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Effects of pravastatin on thoracic aortic atherosclerosis in patients with heterozygous familial hypercholesterolemia
Effects of Pravastatin on Thoracic Aortic Atherosclerosis in Patients With Heterozygous Familial Hypercholesterolemia Christos E. Pitsavos, MD, Konstantina I. Aggeli, MD, John D. Barbetseas, MD, Ioannis N. Skoumas, MD, Spyros G. Lambrou, MD, Alexandra A. Frogoudaki, MD, Christodoulos I. Stefanadis, MD, and Pavlos K. Toutouzas, MD Data regarding the effects of plasma lipid lowering on the evolution of thoracic aortic atherosclerosis (TAA) are scarce. In this study, we performed transesophageal echocardiography to characterize TAA in 16 newly diagnosed patients with heterozygous familial hypercholesterolemia and to follow its evolution after 2 years of statin treatment. TAA was graded as follows: grade I 5 normal intima; grade II 5 increased intimal echo density without thickening; grade IIIA 5 increased intimal echo density with single atheromatous plaque <3 mm; grade IIIB 5 multiple plaques <3mm; grade IV 5 >1 plaque >3 mm; and grade V 5 mobile or ulcerated plaques. Baseline aortic intimal morphology was grade I in one patient, grade II in 4, grade IIIA in 6, grade IIIB in 3, and grade IV in 2 patients. Hypolipidemic treatment resulted in significant reductions in plasma total cholesterol and
low-density lipoprotein (LDL) cholesterol. Follow-up aortic morphology was grade I in 5 patients, grade II in 2, grade IIIA in 3, grade IIIB in 3, and grade IV in 3 patients. TAA remained stable in 7 patients, progressed in 3, and regressed in 6 patients. TAA evolved in a uniform manner in the ascending aorta, aortic arch, and descending aorta. Patients with TAA regression were younger (39 6 14 vs 52 6 8 years, p 5 0.038) and had a greater decrease in plasma LDL cholesterol as a result of treatment (138 6 56 vs 73 6 55 mg/dl, p 5 0.036) than patients with TAA stability or progression. These observations support the hypothesis that hypolipidemic treatment may favorably affect the course of TAA in patients with heterozygous familial hypercholesterolemia. Q1998 by Excerpta Medica, Inc. (Am J Cardiol 1998;82:1484 –1488)
ittle is still known regarding the impact of hypolipidemic treatment on thoracic aortic atheroscleL rosis (TAA). Derivation of such information has re-
Patients: The study group consisted of 16 patients (7 men and 9 women, mean age 47 6 12 years, range 23 to 65) in whom a first diagnosis of HFH was made based on plasma lipid profile, physical examination, and family history. All patients were normotensive, nondiabetic non-smokers, without history of angina or myocardial infarction and with negative maximal treadmill exercise test results before enrollment. No
patient had ever received lipid-lowering medications; none received long-term aspirin or oral anticoagulants during the study period. The study protocol was approved by the ethics committee of our institution and all patients gave written informed consent for participation in the study. Laboratory measurements: Laboratory analyses were performed by the same physician before treatment initiation and every 3 months thereafter for a period of 2 years. Plasma total cholesterol and triglycerides were measured by the enzymatic colorimetric method using a Technicon RA-1000 analyzer (Dublin, Ireland), whereas high-density lipoprotein cholesterol was measured by use of the phosphotungstate precipitation method (Ames Sera-Pac); low-density lipoprotein (LDL) cholesterol was calculated by use of the Friedewald formula. Apolipoproteins A-1 and B and lipoprotein(a) were measured by liquidphase immunochemistry with nephelometric end point using a Behring BNA analyzer (Marburg, Germany). In addition to plasma lipids, serum creatine phosphokinase and transaminase levels were measured during all laboratory evaluations.
From the Department of Cardiology of the University of Athens, Hippokration Hospital, Athens, Greece. This study was supported by a grant from the Hellenic Heart Foundation, Athens, Greece. Manuscript received March 4, 1998; revised manuscript received and accepted July 14, 1998. Address for reprints: Christos E. Pitsavos, MD, 86 Pellis Street, Halandri 152 34, Athens, Greece.
aminations were performed in all patients before treatment initiation and approximately 2 years later (range 23.5 to 24.4 months). All baseline and follow-up studies were recorded on 1/2-inch VHS videotape and were reviewed off-line by 2 independent senior echo-
cently become possible by the application of transesophageal echocardiography, which has enabled accurate visualization of atheromatous lesions across the entire thoracic aorta1,2 and has already been used successfully to clarify the clinical significance of TAA3–9 and to study its natural history.10 In the present study, we performed transesophageal echocardiography in a group of patients with newly diagnosed heterozygous familial hypercholesterolemia (HFH) to characterize TAA and to assess its evolution after 2 years of hypolipidemic diet and pravastatin treatment.
METHODS
1484
©1998 by Excerpta Medica, Inc. All rights reserved.
