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Biomedical subjects

R A Tio

Publications and source records attributed to R A Tio.

At least 37 records · Page 2Linked to original sources
PubMed2001

Pathophysiology of vascular endothelium and circulating platelets: implications for coronary revascularisation and treatment.

Constant vasodilatation, inhibition of platelet and leukocyte adhesion, and local thrombolysis are the mechanisms through which an intact endothelial layer exerts its protective action on coronary circulation. A loss in these features is not only the first step in the development of atherosclerosis, but also a potent trigger for complications after revascularisation procedures. Percutaneous coronary interventions, particularly in the course of stenting, induce endothelial injury that can last up to months after the procedure. On the other hand, the preservation of endothelial function appears the best feature of arterial versus venous grafts after coronary bypass surgery. An early diagnosis either by invasive or non-invasive techniques has important implications for prognosis, and endothelial dysfunction can be effectively counteracted by medical treatment (ACE inhibitors, statins). Activated circulating platelets are present in the course of coronary artery disease, increasing the risk of thrombotic occlusion and/or plaque regrowth, after both percutaneous and surgical revascularisation. New antiplatelet agents are under development to reduce endothelium-platelet interaction. On the basis of the latest studies, coronary revascularisation should be integrated in a more complete treatment, which would take into account the complex processes involving the underlying atherosclerotic plaque.

Angioplasty, Balloon, Coronary↗
PubMed2001

An ultrafiltration catheter for monitoring of venous lactate and glucose around myocardial ischemia.

Early detection of myocardial ischemia is of major importance in critical-care medicine. Changes of lactate or glucose levels in the cardial venous efflux may be useful parameters. We succeeded in integrating an ultrafiltration membrane in a cardiac catheter for continuous sampling. The ultrafiltrate was analyzed outside the body, resulting in a lag-time of about 24 min. Biosensors in a flow-injection analysis system were used for minute by minute sample analyses. The coronary sinus of pigs was catheterized to monitor the effects of 5, 15 or 45 min ischemia by coronary artery obstruction or myocardial stress by dobutamine infusion. A total of 27 h was monitored. The intravascular response time was 1.33+/-0.61 min (10-90%). Linear regression in vivo of blood and ultrafiltrate samples was 0.977 for lactate and 0.994 for glucose. Lactate levels rose 0.38+/-0.10 mM above baseline within 5 min after ischemia. Reperfusion was clearly marked by a promptly peaking lactate release (maximum 9.27 mM). Myocardial stress by dobutamine increased glucose but not lactate levels. Once, a wall effect was noted at the catheter tip. In vivo semi-continuous myocardial monitoring of absolute lactate and glucose concentrations was thus achieved by an ultrafiltration catheter. Ischemia and reperfusion can be detected very early by a lactate level rise. Further, development of the ultrafiltration catheter will be focused on the diagnostic potential of lactate monitoring for patients.

Animals↗
PubMed2001

Autonomic dysfunction in patients with mild heart failure and coronary artery disease and the effects of add-on beta-blockade.

AIM: Autonomic impairment is related to the incidence of sudden death in chronic heart failure (CHF). Our objective was to study autonomic profiles in patients with mild CHF due to coronary artery disease, and to investigate the value of add-on beta-blockade. METHODS AND RESULTS: Measures of autonomic function (plasma norepinephrine, heart rate [HR] variability, autonomic function testing), and exercise capacity, were compared between 24 patients with mild CHF, and 24 healthy controls. In this mechanistic study, we assessed the effect of 26 weeks metoprolol treatment in a double-blind, randomized, placebo-controlled design. All patients received metoprolol sustained release (200 mg; n=12) or placebo (n=12). Assessments were made at baseline and after 10 and 26 weeks' treatment. At baseline, norepinephrine levels were elevated, while HR variability parameters were decreased in patients vs. controls (both P<0.05). Autonomic function testing showed only small differences, although significant alterations were observed with deep breathing and head up tilting (both P<0.05). After 26 weeks', metoprolol did not affect exercise capacity or norepinephrine concentrations. In contrast, HR variability was markedly improved in metoprolol-treated patients vs. placebo-treated patients (P<0.05). In particular, a shift toward normal in the sympathovagal balance was observed (P<0.05). Autonomic function testing showed only small, and generally non-significant trends after metoprolol. CONCLUSIONS: Marked autonomic abnormalities are already present in mild CHF, which may be (partially) reversed by metoprolol. These observations support the reported reduction of sudden death by beta-blockade in patients with CHF.

