Lewis B. Schwartz

Asymptomatic carotid artery stenosis and stroke in patients undergoing cardiopulmonary bypass

PURPOSEnThis study was undertaken to assess the natural history of carotid artery stenosis in patients undergoing cardiopulmonary bypass (CPB) at a Veterans Administration Medical Center.nnnMETHODSnBetween January 1989 and August 1993, all patients undergoing CPB were offered preoperative carotid artery ultrasound screening as part of an investigative protocol. Patients were monitored in-hospital for the occurrence of perioperative neurologic deficit.nnnRESULTSnA total of 582 patients underwent carotid artery ultrasound screening. Greater than 50% stenosis or occlusion of one or both internal carotid arteries was present in 130 patients (22%), with 80% or greater stenosis or occlusion of one or both arteries present in 70 patients (12%). In-hospital stroke or death occurred in 12 (2.1%) and 36 (6.2%) patients, respectively. Of the 12 strokes, five were global and seven were hemispheric in distribution. Of the five patients who had global events, none had evidence of carotid artery stenosis. However, of the seven patients who had hemispheric events, five had significant 50% or greater stenosis or occlusion of the internal carotid artery ipsilateral to the hemispheric stroke. Therefore the presence of carotid artery stenosis or occlusion was significantly associated with hemispheric stroke (no stenosis 0.34% vs stenosis 3.8%; p = 0.0072). Furthermore, the risk of hemispheric stroke in patients with unilateral 80% to 99% stenosis, bilateral 50% to 99% stenosis, or unilateral occlusion with contralateral 50% or greater stenosis was 5.3% (4 of 75). No strokes occurred in patients with unilateral 50% to 79% stenosis (n = 52).nnnCONCLUSIONSnIt is concluded that carotid atherosclerosis is a risk factor for hemispheric stroke in patients undergoing CPB.

Vascular complications of cardiac catheterization

Femoral artery injury after diagnostic and therapeutic cardiac catheterization is a frequently encountered clinical problem. This study reviews 150 femoral artery injuries that occurred in 16,350 patients over a 5-year period. A prospective computerized cardiac catheterization data bank was used to determine significant risk factors associated with the occurrence of vascular injury. Logistic regression analysis revealed that congestive heart failure, female gender, and percutaneous transluminal coronary angioplasty or valvuloplasty procedure were significantly associated with occurrence of vascular injury. Greater age, smaller body surface area, and smaller weight were also associated with injury. Recommendations for management include an aggressive approach to obstruction even if local vascular reconstruction is required. False aneurysms are studied by ultrasonography, and small ones may be observed expectantly. Larger aneurysms and aneurysms that persist beyond a few days are managed by use of general or regional anesthesia and by gaining proximal control of the iliac artery. Arteriovenous fistulas resulting from catheterization are rarely hemodynamically significant and often close spontaneously. Thus repair should be delayed.

Myointimal thickening in experimental vein grafts is dependent on wall tension

This study examines the relative contributions of intraluminal pressure, blood flow, wall tension, and shear stress to the development of myointimal thickening in experimental vein grafts. To study these different hemodynamic parameters, several experimental models were created in 30 New Zealand White rabbits separated into six groups: common carotid interposition vein grafts harvested at 4 weeks (VG-4) or 12 weeks (VG-12), common carotid-linguofacial vein arteriovenous fistulas harvested at 4 weeks (AVF-4) or 12 weeks (AVF-12), AVFs with partial outflow obstruction harvested at 4 weeks (AVFobs), and combination VG-AVFs in series harvested at 4 weeks (VGAVF). Blood pressure and flow in the graft or vein were measured by use of a transducer-tipped pressure catheter and electromagnetic flow meter. At harvest, veins were perfusion-fixed and proximal, middle, and distal sections were subjected to computerized morphometric analysis. Vein grafts were characterized by a high mean pressure (VG-4, 51 +/- 4; VG-12, 62 +/- 3 mm Hg), low mean flow (VG-4, 17 +/- 1; VG-12, 16 +/- 4 ml/min), large luminal area (VG-4, 19.7 +/- 2.4; VG-12, 19.3 +/- 3.9 mm2), high wall tension (VG-4, 17.0 +/- 1.5; VG-12, 19.5 +/- 2.4 x 10(3) dyne/cm), low shear stress (VG-4, 0.75 +/- 0.13; VG-12, 0.96 +/- 0.38 dyne/cm2), and a high degree of myointimal thickening (VG-4, 5.89 +/- 0.90; VG-12, 4.72 +/- 0.83 mm2). Arteriovenous fistulas were characterized by a low mean pressure (AVF-4, 5 +/- 1, AVF-12, 6 +/- 2 mm Hg), elevated blood flow (AVF-4, 82 +/- 16; AVF-12, 82 +/- 17 ml/min), small luminal area (AVF-4, 2.43 +/- 0.58; AVF-12, 7.14 +/- 2.68), low wall tension (AVF-4, 0.62 +/- 0.19; AVF-12, 0.89 +/- 0.24 x 10(3) dyne/cm), elevated shear stress (AVF-4, 108 +/- 32; AVF-12, 71 +/- 50 dyne/cm2), and decreased myointimal area (AVF-4, 1.18 +/- 0.26; AVF-12, 1.90 +/- 0.55 mm2). The addition of outflow obstruction to AVFs (AVFobs) resulted in elevated pressure (48 +/- 2 mm Hg), decreased flow (17 +/- 4 ml/min), larger luminal area (8.71 +/- 2.31 mm2), elevated wall tension (10.3 +/- 1.7 x 10(3) dyne/cm), and a degree of myointimal thickening approaching that of vein grafts (3.79 +/- 0.66 mm2).(ABSTRACT TRUNCATED AT 400 WORDS)

