Gen Thorac Cardiovasc Surg DOI 10.1007/s11748-015-0561-8
ORIGINAL ARTICLE
Differing relationship between hypercholesterolemia and a bicuspid aortic valve according to the presence of aortic valve stenosis or aortic valve regurgitation Masahiro Endo1 • Akihiro Nabuchi1 • Hiroshi Okuyama1 • Yasushi Muto1 • Susumu Hiranuma1 • Takuya Miyazaki1 • Joji Hosokawa2 • Yoshihisa Enjoji2 Yumi Shimura2 • Osamu Hashimoto2
•
Received: 5 October 2013 / Accepted: 16 May 2015 Ó The Japanese Association for Thoracic Surgery 2015
Abstract Objectives To assess the difference in hyperlipidemia between patients with bicuspid aortic valve (BAV) and those with a normal aortic valve (NAV), and to compare aortic valve stenosis (AS), with aortic valve regurgitation (AR). Methods Among 32 patients with BAV and 142 patients with NAV who underwent aortic valve replacement, 81 patients had AR and 91 patients had AS. The preoperative clinical characteristics were compared between the BAV and NAV patients. Patients with replacement of the ascending aorta were included, and those who underwent combined valvular surgery, coronary artery bypass grafting, or statin treatment were excluded. Results The proportions of females patients (p = 0.42), patients with diabetes (p = 0.26) and patients on dialysis (p = 0.69) were similar in the two groups. Mean age was significantly lower, the mean diameter of the ascending aorta was significantly larger, and the rate of surgical intervention for the ascending aorta was significantly higher in the BAV group than in the NAV group (all p \ 0.0001). The mean levels of low-density lipoprotein cholesterol (LDL) (p \ 0.0001) and total cholesterol (TC) (p = 0.0003) were significantly higher in the BAV group than in the NAV group, in the analysis of only patients with AS, whereas these levels did not differ significantly between the groups, when only patients with AR were considered.
& Masahiro Endo [email protected] 1
Department of Cardiovascular Surgery, Tokyo Heart Center, 5-4-12 Kitashinagawa, Shinagawa-ku, Tokyo 140-0001, Japan
2
Department of Cardiology, Tokyo Heart Center, Tokyo, Japan
Conclusion BAV with AS is associated with hypercholesterolemia. However, BAV with AR was not associated with hypercholesterolemia. Keywords Bicuspid aortic valve LDL cholesterol Aortic valve replacement
Introduction Bicuspid aortic valve (BAV) disease is a common congenital cardiac abnormality with an estimated prevalence of 0.46–2 % [1, 2]. Aortic valvular stenosis (AS) is mainly attributed to degenerative (i.e., valve calcification), congenital (i.e., BAV disease), or rheumatic diseases. Factors contributing to aortic stenosis progression include advanced age, diabetes mellitus (DM), hyperlipidemia (HL), hypertension (HT), smoking, male sex, and concomitant coronary artery disease [3]. Although HL often results from dietary and other lifestyle factors, it can be caused by genetic factors; for example, heterozygous familial hypercholesterolemia is a disorder that affects 1 in 500 people [4]. According to annual report (2013) from the Japanese Ministry of Health, Labour and Welfare, the incidence rates of an increased low-density lipoprotein (LDL) level ([140 mg/dL) among Japanese individuals who did not take related medication undergoing health examination were 34.4 % (166/482) (for those aged 50–59 years), 34.0 % (166/482) (for those aged 60–69 years) and 22.2 % (177/797) (for those aged [70 years) [5]. We investigated the prevalence and severity of higher level of LDL cholesterol, total cholesterol (TC), and triglyceride (TG) in patients who underwent aortic valve replacement (AVR) by comparing patients with BAV to those with a normal aortic valve (NAV), and
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by further comparing patients with aortic valve stenosis (AS) to those with aortic valve regurgitation (AR).
frequency or mean ± standard deviation (SD). The characteristics of the patient groups were compared by using the v2 test or Fisher’s exact probability test. Two-tailed values of p \ 0.05 were considered to indicate a statistically significant difference.
