pathogenesis of vasospasm in this vessel as well.

Heterogeneous distribution of receptors in the vascular system is a well-known observation; it is described for {alpha}-adrenoceptors (18), beta-adrenoceptors (29), muscarinic receptors (11), and others (16). Indeed, vessels from different anatomical locations can show different responses to the same mediator (7, 38, 39). Heterogeneous actions due to heterogeneous receptor expression in different types of arteries are also documented for histamine (35). Hence, the differential pattern of histamine H2-receptor expression in RA vs. MA and SV seems to be a consequence of the functional heterogeneity of the vascular system.

Blockade of the H1-receptor blunted contractions to histamine in RA, MA, and SV, indicating that activation of this receptor induces contractions. Consistently, H1-receptor stimulation induces vasoconstriction in rabbit renal arteries as well as in the canine and human coronary circulation (8, 26, 40). The small relaxation of RA at high concentrations of histamine in the presence of pyrilamine may be related to release of low amounts of NO, as the presence of a low number of endothelial H2-receptors cannot be excluded by the real-time PCR analysis. However, because of the absence of any effect of L-NAME and cimetidine on the response to histamine, this interpretation is not probable. Endothelium-derived hyperpolarizing factor (EDHF) may play a role; indeed, EDHF is involved in the regulation of vascular tone in human coronary artery bypass vessels, and histamine induces the formation of this factor (12, 14). Likewise, a contribution of EDHF to the relaxation of MA and SV occurring in the presence of pyrilamine cannot be excluded. The relaxation to histamine in the presence of pyrilamine was shifted to the right in the MA and to a lesser extent the SV. This observation is probably related to a nonspecific effect of pyrilamine. Indeed, histamine H1-receptor antagonists can exert effects not related to receptor binding (23); they can bind to secondary receptor sites (27), can be taken up in cells (24), and can affect signal transduction mechanisms as well as cellular cytokine release (23).

Indomethacin did not affect the response to histamine in MA and RA, indicating that prostaglandins do not play a role in these vessels after stimulation with histamine. However, release of vasoconstrictive prostaglandins was observed in SV, as indomethacin unmasked relaxations to histamine so that the latter reached a similar level as those in MA. Hence, the relaxations to histamine in MA are fully mediated by NO, while those in SV are partially counterregulated by concomitantly formed vasoconstrictive prostaglandins. This effect of indomethacin in the SV is consistent with previous data demonstrating that indomethacin and a thromboxane A2/endoperoxide receptor antagonist similarly modulated the response to histamine by unmasking endothelium-dependent relaxations (37). Release of prostaglandins may also account for the enhanced contractions of SV primarily to low concentrations of histamine in the presence of L-NAME. As this response was not observed in vessels without endothelium, these prostaglandins are derived from the latter. Consistent with this interpretation, maximal contractions to histamine were slightly higher in the presence of L-NAME compared with vessels without endothelium. Furthermore, as the contractions of SV in the presence of cimetidine occurred at higher histamine concentrations than those in the presence of L-NAME, the release of prostaglandins may be related to activation of the H2-receptor. Alternatively, NO production may not have been inhibited completely by cimetidine; however, this is not a probable explanation, as the action of cimetidine and L-NAME was identical in the MA.

The absence of NO production in the RA upon stimulation with histamine may have major clinical implications. Indeed, histamine has been shown to induce vasospasm, and the RA is not protected from this effect at all. As NO does not only induce relaxation, but also inhibits platelet aggregation, the RA may have a higher propensity to thrombus formation at sites of vasospasm. Because platelets are a source of histamine, this enhanced platelet-vessel wall interaction may be even more important for RA graft function. Hence, maximal inhibition of platelet aggregation may prove beneficial for this graft. Because NO impairs monocyte adhesion as well as proliferation and migration of vascular smooth muscle cells, it may not only protect from vasospasm but also from bypass graft disease. Mast cells and histamine are indeed found in both atherosclerotic vessels and bypass grafts; therefore, the absence of NO production in the RA on stimulation with histamine may be relevant for the pathogenesis of bypass graft disease as well.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by Swiss National Science Foundation (Grant Nr. 3200B0–102232/1), Swiss Heart Foundation, Novartis Foundation, and Schweizerische Rentenanstalt.


   ACKNOWLEDGMENTS
 
We thank all the staff of the Clinic for Cardiovascular Surgery, University Hospital Bern and University Hospital Zürich, involved in collection of tissue specimens.


   FOOTNOTES
 

Address for reprint requests and other correspondence: F. C. Tanner, Cardiovascular Research, Physiology Institute, Univ. of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland (e-mail: felix.tanner{at}access.unizh.ch)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

* Both authors contributed equally to this study. Back


   REFERENCES
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