Echocardiographic assessment of thoracic aortic atherosclerosis: Transesophageal echocardiographic ex-
0002-9149/98/$19.00 PII S0002-9149(98)00691-2
cardiographers who were blinded to patient demographics as well as to baseline and follow-up plasma lipid values. A third expert was advised in case of disagreement and the majority view was adopted. Examination of the first 6 consecutive patients was performed by use of an Ultramark 9 (Advanced Technology Laboratories, Bothell, Washington) ultrasound imager equipped with a 5-MHz monoplane probe; an HP Sonos 2500 (Hewlett-Packard Co., Andover, Massachusetts) imager equipped with a 3.5/7-MHz multiplane probe was used in the subsequent 10 patients. Baseline and repeat echocardiograms in each patient were recorded by use of the same equipment. During the examination and after assessment of cardiac chambers, the transducer was rotated posteriorly and advanced to the distal esophagus, from where it was withdrawn slowly to obtain serial short-axis images of the descending thoracic aorta and aortic arch. The transducer was subsequently rotated again and advanced to image the ascending aorta. The entire length of the thoracic aorta was traced twice consecutively. In each patient, gain and instrument settings during the initial examination were adjusted to optimize visualization of the aortic wall and every effort was made to maintain them unaltered during repeat transesophageal echocardiography. Aortic intimal morphology was graded by a modification of the scoring system proposed by Ribakove et al,11 assessing atherosclerotic plaque characteristics and maximum width as follows: grade I 5 normal intima; grade II 5 increased intimal echo density without intimal thickening or lumen irregularity; grade IIIA 5 increased intimal echo density with single well-defined atheromatous plaque #3 mm; grade IIIB 5 multiple atheromas #3 mm; grade IV 5 $1 atheroma .3 mm; and grade V5 mobile or ulcerated plaques. Each patient was characterized on the basis of the most severe identified lesion. Grades $IIIB were considered to represent severe TAA. The exact distance of the transducer from the incisors at the level of visualization of each lesion was marked on video in order to ensure its identification and accurate assessment of evolution at follow-up. Lipid-lowering treatment: After baseline laboratory and echocardiographic examination, patients were placed on the American Heart Association step II diet and drug treatment was initiated with pravastatin at a dose of 40 mg/day. Specialist dietary advice was offered to all patients both before diet initiation as well as during each follow-up visit. Statistics: The paired samples t test was used for comparisons between baseline and follow-up plasma lipid values. The independent samples t test was used for assessment of differences in plasma lipid values and demographic characteristics between patients with and without echocardiographic evidence of TAA regression at follow-up. To identify predictors for TAA regression, logistic regression analysis was performed on the following demographic and biochemical variables: patient age, gender, baseline disease severity (severe vs nonsevere, as previously defined), baseline plasma total cholesterol, baseline plasma LDL choles-
terol, post-treatment plasma LDL cholesterol, and post-treatment decrease in plasma LDL cholesterol. A p value ,0.05 was accepted as statistically significant.
RESULTS In no patient was lipid-lowering treatment discontinued because of adverse effects. During follow-up, neither changes regarding cardiovascular risk factors other than plasma lipids nor cardiovascular events (angina, myocardial infarction, stroke, or peripheral embolism) were documented in any of the patients. Effect of treatment on plasma lipids (Table I): Significant reductions at follow-up compared with baseline were noted regarding mean total cholesterol, LDL cholesterol, and apolipoprotein B plasma levels (from 364 6 59 to 267 6 60 mg/dl [p ,0.001], from 290 6 56 to 193 6 56 mg/dl [p ,0.001], and from 219 6 49 to 166 6 35 mg/dl, p 5 0.002, respectively). Conversely, no significant changes were documented regarding high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-1, and lipoprotein(a) values. Baseline TAA assessment: Disagreement regarding TAA grading between the 2 principal echocardiographers was noted in 2 of the 32 performed examinations (6%). Baseline transesophageal echocardiography characterized thoracic aortic intimal morphology as grade I in 1 patient, grade II in 4 patients, grade IIIA in 6 patients, grade IIIB in 3 patients, and grade IV in 2 patients (Table I). The descending thoracic aorta hosted the grade-defining lesions in 11 patients. Among the remaining 4 patients with TAA identification at baseline, grade-defining lesions of equal severity were located in the aortic arch and the descending aorta in 2, and in the ascending aorta, aortic arch, and descending aorta in another 2. No patient with grade II TAA had intimal calcification: In contrast, calcification of grade-defining lesions was noted in 5 of 6 patients with grade IIIA TAA and in all 5 patients with grade IIIB and grade IV TAA. TAA evolution at follow-up: Follow-up aortic intimal morphology was grade I in 5 patients, grade II in 2, grade IIIA in 3, grade IIIB in 3, and grade IV in 3 patients. Comparison of individual baseline and repeat transesophageal echocardiograms (Figure 1) revealed that TAA progressed in 3 patients (18.8%; in 1 from grade IIIA to grade IIIB, and in 2 from grade IIIB to grade IV); it regressed in 6 patients (37.5%; in 1 patient from grade IV to grade IIIB, in 1 from grade IIIA to grade II, in 1 from grade IIIA to grade I, and in 3 from grade II to grade I), while remaining stable in the remaining 7 patients (43.7%). Among patients with baseline grade IIIA TAA, the most significant improvement (grade I at follow-up) was noted in the one with a noncalcified grade-defining lesion at baseline. Echocardiographic images from a patient with TAA regression are shown in Figure 2. Application of TAA grading separately in the ascending aorta, aortic arch, and descending aorta at baseline and after treatment revealed that the disease evolved in a uniform fashion throughout the entire
PREVENTIVE CARDIOLOGY/EFFECT OF PRAVASTATIN ON AORTIC ATHEROSCLEROSIS
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1486 THE AMERICAN JOURNAL OF CARDIOLOGYT
VOL. 82
59F 23F 62M 65M 26F 45F 54M 53F 50M 36M 42M 38F 42M 44F 58F 55F
Pt
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
TC
401/262 380/240 415/357 449/384 348/224 467/255 364/345 367/315 303/288 323/254 279/230 265/176 358/187 297/235 420/214 384/298
TAA Evolution
Stability Regression Regression Progression Regression Regression Stability Stability Stability Regression Stability Stability Regression Stability Progression Progression
325/188 307/152 341/270 377/300 266/134 385/168 304/277 229/222 242/226 251/171 222/173 214/119 302/128 227/152 355/173 295/237
LDL
TGL 121/119 40/45 189/231 219/171 151/96 162/176 133/187 104/120 94/72 98/74 94/82 66/59 69/117 99/112 175/75 294/160
HDL 51/50 65/79 36/41 32/50 52/71 50/52 33/31 57/69 42/48 52/68 38/41 38/45 42/36 50/61 45/26 30/29
160/161 147/171 137/145 119/165 161/184 159/176 129/120 162/159 156/154 160/193 130/139 116/154 141/124 167/171 139/97 112/113
ApoA-1 210/171 234/157 294/192 291/114 190/129 305/164 256/251 148/195 192/200 194/160 168/172 189/123 220/165 211/145 155/129 243/195
Apo B
Pretreatment IV IIIA IV IIIB II II IIIA IIIB IIIA II II I IIIA IIIA IIIA IIIB
Lp(a) 11/12 38/54 12/12 22/25 13/17 15/16 13/24 45/53 17/19 12/12 10/29 25/36 12/12 24/32 36/67 48/58
IV I IIIB IV I I IIIA IIIB IIIA I II I II IIIA IIIB IV
Post-Treatment
Overall TAA grading
II I II II II I II II II I II I II II II II
AA II I II II II I II II II I II I II II II II
Arch IV IIIA IV IIIB II II IIIA IIIB IIIA II II I IIIA IIIA IIIA IIIB
DA II I II II I I II II II I II I II II II II
AA
II I IIIB II I I II II II I II I II II IIIA IIIB
Arch
DA IV I IIIB IV I I IIIA IIIB IIIA I II I II IIIA IIIB IV
Post-treatment
Segmental TAA grading Pretreatment
AA 5 ascending thoracic aorta; Apo A-1 5 apolipoprotein A-1; Apo B 5 apolipoprotein B; Arch 5 aortic arch; DA 5 descending thoracic aorta; HDL 5 high-density lipoprotein cholesterol; LDL 5 low-density lipoprotein cholesterol; Lp (a) 5 lipoprotein(a); TAA 5 thoracic aortic atherosclerosis; TC 5 total cholesterol; TGL 5 triglycerides.
Age (yr) & Sex
Pretreatment/Post-treatment Plasma Lipid Values (mg/dl)
TABLE I Demographic Characteristics, Plasma Lipid Values, TAA Evolution Description, and TAA Grading at Baseline and After Two Years of Pravastatin Treatment in the Study Population
FIGURE 1. Schematic representation of changes in TAA grading between the initial and follow-up transesophageal echocardiographic examinations in the 16 studied patients.
vessel length (Table I). Thus, in all 7 patients with stable disease at follow-up, TAA remained stable in all aortic segments. In addition, TAA in the aortic segments not containing the major grade-defining lesion either remained stable or progressed (but did not regress in any patient) in the 3 patients with disease progression, and either remained stable or regressed (but did not progress in any patient) in all 6 patients with disease regression at follow-up.
Comparison between patients with and without TAA regression: Comparison of demographic and biochem-
ical variables between patients with TAA regression and those with either TAA stability or progression at follow-up revealed that the former were younger (39 6 14 vs 52 6 8 years, p 5 0.038) and had a significantly greater decrease in plasma LDL cholesterol values as a result of therapy (138 6 56 vs 73 6 55 mg/dl, p 5 0.036). Logistic regression analysis did not identify any significant predictors of TAA regression among the baseline and procedural variables evaluated in this respect.
Baseline TAA assessment: HFH is associated with accelerated development of atherosclerosis.12–15 In the present study, baseline transesophageal echocardiography identified TAA in 15 of 16 asymptomatic patients (94%) with newly diagnosed HFH. Severe involvement was already present in 5 patients (31%) at
DISCUSSION
DECEMBER 15, 1998
FIGURE 2. Baseline and follow-up short-axis echocardiographic images from the descending aorta of a patient in whom TAA regression was observed (patient 3 in Table I). Left panel, baseline echocardiogram demonstrates an atherosclerotic plaque of 3.4-mm maximal width (arrowheads), designating TAA as grade IV; right panel, follow-up echocardiogram of the same lesion after 2 years of hypolipidemic treatment. Maximal plaque width is shown to have been reduced to 2.5 mm; TAA was graded as IIIB due to the presence of an additional lesion <3 mm in the aortic arch of this patient.