Methods Ethics Participants Inclusion criteria The subjects were patients who underwent primary and isolated AVR at our institution between January 2006 and June 2013. Patients undergoing emergent surgery, chronic dialysis, concomitant ascending aorta replacement for aortic aneurysm or dilatation, and/or the Bentall operation were included. Concomitant aortic surgery was performed according to the size of the ascending aorta: replacement for a diameter of [45 mm in patients with BAV and for a diameter of [50 mm in patients with NAV [3]. The study included 172 subjects consisting 30 patients with BAV and 142 with NAV. Exclusion criteria Seven patients who were administered statins and/or other lipid lowering drugs preoperatively were excluded from the study. Patients were also excluded from the study if they had concomitant mitral valve surgery and/or tricuspid valvular surgery, coronary artery bypass grafting, recent percutaneous coronary intervention, annuloaortic ectasia/aortic valve regurgitation (AAE/AR) due to Marfan syndrome or Takayasu disease [6]. Laboratory measurements We compared age, sex, height, weight, maximum ascending aortic diameter, incidence of concomitant surgery involving the ascending aorta, TC level, LDL, high-density lipoprotein (HDL) level, TG level and the proportion of patients with hyper LDL ([140 mg/dL) between patients with BAV and those with NAV. We further compared patients with AS and these with AR, the diagnoses of which were determined on the basis of the operative findings, irrespective of the presence of BAV or NAV. Whether BAV or NAV, final diagnosis was decided due to the operation findings. Statistical analysis The analyses were performed using the SAS System (SAS Institute Inc, Cary, NC, USA). The data are presented as
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The study design was approved by the institutional review board and all patients provided written informed consent.
Results Among overall 172 patients who underwent AVR, no patients died. However, 1 patient with NAV (0.6 %) died due to multiple organ failure on 75 days postoperatively. The patients with BAV were, on average, 14.9 years younger than those with NAV (p \ 0.0001). Specifically, the mean age (43.8 ± 8.8 years old) of patients with the BAV and AR was significantly lower than that (69.0 ± 11.6 years old) of patients with NAV and AR (p \ 0.0001). The mean age (61.4 ± 9.3 years old) of patients with AS was significantly higher than that (43.8 ± 8.8 years old) of the patient with AR in the BAV group (p \ 0.0001). No significant differences were found in the male/female ratio (p = 0.42), height (p = 0.23), weight (p = 0.47), prevalence of DM (p = 0.26) or end-stage renal dysfunction on hemodialysis (p = 0.69) between the two groups. The mean ascending aortic diameters were 44.6 ± 13.2 mm in the BAV group and 36.7 ± 7.1 mm in the NAV group, and the difference was significant (p \ 0.0001). The frequency of concomitant surgery of the ascending aorta was significantly higher in the BAV group than in the NAV group (p \ 0.0001). The mean sizes of the prosthetic valve were 22.9 ± 2.1 mm in the BAV group and 22.2 ± 2.1 mm in the NAV group, although this difference was not statistically significant (p = 0.13). Mechanical valves were used in 33.3 % of patients in the BAV group and in 13 % of patients in the NAV group, and this difference was significant (p = 0.009). Preoperative laboratory tests showed that the mean levels of LDL (p \ 0.0001), TC (p = 0.0003), and TG (p \ 0.0001) and the proportion of patients with a higher LDL ([140 mg/ dL) (p \ 0.0001) were significantly higher in the BAV group than in the NAV group. The HDL level was almost different, but not statistically significant (p = 0.06) (Table 1). The mean values of LDL in patients with AS were significantly higher than those in patients with AR in the NAV group (p \ 0.0001). However, the mean values of LDL in the patients with AS were not significantly higher