Adrenergic beta-Antagonists↗
PubMed2001

Eptifibatide and abciximab exhibit equivalent antiplatelet efficacy in an experimental model of stenting in both healthy volunteers and patients with coronary artery disease.

Platelet deposition and aggregation are the major determinants of acute thrombosis in coronary stents. We aimed to compare the antiplatelet efficacy of different treatments--glycoprotein (Gp) IIb/IIIa inhibitors and conventional antiaggregants--in an experimental model for stenting. Blood samples were obtained from patients with coronary artery disease (n = 15) and healthy volunteers (n = 8) and incubated either with eptifibatide (2.0 microg/ml), abciximab (3.0 microg/ml), indomethacin (15 microg/ml), or saline. Platelet adenosine diphosphate-induced aggregation in whole blood was assessed for all groups. Blood was also tested in an experimental circulation model containing metallic probes, on which platelet deposition in shear flow conditions was assessed by means of fluorescent-labeled platelet-specific (anti-GpIIIa and Ib) antibodies. Eptifibatide and abciximab, in comparison with indomethacin and no treatment, significantly reduced platelet aggregation (0, 0, 4, and 3 arbitrary units [AU], respectively; p < 0.001), anti-GpIIIa (2.25, 1.83, 11.24, and 13.42 counts per second [cps]/mg, respectively; p < 0.001), and anti-GpIb binding (0.61, 0.61, 1.00, and 1.83 cps/mg, respectively; p < 0.001). Anti-GpIIIa and anti-GpIb binding were significantly correlated (R = 0.36; p < 0.01). Patients showed a higher anti-GpIIIa, but not anti-GpIb binding, than controls (8.43 versus 3.33 cps/mg; p < 0.01), irrespective of treatment. In conclusion, eptifibatide and abciximab show equivalent in vitro antiplatelet efficacy, superior to that of indomethacin. Given the occurrence of GpIIb/IIIa platelet overexpression in the course of coronary artery disease, an extended use of GpIIb/IIIa inhibitors may be proposed to prevent acute thrombosis during routine coronary stenting.

Abciximab↗
PubMed2001

Continued cigarette smoking after coronary artery bypass surgery reduces endothelium-dependent vasodilation in internal thoracic artery grafts.

BACKGROUND: Cigarette smoking is known to promote endothelial dysfunction, thus it can be responsible for an impaired endothelium-dependent vasomotility in arterial grafts late after coronary surgery. METHODS: Twenty consecutive patients (mean age 64.5 years), previously submitted to coronary bypass surgery with the internal thoracic artery, underwent quantitative angiography of the implanted graft at long-term follow-up (mean time 2.5 years). To assess both endothelium-dependent and independent vasomotility, angiograms were acquired before and after selective infusions of acetylcholine (10(-6) mmol/ml) and nitroglycerine (500 microg). The predictive value of risk factors, including previous and continued smoking, for an impairment in endothelium-dependent vasomotility was assessed. RESULTS: Continued smoking (p = 0.038), but not a previous history of smoking (p = 0.55) was the only predictor of a reduced endothelium-dependent vasodilation. While previous smokers and non-smokers showed a similar response to acetylcholine, current smokers showed a reduced endothelium-dependent vasodilation vs non-smokers (94.8 +/- 2.6 vs 99.6 +/- 2.3% of the maximal vasodilative capacity, p = 0.001). CONCLUSIONS: Although maintained, the vasodilative response to acetylcholine appears reduced in internal thoracic artery grafts of patients who continued smoking long term after coronary bypass surgery. Whether this could affect the long-term outcome of these patients has to be further investigated.

Acetylcholine↗
PubMed2000

Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that regulates expression of genes involved in O(2) homeostasis, including vascular endothelial growth factor (VEGF), a potent stimulator of angiogenesis. We sought to exploit this native adaptive response to hypoxia as a treatment for chronic ischemia. METHODS AND RESULTS: A hybrid protein consisting of DNA-binding and dimerization domains from the HIF-1alpha subunit and the transactivation domain from herpes simplex virus VP16 protein was constructed to create a strong, constitutive transcriptional activator. After transfection into HeLa, C6, and Hep3B cells, this chimeric transcription factor was shown to activate expression of the endogenous VEGF gene, as well as several other HIF-1 target genes in vitro. The bioactivity of HIF-1alpha/VP16 hybrid gene transfer in vivo was examined in a rabbit model of hindlimb ischemia. Administration of HIF-1alpha/VP16 was associated with significant improvements in calf blood pressure ratio, angiographic score, resting and maximal regional blood flow, and capillary density (all P:<0.01). CONCLUSIONS: The HIF-1alpha/VP16 hybrid transcription factor is able to promote significant improvement in perfusion of an ischemic limb. These results confirm the feasibility of a novel approach for therapeutic angiogenesis in which neovascularization may be achieved indirectly by use of a transcriptional regulatory strategy.