the time of the initial evaluation compared with prevalence rates between 7% and 17% reported in routine transesophageal echocardiographic studies.3,10 Atherosclerotic involvement was more pronounced in the descending thoracic aorta than in the aortic arch and ascending aorta in most cases (11 of 15). The descending aorta hosted the major identified lesions in all 5 patients with severe baseline TAA; the aortic arch was afflicted to the same degree in 2 of these patients. Interestingly, absence of clinically detectable coronary artery disease on enrollment in the study may imply that TAA is not as powerful a predictor of significant coronary artery disease in patients with HFH as in other populations.16 –18 TAA evolution at follow-up: Repeat transesophageal echocardiography performed after 2 years of treatment with pravastatin documented TAA stability in 7 patients, regression in 6 patients, and progression in 3 patients. Identification of improvement in TAA severity in more than one third of patients strongly suggests that a beneficial effect was exerted by hypolipidemic treatment on the course of TAA. Although previous investigators using a similar echocardiographic grading system have described morphologic instability of individual lesions as part of the natural course of TAA,10 spontaneous resolution has only been reported in mobile atherosclerotic lesions, possibly representing dislodgment of atherosclerotic material rather than true regression; none of the cases of TAA regression in the present study involved either mobile lesions or mobile components of stable lesions. Additional support for the concept of treatment influence on TAA evolution was provided by the finding that patients with lesion regression had a better response to pravastatin (as seen by significantly greater decreases in plasma LDL cholesterol at follow-up) than patients with TAA stability or progression. Patients in whom TAA regressed were significantly younger than those in whom TAA remained stable or progressed. Among 8 patients aged #45
years, TAA regressed in 5 and was stabilized in 3; Among the remaining 8 patients aged .45 years, TAA regressed in 1, remained stable in 4, and progressed in 3. Similarly, regression occurred in 5 of 10 patients with less-than-severe (grade #IIIA) lesions, but in only 1 of 5 patients with severe lesions at baseline. These findings may indicate a role of early diagnosis in the amenability of TAA to subsequent therapeutic intervention in HFH patients. Although neither age nor baseline disease severity were identified as predictors of TAA evolution in our study, we believe their significance in this respect merits assessment in larger patient groups. Previous investigations: Only 2 transesophageal echocardiographic studies have previously addressed the issue of TAA evolution in patients with familial hypercholesterolemia undergoing lipid-lowering treatment. In their group of 8 patients, Herrera et al19 demonstrated a decrease in the TAA burden in 5 patients undergoing low-density lipoprotein apheresis for a period of 20 months, but not in 3 patients treated with standard lipid-lowering drug therapy for 7 months; at the time of repeat echocardiography, however, treatment in the latter group had proved unsuccessful in reducing plasma LDL cholesterol values. More recently, Tomochika et al20 described significant improvement in TAA expressed by means of an echocardiographic score in 12 patients after 13 months of combined lipid-lowering drug treatment with probucol and pravastatin. Both previous studies reported exclusively on TAA alterations occurring in the descending thoracic aorta. Our study was the first to monitor disease evolution in the entire thoracic aorta. We were thus able to describe a uniform fashion of TAA evolution in the different thoracic aortic segments and to demonstrate regression in lesions located also in the aortic arch and the ascending aorta. Clinical implications of these latter observations may be significant, because TAA
PREVENTIVE CARDIOLOGY/EFFECT OF PRAVASTATIN ON AORTIC ATHEROSCLEROSIS
1487
in these sites has been recognized as a source of cerebral and peripheral embolism.21–25 1. Nihoyannopoulos P, Joshi J, Athanasopoulos G, Oakley CM. Detection of
atherosclerotic lesions in the aorta by transesophageal echocardiography. Am J Cardiol 1993;71:1208 –1212. 2. Vaduganathan P, Ewton A, Nagueh SF, Weilbaecher DG, Safi HJ, Zoghbi WA. Pathologic correlates of aortic plaques, thrombi and mobile “aortic debris” imaged in vivo with transesophageal echocardiography. J Am Coll Cardiol 1997;30:357–363. 3. Karalis DG, Chandrasekaran K, Victor MF, Ross JJ, Mintz GS. Recognition and embolic potential of intraaortic atherosclerotic debris. J Am Coll Cardiol 1991;17:73–78. 4. Tunick PA, Perez JL, Kronzon I. Protruding atheromas in the thoracic aorta and systemic embolization. Ann Intern Med 1991;115:423– 427. 5. Toyoda K, Yasaka M, Nagata S, Yamaguchi T. Aortogenic embolic stroke: a transesophageal echocardiographic approach. Stroke 1992;23:1056 –1061. 6. Katz ES, Tunick PA, Rusinek H, Ribakove G, Spencer FC, Kronzon I. Protruding aortic atheromas predict stroke in elderly patients undergoing cardiopulmonary bypass: experience with intraoperative transesophageal echocardiography. J Am Coll Cardiol 1992;20:70 –77. 7. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, Chauvel C, Touboul P-J, Bousser M-G. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994;331:1474 –1479. 8. Tunick PA, Rosenzweig BP, Katz ES, Freedberg RS, Perez JL, Kronzon I. High risk for vascular events in patients with protruding aortic atheromas: a prospective study. J Am Coll Cardiol 1994;23:1085–1090. 9. Cohen A, Tzourio C, Bertrand B, Chauvel C, Bousser M-G, Amarenco P, on behalf of the FAPS Investigators. Aortic plaque morphology and vascular events. A follow-up study in patients with ischemic stroke. Circulation 1997;96:3838 – 3841. 10. Montgomery DH, Ververis JJ, McGorisk G, Frohwein S, Martin RP, Taylor WR. Natural history of severe atheromatous disease of the thoracic aorta: A transesophageal echocardiographic study. J Am Coll Cardiol 1996;27:95–101. 11. Ribakove GH, Katz ES, Galloway AC, Grossi EA, Esposito RA, Baumann FG, Kronzon I, Spencer FC. Surgical implications of transesophageal echocardiography to grade the atheromatous aortic arch. Ann Thorac Surg 1992;53:758 – 761. 12. Jensen J, Blankenhorn DH, Kornerup V. Coronary artery disease in familial hypercholesterolemia. Circulation 1967;36:77– 82.