Gen Thorac Cardiovasc Surg Table 1 Preoperative parameters
BAV (n = 30)
NAV (n = 142)
p value
Height (cm)
161.1 ± 9.4
158.9 ± 9.1
0.23
Weight (kg)
59.4 ± 10.6
57.8 ± 11.3
0.47
Body mass index
23.1 ± 3.4
22.9 ± 2.9
0.61
Age (years)
56.7 ± 12.0
71.6 ± 11.2
\0.0001
Female/male ratio
12/18
71/71
0.42
Diabetes mellitus
2 (6.7 %)
22 (15.5 %)
0.26
Dialysis
1 (3.3 %)
10 (7.0 %)
0.69
LDL [140 mg/dL
19 (63.3 %)
25 (17.6 %)
\0.0001
LDL (mg/dL)
140 ± 30.6
112.3 ± 31.6
\0.0001
HDL (mg/dL)
52.8 ± 11.1
59.1 ± 17.2
0.06
LDL/HDL ratio
2.83 ± 0.9
2.11 ± 0.87
\0.0001
Total cholesterol (mg/dL)
222.3 ± 38.7
196.1 ± 34.9
0.0003
Triglyceride (mg/dL)
146.2 ± 65.0
102.1 ± 49.0
\0.0001
Maximal diameter of ascending aorta (mm)
44.6 ± 13.2
36.7 ± 7.1
\0.0001
Required aortic surgery Size of prosthesis (mm)
16 (53.3 %) 22.9 ± 2.1
14 (9.9 %) 22.2 ± 2.1
\0.0001 0.13
Mechanical prosthesis
10 (33.3 %)
13 (9.2 %)
0.009
Values are expressed as mean ± standard deviation NAV normal cuspid aortic valve, BAV bicuspid aortic valve, LDL low-density lipoprotein cholesterol, HDL high-density-lipoprotein cholesterol
Table 2 Preoperative lipid value of study patients with BAV or NAV, and patients with AR or AS
BAV (n = 30)
NAV (n = 142)
p value
Total (n = 172)
140.7 ± 30.6
112.3 ± 31.6
\0.0001
AR (n = 81)
127.0 ± 37.6 (n = 8)
119.1 ± 32.8 (n = 73)
0.52
AS (n = 91)
145.7 ± 26.9 (n = 22)
105.9 ± 28.8 (n = 69)
\0.0001
Total (n = 172)
222.3 ± 38.7
196.1 ± 34.9
AR (n = 81)
205.1 ± 50.5
202.8 ± 39.1
0.87
AS (n = 91)
228.5 ± 32.6
188.8 ± 28.3
\0.0001
Total (n = 172)
146.2 ± 65.0
102.1 ± 49.0
\0.0001
AR (n = 81)
168.4 ± 90.2
104.7 ± 50.2
0.003
AS (n = 91)
138.1 ± 47.3
99.3 ± 47.8
0.0013
Total (n = 172)
52.8 ± 13.1
59.1 ± 17.2
0.06
AR (n = 81) AS (n = 91)
55.0 ± 15.7 52.0 ± 12.3
59.1 ± 17.2 57.8 ± 16.6
0.42 0.14
LDL (mg/dL)
TC (mg/dL) 0.0003
Triglyceride (mg/dL)
HDL (mg/dL)
Value are expressed as mean ± standard deviation AR aortic valve regurgitation, AS aortic valve stenosis, BAV bicuspid aortic valve, NAV normal aortic valve, TC total cholesterol, LDL low-density lipoprotein cholesterol, HDL high-density lipoprotein cholesterol
than those in patients with AR in the BAV group (p = 0.52; Table 2). The mean values of TG were significantly higher in the BAV group than that in the NAV group, in patients with AS (p = 0.003) and in those with AR (p = 0.0013).
The proportion of patients with higher level of LDL ([140 mg/dL) was significantly higher in the BAV group (19/30) than in Japanese individual, aged 50–59 years (166/433; p = 0.0015) as reported by the Japanese Ministry of Health, Labour and Welfare in 2013 [5].
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The macro-morphology of the aortic valve was evaluated by inspecting of the valve during surgery. Based on appearance, the valve was classified according to number of cusps and commissures. Three cusps and three commissures denoted a tricuspid valve: while two cusps and two commissures denoted a bicuspid valve.
