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Biomedical subjects

J R Pepper

Publications and source records attributed to J R Pepper.

At least 73 records · Page 4Linked to original sources
PubMed1998

Differential induction of cyclooxygenase-2 in human arterial and venous smooth muscle: role of endogenous prostanoids.

Two isoforms of cyclooxygenase (COX) have been identified: a constitutive isoform (COX-1), found in abundance in platelets and the vascular endothelium, and an "inflammatory" cytokine-inducible isoform (COX-2). Because COX metabolites regulate vascular smooth muscle cell (SMC) function and the interaction between the vessel and circulating components, we have investigated the possibility that COX-2 can be induced in human arterial or venous SMC. Untreated venous or arterial cells contained undetectable levels of COX-1 or COX-2 and released low levels of metabolites. After stimulation with interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and bacterial lipopolysaccharide, both venous and arterial SMC expressed COX-2 protein and released increased amounts of prostaglandins. In addition, the induced release of PGE2 was inhibited by the COX-2-selective inhibitor, L-745,337. When cells were treated with the mixture of cytokines, venous SMC expressed greater amounts of COX-2 protein and released more prostaglandins than arterial SMC. Furthermore, when COX-2 activity was blocked by L-745,337, COX-2 expression in arterial SMC, but not in venous SMC, increased. Thus, this article describes, for the first time, that COX-2 is expressed in greater amounts in venous SMC than in arterial SMC. Moreover, we show that this "differential induction" is due to a negative-feedback pathway for COX-2 expression in arterial SMC but not in venous SMC. The ability of COX-2 activity to limit COX-2 expression in some cells but not others may contribute to the highly developed mechanisms involved in prostanoid release.

Cells, Cultured↗
PubMed1997

Coronary artery problems during homograft aortic valve replacement: role of transesophageal echocardiography.

We describe 2 cases in which intraoperative transesophageal echocardiography detected complications related to the proximal coronary arteries during homograft aortic valve and root replacement. In both cases, cardiopulmonary bypass could not be discontinued despite the use of large doses of inotropic drugs. Transesophageal echocardiography demonstrated aliasing on color flow mapping in the left main coronary artery in 1 case and proximal right coronary artery in the other, along with severely depressed left ventricular anterior wall and right ventricular function, respectively. Coronary artery bypass grafting was performed in both cases, and the outcome was successful.

Aged↗
PubMed1997

Regional perfusion and oxygenation in the pedicled latissimus dorsi muscle flap: the effect of mobilisation and electrical stimulation.

BACKGROUND: The pedicled latissimus dorsi muscle flap is dependent upon an adequate blood supply via a single nutrient artery arising at its most proximal point. It has been suggested that when the latissimus dorsi muscle is used for cardiomyoplasty there is a risk of ischaemic damage to the distal regions of the flap under the additional metabolic stress of repeated electrical stimulation. METHODS: A rabbit model was developed in which the latissimus dorsi muscle was raised as a pedicled flap (n = 10). Needle microelectrodes were used to measure oxygenation and perfusion simultaneously in different regions of the muscle. Perfusion was measured using a gas tracer technique in which nitrous oxide was used as the marker. Muscle performance was measured by electrical stimulation of the mobilised flap. RESULTS: The mean (standard error) perfusion of the distal muscle fell significantly from 19.5 (6.2) to 11.9 (3.8) ml.min-1 100 g-1 (P < 0.05) as a consequence of mobilisation, although tissue oxygenation was maintained. Perfusion and pO2 of the proximal regions of the flap were unchanged. During electrical stimulation perfusion increased by 72 (12)% from resting levels in the proximal region, but by only 39 (8)% in the distal muscle. Tissue pO2 decreased during stimulation by 5.7 (1.8) mmHg proximally compared to 11.7 (3.7) mmHg distally P < 0.05). During recovery the pO2 remained below baseline for 24 minutes in the proximal muscle compared to 32 minutes in the distal muscle. CONCLUSIONS: Mobilisation results in a reduction in the perfusion of distal areas of the latissimus dorsi muscle flap. During repeated contraction the perfusion remains reduced and is unable to maintain tissue oxygen requirements. This has implications for dynamic applications of the latissimus dorsi muscle flap and supports the suggestion that ischaemia is the cause of distal muscle atrophy and fibrosis in cardiomyoplasty. Combined perfusion and pO2 data provide a new insight into muscle viability studies.

