Q J Med 2015; 108:795–801 doi:10.1093/qjmed/hcv032 Advance Access Publication 6 February 2015
LDL cholesterol and apolipoprotein B are associated with ascending aorta dilatation in bicuspid aortic valve patients J.M. ALEGRET1, L. MASANA2, N. MARTINEZ-MICAELO1, M. HERAS2 and ´ N1 R. BELTRA´N-DEBO From the 1Grup de Recerca Cardiovascular, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Reus, Spain and 2Unitat de Recerca en Lı´pids i Arteriosclerosi, Universitat Rovira i Virgili, Hospital Universitari de Sant Joan, IISPV, CIBERDEM, Reus, Spain Address correspondence to J.M. Alegret, Grup de Recerca Cardiovascular, Hospital Universitari de Sant Joan, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili, c/ Dr Josep Laporte, 1, 43204 Reus, Spain. email: [email protected] Received 10 October 2014 and in revised form 15 January 2015
Background: The factors related to ascending aorta dilation (AAD) in patients with bicuspid aortic valve (BAV) are not completely understood. In addition, the role of cholesterol metabolism in AAD has not been studied. Methods: We analyzed the relationship between different lipid parameters and the ascending aorta diameter/presence of aortic dilatation in 91 consecutive patients with BAV. Results: We observed a positive linear correlation between the total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) levels and the ascending aorta diameter. The
patients with AAD had higher LDL cholesterol and ApoB levels. Whereas LDL cholesterol and ApoB were identified as independent factors predictors of the aortic root diameter, only ApoB predicted the diameter of the ascending aorta. On the other hand, the levels of ApoB were an independent factor related to the dilatation of the aortic root. Conclusions: We have observed that cholesterol is associated with ascending aorta diameter and dilation in BAV patients. Further experimental and clinical studies are needed to explain the pathobiology of this association.
Introduction Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation. BAV is commonly associated with the development of clinically relevant complications, such as aortic valve dysfunction, infectious endocarditis, ascending aorta dilatation (AAD) and aortic dissection.1 AAD is especially problematic because it is involved in the mechanism of aortic regurgitation in BAV,2 and it increases aortic stiffness3 and the risk of aortic dissection,4 which frequently leads to the need for prophylactic aortic surgery.5 The mechanisms that underlie aortic dilatation have been a matter of debate for years; the proposed causes
include anomalous flow in the ascending aorta generated by the anomalous dynamics of BAV6,7 and genetic causes responsible for the anomalous structure of the aortic media.8,9 However, to date, the physiopathology of AAD in BAV patients has not been completely explained, which suggests that other mechanisms are implicated. Serum lipoproteins have been related to abdominal aortic dilatation10–13. Thus, the aim of this study was to analyze the potential role of lipid metabolism-related parameters on the ascending aorta diameter and aortic dilation in patients with BAV.
! The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected]
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Summary
796
J.M. Alegret et al.
Patients and methods
Results The baseline clinical characteristics of the patients are shown in Table 1. Most patients were men, and there was a high prevalence of valve dysfunction and aortic dilatation. We observed significant linear correlations when comparing both the aortic root and ascending aorta diameters, with the levels of total cholesterol, LDL cholesterol and ApoB; these relationships were more evident after excluding those patients treated with statins (Table 2; Figure 1). Furthermore, the relationship between ascending aorta diameter
Table 1 Clinical, echocardiographic and analytical characteristics of the patients N (%) or mean SD Age (years) Men Hypertension Diabetes mellitus Smoker Peripheral arterial disease Stroke Ischemic heart disease Treatment with statins Typical BAV morphologya Ascending aorta dilatation Root phenotype Ascending phenotype Aortic stenosis (mean gradient 20 mmHg) Aortic regurgitation (II) Aortic root (mm) Ascending aorta (mm) Left ventricle diastolic diameter (mm) Left ventricle systolic diameter (mm) Left ventricular ejection fraction (%) Total cholesterol (mmol/l) Triglycerides (mmol/l) HDL (mmol/l) LDL (mmol/l) Lipoprotein (a) (mg/dl) ApoA (mg/dl) ApoB (mg/dl) C-reactive protein (mg/dl) a
49 17 68 (73) 32 (36.0) 8 (9.2) 14 (16.5) 3 (3.4) 1 (1.1) 2 (2.1) 9 (9.8) 59 (73.8) 59 (61.5) 14 (14.6) 45 (46.9) 34 (36.6) 48 (51.6) 37.3 5.5 40.5 7.3 52.2 5.8 32.4 6.3 70.0 8.2 4.9 1.0 1.2 1.0 1.5 0.3 2.8 0.8 13.4 15.6 138.8 25.3 91.1 22.4 2.6 2.6
BAV morphology was only feasible in 80 patients.
