Background: To investigate the significance of lipid disorders and endothelial dysfunction in
the pathogenesis of microvascular angina.
Methods: Levels of plasma lipids, lipoproteins and apolipoproteins were assessed in 21 patients
with microvascular angina and 24 healthy subjects as controls. Also, the endothelium-dependent
vasodilatation function was determined with high-resolution ultrasound in both groups.
Results: Levels of serum total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C),
apolipoprotein B100 (ApoB100) and lipoprotein(a) [Lp(a)] in microvascular angina group
were significantly higher than those in healthy subjects (each p < 0.05). The flow-mediated
dilatation (FMD) in brachial arteries in patients with microvascular angina declined significantly
as compared with that in control subjects (4.7 &#177; 1.9% vs. 12.8 &#177; 3.7%, p < 0.001).
However, no significant difference was observed in response to nitroglycerin between groups
(19.7 &#177; 8.1% vs. 21.2 &#177; 6.6%; p > 0.05). Linear correlation analysis revealed a significant
negative correlation between the FMD of brachial arteries and the serum levels of LDL-C and
Lp(a) in the microvascular angina group (r = -0.5125 and -0.4271, respectively, both p < 0.001). Subsequently, all subjects were pooled and divided into two groups (groups A and B)
according to the degree of FMD in brachial arteries (A &#163; 4% and B > 4%). The serum LDL-C
level was found to be significantly higher in group A than in group B (4.09 &#177; 0.65 mmol/L vs.
2.59 &#177; 0.49 mmol/L; p < 0.05).
Conclusions: Plasma lipid disorders and vascular endothelial dysfunction may play important
roles in the development of microvascular angina. The dysfunction of endothelium-dependent vasodilation was mainly associated with anomalies in LDL-C and Lp(a), and
myocardial endothelial dysfunction was aggravated by lipid abnormalities in patients with
microvascular angina