Animals↗
PubMed1997

Psychological stress does not affect plasma catecholamines in subjects with cardiovascular disorder.

Whereas the effects of cardiac transplantation on the catecholamine response to physical exercise have been studied previously, the impact on psychological stress is unknown. Here, the arterial catecholamine response to the Stroop test of patients with an orthotopic heart transplant (OHT) was compared with that in subjects who had received a coronary artery bypass graft (CABG) or who were in heart failure and destined for a heart transplant (HF). Subjects were tested whilst sitting and their usual drug therapy was maintained. The Stroop test increased subjects' subjective tension but did not affect arterial concentrations of adrenaline or noradrenaline in any group of subjects. Also, the concentration of both catecholamines was significantly higher in OHT and CABG subjects than in the HF group, but their relative concentration was unaffected by cardiovascular status or stress. It is concluded that the absolute concentrations of arterial catecholamines, but not their relative concentrations, depend on clinical status. Moreover, under these test conditions, subjects with a history of cardiovascular disorder do not show the normal catecholamine response to psychological stress.

Adolescent↗
PubMed1997

Assessment of human long saphenous vein function with minimally invasive harvesting with the Mayo stripper.

BACKGROUND: The use of the Mayo Stripper to harvest the long saphenous vein has been shown to improve morbidity from leg wound incisions. It has not been universally accepted because of a perceived increase in injury to the venous conduit. OBJECTIVE: To compare the function of undistended autologous long saphenous vein harvested by a Mayo stripper with the traditional 'open' technique in the same patient (n = 12) appearance. METHODS: Vascular reactivity was assessed in isolated organ baths. Contractile function was measured in response to increasing concentrations (10(-9)-10(-5) mol) of 5-hydroxytryptamine and noradrenaline. This was calculated as a percentage of the maximum contractile response to 90 mM KCl measured in millinewtons (mN) (control 41.4 +/- 12.1, (n = 11), open technique 35.8 +/- 11.1, (n = 11), Mayo stripper 33.7 +/- 15.9, (n = 11)). The endothelial dependent and independent function was assessed with acetylcholine and sodium nitroprusside, respectively. RESULTS: There was no significant difference in response to both constrictors and dilators between vein taken with the Mayo stripper compared with the traditional open technique (n = 6 for each observation; P > 0.05 by ANOVA). Histological examination by light microscopy of the vessel segments removed with the Mayo stripper was unable to show any significant damage to the vessel wall. Both functional and morphological studies were conducted by 'blinded' observers. One-year follow-up with magnetic resonance angiography (MRA) and stress thallium tomography demonstrated a patency rate with lower and upper estimates of 80 and 94%. CONCLUSIONS: We have shown that harvesting the long saphenous vein with a Mayo stripper does not compromise vascular reactivity of the long saphenous vein or long-term patency.

Analysis of Variance↗
PubMed1997

Measurements of oxygenation and perfusion in skeletal muscle using multiple microelectrodes.

This paper describes an apparatus to measure tissue oxygenation and perfusion (as measured by the wash-in rate of gaseous hydrogen) simultaneously at multiple points in muscle using needle microelectrodes. The development of suitable electrodes and apparatus is described, as well as the development of the method and its validation. In particular, the potential for tissue damage secondary to electrode insertion, the need for in vivo voltammetric determination of the operating potential and the extent of any electrode-tissue and of electrode-electrode interactions are explored, and are shown to be insufficient in magnitude to affect the technique. Its subsequent use to characterise oxygenation and perfusion in rabbit skeletal muscle at rest is also described. In resting tibialis anterior muscle of the rabbit the mean pO2 was 18 +/- 13.3 mm Hg and the mean perfusion was 4.4 +/- 1.3 ml s-1 100 g-1. There was a heterogeneity in simultaneously-measured values of pO2 and perfusion at different points within muscle, and also a temporal variation at the same site. The spans between the highest and lowest simultaneously-measured values of pO2 in muscle ranged from 14 to 80 mm Hg, and for perfusion, from 1 to 12 mls-1 100 g-1. No significant correlation was evident from histological examination between either pO2 or perfusion and surrounding fibre type or capillary density.