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We studied 91 consecutive patients diagnosed with BAV who were prospectively introduced in our database. All patients underwent an echocardiogram upon inclusion. BAV was diagnosed when two aortic leaflets were clearly visualized with or without raphe on the parasternal short-axis view of a transthoracic echocardiogram.14 When this procedure was considered insufficient for a definitive diagnosis of BAV, a transesophageal echocardiogram14 or cardiac magnetic resonance imaging15 was performed according to the clinical criteria. All explorations were performed or reviewed upon inclusion by the same observer (J.M.A.). Valve morphotype (i.e. the pattern of cusp fusion) was categorized as typical (fusion between right and left coronary cusps) or atypical (other morphotypes, mainly fusion between right and non coronary cusps).16 Once BAV was diagnosed, a blood sample was obtained and stored in our BAV biobank. Dilatation of the aortic root or ascending aorta was diagnosed when the corresponding diameter was 40 mm. The aortic morphology was categorized in three phenotypes depending on the aortic dilatation pattern: non-dilation phenotype, ascending phenotype (dilatation on the ascending aorta with normal or less dilatation on the aortic root) and root phenotype (dilatation in the aortic root with normal or less dilatation on the ascending aorta).16 This study was approved by the Institutional Review Board (the Clinical Ethics Committee) of our institution. Written informed consent was obtained from all patients who participated in this study. Biochemical parameters, including the levels of cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), apolipoproteins AI and B100, lipoprotein (Lp) (a) and C-reactive protein, were measured using colorimetric, enzymatic and immunoturbidimetric assays (Spinreact, SA, Girona, Spain; HORIBA ABX, Montpellier, France) adapted to a Cobas Mira Plus autoanalyzer (Roche Diagnostics, Madrid, Spain). The categorical variables are expressed as percentages, and significant differences were identified using the chi-square test or Fisher’s exact test, as appropriate. The quantitative variables, represented as the mean standard deviation (SD), were analyzed using Student’s t-test. Spearman’s correlation was used to identify linear relationships between the ascending aorta diameter and the parameters related to cholesterol metabolism. Stepwise linear regression models were used to identify independent predictors of the ascending aorta diameter, and stepwise logistic regression was used to identify
independent predictors of AAD. Variables with a P value
LDL cholesterol and apolipoprotein B are associated with ascending aorta dilatation in bicuspid aortic valve patients J.M. ALEGRET1, L. MASANA2, N. MARTINEZ-MICAELO1, M. HERAS2 and ´ N1 R. BELTRA´N-DEBO From the 1Grup de Recerca Cardiovascular, Hospital Universitari de Sant Joan, IISPV, Universitat Rovira i Virgili, Reus, Spain and 2Unitat de Recerca en Lı´pids i Arteriosclerosi, Universitat Rovira i Virgili, Hospital Universitari de Sant Joan, IISPV, CIBERDEM, Reus, Spain Address correspondence to J.M. Alegret, Grup de Recerca Cardiovascular, Hospital Universitari de Sant Joan, Departament de Medicina i Cirurgia, Universitat Rovira i Virgili, c/ Dr Josep Laporte, 1, 43204 Reus, Spain. email: [email protected] Received 10 October 2014 and in revised form 15 January 2015
Background: The factors related to ascending aorta dilation (AAD) in patients with bicuspid aortic valve (BAV) are not completely understood. In addition, the role of cholesterol metabolism in AAD has not been studied. Methods: We analyzed the relationship between different lipid parameters and the ascending aorta diameter/presence of aortic dilatation in 91 consecutive patients with BAV. Results: We observed a positive linear correlation between the total cholesterol, low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) levels and the ascending aorta diameter. The
patients with AAD had higher LDL cholesterol and ApoB levels. Whereas LDL cholesterol and ApoB were identified as independent factors predictors of the aortic root diameter, only ApoB predicted the diameter of the ascending aorta. On the other hand, the levels of ApoB were an independent factor related to the dilatation of the aortic root. Conclusions: We have observed that cholesterol is associated with ascending aorta diameter and dilation in BAV patients. Further experimental and clinical studies are needed to explain the pathobiology of this association.
Introduction Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation. BAV is commonly associated with the development of clinically relevant complications, such as aortic valve dysfunction, infectious endocarditis, ascending aorta dilatation (AAD) and aortic dissection.1 AAD is especially problematic because it is involved in the mechanism of aortic regurgitation in BAV,2 and it increases aortic stiffness3 and the risk of aortic dissection,4 which frequently leads to the need for prophylactic aortic surgery.5 The mechanisms that underlie aortic dilatation have been a matter of debate for years; the proposed causes
include anomalous flow in the ascending aorta generated by the anomalous dynamics of BAV6,7 and genetic causes responsible for the anomalous structure of the aortic media.8,9 However, to date, the physiopathology of AAD in BAV patients has not been completely explained, which suggests that other mechanisms are implicated. Serum lipoproteins have been related to abdominal aortic dilatation10–13. Thus, the aim of this study was to analyze the potential role of lipid metabolism-related parameters on the ascending aorta diameter and aortic dilation in patients with BAV.