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13. Slach J. Risk of ischemic heart disease in familial hyperlipoproteinaemic
states. Lancet 1969;2:1380 –1383. 14. Mabuchi H, Tanami R, Haba T, Ueda K, Oota M, Takeguchi T, Wakasugi T,
Takeda R. Cause of death in patients with familial hypercholesterolemia. Atherosclerosis 1986;61:1– 6. 15. Mabuchi H, Koizumi J, Shimizu M, Takeda R, Hokuriku FH, and the CHD Study Group. Development of coronary heart disease in familial hypercholesterolemia. Circulation 1989;79:225–232. 16. Fazio GP, Redberg RF, Winslow T, Schiller NB. Transesophageal echocardiographically detected atherosclerotic aortic plaque is a marker for coronary artery disease. J Am Coll Cardiol 1993;21:144 –150. 17. Khoury Z, Gottlieb S, Stern S, Keren A. Frequency and distribution of atherosclerotic plaques in the thoracic aorta as determined by transesophageal echocardiography in patients with coronary artery disease. Am J Cardiol 1997; 79:23–27. 18. Tribouilloy C, Peltier M, Colas L, Rida Z, Rey J-L, Lesbre J-P. Multiplane transesophageal echocardiographic absence of thoracic aortic plaque is a powerful predictor for absence of significant coronary artery disease in valvular patients, even in the elderly. A large prospective study. Eur Heart J 1997;18:1478 – 1483. 19. Herrera CJ, Frazin LJ, Dau PC, DeFrino P, Stone NJ, Mehlman DJ, Vonesh MJ, Talano JV, McPherson DD. Atherosclerotic plaque evolution in the descending thoracic aorta in familial hypercholesterolemic patients. A transesophageal echo study. Arterioscler Thromb 1994;14:1723–1729. 20. Tomochika Y, Okuda F, Tanaka N, Wasaki Y, Tokisawa I, Aoyagi S, Morikuni C, Ono S, Okada K, Matsuzaki M. Improvement of atherosclerosis and stiffness of the thoracic descending aorta with cholesterol-lowering therapies in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 1996;16:955–962. 21. Tunick PA, Kronzon I. Protruding atherosclerotic plaque in the aortic arch of patients with systemic embolization: a new finding seen by transesophageal echocardiography. Am Heart J 1990;120:658 – 660. 22. Tunick PA, Culliford AT, Lamparello PJ, Kronzon I. Atheromatosis of the aortic arch as an occult source of multiple systemic emboli. Ann Intern Med 1991;114:391–392. 23. Amarenco P, Cohen A, Baudrimont M, Bousser M-G. Transesophageal echocardiographic detection of aortic arch disease in patients with cerebral infarction. Stroke 1992;23:1005–1009. 24. Belkin RN, Chaudhry S, Chung J, Kay RH, Pooley RA, Shah P, Reed GE. Detection of acsending aorta thrombi with transesophageal echocardiography in patients with systemic embolization. Am Heart J 1995;130:1294 –1295. 25. Lehmann ED, Hopkins KD, Gosling RG. Atherosclerosis in the ascending aorta and risk of ischaemic stroke. Lancet 1995;346:589 –590.
DECEMBER 15, 1998
low-density lipoprotein (LDL) cholesterol. Follow-up aortic morphology was grade I in 5 patients, grade II in 2, grade IIIA in 3, grade IIIB in 3, and grade IV in 3 patients. TAA remained stable in 7 patients, progressed in 3, and regressed in 6 patients. TAA evolved in a uniform manner in the ascending aorta, aortic arch, and descending aorta. Patients with TAA regression were younger (39 6 14 vs 52 6 8 years, p 5 0.038) and had a greater decrease in plasma LDL cholesterol as a result of treatment (138 6 56 vs 73 6 55 mg/dl, p 5 0.036) than patients with TAA stability or progression. These observations support the hypothesis that hypolipidemic treatment may favorably affect the course of TAA in patients with heterozygous familial hypercholesterolemia. Q1998 by Excerpta Medica, Inc. (Am J Cardiol 1998;82:1484 –1488)
ittle is still known regarding the impact of hypolipidemic treatment on thoracic aortic atheroscleL rosis (TAA). Derivation of such information has re-
Patients: The study group consisted of 16 patients (7 men and 9 women, mean age 47 6 12 years, range 23 to 65) in whom a first diagnosis of HFH was made based on plasma lipid profile, physical examination, and family history. All patients were normotensive, nondiabetic non-smokers, without history of angina or myocardial infarction and with negative maximal treadmill exercise test results before enrollment. No
patient had ever received lipid-lowering medications; none received long-term aspirin or oral anticoagulants during the study period. The study protocol was approved by the ethics committee of our institution and all patients gave written informed consent for participation in the study. Laboratory measurements: Laboratory analyses were performed by the same physician before treatment initiation and every 3 months thereafter for a period of 2 years. Plasma total cholesterol and triglycerides were measured by the enzymatic colorimetric method using a Technicon RA-1000 analyzer (Dublin, Ireland), whereas high-density lipoprotein cholesterol was measured by use of the phosphotungstate precipitation method (Ames Sera-Pac); low-density lipoprotein (LDL) cholesterol was calculated by use of the Friedewald formula. Apolipoproteins A-1 and B and lipoprotein(a) were measured by liquidphase immunochemistry with nephelometric end point using a Behring BNA analyzer (Marburg, Germany). In addition to plasma lipids, serum creatine phosphokinase and transaminase levels were measured during all laboratory evaluations.