Animals↗
PubMed1997

Early changes in left ventricular anterior wall dynamics and coordination after coronary artery surgery.

OBJECTIVE: To study how asynchronous left ventricular wall motion changes early after uncomplicated coronary artery surgery. DESIGN: A prospective study done before, and at 0.5, 1, and 3 hours after coronary artery grafting, with intraoperative transoesophageal cross sectional guided M mode echocardiograms, high fidelity left ventricular pressure, and thermodilution cardiac output measurements. The extent and velocity of left ventricular anterior wall thickening were measured, along with regional work and power production. Abnormal thickness changes during the isovolumic periods were detected, and their effect on energy transfer quantified as cycle efficiency. SETTING: Tertiary referral cardiac centre. PATIENTS: 25 patients with a history of chronic stable angina, mean (SD) age 60 (9) years with three vessel coronary artery disease, undergoing uncomplicated coronary artery bypass grafting. RESULTS: 4 patients had primary incoordination, as shown by wall thinning during isovolumic contraction and delayed onset of thickening (group A), and nine had premature thickening due to incoordination elsewhere (group B). The extent (thickening fraction 43 (12)% v 73 (19)%) and velocity (1.7 (0.4) v 2.5 (0.6) cm/s) of thickening were reduced in group A v group B (P < 0.001), as were regional stroke work (2.2 (0.8) v 3.3 (0.4) mJ/cm2) and peak power production (19 (5) v 32 (7) mW/cm2), P < 0.05. In group A, these values all increased significantly within 30 minutes of operation. In group B, the extent of wall thickening and peak power production were unaffected by surgery, though cycle efficiency and regional stroke work both improved by 30 minutes v before operation (73 (9)% v 61 (8)%, 4.5 (0.9) v 3.3 (0.4) mJ/cm2, P < 0.01). Surgery had no consistent effect on left ventricular cavity size, shortening fraction, or cardiac output in either group. CONCLUSIONS: Even in the absence of evidence of overt ischaemia, major disturbances of ventricular synchrony--both regional and generalised--are present in patients with a history of chronic stable angina requiring coronary artery bypass grafting. They regress within 30 minutes of revascularisation, suggesting that they are the direct result of coronary stenosis.

Analysis of Variance↗
PubMed1997

Induction of cyclooxygenase-2 in human saphenous vein and internal mammary artery.

Within vessels, cyclooxygenase (COX) is expressed constitutively (COX-1) in endothelial cells where its production of prostacyclin is thought to contribute to the maintenance of vascular integrity. Recently, a novel isoform of COX, COX-2, has been described that is induced in animal arterial vessels after physical damage or exposure to proinflammatory cytokines. However, induction of COX-2 in human vessels has not been characterized. Moreover, the relative ability of arteries and veins to express COX-2 has not been addressed. Thus, we have compared the ability of segments of human saphenous vein and internal mammary artery, obtained from the same patient, to express COX-2 activity and mRNA after organ culture in the presence and absence of interleukin-1 beta. COX-2 metabolites, measured by radioimmunoassay, were released by both the internal mammary artery and saphenous vein in the following rank order: prostaglandin E2 > or = prostacyclin thromboxane A2. Inclusion of interleukin-1 beta in the culture medium increased the release of prostanoids by the saphenous vein but not by the internal mammary artery. However, the selective COX-2 inhibitor NS-398 significantly attenuated prostacyclin release from both tissues. Northern blot analysis showed no detectable COX-2 mRNA in freshly prepared saphenous vein or internal mammary artery. In contrast, after 48 hours in organ culture, low levels of COX-2 mRNA were detected in both internal mammary artery and saphenous vein, an effect that was greatly increased by interleukin-1 beta. These observations show that COX-2 is induced in human saphenous vein and internal mammary artery and suggest that this may occur in humans after coronary artery bypass graft surgery. The induction of COX-2 and subsequent release of prostacyclin may represent an endogenous defense mechanism against endothelial damage incurred during surgical preparation of these vessels for bypass.