Chronic Ace Inhibition Reduces Intimal Hyperplasia in Experimental Vein Grafts

Intimal hyperplasia is an important factor in the pathophysiology of vein graft failure. Local renin-angiotensin systems recently have been shown to modulate the development of intimal hyperplasia in arteries after intimal injury. The effect of chronic angiotensin-converting enzyme (ACE) inhibition on the development of intimal hyperplasia in experimental vein grafts was examined in this study. Ten New Zealand White rabbits received 10 mg/kg of captopril daily in their drinking water. One week later the right carotid artery was divided and bypassed with the reversed right external jugular vein in these rabbits and in 10 matched controls. Captopril was continued for 28 days after operation, when all the grafts were harvested. Five grafts from each group were perfusion fixed, and the intimal thickness in the proximal, middle, and distal segments was determined. Rings from the remaining grafts (n = 20 in each group) were studied in vitro under isometric tension, and their responses to norepinephrine (NE), histamine (HIST), serotonin (S-HT), angiotensin I (AI), and angiotensin II (All) was measured. The intimal thickness of the proximal, middle, and distal segments of the captopril-treated grafts were significantly less than controls, being reduced in all segments by approximately 40% (p < 0.0001). With regard to vasoreactivity, the captopril-treated grafts were hypersensitive to 5-HT (control ED50 5.5 ± 0.5 ± 10-7 mol/L vs. captopril-treated 1.1 ± 0.2 ± 10-6 mol/L; p < 0.005) although the maximal response was significantly reduced (control 1.6 ± 0.3 g vs. captopril-treated 0.8 ± 0.1 g; p < 0.05). There were no differences in sensitivity between control and captopril-treated rings with respect to NE, HIST, AI, or AIL Four of the ten captopril-treated segments, however, failed to respond to AI, and the maximal active tension of the responders was significantly reduced (control 0.47 ± 0.06 g vs. 0.20 ± 0.05 g; p < 0.02). These results suggest that ACE is involved in the modulation of vein graft intimal hyperplasia, and that ACE inhibitors may have therapeutic applications in patients undergoing vein bypass procedures.

Alterations in serotonergic receptor expression in experimental vein grafts

Rabbit external jugular veins, normally unresponsive to serotonin (5-HT), develop a constrictive response when grafted into the arterial circulation. The mechanisms responsible for this alteration were examined in this study. The right external jugular vein was grafted into the right carotid artery in 37 New Zealand white rabbits. The vein grafts were harvested at 3, 7, 9, 14, and 28 days after operation; contralateral external jugular veins were harvested at 9 days in six animals. Rings of these vessels were mounted under isometric tension, and dose-response curves to 5-HT were obtained. None of the grafts harvested at day 3 responded to 5-HT. All the grafts harvested from day 7 through day 28 constricted to 5-HT. The maximal response increased from 258 +/- 30 mg at 7 days to 734 +/- 108 mg at 28 days. No change occurred in the sensitivity to 5-HT with time. The increase in maximal response was paralleled by a linear increase in percent intimal area (intimal area/intimal + media areas) from 11.6% +/- 2.1% at 3 days to 48.7% +/- 1.9% at 28 days. Preincubation with ketanserin, a 5-HT2 and alpha 1-adrenergic antagonist, produced a concentration-dependent rightward shift in the 5-HT dose-response curve. The median effective dose for 5-HT increased progressively from 1.9 +/- 0.3 x 10(-6) mol/L (in the absence of ketanserin) to 6.1 +/- 1.7 x 10(-5) mol/L (ketanserin 8 x 10(-7) mol/L; p less than 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of calcium channel blocker induced smooth muscle relaxation using a model of isolated corpus cavernosum