From the Department of Cardiology of the University of Athens, Hippokration Hospital, Athens, Greece. This study was supported by a grant from the Hellenic Heart Foundation, Athens, Greece. Manuscript received March 4, 1998; revised manuscript received and accepted July 14, 1998. Address for reprints: Christos E. Pitsavos, MD, 86 Pellis Street, Halandri 152 34, Athens, Greece.
aminations were performed in all patients before treatment initiation and approximately 2 years later (range 23.5 to 24.4 months). All baseline and follow-up studies were recorded on 1/2-inch VHS videotape and were reviewed off-line by 2 independent senior echo-
cently become possible by the application of transesophageal echocardiography, which has enabled accurate visualization of atheromatous lesions across the entire thoracic aorta1,2 and has already been used successfully to clarify the clinical significance of TAA3–9 and to study its natural history.10 In the present study, we performed transesophageal echocardiography in a group of patients with newly diagnosed heterozygous familial hypercholesterolemia (HFH) to characterize TAA and to assess its evolution after 2 years of hypolipidemic diet and pravastatin treatment.
METHODS
1484
©1998 by Excerpta Medica, Inc. All rights reserved.
Echocardiographic assessment of thoracic aortic atherosclerosis: Transesophageal echocardiographic ex-
0002-9149/98/$19.00 PII S0002-9149(98)00691-2
cardiographers who were blinded to patient demographics as well as to baseline and follow-up plasma lipid values. A third expert was advised in case of disagreement and the majority view was adopted. Examination of the first 6 consecutive patients was performed by use of an Ultramark 9 (Advanced Technology Laboratories, Bothell, Washington) ultrasound imager equipped with a 5-MHz monoplane probe; an HP Sonos 2500 (Hewlett-Packard Co., Andover, Massachusetts) imager equipped with a 3.5/7-MHz multiplane probe was used in the subsequent 10 patients. Baseline and repeat echocardiograms in each patient were recorded by use of the same equipment. During the examination and after assessment of cardiac chambers, the transducer was rotated posteriorly and advanced to the distal esophagus, from where it was withdrawn slowly to obtain serial short-axis images of the descending thoracic aorta and aortic arch. The transducer was subsequently rotated again and advanced to image the ascending aorta. The entire length of the thoracic aorta was traced twice consecutively. In each patient, gain and instrument settings during the initial examination were adjusted to optimize visualization of the aortic wall and every effort was made to maintain them unaltered during repeat transesophageal echocardiography. Aortic intimal morphology was graded by a modification of the scoring system proposed by Ribakove et al,11 assessing atherosclerotic plaque characteristics and maximum width as follows: grade I 5 normal intima; grade II 5 increased intimal echo density without intimal thickening or lumen irregularity; grade IIIA 5 increased intimal echo density with single well-defined atheromatous plaque #3 mm; grade IIIB 5 multiple atheromas #3 mm; grade IV 5 $1 atheroma .3 mm; and grade V5 mobile or ulcerated plaques. Each patient was characterized on the basis of the most severe identified lesion. Grades $IIIB were considered to represent severe TAA. The exact distance of the transducer from the incisors at the level of visualization of each lesion was marked on video in order to ensure its identification and accurate assessment of evolution at follow-up. Lipid-lowering treatment: After baseline laboratory and echocardiographic examination, patients were placed on the American Heart Association step II diet and drug treatment was initiated with pravastatin at a dose of 40 mg/day. Specialist dietary advice was offered to all patients both before diet initiation as well as during each follow-up visit. Statistics: The paired samples t test was used for comparisons between baseline and follow-up plasma lipid values. The independent samples t test was used for assessment of differences in plasma lipid values and demographic characteristics between patients with and without echocardiographic evidence of TAA regression at follow-up. To identify predictors for TAA regression, logistic regression analysis was performed on the following demographic and biochemical variables: patient age, gender, baseline disease severity (severe vs nonsevere, as previously defined), baseline plasma total cholesterol, baseline plasma LDL choles-
terol, post-treatment plasma LDL cholesterol, and post-treatment decrease in plasma LDL cholesterol. A p value ,0.05 was accepted as statistically significant.