6-Ketoprostaglandin F1 alpha↗
PubMed1996

Effect of capacitive coupled electrical stimulation on regenerate bone.

An in vivo study was carried out to determine if capacitive coupled electrical stimulation increased the rate of recovery of strength of regenerate bone produced as a result of lengthening by the Ilizarov technique. Thirty-four adult male beagles underwent a right tibial mid-diaphyseal corticotomy, followed by a 5-day delay, and then 21 days of lengthening (1 mm/day). At the start of the post-distraction period (day 27), stimulation (3-6.3 V peak to peak, 5-10 mA root-mean-square at 60 kHz) was applied for 28 days to one group. The nonstimulated group (n = 17) underwent a 28-day period with no stimulation. From each group, four tibiae were prepared for histology; both ends of the remaining bones were embedded in polymethylmethacrylate and tested in torsion (internal rotation at 4.7 degrees/sec) until failure. Statistically significant changes included a 37% lower maximum torque capacity and a 40% decrease in strain energy to failure in the stimulated group compared with the nonstimulated group. The findings are supported by measured trends to a lower modulus of rigidity (37% decrease) and a smaller percentage of active osteoid perimeter (20% decrease) for the stimulated group. The experimental data suggest that when this dose of capacitive coupled electrical stimulation is applied to the regenerating bone created during distraction osteogenesis, it delays the recovery of bone strength compared with an untreated control.

Animals↗
PubMed1996

Effects of valve substitute on changes in left ventricular function and hypertrophy after aortic valve replacement.

BACKGROUND: Residual left ventricular hypertrophy adversely affects long-term outcome after aortic valve replacement. A stentless biological valve in the aortic position has been shown to offer a better hemodynamic profile than a stented one. However, it remains to be defined whether this difference is translated into inter-mediate-term effects on left ventricular structure and function. METHODS: One hundred thirty-seven patients receiving single aortic valve replacement (52 with concomitant coronary artery bypass graft) were enrolled in this study. Ninety-eight were men, and the mean age was 68 years (range, 55 to 90 years). Of the 137 patients, 39 had an aortic homograft, 72 a Toronto stentless porcine valve, and 26 had a stented porcine or bileaflet mechanical valve, with mean valve size of 25 +/- 2.5 mm (mean +/- standard deviation). Left ventricular muscle mass and function were assessed by M-mode echocardiography performed before and 0.5, 6, 12, 24, and 36 months after operation, and recorded on paper for off-line digitizing. Peak valve prosthesis pressure gradients were quantified by continuous wave Doppler. RESULTS: A total of 330 echocardiograms obtained during this study were adequate for computer digitizing. Clinical data, preoperative left ventricular function, and hypertrophy were similar between the three groups. Significant improvement in left ventricular function and major regression of left ventricular hypertrophy had occurred in the entire population by 6 months after operation. Multivariate analysis of variance showed that patients with previous aortic regurgitation had a larger left ventricular cavity size (p < 0.001) and greater mass index (p = 0.001) postoperatively than those with previous aortic stenosis. In addition, peak valvular gradient was lower (p < 0.001), mass index less (p < 0.001), and left ventricular function more normal both systolic, by a greater peak velocity of dimension shortening (p = 0.05) and wall thickening (p = 0.002), and diastolic, by a greater peak velocity of dimension lengthening (p = 0.046), with an aortic homograft or stentless porcine valve compared with a mechanical or stented biological valve. There was no significant difference in peak valve gradient, left ventricular mass index, or function between the aortic homograft and the stentless porcine valve. Age, sex, and concomitant coronary artery bypass graft, as well as aortic cross-clamp time, cardioplegia method, and valve size all proved to be insignificant determinants of postoperative left ventricular hypertrophy or function. CONCLUSIONS: In the first 2 years after implantation, the superior hemodynamic performance of aortic homograft and stentless porcine valve appears to result in more extensive regression of ventricular hypertrophy and greater improvement of left ventricular function than occurs with a mechanical or stented biological valve. These findings encourage the use of a stentless biological valve in older patients requiring aortic valve replacement, and a larger scale long-term randomized study of stentless versus stented biological valve or mechanical valve seems warranted.

