Ann Thorac Surg 1998;66:455-461
© 1998 The Society of Thoracic Surgeons
Original articles: cardiovascular
Mechanical properties of human saphenous veins from normotensive and hypertensive patients
Veronica Milesi, PhDa,
Alejandro Rebolledo, BSca,
Felix Ayala Paredes, MDa,b,
Nora Sanz, MDb,
Juan Tommasi, MDb,
Gustavo J. Rinaldi, MDa,
Angela O. Grassi, MDa
a Department of Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata, Argentina
b Department of Hospital San Juan de Dios, Ministerio de Salud de la Provincia de Buenos Aires, La Plata, Argentina
Accepted for publication March 17, 1998.
Address reprint requests to Dr Grassi, CC 219, Correo Central, 1900 La Plata, Argentina
e-mail: (rinaldi{at}nahuel.biol.unlp.edu.ar)
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Abstract
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Background. Different reactivities of saphenous vein grafts in hypertensive and normotensive patients could lead to differences in the postoperative patency of the grafts.
Methods. In saphenous vein rings isolated from remnants of aorta-coronary grafts obtained from hypertensive and normotensive patients we studied the length-tension relationship; response to high levels of potassium, norepinephrine, and epinephrine; and relaxation in response to calcium deprivation.
Results. The rings from hypertensive patients were stiffer and developed more force (grams force/grams weight) than the rings from normotensive subjects to 80 mmol/L potassium (59 ± 16 versus 25 ± 5, p < 0.05) and to 1 µmol/L norepinephrine (61 ± 8 versus 36 ± 7, p < 0.05), but not to 10 µmol/L epinephrine (57 ± 11 and 54 ± 11; not significant). The rings from hypertensive patients relaxed more slowly than those of the normotensive subjects in a calcium-free medium (time to half-relaxation of 976 ± 180 versus 548 ± 81 seconds; p < 0.05).
Conclusions. The saphenous vein from hypertensive patients is less distensible, slower to relax, and more reactive to at least two agonists. These differences could influence the graft’s patency and the clinical outcome.
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Introduction
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Although human saphenous vein (HSV) grafts have generally been depicted as inert conduits devoid of vasomotion in vivo [1], other studies provide different evidence. Vasospasm of implanted HSVs has been reported in both short-term [2] and long-term [3] studies, suggesting that implanted HSV is capable of contractions strong enough to decrease the bypass flow. Reactivity of HSV to a variety of agents has also been tested in vitro [4, 5] and in a recent study it was demonstrated that the isolated HSV is also reactive at arterial perfusion pressures [6].
Altered vascular reactivity is one of the key elements in established hypertension in both animal models and in humans [7]. Altered reactivity in veins has even been proposed as occurring earlier than in arteries during the development of this disease [8]. Different reactivities of HSVs between normotensive and hypertensive patients could lead to different contractile behaviors of the implanted segments, with potentially important consequences in the postoperative period and in the long-term patency of the grafts.
In this study we report active and passive differences between HSV segments used for aorta-coronary bypass in normotensive and hypertensive patients.
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Material and methods
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The HSVs employed in this study were obtained from patients undergoing primary coronary artery bypass grafting at the Service of Cardiothoracic Surgery of the Hospital San Juan de Dios, Ministerio de Salud de la Provincia de Buenos Aires, La Plata, Argentina. The preparations were classified as surgical specimens and thus were exempted from patient consent requirements. The patients from whom the veins were obtained were classified as hypertensive (blood pressure exceeding 140/90 mm Hg) or normotensive based on their clinical records. Existing antihypertensive treatment was discontinued 1 week before the operation. Clinical data of the patients are shown in Table 1.
After the bypass operation was finished the remnant venous segments, which belonged to the thigh section of the vessel, were transported to our laboratory in a special culture medium or in a 0.9% NaCl solution. In either case, the container was kept in ice. The veins were studied within 24 hours of their arrival at the laboratory. In all, 64 specimens were obtained, of which 39 belonged to HSVs of normotensive patients and 25 to HSVs of hypertensive patients.