RESULTS In no patient was lipid-lowering treatment discontinued because of adverse effects. During follow-up, neither changes regarding cardiovascular risk factors other than plasma lipids nor cardiovascular events (angina, myocardial infarction, stroke, or peripheral embolism) were documented in any of the patients. Effect of treatment on plasma lipids (Table I): Significant reductions at follow-up compared with baseline were noted regarding mean total cholesterol, LDL cholesterol, and apolipoprotein B plasma levels (from 364 6 59 to 267 6 60 mg/dl [p ,0.001], from 290 6 56 to 193 6 56 mg/dl [p ,0.001], and from 219 6 49 to 166 6 35 mg/dl, p 5 0.002, respectively). Conversely, no significant changes were documented regarding high-density lipoprotein cholesterol, triglycerides, apolipoprotein A-1, and lipoprotein(a) values. Baseline TAA assessment: Disagreement regarding TAA grading between the 2 principal echocardiographers was noted in 2 of the 32 performed examinations (6%). Baseline transesophageal echocardiography characterized thoracic aortic intimal morphology as grade I in 1 patient, grade II in 4 patients, grade IIIA in 6 patients, grade IIIB in 3 patients, and grade IV in 2 patients (Table I). The descending thoracic aorta hosted the grade-defining lesions in 11 patients. Among the remaining 4 patients with TAA identification at baseline, grade-defining lesions of equal severity were located in the aortic arch and the descending aorta in 2, and in the ascending aorta, aortic arch, and descending aorta in another 2. No patient with grade II TAA had intimal calcification: In contrast, calcification of grade-defining lesions was noted in 5 of 6 patients with grade IIIA TAA and in all 5 patients with grade IIIB and grade IV TAA. TAA evolution at follow-up: Follow-up aortic intimal morphology was grade I in 5 patients, grade II in 2, grade IIIA in 3, grade IIIB in 3, and grade IV in 3 patients. Comparison of individual baseline and repeat transesophageal echocardiograms (Figure 1) revealed that TAA progressed in 3 patients (18.8%; in 1 from grade IIIA to grade IIIB, and in 2 from grade IIIB to grade IV); it regressed in 6 patients (37.5%; in 1 patient from grade IV to grade IIIB, in 1 from grade IIIA to grade II, in 1 from grade IIIA to grade I, and in 3 from grade II to grade I), while remaining stable in the remaining 7 patients (43.7%). Among patients with baseline grade IIIA TAA, the most significant improvement (grade I at follow-up) was noted in the one with a noncalcified grade-defining lesion at baseline. Echocardiographic images from a patient with TAA regression are shown in Figure 2. Application of TAA grading separately in the ascending aorta, aortic arch, and descending aorta at baseline and after treatment revealed that the disease evolved in a uniform fashion throughout the entire
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59F 23F 62M 65M 26F 45F 54M 53F 50M 36M 42M 38F 42M 44F 58F 55F
Pt
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
TC
401/262 380/240 415/357 449/384 348/224 467/255 364/345 367/315 303/288 323/254 279/230 265/176 358/187 297/235 420/214 384/298
TAA Evolution
Stability Regression Regression Progression Regression Regression Stability Stability Stability Regression Stability Stability Regression Stability Progression Progression
325/188 307/152 341/270 377/300 266/134 385/168 304/277 229/222 242/226 251/171 222/173 214/119 302/128 227/152 355/173 295/237
LDL
TGL 121/119 40/45 189/231 219/171 151/96 162/176 133/187 104/120 94/72 98/74 94/82 66/59 69/117 99/112 175/75 294/160
HDL 51/50 65/79 36/41 32/50 52/71 50/52 33/31 57/69 42/48 52/68 38/41 38/45 42/36 50/61 45/26 30/29
160/161 147/171 137/145 119/165 161/184 159/176 129/120 162/159 156/154 160/193 130/139 116/154 141/124 167/171 139/97 112/113
ApoA-1 210/171 234/157 294/192 291/114 190/129 305/164 256/251 148/195 192/200 194/160 168/172 189/123 220/165 211/145 155/129 243/195
Apo B
Pretreatment IV IIIA IV IIIB II II IIIA IIIB IIIA II II I IIIA IIIA IIIA IIIB
Lp(a) 11/12 38/54 12/12 22/25 13/17 15/16 13/24 45/53 17/19 12/12 10/29 25/36 12/12 24/32 36/67 48/58
IV I IIIB IV I I IIIA IIIB IIIA I II I II IIIA IIIB IV
Post-Treatment
Overall TAA grading
II I II II II I II II II I II I II II II II
AA II I II II II I II II II I II I II II II II
Arch IV IIIA IV IIIB II II IIIA IIIB IIIA II II I IIIA IIIA IIIA IIIB
DA II I II II I I II II II I II I II II II II
AA
II I IIIB II I I II II II I II I II II IIIA IIIB
Arch
DA IV I IIIB IV I I IIIA IIIB IIIA I II I II IIIA IIIB IV
Post-treatment
Segmental TAA grading Pretreatment
AA 5 ascending thoracic aorta; Apo A-1 5 apolipoprotein A-1; Apo B 5 apolipoprotein B; Arch 5 aortic arch; DA 5 descending thoracic aorta; HDL 5 high-density lipoprotein cholesterol; LDL 5 low-density lipoprotein cholesterol; Lp (a) 5 lipoprotein(a); TAA 5 thoracic aortic atherosclerosis; TC 5 total cholesterol; TGL 5 triglycerides.