Angiography↗
PubMed2000

Re-evaluation of the cold face test in humans.

The cold face test has been found to be a simple clinical test to elicit the diving reflex, which assesses function of the sympathetic and parasympathetic nerve systems at the same time. However, there is no consensus about how the test should be performed without confounding the results by eliciting other reflexes, such as the oculocardiac reflex. The object of this study was to compare and standardize methods for performing the cold face test. Reproducibility of results was assessed. Groups of 6 to 11 subjects participated in each protocol. To act as a cold stimulus a bag filled with iced-water and having a wet surface was used. The effects of allowing breathing to continue, of different masses of the bag, and of avoiding ocular pressure by wearing diving goggles were investigated. Blood pressure and heart rate were measured beat to beat using an automatic blood pressure measuring device. The cold stimulus used in this study was too small to elicit the oculocardiac reflex: wearing diving goggles and different masses of the bag had no influence on the response. The prevention of breathing, however, tended to enhance the fall in heart rate during the cold stress. Reproducibility was highest when the subjects were habituated to the intensity of the stimulus. We recommend practising the test method in advance and performing it in a setting where the subject is unable to breathe.

Adult↗
PubMed2000

Negative inotropic effects of recombinant interleukin 2 in patients without left ventricular dysfunction.

UNLABELLED: Experimental data have shown that rIL2 has negative inotropic properties. This has not been investigated in humans with normal left ventricular function. Seventeen consecutive renal cell carcinoma patients who received rIL2 therapy because of dissemination were analyzed before and after treatment with a low dose of rIL2 subcutaneously. Left ventricular ejection fraction (echocardiography), heart rate variability parameters (24 h electrocardiography), and TNF alpha, IL1 beta and nitric oxide metabolites (NO(x)) were measured. LVEF decreased from 54+/-7 to 50+/-6% (mean+/-S.D.; P=0.012), with a concomitant increase in heart rate from 87+/-13 to 94+/-13 beats/min (P=0.031). All frequency domain HRV parameters decreased: the total power from 18.0+/-7.9 to 14.0+/-5.0 ms (P=0.001), the low frequency from 10.3+/-5.4 to 8. 3+/-3.4 ms (P=0.001), and the high frequency from 6.3+/-2.6 to 4. 5+/-1.1 ms (P=0.001). There was no measurable effect on TNF alpha, IL1 beta concentrations. Plasma levels of nitrate (NO(x)) increased from 22.8+/-14.4 to 41.8+/-26.6 micromol/l (P=0.007). CONCLUSIONS: A low dose of rIL2 has a negative inotropic effect that may be mediated by increased NO concentrations. It also reduces sympathetic activity as reflected in HRV parameters.

Adult↗
PubMed2000

Comparison of zofenopril and lisinopril to study the role of the sulfhydryl-group in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure.

We evaluated the role of SH-groups in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure. To this end, we compared the vasoprotective effect of chronic treatment with zofenopril (plus SH-group) versus lisinopril (no SH-group), or N-acetylcysteine (only SH-group) in myocardial infarcted (MI) heart failure rats. After 11 weeks of treatment, aortas were obtained and studied as ring preparations for endothelium-dependent and -independent dilatation in continuous presence of indomethacin to avoid interference of vasoactive prostanoids, and the selective presence of the NOS-inhibitor L-NMMA to determine NO-contribution. Total dilatation after receptor-dependent stimulation with acetylcholine (ACh) was attenuated (-49%, P<0.05) in untreated MI (n=11), compared to control rats with no-MI (n=8). This was in part due to impaired NO-contribution in MI (-50%, P<0.05 versus no-MI). At the same time the capacity for generation of biologically active NO after receptor-independent stimulation with A23187 remained intact. Chronic treatment with n-acetylcysteine (n=8) selectively restored NO-contribution in total dilatation to ACh. In contrast, both ACE-inhibitors fully normalized total dilatation to ACh, including the part mediated by NO (no significant differences between zofenopril (n=10) and lisinopril (n=8)). Zofenopril, but not lisinopril, additionally potentiated the effect of endogenous NO after A23187-induced release from the endothelium (+100%) as well as that of exogenous NO provided by nitroglycerin (+22%) and sodium nitrite (+36%) (for all P<0.05 versus no-MI). We conclude that ACE-inhibition with a SH-group has a potential advantage in improvement of endothelial dysfunction through increased activity of NO after release from the endothelium into the vessel wall. Furthermore, this is the first study demonstrating the selective normalizing effect of N-actylcysteine on NO-contribution to ACh-induced dilatation in experimental heart failure.