The day of the study the veins were placed in a Petri dish filled with oxygenated Krebs solution, cleaned of adherent connective tissue, and cut into rings 3 to 4 mm wide. Special care was taken in not damaging the endothelial layer or overdistending the vessel during this procedure. Contractile responses were carried out in a water-jacketed organ bath filled with a modified Krebs solution of the following composition (in mmol/L): NaCl, 130, KCl, 4.7, Na2HPO4, 1.17, MgSO4, 1.16, HCO3Na, 24.0, CaCl2, 1.6, and glucose, 11.0. The organ bath was kept at 37°C and bubbled with a mixture of 5% CO2 and 95% O2, giving a pH of 7.40. The ring was gently suspended between two stainless steel wires that could be separated with a micrometer to achieve the desired length or passive force. The lower wire was fixed to a vertical plastic rod immersed in the organ bath, and the upper one was rigidly vinculated to a force transducer (Grass FT.03D, West Warwick, RI, or Letica TRI-201, Barcelona, Spain). The output of the transducer was amplified and fed into an analog-digital board (DT16EZ; Data Translation, Inc, Marlboro, MA) mounted in a desktop computer. Online recordings and files were obtained with an appropriated software (Labtech Notebook Pro; Laboratory Technology Corp, Wilmington, MA) for later processing.
Passive studies
After placing the ring in the organ bath, the steel wires were separated until the first increment in force was detected, and this was regarded as the maximal unstressed length (L0). The diameter of the rings before applying tension was 3.27 ± 0.52 mm in hypertensive patients (n = 6) and 4.25 ± 0.40 mm in normotensive subjects (n = 9). Further stepwise length increments were imposed, and at each length (L) the corresponding force was recorded. These stress-strain curves were continued up to an L/L0 of approximately 1.6. Stress was expressed as the quotient between the force in grams supported by the ring and its corresponding weight, also in grams (gF/gW). Strain was expressed as the quotient between the length at any given stress and the maximal unstressed length (L/L0). The elastic stiffness (
stress/strain), which defines the slope at any point of the stress-strain curve, was plotted as a function of the stress, giving a linear relationship. The slope of the regression line defines the stiffness constant, which was calculated for rings of normotensive and hypertensive patients [9]. The rings used in passive length-tension relationships were not used in further contractile studies because of the overdistention supported by the preparations.
Preservation studies
In rings studied immediately after arrival at the laboratory, a first contraction with 80 mmol/L KCl was performed, and it was taken as the control contraction. The rings were then washed and kept in the refrigerator at 4°C in either 0.9% NaCl or culture medium, and every 24 hours thereafter the rings were suspended again in the organ bath and a KCl contraction was elicited. The procedure was repeated every day until the segments lost their contractile ability. In these experiments no distinction was made between rings of hypertensive and normotensive patients because of the small number of cases involved.
Active studies
After the ring was suspended in the organ bath a passive force of 2 g was imposed and the preparation was stabilized during 1 hour, with washing and readjustment of the force every 20 minutes. At the end of the stabilization period the baseline was regained electronically and appropriate amounts of stock solutions of contractile agents were added to the bath to get the desired concentrations. High potassium concentrations were elicited with a special Krebs solution in which KCl was raised to 80 mmol/L and NaCl was lowered to keep osmolarity constant. Contraction was calculated with respect to the baseline. When a relaxant agent was employed it was added to the bath at the top of an agonist-induced contraction, and the relaxation was expressed as a percent of the previous contraction. The time to reach 50% of relaxation was taken as an index of relaxation. The responses were separated between hypertensive and normotensive patients.
Statistics
The data were expressed as means ± 1 standard error. Differences between means were evaluated with the t test for paired or unpaired samples, and significance was accepted at p less than 0.05.
Drugs
Ethylene glycol-bis(ß-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), norepinephrine, and culture medium (Leibovitz L-15) were purchased from Sigma Chemical Co. (St. Louis, MO). Epinephrine was obtained from hospital sources. The rest of the drugs were of analytical grade and were purchased from local vendors.
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Results
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We observed a great variability in the contractile responses among veins from different patients. However, different segments of a given vein showed a similar reactivity when tested in the organ bath.