Several classes of smooth muscle relaxing agents have proven effective in relaxing cavernosal smooth muscle and useful in the pharmacotherapy of erectile dysfunction. The purpose of this investigation was to determine whether the calcium channel blockers (CCB) relax cavernosal smooth muscle. Thirty-two rabbit cavernosal strips were contracted by electrical field stimulation, and contraction inhibition was tested in response to cumulative doses (10(-8) M. to 10(-4) M.) of verapamil (V), diltiazem (D), isradipine (I), nicardipine (Nc) and nifedipine (Nf). All of the calcium channel blockers were effective at inhibiting electrically induced contractions (p < 0.0001 when CCB was compared with control; p < 0.05 when V or D was compared with I, Nc or Nf). Sixteen cavernosal strips were precontracted with 10(-5) M. norepinephrine. Relaxation in response to cumulative doses of each CCB was determined. Verapamil and the dihydropyridines (isradipine, nicardipine and nifedipine), but not diltiazem, were effective at relaxing norepinephrine induced contractions at 10(-5) and 10(-4) M. with verapamil most effective at 10(-4) M. concentration (p < 0.0001 by ANOVA at both concentrations when V, I, Nc, or Nf was compared with control). Sixteen cavernosal strips were incubated in solutions of 10(-5) and 10(-4) M. of each CCB followed by cumulative addition of norepinephrine (concentration range 10(-8) to 10(-4) M.). Preincubation with CCB did not affect the concentration of norepinephrine at which 50% of maximal cavernosal contractile response occurred (ED50). Maximum active tension of norepinephrine induced contractions was moderately decreased after CCB preincubation with 10(-4) M. of each dihydropyridine. It is concluded that the calcium channel blockers are effective in relaxing cavernosal smooth muscle and therefore possess potential as intracavernous pharmacotherapeutic agents for the treatment of erectile dysfunction. Verapamil appears to be the best candidate for further testing and clinical trial.

Effects of Pulsatile Perfusion on Human Saphenous Vein Vasoreactivity: A Preliminary Report

This study examined the effects of exposure to arterial blood pressure and flow on human saphenous vein catecholamine sensitivity. Unused portions of saphenous vein from eight patients undergoing peripheral bypass procedures were mounted parallel in a specially designed organ culture apparatus and perfused with tissue culture medium with 95% CO(2) at 37 degrees C. One segment was fixed between two cannulas while the medium was gently agitated (control) and the other was actively perfused via a pulsatile pump system at a rate of 60 beats/min, peak pressure of 100 mmHg and peak flow of 200 ml/min (pulsed; mean pressure 60 mmHg; mean flow 115 ml/min). After 48 h, vein segments were removed and tested for in vitro isometric contraction in response to KCI, norepinephrine and histamine, and relaxation in response to acetylcholine, calcium ionophore A23187, and sodium nitroprusside. There were no differences in mean(s.e.m.) maximal contraction in response to KCI (control 0.61(0.16) g versus pulsed 0.72(0.27)g; P = n.s.), norepinephrine (control 1.00(0.56) g versus pulsed 1.51(0.54) g; P= n.s.), or histamine (control 1.47(0.85) g versus pulsed 1.95(0.64) g; P= n.s.). However, pulsed veins exhibited increased sensitivity to both norepinephrine (control -logED50 6.20(0.23) versus pulsed mean(s.e.m.) 6.60(0.17); P< 0.05) and histamine (control -logED(50) 5.60(0.27) versus pulsed 6.24(0.20); P = 0.05). Pulsed veins exhibited slightly less acetylcholine-induced relaxation although the difference did not reach statistical significance (control mean(s.e.m.) relaxation at 1 x 10(6)M 9.2(14.0)% versus pulsed -13.3(6.4)%; P = n.s.). There were no differences in relaxation in response to either A23187 (control 1 x 10-(4)M 178(19)% versus pulsed 191(68)% or sodium nitroprusside (control 225(15)% versus pulsed 254(17)%; P = n.s.). The data presented herein indicate that exposure of human saphenous vein to the hemodynamics of the arterial environment for 48 h results in catecholamine supersensitivity while contractile and relaxant function are not affected.