Liu, Qi-ming

Minghuib, Liu

Qi, Shu-shan

Zhao, Shui-ping

Zhou, Sheng-hua

English

Via Medica Journals

ORIGINAL ARTICLECardiology Journal2008, Vol. 15, No. 4, pp. 324–328Copyright © 2008 Via MedicaISSN 1897–5593www.cardiologyjournal.org324Address for correspondence: Qi-ming Liu, MD, Department of Cardiology, the Second Xiangya Hospital of Central SouthUniversity, Changsha, Hunan, 410011, PR China, tel: +86-731-5292013; fax: +86-731-5533525;e-mail: qimingliu@yahoo.com.cnReceived: 20.02.2008 Accepted: 16.03.2008Significance of the lipid profile and endothelium--dependent vasodilatation in the pathogenesisof microvascular anginaQi-ming Liu1, Sheng-hua Zhou1, Shu-shan Qi1, Shui-ping Zhao1 and Liu Minghuib21Department of Cardiology, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China2Department of Ultrasound, the Second Xiangya Hospital of Central South University, Changsha, Hunan, ChinaAbstractBackground: To investigate the significance of lipid disorders and endothelial dysfunction inthe pathogenesis of microvascular angina.Methods: Levels of plasma lipids, lipoproteins and apolipoproteins were assessed in 21 patientswith microvascular angina and 24 healthy subjects as controls. Also, the endothelium-depend-ent vasodilatation function was determined with high-resolution ultrasound in both groups.Results: Levels of serum total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C),apolipoprotein B100 (ApoB100) and lipoprotein(a) [Lp(a)] in microvascular angina groupwere significantly higher than those in healthy subjects (each p < 0.05). The flow-mediateddilatation (FMD) in brachial arteries in patients with microvascular angina declined signifi-cantly as compared with that in control subjects (4.7 ± 1.9% vs. 12.8 ± 3.7%, p < 0.001).However, no significant difference was observed in response to nitroglycerin between groups(19.7 ± 8.1% vs. 21.2 ± 6.6%; p > 0.05). Linear correlation analysis revealed a significantnegative correlation between the FMD of brachial arteries and the serum levels of LDL-C andLp(a) in the microvascular angina group (r = –0.5125 and –0.4271, respectively, both p << 0.001). Subsequently, all subjects were pooled and divided into two groups (groups A and B)according to the degree of FMD in brachial arteries (A £ 4% and B > 4%). The serum LDL-Clevel was found to be significantly higher in group A than in group B (4.09 ± 0.65 mmol/L vs.2.59 ± 0.49 mmol/L; p < 0.05).Conclusions: Plasma lipid disorders and vascular endothelial dysfunction may play impor-tant roles in the development of microvascular angina. The dysfunction of endothelium--dependent vasodilation was mainly associated with anomalies in LDL-C and Lp(a), andmyocardial endothelial dysfunction was aggravated by lipid abnormalities in patients withmicrovascular angina. (Cardiol J 2008; 15:  324–328)Key words: lipid profile, vasodilatation, endothelium, vascular, ultrasonography,microvascular anginaEditorial p. 299325Qi-ming Liu et al., Significance of the lipid profile and endothelium-dependent vasodilatationwww.cardiologyjournal.orgIntroductionMicrovascular angina has recently been disco-vered as a new type of angina. Patients with thiscondition have symptoms of typical exertional an-gina with a positive exercise test along with nor-mal coronary angiography and left ventricular func-tion, but without large coronary artery spasm, extra-cardiac factors or established heart disease. Recentresearch has shown that anomalous blood flow re-serve of the coronary arteries is an important fe-ature, but mechanisms for this have not been fullydefined though there may be a close associationwith lipid disorders and coronary endothelial dys-function [1, 2]. In this study, we observed changesin blood lipid levels and changes in vascular endo-thelial function by high-resolution ultrasound inpatients with microvascular angina to explore thesignificance of the two indexes in the pathogenesisof microvascular angina.MethodsSubjectsA total of 21 patients [8 males and 13 females,aged 38–59 years (44 ± 8)] were recruited for themicrovascular angina group. These patients hadbeen diagnosed with microvascular angina and ad-mitted to our hospital during the period from May2003 to October 2007. All patients were selectedaccording to the following criteria: history of typi-cal exertional angina pectoris; positive results froman exercise test, Dobutamine stress test or Holtermonitoring over 24 hours; sparse radioactive areason movement and partial or complete refilling of ra-dioactivity at rest as shown by 201TL myocardial ima-ging, without radioactive defects; normal coronaryangiography and left ventricular function, with theexclusion of large coronary artery spasm by nega-tive ergonovine provocation testing in 16 patients;exclusion of angina possibly caused by hypertensionand/or hypertensive heart disease, cardiac valvedisease, myocardiopathy, pericarditis, etc. or non-cardiogenic chest pain caused by diseases of bre-ast, lung, oesophagus, etc. or myocardial ischemicfactors associated with anemia, diabetes mellitus,peripheral vascular lesions, etc. The control groupconsisted of 24 healthy volunteers, comprising10 men and 14 women aged 35–60 years (46 ± 10),who underwent history and physical examination,electrocardiogram and tests for blood sugar and uricacid, and heart, kidney and liver function tests. Noneof the subjects were permitted to take medicinesfor 48 hours prior to testing.The study was approved by the local bioethi-cal committe and all patients gave their informedconsent.Measurement of blood lipidVenous blood was collected from subjects after12 h of