Cold storage preservation did not alter the contractile response of the rings to KCl up to 24 hours (Fig 1). Actually, the contractile response was slightly diminished after preservation in culture medium and slightly increased after preservation in 0.9% NaCl. After 24 hours the contraction deteriorated very rapidly with 0.9% NaCl preservation and at a slower pace with culture medium. In any case the contraction was severely impaired or absent after 3 days of storage. Based on these preliminary studies, vessels were used for up to 24 hours of cold storage in 0.9% NaCl for the rest of the experiments.
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Fig 1. Repeated stimulation with 80 mmol/L KCl in human saphenous vein (HSV) rings (n = 11) stored for up to 7 days in culture medium (open circles) or 0.9% NaCl (closed circles). Deterioration was faster and more complete in 0.9% NaCl, but during the first 24 hours there was a good response in both conditions.
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The stress for any given strain was greater in rings from hypertensive patients than in those from normotensive subjects; with the difference being significant at an L/L0 of 1.3 to 1.6, the maximum attained (Fig 2, upper panel). The stiffness constant (Fig 2, lower panel) was significantly greater in hypertensive rings than in normotensive ones (1.81 ± 0.36 versus 0.71 ± 0.11; p < 0.05).
The contractile response to 80 mmol/L KCl (Fig 3) was significantly greater in rings from hypertensive patients than in rings from normotensive ones (59 ± 16 versus 25 ± 5 gF/gW; p < 0.05). The same finding was obtained with 1 µmol/L norepinephrine (Fig 4), which produced a significantly greater contraction in hypertensive patients than in normotensive subjects (maximal force, 61 ± 8 versus 36 ± 7 gF/gW; p < 0.05).
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Fig 3. (Upper panel): Single experiment showing exposure to 80 mmol/L KCl in two human saphenous vein (HSV) rings from 1 hypertensive and 1 normotensive patient, respectively. The contraction is stronger in the ring from the hypertensive patient. Unlabeled vertical arrows indicate washout. (Lower panel): Average responses to 80 mmol/L KCl in HSV rings from hypertensive (n = 6) and normotensive (n = 9) patients, showing a significantly stronger response in the hypertensive patients (p < 0.05). (gF/gW = stress, measured as grams force/grams weight.)
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Fig 4. (Upper panel): Single experiment showing exposure to 1 µmol/L norepinephrine in two human saphenous vein (HSV) rings from 1 hypertensive and 1 normotensive patient, respectively. The contraction is stronger in the hypertensive ring. Unlabeled vertical arrow indicates the addition of norepinephrine to the bath. (Lower panel): Average responses to 1 µmol/L norepinephrine in HSV rings from hypertensive (closed circles, n = 7) and normotensive (open circles, n = 12) patients, showing a significant stronger response in the hypertensive patients from the second time point (p < 0.05). Addition of norepinephrine to the bath occurred at time 0. (gF/gW = stress, measured as grams force/grams weight.)
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In contrast, the response to epinephrine (Fig 5) was not different between hypertensive patients and normotensive subjects, in whom the concentration-contraction curves revealed a median effective dose (in -log[M]) of 6.5 ± 0.3 and 6.5 ± 0.1, respectively (not significant) and maximal responses at 10-4 mol/L of 57 ± 11 and 54 ± 11 gF/gW, respectively (not significant).
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Fig 5. (Upper panel): Single experiment showing exposure to epinephrine from 10-10 to 10-4 mol/L in two human saphenous (HSV) rings from 1 hypertensive and 1 normotensive patient, respectively. The contraction is similar in both cases. (Lower panel): Concentration-response curves to epinephrine from 10-10 to 10-4 mol/L in HSV rings from hypertensive (n = 6) and normotensive (n = 9) patients, showing a similar response at all concentrations. Maximal responses were 57 ± 11 and 54 ± 11 grams force/grams weight (gF/gW) in hypertensive and normotensive patients, respectively.
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Exposure to 2 mmol/L EGTA during an epinephrine contraction produced a relaxation that was faster and more pronounced in rings of normotensive patients than in rings of hypertensive ones (Fig 6, upper panel). The time to reach 50% of relaxation was shorter in normotensive rings than in hypertensive ones (548 ± 81 versus 976 ± 180 seconds; p < 0.05) (Fig 6, lower panel).