Aged↗
PubMed1996

Histological abnormalities of muscle from limb, thorax and diaphragm in chronic heart failure.

The aim of the study was to compare histological findings in limb and respiratory muscles from control subjects and patients with heart failure of two different aetiologies. Biopsies of the quadriceps femoris, strap, diaphragm and pectoralis major muscles were taken from each group. The control subjects all had normal left ventricular function, and comprised seven undergoing surgical ablation of electrical pathways and 10 undergoing coronary artery surgery. The heart failure group had severely impaired left ventricular function, and were undergoing cardiac transplantation in all except one case. Ten patients with idiopathic dilated cardiomyopathy and seven with heart failure of ischaemic origin were studied. Conventional histochemical techniques and specific anti-myosin immunofluorescent stains were used. There were no consistent differences in fibre type prevalence or diameter between the groups. There were no important histological abnormalities in the two control groups. There were minor/major changes in four of seven patients with ischaemic heart failure but no major abnormality, whilst in the dilated cardiomyopathy group there were five of 10 patients with minor/major changes and three of 10 with major abnormalities (P < 0.001 vs controls). A variety of changes were seen in both groups of heart failure subjects. These were more marked in the dilated cardiomyopathy than ischaemic group, and suggest the presence of fibre type regeneration and/or transformation. Amongst the findings were tubular aggregates, internalization of nuclei, bizzare staining of myosin and staining of neonatal myosin (seven of 14) and the presence of cores (five of 14). Such changes were more prominent in the diaphragm than in the other muscles. In conclusion, histological abnormalities are present in the limb and respiratory muscles from subjects with heart failure. The changes are most marked in subjects with idiopathic dilated cardiomyopathy, suggesting that there may be a generalized cardiac and skeletal myopathy in these subjects. The presence of histological abnormalities in the respiratory muscles may contribute to the pathogenesis of dyspnoea in heart failure.

Adolescent↗
PubMed1996

Effects of incoordination on left ventricular force-velocity relation in aortic stenosis.

OBJECTIVE: Tension development is often incoordinate in the hypertrophic left ventricle (LV). The present study aimed to elucidate the possible effects of incoordination on standard LV force-velocity relations in patients with aortic stenosis (AS). DESIGN: Prospective study during aortic valve replacement with transoesophageal cross sectionally guided M mode echocardiogram, combined with high-fidelity LV pressure recorded by pressure transducer tip catheter, and thermodilution cardiac output. SETTING: Tertiary cardiac referral centre. PATIENTS: 37 patients (mean (SD) age 63 (12)) years were studied before and 20 hours after aortic valve replacement. MAIN OUTCOME MEASURES: LV function was assessed regionally by peak velocity of circumferential fibre shortening (peak Vcf), mean systolic wall stress, and peak myocardial power; and globally by LV stroke work index. LV coordination was quantified as cycle efficiency, derived from LV pressure-dimension loop (lower normal limit > or = 76%). RESULTS: 22 patients with a coordinate LV had significantly higher peak Vcf (1.85 (0.47) v 1.46 (0.64) s-1) peak myocardial power (20.8 (8.5) v 12.0 (6.1) mW.cm-3) and global stroke work index (440 (155) v 325 (150) mJ.m-2) than those of 15 patients with an incoordinate ventricle, all P < 0.05; though there was no significant difference in LV end diastolic dimension, mean systolic wall stress, LV mass index, or the incidence of coronary artery disease (P > 0.05, respectively). Furthermore, when contraction was coordinate, mean systolic circumferential wall stress correlated inversely with peak Vcf (r = - 0.71) and positively with peak myocardial power (r = 0.83), both P < 0.01. When contraction was incoordinate, these correlations did not apply; instead peak Vcf (r = 0.65) and peak myocardial power (r = 0.73) both correlated positively with cycle efficiency (P < 0.02 and 0.01, respectively). By 20 hours after surgery, values of cycle efficiency, peak Vcf, and myocardial power were indistinguishable in the previously coordinate and incoordinate groups. CONCLUSIONS: In aortic stenosis, incoordination causes a fall in LV peak Vcf proportional to the increase in systolic wall stress, and thus modifies the standard LV force-velocity relation to mimic depressed contractility. However, incoordination and subsequent ventricular dysfunction were largely reversible once the aortic stenosis had been relieved.