Quantitation of vascular outflow by measurement of impedance

One of the most important determinants of graft patency is the degree and character of vascular outflow. This study was designed to evaluate input impedance as a functional assessment of the outflow bed of vascular grafts. Four distinct outflow environments were created for external jugular vein conduits in 42 New Zealand white rabbits. Vein grafts (n = 14) were fashioned as end-to-side common carotid interposition bypass grafts. Arteriovenous fistulas (n = 15) were created by side-to-side anastomosis of the distal common carotid artery and linguofacial vein. Arteriovenous fistulas with outflow obstruction (n = 7) were fistulas with a metal clip partially obstructing the distal outflow channel (1 mm lumen). Vein graft/arteriovenous fistula combinations (n = 6) consisted of a vein graft and arteriovenous fistula in series. Pressure and flow in the external jugular vein were measured, and input impedance spectra were calculated by Fourier methods. By use of a PC-based acquisition and processing system, impedance results for 20 cardiac cycles could be obtained in approximately 10 minutes. The results revealed that vein grafts typically demonstrated high resistance to steady state flow (Rin = 235 +/- 50 x 10(3) dyne . sec/cm-5) and steadily decreasing impedance to pulsatile flow resulting in a characteristic impedance (Z0; average of fourth to tenth harmonics) of 35.5 +/- 8.0 x 10(3) dyne . sec/cm-5. Phase angle values were usually negative, especially at low harmonics (first harmonic phase angle = -1.11 +/- 0.10 radians) indicating that flow led pressure. In contrast, arteriovenous fistula Rin was minimal (6.3 +/- 1.4 x 10(3) dyne . sec/cm-5; p less than 0.05 compared to vein graft, and the impedance was flat across the frequency spectrum (Z0 = 8.5 +/- 1.5 x 10(3) dyne . sec/cm-5; p less than 0.05) with pressure and flow nearly in phase (first harmonic phase angle = -0.05 +/- 0.10 radians). Creation of outflow obstruction in arteriovenous fistulas resulted in significantly elevated Rin (136 +/- 41 x 10(3) dyne/sec . cm-5; p less than 0.05 compared to arteriovenous fistula and Z0 (23 +/- 9 x 10(3) dyne . sec/cm-5, p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

Saphenous vein endothelium-dependent relaxation in patients with peripheral vascular disease

In vitro vasomotor responses of saphenous veins of 15 patients undergoing peripheral vascular bypass procedures were studied. Vessels were harvested by standard techniques, sectioned into 4 mm rings, and suspended in organ baths under isometric tension. Stimulation with cumulative doses of norepinephrine revealed a −logED50 of 6.85±0.12 M and maximal tension of 8.64±1.77 g. Patient characteristics suggesting high maximal response (by univariate analysis) included male sex (male 11.69±2.49 g versus female 5.08±1.69 g; p=0.058). Intact and denuded rings were additionally tested for endothelium-dependent relaxation following submaximal norepinephrine precontraction. The vessels relaxed in response to acetylcholine (maximal relaxation 31.1±10.7% at 1 × 10−6 M), calcium ionophore A23187 (85.3±11.8% at 1 × 10−5 M), and sodium nitroprusside (150.8±15.2% at 1 × 10−5 M), but only acetylcholine relaxation was completely endothelium-dependent. Calcium ionophore A23187 relaxation was partially dependent on the endothelium while sodium nitroprusside relaxation was entirely endothelium-independent. Negligible relaxation was observed in response to adenosine diphosphate (ADP) (12.1±12.8% at 1 × 10−5 M) while histamine and serotonin caused additional contraction only. We concluded that, in patients undergoing vascular surgical procedures, the saphenous vein (1) demonstrates variable contractile function which appears to be greater in males following spinal anesthesia, and (2) exhibits moderate endothelium-dependent relaxation in response to acetylcholine and calcium ionophore A23187 but not to ADP, histamine, or serotonin.

Loss of Tachyphylaxis and Increased Sensitivity to Angiotensin II in Experimental Vein Grants

Intimal hyperplasia and atherosclerosis have been implicated in the pathophysiology of vein graft failure. Several recent studies have also reported alterations in the vasoreactivity of vein grafts. These alterations in vasoreactivity could contribute to vein graft spasm and lead to graft occlusion. This study examined the vasomotor responses of experimental vein grafts to angiotensin II, the most potent natural vasoconstrictor known. The right carotid artery was divided and bypassed in 12 rabbits with use of the right external jugular vein. The left external jugular vein was used as a control. Eight vein grafts and jugular veins were harvested after fourteen days and 4 vein grafts after twenty-eight days. Segments of vein graft and control vein were mounted under isometric tension in an organ bath, and the dose response curves to angiotensin II obtained. On day 14, the response of the jugular veins was triphasic, while the respnse of the vein grafts was sigmoidal. The vein grafts were hypersensitive to angiotensin II. The ED50 was reduced from 8.4 ± 2.5 x 10-6 M in the jugular veins to 1.62 ± 0.24 x 10-8 M in the vein grafts (p < 0.005). The maximal response to angiotensin II was also increased from 342 ± 24 mg in the jugular veins to 558 ± 108 mg in the vein grafts on day 14 (p < 0.05). There was no significant difference in either the ED50 or the maximal response of the vein grafts on day 14 or 28. Tachyphylaxis (desensitization with repeated doses of agonist) was observed in the jugular veins but not in the vein grafts. The results show that experimental vein grafts are hypersensitive to angiotensin II, with either single or repeated exposure. This increased vasoreactivity to angiotensin II may have important clinical implications, particularly when vein grafts are used in patients with renovascular hypertension.