2P-0534 Association of coronary atheorosclerosis with coronary flow velocity reserve evaluated by transthoracic Doppler echocardiography

Tuesday September 30, 2003: Poster Session Diagnosis

156 2P-0529

A novel family of compounds with beneficial effects in mouse models of dyslipidemia and ischemic stroke

L. Millatt 1 , K. Bertrand 1 , R. Darteil 1 , P. Verwaerde 1 , D.W. Hum 1 , N. Provost 1 , P. Poulain 1 , Z. Majd 1 , S. Helleboid 1 , J.-F. Delhomel 1 , R. Bordet 2 , J. Fruchart 3 , B. Staels 4 , J.-C. Fruchart 4 . 1 Genfit, Parc Eurasante, Loos, 2 University of Lille II, 3 Genfit, Institut Pasteur de Lille, 4 Institut Pasteur de Lille, France Objectives: Dyslipidemia is implicated as a risk factor for ischemic stroke, and hypolipidemic agents are therapeutic candidates for stroke prevention. Oxidative stress is implicated in neuronal injury following ischemia-reperfusion, and anti-oxidant compounds are thus neuroprotective. Here we present a novel class of proprietary molecules (GFTs) designed to have pleiotropic protective effects in ischemic stroke. Methods: In vitro studies addressed the ability of GFT family members to activate the transcription factor PPARα and to inhibit LDL oxidation. The hypolipidemic effects of GFT family members were investigated in dyslipidemic human apolipoprotein E2 (apoE2) transgenic mice. The neuroprotective activity of GFT family members was tested using a mouse model of focal ischemia induced by transient middle cerebral artery occlusion (MCAO). Results: In vitro studies revealed that selected GFT family members activate PPARα, and selected compounds showed the ability to inhibit LDL oxidation. In apoE2 transgenic mice, 8 days of treatment with selected GFT family members reduced plasma lipid levels. In the C57BL/6 mouse MCAO model of ischemic stroke, selected GFT family members reduced cerebral infarct size when they were administered during the 72 hours immediately following MCAO injury. Moreover, the compounds shown by in vitro studies to possess both PPARα activation and anti-oxidant properties reduced mortality in the mouse MCAO model. Conclusion: We demonstrate that selected GFT family members have both hypolipidemic and neuroprotective effects, likely mediated via their anti-oxidant properties and their ability to activate PPARα. By virtue of their pleiotropic properties, these GFT compounds therefore represent novel therapeutic candidates for the treatment of dyslipidemia and/or the prevention of stroke-induced brain damage.

DIAGNOSIS 2P-0531

Associations of coronary artery disease (CAD) with plaques in thoracic and abdominal aorta, detected by magnetic resonance imaging (MRI)

K. Ashida 1 , Y. Momiyama 1 , H. Taniguchi 1 , R. Ohmori 1 , T. Kihara 2 , A. Kameyama 2 , K. Noya 2 , M. Nagata 2 , F. Ohsuzu 1 . 1 National Defense Medical College, Saitama; 2 Iruma Heart Hospital, Japan Recently, MRI can detect atherosclerotic plaques in aorta (Ao). Using MRI, we studied associations of CAD with plaques in both thoracic and abdominal Ao. MRI was performed using a double inversion recovery fast SE sequence in 100 patients (pts) who had elective coronary angiography. T2W images of Ao were obtained every 12 mm and, in each pt, we assessed the presence of plaques in 9 slices of thoracic descending Ao and 9 slices of abdominal Ao. Results: Of the 100 pts, 77 (77%) had CAD (>50% stenosis). In MRI, plaques in thoracic and abdominal Ao were found in 60 (60%) and 90 (90%) pts, respectively. Compared with 23 pts without CAD, 77 with CAD more often had plaques in thoracic (70% vs 26%) and abdominal Ao (95% vs 74%) (P<0.025). There were stepwise increases in the prevalence of both thoracic and abdominal Ao plaques depending on the number of >50% stenotic coronary vessels. The extents of plaques (the numbers of slices with plaques) in thoracic and abdominal Ao also correlated with the number of >50% stenotic segments (r=0.30 and r=0.34, P<0.005) by Spearman’s rank test. As for the prediction of CAD, the presence of thoracic Ao plaques had a sensitivity of 70% and a specificity of 74%. The presence of 2 or more plaques in abdominal Ao had a higher sensitivity (90%) but a much lower specificity (39%). CAD was predicted better by assessing both Ao, and the presence of 4 or more plaques in Ao predicted CAD with a sensitivity of 86% and a specificity of 65%. The sensitivity was similar in pts 70 yrs or older and pts <70 yrs (89% vs 84%), but the specificity was much lower in pts 70 yrs or older (43% vs 75%). Conclusion: MRI is useful to detect plaques in thoracic and abdominal Ao noninvasively. CAD was related to plaques in both Ao and could be predicted better by assessing both Ao than either thoracic or abdominal Ao alone. However, the prediction of CAD by Ao plaques is useful only in pts <70 yrs.