Aortic Valve↗
PubMed1996

Impairment of endothelium-dependent pulmonary vasodilation in patients with primary pulmonary hypertension.

BACKGROUND: Pulmonary vascular tone may be modulated by endothelium-derived vasoactive mediators. Endothelial dysfunction is thought to occur in primary pulmonary hypertension. The aim of this study was to evaluate the vascular responses of patients with severe primary pulmonary hypertension to endothelium-dependent vasodilators (for example, substance P) and non-endothelium-dependent vaasodilators (for example, adenosine). METHODS: Six patients with primary pulmonary hypertension (mean (SE) systolic, diastolic, and pulmonary artery pressures 91.1 (7), 45.2 (3), and 62 (4.2) mm Hg, respectively, and baseline total pulmonary vascular resistance (TPVR) 1949 (164) dynes.s.cm-5) underwent sequential infusions of substance P (5-100 pmol/min) and adenosine (5-50 micrograms/kg/min) in random order. Pulmonary and systemic haemodynamics were monitored by indwelling radial and pulmonary arterial catheters. RESULTS: Substance P caused a marked fall in systemic vascular resistance (SVR) but minimal pulmonary vasodilation (mean maximal percentage change from baseline in TPVR:SVR ratio 27.85 (6.5)%, p < 0.01). Adenosine caused TPVR to fall, but resulted in no change in SVR (mean maximum percentage change from baseline in TPVR:SVR ratio -9.85 (3.5)%, p < 0.05). CONCLUSION: Endothelium-dependent vasodilation is deficient in the pulmonary circulation of patients with primary pulmonary hypertension and may contribute to the abnormalities of pulmonary vascular tone and reactivity seen in that condition.

Adenosine↗
PubMed1995

Early changes in regional and global left ventricular function after aortic valve replacement. Comparison of crystalloid, cold blood, and warm blood cardioplegias.

BACKGROUND: The clinical effects of different cardioplegic methods on left ventricular (LV) function have not been fully elucidated, particularly in the setting of myocardial hypertrophy. METHODS AND RESULTS: Sixty-four patients (mean age, 62 +/- 12 years; 41 men, 23 women) who were undergoing elective aortic valve replacement (stenosis, 49; regurgitation, 15; concomitant coronary artery bypass grafting, 22), with LV mass index 230 +/- 70 g/m2, were randomized to the following groups: antegrade crystalloid cardioplegia (CCP, 21 patients), antegrade/retrograde cold blood cardioplegia (CBP, 23 patients), or continuous retrograde warm (37 degrees C) blood cardioplegia (WBP, 20 patients). Mean aortic cross-clamp and cardiopulmonary bypass times were 100 +/- 20 and 126 +/- 24 minutes. Positive inotropic drug therapy was required postoperatively in 9 patients after CBP, 14 after CCP, and 18 after WBP. Perioperative LV function was assessed using transesophageal M-mode echocardiography, combined with high-fidelity LV pressure recording and thermodilution cardiac output, before bypass and 0.5, 1, 3, 6, 12, and 20 hours after cross-clamp removal. There was a similar fall in LV peak circumferential wall stress at constant LV end-diastolic dimension in each group after aortic valve replacement. The increase in contraction velocity was significant from 0.5 hour with CBP; however, no significant increase occurred until 12 hours with CCP and until 20 hours with WBP. The rate and extent of LV pressure fall and early diastolic filling rate both increased with CBP, and only in this group did ventricular coordination improve. LV stroke work index was maintained with CBP throughout the postoperative period with less inotropic support than with the other two methods. CONCLUSIONS: In the hypertrophied LV, CBP offers the best preservation of myocardial physiological response and ventricular function with less inotropic support.

Adult↗