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Fig 6. (Upper panel): Single experiment showing exposure to 2 mmol/L EGTA during a contraction with 1 µmol/L epinephrine. Horizontal arrows denote the time employed to relax to 50% of the maximal response (T1/2), which was longer in the hypertensive than in the normotensive patients. (Lower panel): Average T1/2 in rings from normotensive (n = 9) and hypertensive (n = 6) patients, showing a significantly longer T1/2 in rings from hypertensive than from normotensive patients (p < 0.05).
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Comment
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The study of the mechanical responsiveness of isolated HSV segments acquired particular importance because of their use as aorta-coronary grafts, and more so after it was demonstrated that these grafts can behave as active conduits after implantation [2, 3].
Several studies have been performed in HSV focusing on the pharmacologic aspects of their response [4, 5], including the contractile behavior of HSV at arterial perfusion pressures [6]. All the topics addressed by these papers may have a potential influence on the postoperative contractile behavior of the graft and thus on the clinical outcome of the patients.
Although it is widely known that systemic hypertension is characterized by an abnormally elevated peripheral vascular resistance and important changes in the passive and active properties of arteries [7], less is known about the behavior of veins in hypertension. If the veins of normotensive and hypertensive individuals react differently to various types of stimulation, this could imply different behaviors of the saphenous aorta-coronary grafts.
The HSV specimens maintained an undiminished contractile response for up to 24 hours of cold storage. These results are in good agreement with experiments performed in our laboratory (unpublished data) in rings of rat aorta, in which contractile ability remained essentially unchanged under similar conditions. From these experiments we concluded that the data collected within 24 hours of cold storage could be reasonably pooled with the data obtained on the same day of HSV excision, and we chose 0.9% NaCl for transport and preservation in the remaining experiments.
The next finding was a stiffness constant that was more than two times greater in hypertensive than in normotensive patients. Although an increased stiffness has been described in arteries as a consequence of a chronically elevated arterial pressure [9], this explanation seems less likely in the HSV, which presumably does not support highly elevated intravascular pressures even in hypertensive patients. However, the effects of a seemingly minor change of intravascular pressure on venous reactivity cannot be completely ruled out, as the studies of Monos and colleagues [10] have reported mechanical and electrical changes in rat saphenous veins after tilting, which produced intravenous pressure increases of only a few millimeters of mercury.
Exposure to high levels of extracellular potassium opens voltage-operated calcium channels, allowing calcium influx through its extracellular/intracellular gradient. This intracellular calcium increase results in formation of the calcium-calmodulin complex, activation of myosin light-chain kinase, and phosphorylation of contractile proteins that trigger contraction of smooth muscle [11]. The contractile response to 80 mmol/L KCl was significantly more intense in HSV of hypertensive patients than in HSV of normotensive patients, indicating an altered venous reactivity in this disease. Norepinephrine, which contracts smooth muscle by releasing calcium from intracellular stores and by promoting its influx through receptor-operated channels [11, 12], also produced an increased response in HSV of hypertensive patients. Surprisingly, we failed to demonstrate any difference in the response to epinephrine between HSV of hypertensive and normotensive patients.
Because we measured contraction, which is the result of a long chain of physical and biochemical events, it is difficult to speculate about which of these events is altered in the hypertensive rings. Concerning the high potassium stimulation, voltage-operated calcium channels were reported [13] to have similar total current in azygos vein smooth muscle from normotensive and spontaneously hypertensive rats. Only in stroke-prone rats was the current of voltage-operated channels greater than in normotensive rats [14], and this finding could be integrated into our results in hypertensive HSV. However, in experiments performed in rat aorta the influx of 45Ca after high-potassium stimulation was not different between hypertensive and normotensive rats [15]. Regarding the adrenergic responses, hypertensive rats have exaggerated vascular responses to norepinephrine [16]. The 
-adrenoceptors that mediate catecholamine-induced vasoconstriction are of the 2 type in HSV [17], and it has been proposed that 2-adrenoceptors are selectively activated in hypertension [18]. We would therefore interpret the increased response to norepinephrine that we found in hypertensive individuals as reflecting an increased activity of 2-adrenoceptors with respect to normotensive subjects. Although a lower density of ß-adrenoceptors has been described in hypertension [19], we did not find any change in affinity or maximal responses to epinephrine between HSVs of hypertensive and normotensive subjects. Alternatively, a vasorelaxant component associated with nitric oxide release by noradrenergic stimulation may be involved in the augmented reactivity to norepinephrine in HSV of hypertensive patients, as an impaired production of nitric oxide has been demonstrated in hypertension [20]. In accordance with this, in unpublished experiments performed in our laboratory we found that blockade of nitric oxide synthesis by exposure to N
-nitro-L-arginine methyl esther potentiated the contractile response to norepinephrine but not to epinephrine in HSV rings.