Age (yr) & Sex
Pretreatment/Post-treatment Plasma Lipid Values (mg/dl)
TABLE I Demographic Characteristics, Plasma Lipid Values, TAA Evolution Description, and TAA Grading at Baseline and After Two Years of Pravastatin Treatment in the Study Population
FIGURE 1. Schematic representation of changes in TAA grading between the initial and follow-up transesophageal echocardiographic examinations in the 16 studied patients.
vessel length (Table I). Thus, in all 7 patients with stable disease at follow-up, TAA remained stable in all aortic segments. In addition, TAA in the aortic segments not containing the major grade-defining lesion either remained stable or progressed (but did not regress in any patient) in the 3 patients with disease progression, and either remained stable or regressed (but did not progress in any patient) in all 6 patients with disease regression at follow-up.
Comparison between patients with and without TAA regression: Comparison of demographic and biochem-
ical variables between patients with TAA regression and those with either TAA stability or progression at follow-up revealed that the former were younger (39 6 14 vs 52 6 8 years, p 5 0.038) and had a significantly greater decrease in plasma LDL cholesterol values as a result of therapy (138 6 56 vs 73 6 55 mg/dl, p 5 0.036). Logistic regression analysis did not identify any significant predictors of TAA regression among the baseline and procedural variables evaluated in this respect.
Baseline TAA assessment: HFH is associated with accelerated development of atherosclerosis.12–15 In the present study, baseline transesophageal echocardiography identified TAA in 15 of 16 asymptomatic patients (94%) with newly diagnosed HFH. Severe involvement was already present in 5 patients (31%) at
DISCUSSION
DECEMBER 15, 1998
FIGURE 2. Baseline and follow-up short-axis echocardiographic images from the descending aorta of a patient in whom TAA regression was observed (patient 3 in Table I). Left panel, baseline echocardiogram demonstrates an atherosclerotic plaque of 3.4-mm maximal width (arrowheads), designating TAA as grade IV; right panel, follow-up echocardiogram of the same lesion after 2 years of hypolipidemic treatment. Maximal plaque width is shown to have been reduced to 2.5 mm; TAA was graded as IIIB due to the presence of an additional lesion <3 mm in the aortic arch of this patient.
the time of the initial evaluation compared with prevalence rates between 7% and 17% reported in routine transesophageal echocardiographic studies.3,10 Atherosclerotic involvement was more pronounced in the descending thoracic aorta than in the aortic arch and ascending aorta in most cases (11 of 15). The descending aorta hosted the major identified lesions in all 5 patients with severe baseline TAA; the aortic arch was afflicted to the same degree in 2 of these patients. Interestingly, absence of clinically detectable coronary artery disease on enrollment in the study may imply that TAA is not as powerful a predictor of significant coronary artery disease in patients with HFH as in other populations.16 –18 TAA evolution at follow-up: Repeat transesophageal echocardiography performed after 2 years of treatment with pravastatin documented TAA stability in 7 patients, regression in 6 patients, and progression in 3 patients. Identification of improvement in TAA severity in more than one third of patients strongly suggests that a beneficial effect was exerted by hypolipidemic treatment on the course of TAA. Although previous investigators using a similar echocardiographic grading system have described morphologic instability of individual lesions as part of the natural course of TAA,10 spontaneous resolution has only been reported in mobile atherosclerotic lesions, possibly representing dislodgment of atherosclerotic material rather than true regression; none of the cases of TAA regression in the present study involved either mobile lesions or mobile components of stable lesions. Additional support for the concept of treatment influence on TAA evolution was provided by the finding that patients with lesion regression had a better response to pravastatin (as seen by significantly greater decreases in plasma LDL cholesterol at follow-up) than patients with TAA stability or progression. Patients in whom TAA regressed were significantly younger than those in whom TAA remained stable or progressed. Among 8 patients aged #45
years, TAA regressed in 5 and was stabilized in 3; Among the remaining 8 patients aged .45 years, TAA regressed in 1, remained stable in 4, and progressed in 3. Similarly, regression occurred in 5 of 10 patients with less-than-severe (grade #IIIA) lesions, but in only 1 of 5 patients with severe lesions at baseline. These findings may indicate a role of early diagnosis in the amenability of TAA to subsequent therapeutic intervention in HFH patients. Although neither age nor baseline disease severity were identified as predictors of TAA evolution in our study, we believe their significance in this respect merits assessment in larger patient groups. Previous investigations: Only 2 transesophageal echocardiographic studies have previously addressed the issue of TAA evolution in patients with familial hypercholesterolemia undergoing lipid-lowering treatment. In their group of 8 patients, Herrera et al19 demonstrated a decrease in the TAA burden in 5 patients undergoing low-density lipoprotein apheresis for a period of 20 months, but not in 3 patients treated with standard lipid-lowering drug therapy for 7 months; at the time of repeat echocardiography, however, treatment in the latter group had proved unsuccessful in reducing plasma LDL cholesterol values. More recently, Tomochika et al20 described significant improvement in TAA expressed by means of an echocardiographic score in 12 patients after 13 months of combined lipid-lowering drug treatment with probucol and pravastatin. Both previous studies reported exclusively on TAA alterations occurring in the descending thoracic aorta. Our study was the first to monitor disease evolution in the entire thoracic aorta. We were thus able to describe a uniform fashion of TAA evolution in the different thoracic aortic segments and to demonstrate regression in lesions located also in the aortic arch and the ascending aorta. Clinical implications of these latter observations may be significant, because TAA
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