2P-0532

High brachial-ankle pulse wave velocity is an independent predictor for the presence of coronary artery disease in men

R. Imanishi, S. Seto, G. Toda, Y. Koide, T. Baba, K. Yano. Department of Cardiovascular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Japan Objective: Pulse wave velocity (PWV) is an index of arterial stiffness. Recently, brachial-ankle PWV (baPWV) has been developed as a simple measurement device, in place of carotid-femoral PWV. However the clinical application of baPWV in patients with coronary artery disease (CAD) remains to be fully evaluated. This cross-sectional study was conducted to evaluate whether a higher baPWV predicts the presence of CAD. Methods: baPWV was measured in 135 patients (83 males, 52 females; 63.8±11.8 years) who were undergoing coronary angiogram. CAD was defined as >50% diameter stenosis. Hemodynamic data and cardiovascular risk factors were examined according to the presence or absence of CAD. Results: Patients with CAD were significantly older across both sexes. Pulse pressure, body mass index, and hypertension were correlated with CAD in females. baPWV, diabetes and hyperlipidemia were related to the presence of CAD in males. Multivariate logistic regression analysis in male patients showed that baPWV, diabetes, and hyperlipidemia were independent factors to the presence of CAD. Furthermore, a high baPWV in males without diabetes and hyperlipidemia produced a positive predictive value of 81% for the presence of CAD. Conclusion: High baPWV is a strongly independent predictor for the presence of CAD in men. 2P-0533

Plasma and whole blood serotonin concentrations are novel makers for vasospastic angina pectoris

H. Takahashi 1 , K. Hara 1 , M. Yoshika 1 , Y. Nagahama 1 , Y. Tshuka 1 , T. Iwasak 1 , Y. Hirowatari 2 . 1 Kansai Medical University; 2 TOSOH Corporation, Japan Serotonin is taken up into platelets and condensed there, which is released at the site of activation of platelets. Atherosclerotic vessels potentially stimulate platelets via exposed subendothelial matrix, increased catecholamines due to sympathetic activation, and increased proinflammatory cytokines. We have previously found that plasma levels of serotonin are elevated, but the whole blood levels are decreased in patients with ischemic heart diseases. The ratio, plasma/whole blood serotonin levels, was markedly elevated in those patient groups. In the present study, we selected patients with vasospastic angina pectoris by the provocation test with ergonovin during the coronary angiogram. The patients were divided into three groups according to the vasospastic response, which were normal (N), incomplete vasospastic (BL), and complete vasospastic groups (VSA). The plasma levels of serotonin are markedly elevated in the VSA group, and were also significantly elevated in the BL group as compared to the N group. On the other hand, the whole blood levels are decreased patient groups as the mirror image of the plasma level. Therefore, the ratio, plasma/whole blood serotonin levels, was greatly elevated in the VSA groups. The sampling was continued for several months after the coronary angiography in a few patients. The plasma serotonin level was markedly elevated initially, and then rapidly decreased to about less than 10% of the initial value with proper medications. Plasma serotonin levels are tended to decrease with combination therapy of aspirin and ticlopidine. These findings strongly suggested that serotonin is deeply involved in the pathophysiology of vasospastic angina. 2P-0534

Association of coronary atherosclerosis with coronary flow velocity reserve evaluated by transthoracic Doppler echocardiography

K. Yamashita, H. Tasaki, H. Suzuka, S. Nihei, N. Hirakawa, Y. Nakashima. 2nd Internal Medicine, Univ. Occup. Environ. Health, Japan Background: To examine the usefulness of coronary flow velocity reserve (CFVR) with transthoracic Doppler echocardiography (TTDE) in detection of coronary artery atherosclerosis, we measured CFVR in left anterior descending coronary artery (LAD). Methods: We studied in 184 patients who had subsequently undergone coronary angiography. CFVR was defined as the ratio of hyperemic coronary flow velocity (CFV) during ATP infusion to basal CFV. We divided patients into two groups according to the value of CFVR (CFVR >2; Normal group,

XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan

Tuesday September 30, 2003: Poster Session Diagnosis CFVR<2; Abnormal group), percent diameter stenosis (%DS) of quantitative coronary angiography (QCA) in LAD (%DS > 50%; Stenosis(S) group, %DS < 50%; non-S group). Results: CFVR from mean CFV in Normal and Abnormal group was 2.71 (n=117) and 1.46 (n=67) (p<0.0001), and %DS in S group (n=126) and non-S group (n=58) was 69% and 14% (p<0.0001), respectively. CFVR<2 predicted significant stenosis with a sensitivity of 79% and a specificity of 83%. CFVR significantly correlated with %DS (r=0.555, p<0.0001). Conclusion: CFVR with TTDE can non-invasively provide the equivalent information of significance of coronary artery atherosclerosis to coronary angiography. 2P-0535

Short term remodelling of the aorta of cholesterol fed New Zealand White (NZW) rabbits shown by high-resolution magnetic resonance imaging (MRI)

L. Hegyi 1 , A.L. Busza 2 , P.D. Hockings 2 , J.N. Skepper 3 , T.A. Carpenter 4 , G.A. Whelan 2 , D.C. Grimsditch 2 , P. Overend 2 , G.M. Benson 2 , D.G. Reid 2 , K.E. Suckling 2 , P.L. Weissberg 1 . 1 Department of Medicine, Cambridge University; 2 GlaxoSmithKline, Welwyn, Herts.; 3 Multi-Imaging Centre, Cambridge University; 4 Wolfson Brain Imaging Centre, Cambridge University, United Kingdom

2P-0536

A new method of determining pulse wave velocity among individuals with one or two parents afflicted with coronary artery disease

H. Marcoyannopoulou Fojas, N. Papageorgakis, A. Melpidou, G. Fojas, G. Jullien. Evangelismos University Hospital, Greece Purpose: To compare the Pulse Wave Velocity (P.W.V.) in subjects with negative family history (FH) of coronary artery disease (CAD) and individuals with one or two parents afflicted with the disease. Method: Arterial wall elasticity was determined indirectly by P.W.V. using a new and original method patented by the senior author (H.M.F) in the USA and Europe. We use an electronic device which records the LEFT EXTERNAL CAROTID and LEFT DORSALIS PEDIS arterial pulses simultaneously with a single lead ECG. The time delay between the two pulses is computed automatically. A SHORTER TIME OF P.W.V. indicates DECREASED ARTERIAL WALL ELASTICITY. Materials: A total of 108 asymptomatic subjects of average heights, normal body mass, with normal BP and ECG in sinus rhythm, normal blood sugar and lipid profiles were studied. Of these 108 subjects, 63 had negative FH of CAD; 32 had one parent with CAD, and 13 had two parents with CAD. Results: The mean time of P.W.V. (sec.) for each group were: l) (-) FH -0.1613; 2) One affected parent - 0.1553; and 3) Two affected parents -0.1354. The differences are statistically significant, i.e., Linear Regression Model - p = 0.011. P.W.V time reduces by 0.009 sec. comparing (-) FH cases vs. (+) FH cases and by 0.018 sec. for one parent vs. two parents.

Conclusion: Subjects without FH of CAD have longer time of PWV and thus have lower risk of developing the disease compared to those with positive history. Individuals with two parents affected with CAD have shorter time of P.W.V. and thus have higher risk of developing the disease compared with those with only one affected parent. 2P-0537

Pulse wave analysis (PWA) and experimental stressors can be used to study vascular reactivity

C. Åhlund 1 , K. Pettersson 2 , L. Lind 2 . 1 Experimental Medicine, AstraZeneca, Sahlgrenska University Hospital, Gothenburg, Sweden; 2 AstraZeneca R&D Mölndal, Sverige Objectives: PWA of reflected pulse waves is largely used to study systolic augmentation due to pulse wave reflection. Attempts have been made to study reactivity in peripheral vascular beds, normally including the use of vasoactive drugs. Here we describe a method to study peripheral circulation non-invasively. Methods: Digital blood pressure was recorded non-invasively using a Portapres® device. Two reflected waves were identified, one systolic and one diastolic. We analysed the magnitude of these peaks in relation to pulse pressure, and timing in relation to the systolic pressure peak. As stressors we used mental arithmetic (MAT) and cold pressor (COP) tests and bicycle exercise. Results: The reflected pressure peak seen during systole arrived earlier and was increased slightly in amplitude during MAT and markedly during COP (p< 0.05). The diastolic peak arrived earlier and was reduced in amplitude compared to the systolic peak during MAT (p<0.01), while COP induced smaller effects. Bicycle exercise at 100 and 140 heart beats per minute caused the reflected peak in systole to be undetectable in most subjects and induced a marked reduction in the amplitude of the first diastolic reflected peak (p<0.01), and time to its appearance was markedly reduced at 140 bpm. Conclusions: The systolic and diastolic peaks reacted differently to the stressors, indicating that they arise in different vascular beds. Pulse wave velocity comparisons indicate the systolic wave originates in the abdomen and the diastolic wave in the legs. Stressors known to change vascular resistance affected pulse wave reflection in predictable ways. This non-invasive technique can be used to study vascular reactivity in abdominal and limb segments during disease development. 2P-0538