Acetylcholine↗
PubMed2000

Functional integrity and aging of the left internal thoracic artery after coronary artery bypass surgery.

OBJECTIVE: To study the endothelial function in the left internal thoracic artery after coronary artery bypass surgery and to identify predictors of early dysfunction, we performed a provocative test with acetylcholine in 23 male patients who underwent routine postoperative coronary angiography. METHODS: The change in mean diameter of the proximal thoracic artery was assessed by quantitative angiography after selective injections of acetylcholine and nitroglycerin. RESULTS: The thoracic artery showed a 6.8% (P <. 001) and 9.0% (P <.001) increase in mean diameter after acetylcholine and nitroglycerin administration, respectively. Vasodilative responses to acetylcholine and nitroglycerin administration were strongly correlated (R: 0.88; P <.001). Among the common risk factors, only age was associated with an impairment in the vasodilative response of the arterial graft (P =.001), and acetylcholine-induced vasodilation was inversely correlated to the age of the patient (R: 0.69; P <.001). CONCLUSIONS: Endothelium-dependent vasodilative response to acetylcholine administration seems well preserved in the left internal thoracic artery after surgery. Common risk factors, except for age, do not affect the functional integrity of the arterial graft. The vasodilative properties of the graft depend on the age of the patient and do not deteriorate over time after operation.

Acetylcholine↗
PubMed1999

Intramyocardial gene therapy with naked DNA encoding vascular endothelial growth factor improves collateral flow to ischemic myocardium.

Both VEGF protein and VEGF DNA in combination with an adenoviral vector have been shown to enhance collateral formation in a porcine model of chronic myocardial ischemia. We sought to determine whether direct intramyocardial injection of naked DNA encoding for VEGF could similarly improve myocardial perfusion. Initially, 23 nonischemic pigs received either 200 microg of plasmid DNA encoding beta-galactosidase (pCMVbeta, n = 11) or 500 microg of phVEGF165 (n = 12) into four separate sites in the myocardium via a small anterolateral thoracotomy incision in the fourth intercostal space. Two additional groups of pigs received an intramyocardial injection of either phVEGF165 (n = 6) or pCMVbeta (n = 7) 3 to 4 weeks after implantation of an ameroid constrictor around the left circumflex coronary artery. The injections caused no change in heart rate or blood pressure, and no ventricular arrhythmias or histologic evidence of inflammation. VEGF protein was detected by Western blot in VEGF-treated animals, with the strongest bands closest to the injection site. Plasma VEGF concentration (ELISA) increased from 3+/-2 to 27+/-13 pg/ml (p = 0.035) by day 4 after treatment. No increase in VEGF protein was noted in pCMVbeta-treated animals whereas these did stain positive for beta-Gal. Resting myocardial blood flow (colored microspheres) was significantly reduced in the ischemic versus nonischemic territory in control animals (1.07+/-0.05 versus 1.32+/-0.05; p < 0.05) but not VEGF-treated pigs (1.32+/-0.24 versus 1.13+/-0.12; p = NS). Maximal vasodilatation with adenosine significantly increased flow to the ischemic region in VEGF-treated pigs (2.16+/-0.57 versus 1.32+/-0.24; p < 0.05) but not controls (1.31+/-0.05 versus 1.17+/-0.06;p = NS). Collateral filling of the occluded circumflex artery improved in five of six VEGF-treated pigs (mean change in Rentrop score, +1.5). We conclude that direct intramyocardial transfection phVEGF165 is safe and capable of producing sufficient VEGF protein to enhance collateral formation and myocardial perfusion. This approach may offer an alternative therapy for patients with intractable myocardial ischemia not amenable to PTCA or CABG.

Animals↗
PubMed1999

Clinical follow-up after cessation of chronic electrical neuromodulation in patients with severe coronary artery disease: a prospective randomized controlled study on putative involvement of sympathetic activity.