Although epinephrine contractions reached the same force in normotensive and hypertensive HSV rings, exposure to EGTA, a chelating agent, relaxed the rings more rapidly in the case of normotensive rings. Exposure to EGTA was chosen because it abruptly lowers extracellular calcium concentration, and the cell must extrude the calcium accumulated during the previous exposure to the agonist. The rate and extent of relaxation reflects the action of the various calcium extrusion or sequestering mechanisms available for the cell, namely the sodium-calcium exchanger, the plasma membrane calcium pump, and the sarcoplasmic reticulum calcium pump [21]. One or more of these mechanisms was evidently less active in the hypertensive HSV rings, but here again the use of contractile measurements alone did not allow us to identify whether there is a predominance of any of them. In connection with this, a lesser activity of the sarcoplasmic reticulum has been reported in aortas of spontaneously hypertensive rats [22], and a depression of the sodium-calcium exchanger has been suggested in tail arteries of stroke-prone spontaneously hypertensive rats [21].
It is interesting that we were able to detect an altered reactivity to various agonists in venous rings belonging to vessels that were certainly not exposed to high pressures during the hypertensive state. Similar changes have been detected in the portal vein of spontaneously hypertensive rats and in femoral arteries of desoxycorticosterone acetate-hypertensive rats and pigs that have been protected from the high pressure by ligation [7]. All this evidence points to an altered reactivity that is not a consequence of high blood pressure but a preceding or concomitant phenomenon affecting the entire vascular system.
It must be noted that the passive force imposed on the preparations before the active studies was around 2 g in rings that measured 3 to 4 mm in length. Taking into account the average dimensions of the preparations, that tension corresponds to an intravascular pressure of approximately 10 mm Hg. This means that the vessels were tested under conditions that are more likely to reproduce the saphenous pressure when the vessel is intact and in situ than the arterial pressures prevailing when it is used for the aorta-coronary bypass. Nevertheless, it has been proved that these vessels are also responsive in vitro when tested under arterial pressures [6].
We are aware that the forces we obtained in our HSV rings—even in the hypertensive ones, which were the best contracting—were two to three times smaller than those reported by Grohs and associates [5] in rings of similar size. A probable explanation is that we used remnants of HSV that have been subjected to injections at high pressures to detect and occlude side branches, and sometimes exposed to vasodilators such as papaverine to prevent spontaneous tone, whereas their segments were obtained before such procedures. However, in our case the preparation of the veins was similar for all specimens obtained, and therefore the differences detected between normotensive and hypertensive subjects are still valid.
Even taking into account the limitations of our experimental methods and the difficulties in extrapolating in vitro experimental data to the clinical setting, we can draw the following conclusions: (1) The HSV grafts used during the surgical procedure are fully capable of contracting in response to diverse agonists and are not affected to a great extent by preservation procedures within 24 hours. (2) The HSVs from hypertensive patients exhibit distinctive characteristics, such as increased stiffness, increased reactivity to high extracellular potassium and norepinephrine, and depressed relaxation capability, when deprived of extracellular calcium. This opens up the interesting possibility of an increased response to these and other drugs during the perioperative period, which could eventually lead to a critical reduction in flow or even graft occlusion in these patients.
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Acknowledgments
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This work received funding from Universidad Nacional de La Plata, Facultad de Ciencias Exactas, Comisión de Investigaciones Científicas de la Provincia de Buenos Aires and PICT #0145 from CONICET. The technical assistance of Mrs Silvia Salemme is greatly appreciated.
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Abstract
Introduction