! The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: [email protected]
Downloaded from by guest on November 17, 2015
Summary
796
J.M. Alegret et al.
Patients and methods
Results The baseline clinical characteristics of the patients are shown in Table 1. Most patients were men, and there was a high prevalence of valve dysfunction and aortic dilatation. We observed significant linear correlations when comparing both the aortic root and ascending aorta diameters, with the levels of total cholesterol, LDL cholesterol and ApoB; these relationships were more evident after excluding those patients treated with statins (Table 2; Figure 1). Furthermore, the relationship between ascending aorta diameter
Table 1 Clinical, echocardiographic and analytical characteristics of the patients N (%) or mean SD Age (years) Men Hypertension Diabetes mellitus Smoker Peripheral arterial disease Stroke Ischemic heart disease Treatment with statins Typical BAV morphologya Ascending aorta dilatation Root phenotype Ascending phenotype Aortic stenosis (mean gradient 20 mmHg) Aortic regurgitation (II) Aortic root (mm) Ascending aorta (mm) Left ventricle diastolic diameter (mm) Left ventricle systolic diameter (mm) Left ventricular ejection fraction (%) Total cholesterol (mmol/l) Triglycerides (mmol/l) HDL (mmol/l) LDL (mmol/l) Lipoprotein (a) (mg/dl) ApoA (mg/dl) ApoB (mg/dl) C-reactive protein (mg/dl) a
49 17 68 (73) 32 (36.0) 8 (9.2) 14 (16.5) 3 (3.4) 1 (1.1) 2 (2.1) 9 (9.8) 59 (73.8) 59 (61.5) 14 (14.6) 45 (46.9) 34 (36.6) 48 (51.6) 37.3 5.5 40.5 7.3 52.2 5.8 32.4 6.3 70.0 8.2 4.9 1.0 1.2 1.0 1.5 0.3 2.8 0.8 13.4 15.6 138.8 25.3 91.1 22.4 2.6 2.6
BAV morphology was only feasible in 80 patients.
Downloaded from by guest on November 17, 2015
We studied 91 consecutive patients diagnosed with BAV who were prospectively introduced in our database. All patients underwent an echocardiogram upon inclusion. BAV was diagnosed when two aortic leaflets were clearly visualized with or without raphe on the parasternal short-axis view of a transthoracic echocardiogram.14 When this procedure was considered insufficient for a definitive diagnosis of BAV, a transesophageal echocardiogram14 or cardiac magnetic resonance imaging15 was performed according to the clinical criteria. All explorations were performed or reviewed upon inclusion by the same observer (J.M.A.). Valve morphotype (i.e. the pattern of cusp fusion) was categorized as typical (fusion between right and left coronary cusps) or atypical (other morphotypes, mainly fusion between right and non coronary cusps).16 Once BAV was diagnosed, a blood sample was obtained and stored in our BAV biobank. Dilatation of the aortic root or ascending aorta was diagnosed when the corresponding diameter was 40 mm. The aortic morphology was categorized in three phenotypes depending on the aortic dilatation pattern: non-dilation phenotype, ascending phenotype (dilatation on the ascending aorta with normal or less dilatation on the aortic root) and root phenotype (dilatation in the aortic root with normal or less dilatation on the ascending aorta).16 This study was approved by the Institutional Review Board (the Clinical Ethics Committee) of our institution. Written informed consent was obtained from all patients who participated in this study. Biochemical parameters, including the levels of cholesterol, triglycerides, high-density lipoprotein cholesterol (HDL-C), apolipoproteins AI and B100, lipoprotein (Lp) (a) and C-reactive protein, were measured using colorimetric, enzymatic and immunoturbidimetric assays (Spinreact, SA, Girona, Spain; HORIBA ABX, Montpellier, France) adapted to a Cobas Mira Plus autoanalyzer (Roche Diagnostics, Madrid, Spain). The categorical variables are expressed as percentages, and significant differences were identified using the chi-square test or Fisher’s exact test, as appropriate. The quantitative variables, represented as the mean standard deviation (SD), were analyzed using Student’s t-test. Spearman’s correlation was used to identify linear relationships between the ascending aorta diameter and the parameters related to cholesterol metabolism. Stepwise linear regression models were used to identify independent predictors of the ascending aorta diameter, and stepwise logistic regression was used to identify
independent predictors of AAD. Variables with a P value