fasting. Serum was immediately separatedby centrifugation and stored at –70°C for later use.Serum total triglyceride (TG) and total cholesterol(TC) were measured by enzymatic methods on anautomatic biochemical analyzer. Serum high-den-sity lipoprotein-cholesterol (HDL-C) was tested bymagnesium tungstate phosphate sedimentation andthe concentration of low-density lipoprotein-chole-sterol (LDL-C) was calculated by the Friedewaldformula as follows: LDL-C (mmol/L) = TC – HDL-C– TG/2.2 (TG < 4.5 mmol/L). Concentrations ofapolipoprotein A1 (ApoA1) and B100 (ApoB100) weredetermined by circular immunoprecipitation. Theconcentration of lipoprotein(a) [LP(a)] was measu-red by sandwich ELISA assay.Examination of vascular endothelial functionAll tests were performed by an experiencedultrasonic doctor without prior knowledge of thisstudy. Using the methods described previously [3, 4],we examined the brachial artery flow-mediated di-lation (FMD) using an Acuson 128XP/10 colourDoppler sonograph (Acuson, Mountain View, CA,USA) with a 7.0 MHz array detecting head at anexploration depth of 4 cm; simultaneous electrocar-diograph readings were recorded. At the time ofmeasurement, subjects were in supine position withright upper extremities abducted 15 degrees andpalms facing upward. The brachial artery 2–15 cmabove the elbow was scanned by two-dimensionalultrasound imaging and longitudinal sections wereobserved. When the arterial intima of both anteriorand posterior walls were most clearly defined, am-plification was adjusted to satisfactorily identify lu-men interfaces. At the ventricular diastasis (ECGshowing R wave), the distance between the ante-rior and posterior intima of the brachial artery wasmeasured for three different cardiac cycles and theaverage was calculated.Brachial arterial calibre at rest and its changesin response to reactive hyperemia and sublingualnitroglycerin were measured in all subjects. Befo-re the reactive hyperemia test, subjects were allo-wed to rest for 10 min and the baseline value of ar-terial calibre (D0) was determined. A sphygmoma-nometer cuff was placed below the elbow, inflatedto 300 mm Hg and deflated quickly after 4 min. Thebrachial arterial calibre (D1) was measured within326Cardiology Journal 2008, Vol. 15, No. 4www.cardiologyjournal.org60–90 s of the deflation. Vascular calibre was allo-wed to return to baseline status after resting for10 min. Then the subjects were given 0.5 mg sub-lingual nitroglycerin, and brachial arterial calibre(D2) was measured after 4 min. All calibre measu-rements were performed at the same site. Calibrechanges of the brachial artery in response to reac-tive hyperemia and sublingual nitroglycerin wereexpressed as percentages of D0. (D1–D0)/D0 ×× 100% represents endothelium-dependent, flow-mediated vasodilation; (D2–D0)/D0 × 100% repre-sents nitroglycerin-mediated, non-endothelium-dependent vascular relaxation.Statistical analysisSPSS10.0 for Windows statistical software wasutilized to analyze the data and all results expres-sed as the mean ± standard deviation. Student t testwas employed to determine differences betweenthe groups. The relationship between plasma lipidsand brachial arterial calibre was determined by li-near correlation analysis and multivariate linearstepwise regression analysis. P < 0.05 was regar-ded as statistically significant.ResultsGeneral informationNo significant differences were found betwe-en the microvascular angina group and control gro-up with regard to sex and age, systolic and diasto-lic pressure, body mass index, number of cigarettesmoking subjects, baseline heart rate, blood sugarand uric acid, hemorheology, etc. (all p > 0.05).Levels of blood lipidsFor fasting levels of TC, LDL-C, ApoB100 andLp(a), the microvascular angina group was signifi-cantly higher than the control group (each p < 0.05).However, there were no differences in serum TG,HDL-C and ApoA1 between the groups (p > 0.05,Table 1).Changes in brachial arterial calibreThere was no significant difference in the ba-seline values of brachial arterial calibre between themicrovascular angina and control groups (p > 0.05).Calibre changes in response to reactive hyperemiain microvascular angina patients had significantlydecreased as compared with those in healthy con-trols (p < 0.001). Administration of sublingual ni-troglycerin led to obvious dilatation of the brachialartery with no significant difference observed be-tween the groups (p > 0.05, Table 2).Association between lipid levels and FMDUnivariate correlation analysis indicated thatbrachial artery FMD was inversely related to LDL-Cand Lp(a) levels (r = –0.5125 and –0.4271, respec-tively, p < 0.001); multivariate stepwise regressionanalysis revealed that the plasma level of LDL-Cwas the major lipid component influencing FMD.According to the degree of FMD of the brachial ar-tery (£ 4% and > 4%), all subjects (n = 45) fromboth groups were pooled and then divided into twogroups: group A (n = 25) and group B (n = 20). Themean FMD for groups A and B were 1.41 ± 1.20%and 8.35 ± 3.02%, respectively. It was found thatthe lipid disorders in group A were dominated bythe increase in LDL-C (4.09 ± 0.65 mmol/L) andby the decrease in LDL-C in group B (2.59 ±± 0.49 mmol/L). LDL-C levels differed significan-tly between the two groups (p < 0.05), while nosignificant differences were observed in the otherlipid components (all p > 0.05).Table 1. Comparison of blood lipids between themicrovascular angina and control groups.Microvascular Controlangina  group(n = 21)  (n = 24)TC [mmol/L] 5.42±0.53* 4.69±0.61TG [mmol/L] 1.45±0.39 1.46±0.52LDL-C [mmol/L] 3.98±0.42* 2.56±0.54HDL-C [mmol/L] 1.43±0.30 1.44±0.47ApoA1 [g/L] 1.21±0.36 1.23±0.25ApoB100 [g/L] 1.01±0.37* 1.19±0.18Lp(a) [mg/L] 282.4±220.3* 161.8±116.5*Comparison with the control group: p < 0.05; all values are presentedas mean ±SDTable 2. Comparison of changes in brachialartery calibre between the microvascular anginaand the control groups.Microvascular Controlangina group (n = 21) (n = 24)Baseline calibre [mm] 3.79±0.63 3.81±0.50Flow-mediated 4.7±1.9* 12.8±3.7dilation (%)Nitroglycerin-mediated 19.7±8.1 21.2±6.6dilation (%)*Comparison with control group: p < 0.001; all values are presentedas mean ±SD327Qi-ming Liu et al., Significance of the lipid profile and endothelium-dependent vasodilatationwww.cardiologyjournal.orgDiscussionMicrovascular angina, characterized mainly bya reduction in coronary artery dilatation reserve,differs from coronary artery disease; however, in-tra-coronary artery ultrasound and Doppler revealearly changes of coronary atherosclerosis in somepatients displaying focal or eccentric lesions withpathologically-confirmed fatty deposits, infiltrationof foam cells of macrophage origin, microarterialfibromuscular hyperplasia, vascular wall thickening,endothelial degeneration, etc. [5, 6]. The results ofthe present study indicated that lipid disorders inpatients with microvascular angina mainly featuredincreased levels of TC, LDL-C, ApoB100 and Lp(a),while TG, HDL-C and ApoA1 were notably unchan-ged, in accordance with previous reports [7, 8].Lipid disorders may result in fatty deposits in thevascular wall including microvessels. As an essen-tial structural protein of lipoprotein, apolipoprote-ins are metabolic procedural agents which encodeand regulate lipoprotein metabolism and balancecholesterol in the body. ApoB100 exerts a strong ef-fect to stimulate the esterization of cholesterol inmicrophages, which promotes foam cell formation.An elevated Lp(a) level is an independent risk fac-tor for atherosclerosis. Its unique apolipoprotein,Apo(a), for the most part outside of the cell, is ableto penetrate through arterial endothelium into theintima and bind to glycoprotein and collagen fibresto impair vascular endothelium, which, togetherwith aberrant lipids, lead to eventual endothelialdysfunction [9, 10].Endothelium-dependent vasodilation refers tovascular relaxation caused by endothelium-derivedrelaxing factor (EDRF) released by endothelial cellsin response to physiological stimulations (e.g. re-active hyperemia) or drugs (e.g. acetylcholine), andis dependent on the complete structure and normalfunction of the vascular endothelium [11, 12]. Incontrast, non-endothelium-dependent vasodilata-tion refers to that caused by nitric oxide (NO) di-rectly released by drugs, e.g. nitroglycerin and so-dium nitroprusside. In this study, we used calibrechanges of the brachial artery in response to reac-tive hyperemia to reflect changes in endothelium-dependent vasodilation. Studies have demonstratedthat endothelium-dependent dilation changes inperipheral vessels not only reflect endothelial func-tion of peripheral vessels, but also correlate wellwith coronary endothelial function; therefore, bra-chial artery FMD could indirectly reveal coronaryendothelial function in patients with microvascularangina [13, 14]. Results of this study have demon-strated marked impairment in endothelium-depen-dent vasodilation of peripheral brachial arteries inpatients with microvascular angina, with unapparentchanges in non-endothelium-dependent vasodila-tion, indirectly reflecting the dysfunction of thecoronary endothelium. With the exclusion of largecoronary artery spasm by negative Ergonovine pro-vocation test, endothelial dysfunction may lead toa decrease in the reserve of coronary artery dila-tion and dynamic abnormalities which play an im-portant role in the development of microvascularangina.ConclusionsIn the study, LDL-C and Lp(a) levels in serumwere demonstrated to be negatively associated withendothelium-dependent dilation, and LDL-C wasshown to be the major contributing factor determi-ned by multivariate analysis. Also, the groupingstudy based on the degree of brachial artery FMDrevealed that an elevated LDL-C level was a majorlipid component resulting in the impairment of en-dothelium-dependent dilation function. These re-sults suggest that lipid disorders in microvascularangina aggravate endothelial impairment and havea role in the pathogenesis of microvascular angina.Therefore, positive monitoring of the lipid profileand endothelium-dependent dilation is valuable inearly prophylaxis and diagnosis of microvascularangina. Balancing plasma lipid levels and protectingvascular endothelial function are critical in the pre-vention and cure of microvascular angina.AcknowledgementsThe authors do not report any conflict of inte-rest regarding this work.References1. Hoffmann E, Assennato P, Donatelli M, Colletti I, Valenti TM.Plasma endothelin-1 levels in patients with angina pectoris andnormal coronary angiograms. Am Heart J, 1998; 135: 684–688.2. Li Xiangping, Li Jiang, Zhao Shuiping, Zhou Qichang, Gao Mei,Lu Shukun. A non-invasive method for detecting endothelium-dependent dilation. Bull Hunan Med Univ, 1997; 22: 387–389.3. 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Significance of the lipid profile and endothelium-dependent vasodilatation in the pathogenesis of microvascular angina

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Significance of the lipid profile and endothelium-dependent vasodilatation in the pathogenesis of microvascular angina

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