The present study assessed the reoccurrence of myocardial ischemia after withholding electrical neurostimulation. After randomization, in the study or withdrawal group, spinal cord stimulation (SCS) was set active during the first 4 weeks, followed by 4 weeks of withholding stimulation. In the control group, SCS was switched off during 4 weeks before the end of the study. The control group had no crossover period. Measurements were done at baseline, then after 4 and 8 weeks. The first periods at 4 weeks of each sequence of both groups were compared. In addition, a comparison of clinical variables was performed between the study group 4 weeks after withholding stimulation and the control group 4 weeks following randomization. A total number of 24 patients with refractory angina and an implanted spinal cord stimulator were included in the study (n = 12) and control group. Angina pectoris complaints, nitroglycerin intake, ischemia, and heart rate variability using 48-hour ambulatory electrocardiographic monitoring were assessed. In addition, neurohormonal status and symptom-limited aerobic capacity were evaluated. There was no increase of anginal complaints or ischemia after withholding stimulation. Neurohormonal levels and aerobic capacity were not altered. We conclude that there is no adverse clinical rebound phenomenon after withholding neurostimulation in patients with refractory angina pectoris.

Aged↗
PubMed1999

Humoral immune response to human cytomegalovirus in patients undergoing percutaneous transluminal coronary angioplasty.

Possible causal relations between prior human cytomegalovirus (HCMV) infection and atherosclerosis and between HCMV reactivation and restenosis after coronary angioplasty have been suggested. We investigated patterns of antibodies directed to HCMV in 112 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and in a group of sex- and age-matched controls (blood donors without evidence of atherosclerosis). Levels of antibodies to HCMV were measured by enzyme-linked immunosorbent assay (ELISA) of serum samples drawn before and 5 weeks after PTCA. To further differentiate the humoral immune response, we specifically tested antibody reactivity towards four single HCMV proteins (IE2, p52, pp150, and pp65) by recombinant ELISAs. We found that 73% of PTCA patients and 69% of sex- and age-matched controls were seropositive for HCMV (odds ratio, 1.2 [not significant]). The corresponding odds ratios for matched pairs ranged in the recombinant ELISAs from 1.2 to 1.4. Patients had more often high titers of anti-HCMV antibodies (11 versus 4%; odds ratio = 3.3 [0.9 to 15.2]; P = 0.052) and high titers of anti-pp150 antibodies (13 versus 4%; odds ratio = 6.0 [1.3 to 38.8]; P = 0.008). Anti-HCMV immunoglobulin M antibodies were not detected in any patient. There was no evidence of acute HCMV reactivation after PTCA, since the titers of antibodies to the investigated recombinant proteins did not increase at 5 weeks after PTCA. Our results show a limited association between prior HCMV infection and coronary artery disease. We infer that positive anti-HCMV titers are not a major risk factor at the time of disease manifestation. However, this study cannot rule out a possible role of HCMV at earlier stages of the atherosclerotic process. Recombinant ELISAs provide a valuable tool for investigating the antiviral immune response.

Adult↗
PubMed1999

Coronary angioplasty induces rise in Chlamydia pneumoniae-specific antibodies.

Chlamydia pneumoniae is frequently found in atherosclerotic lesions, and high titers of specific antibodies are associated with increased risk for acute myocardial infarction. However, a causative relation has not been established yet. We performed a prospective study of 93 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) to investigate whether angioplasty influences Chlamydia-specific antibody titers and whether there is an association with restenosis. Blood samples were obtained before and 1 and 6 months after angioplasty. Antibodies against chlamydial lipopolysaccharide and against purified C. pneumoniae elementary bodies were measured by enzyme-linked immunosorbent assay (ELISA). After angioplasty, the prevalence of antibodies to lipopolysaccharide rose from 20 to 26% for immunoglobulin A (IgA), from 53 to 64% for IgG, and from 2 to 7% for IgM (P = 0.021, 0.004, and 0.046, respectively). There was a rapid increase of mean antibody titers of all antibody classes within 1 month of PTCA. During the following 5 months, antibody titers decreased slightly but were still higher than baseline values. Results of the C. pneumoniae-specific ELISA were essentially the same. The rise of anti-Chlamydia antibodies was not caused by unspecific reactivation of the immune system, as levels of antibodies against cytomegalovirus did not change. Neither seropositivity nor antibody titers were related to restenosis. However, increases in mean IgA and IgM titers were restricted to patients who had suffered from myocardial infarction earlier in their lives. In conclusion, we show that PTCA induces a stimulation of the humoral immune response against C. pneumoniae. These data support the idea that plaque disruption during angioplasty might make hidden chlamydial antigens accessible to the immune system.

Adult↗