Can we screen postprandial hyperlipidemia with a single blood sample obtained after lunch?

Y. Nakamura, T. Miida, Y. Makiyama, T. Mezaki, T. Tanaka, T. Saigawa, T. Ozawa, R. Watanabe, K. Tsuchida, S. Minagawa, O. Hanyu, S. Hirayama, Y. Aizawa. First Department of Internal Medicine, Niigata University Hospital, Niigata, Japan Back ground: As highly atherogenic TG rich lipoprotein is elevated in patients with postprandial hyperlipidemia(PPHL), they are considered high risk population for coronary heart disease. Complicated test such as fat loading are required to diagnose PPHL so it is an urgent clinical need to establish easier screening method for PPHL. We have already reported that fasting TG concentrations can be estimated with estimation equation (A): TG(fasting) = 1.0 ∗ Exp(4.342 - 0.01873 ∗ HDLC(after lunch)+0.1403 ∗ ApoC3(after lunch) (R2=0.72, p=0.000001) (The 34th Annual Meeting of the Japan Ahtherosclerosis Society) Objective: To investigate whether PPHL can be screened with blood samples obtained after lunch by using Equation (A). Method: Blood samples were collected after overnight fast and 2 hours after lunch(al), then serum concentrations of TG, High density lipoproteincholesterol(HDLC) and apolipoproteinsC3(ApoC3) were measured. Hypertriglyceridemia was defined as serum TG of 150 mg/dl or over. Hyperlipidemic and PPHL patients were defined as patients who had high fasting TG and and high alTG and who had normal fasting TG and high alTG. Diagnosis of each patient was made according to actual and estimated TG concentration and validity of diagnosing PPHL with Equation(A) was examined. Result: 58 inpatients (35 normolipidemia (NL), 8 hyperlipidemia (HL), and 15 PPHL) were investigated. We diagnosed them as 35 NL, 10 HL and 13 PPHL with Equation(A). Sensitivity, specificity and positive predictive value for diagnosing PPHL with Equation(A) were 60%, 91% and 69%, respectively. Conclusion: It is possible to screen PPHL with single blood sample taken after lunch by using Equation(A).

XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan

TUESDAY

Objectives: To study the effects of atherosclerotic plaque progression and regression on vessel remodelling by high-resolution longitudinal MRI in a rabbit model of atherosclerosis.Methods: 18 NZW rabbits were fed a diet containing 0.2% cholesterol for 12 weeks, followed by a normal diet for a further 12 weeks. After 14 days on the diet, the animals underwent balloon injury to the abdominal aorta. MRIs of the abdominal aorta were acquired on a 2T Bruker Medspec scanner. A respiratory- and ECG-gated 2D Fast Spin Echo sequence was used. Acquisition was performed with and without fat suppression. In-plane resolution was 250 µm. MRI was performed immediately after the start of the diet and then at 8, 12, 16, 20 and 24 weeks. After the last image the rabbits were culled and their aortas were examined by histology. Results: All rabbits developed atherosclerosis measured as an increase in vessel wall volume. Over the 12-week cholesterol feeding period wall volume over the entire imaged aorta increased by 0.156 ± 0.1 cm3 (p = 0.0001). Vessel wall volume did reduce after the return to normal diet but not until week 24 (0.175 ± 0.07 cm3 , p = 0.0001 compared with week 12), by which time wall volume had returned almost to normal (0.143 ± 0.04 cm3 ). Lumen volume increased significantly over the first 8 weeks (p=0.0001), and then remained unchanged throughout the rest of the study. Histology at the end of the study showed that lesions, if present, as small as 0.3 mm in thickness were clearly visible by MRI. Conclusions: MRI is an appropriate method to detect vessel remodelling during progression and regression of atherosclerotic lesions in short term experiments. High-resolution MRI should prove of great benefit in monitoring of potential therapeutic agents in anti-atherosclerosis studies.

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