Discussion The BAV sketched by Leonardo Da Vinci (1452–1519) approximately 500 years ago is featured on the home page of the Bicuspid Aortic Foundation. To the best of our knowledge, no studies have yet examined the relationship between aortic valvular disease and hypercholesterolemia by comparing subjects with BAV and those with NAV, and further comparing subgroups of patients with AS and those with AR. We assessed patients with aortic valvular disease who underwent AVR, and compared patients with BAV to those with NAV. No significant differences were found between the two groups with respect to the male/female ratio, or the prevalence of DM, or chronic dialysis. However, patients with BAV were significantly younger than those with NAV. The proportions of patients using a mechanical valve and those undergoing concomitant surgery were significantly higher in the BAV group than in NAV group, but there was no significant difference in the sizes of prosthetic valves used. The mean values of TC, LDL cholesterol, TG, and the proportion of patients with hyper LDL [140 mg/dL were significantly higher in the BAV group than in the NAV group. Additionally, the levels of hypercholesterolemia were not significantly different between the BAV group and in the NAV group when the analysis was limited to patients with AR. The mean values of TG in the BAV group were significantly higher than those in the NAV group, both in patients with AS and in those with AR. In the present study, 30 of 172 (17.2 %) patients with AVR had BAV, consistent with the findings of previous studies [8]. For example, Tutar et al. assessed 567 male neonates and 508 female neonates using echocardiography and reported the prevalence of BAV to be 0.46 % [1]. In a consecutive autopsy series of 4000 cases of patients [60 years of age, Ohkawa and colleagues found that 9 of 458 patients (2 %) with valvular disease had BAV [7]. Yoshimoto and co-workers reported that 63 of 375 (16.8 %) patients with AVR had BAV [8]. The main purpose of AVR in patients with BAV was the prevention of rupture or dissection of the ascending aorta rather than clinical symptoms. The concomitant diseases reported were dilatation of the ascending aorta [9, 10], aortic aneurysm [11], dissecting aortic aneurysm [12], and infective
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endocarditis [13, 14]. These reports are also consistent with the present findings. Novaro et al. investigated lipid profiles of 2356 patients undergoing aortic valve replacement at the Cleveland Clinic Foundation. They reported that AS was more strongly associated with HL than AR [15]. Additionally, statins were effective in slowing the progression of AS [16]. Tanabe and colleagues compared the predictive values of LDL and non-HDL cholesterol for myocardial infarction (MI) and stroke. Both LDL and non-HDL cholesterol levels were significantly associated with the incidence of MI. However, there was no relationship between the incidence of stroke and levels either LDL or non-HDL cholesterol [17]. Several studies have investigated the relationship between AS and dyslipidemia [15–17]. Chan et al. reported that TC and HT were associated with progression in patients with BAV and AS without AVR; however, there is a lack of data on patients with BAV and AR [18]. In this study, the proportion of mechanical prosthetic valves for patients with BAV was significantly higher than that for patients with NAV. Our surgical strategy, mechanical prosthetic valve should be selected in patients with BAV, even patient is not younger age. Additionally, increased serum cholesterol level may be risk factor for bioprosthetic valve calcification requiring explantation [19]. Although total management of the risk factors such as HT, DM, and smoking is important for the prevention of bioprosthetic valve degeneration, the management of dyslipidemia may be the most important. The effect of statin treatment on bioprosthetic valve degeneration found a beneficial effect of statin in slowing bioprosthetic degeneration [20]. Goel and associates compared ascending aortic diameters between patients with BAV taking statins and those not taking statin. They reported that patients with statin-treated BAV stenosis have a smaller ascending aortic size than those with statin-untreated BAV [21]. Yasuda et al. examined the ascending aortic dilatation rate after AVR. They found that the annual dilatation rate in patients with BAV tended to exceed the rate in patients with NAV [22]. Sievers and co-workers identified three major classification of BAV: type 0 (no raphe), type 1 (one raphe), and type 2 (two raphes) in the patients with BVA [23]. Yoshioka et al. reported that type 1 of the Sievers classification was the most common in patients with BAV [24]. According to Padang and colleagues, the genetic and molecular backgrounds of BAV patients are associated with aortic complications [25]. Unfortunately, we do not have the genetic data of patients with BAV and hyper LDL cholesterol, or the postoperative long-term results of BAV patients with or without statin treatment.
Gen Thorac Cardiovasc Surg
Study limitation This study was subject to the limitations inherent to a retrospective design, and no genetic data were available.
Conclusion
13.
Our results suggest that BAV with AS was significantly associated with hyper TC and LDL. However, BAV with AR was not associated with hyper TC and LDL. These findings may be helpful in guiding the decision-making process for the application of prosthetic valves, delay in aortic valve replacement and postoperative management. Conflict of interest interest.
12.
All the authors have declared no competing
References 1. Tutar E, Ekici F, Atalay S, Nacar N. The prevalence of bicuspid aortic valve in newborns by echocardiographic screening. Am Heart J. 2005;150:513–5. 2. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;19:1890–900. 3. Guntheroth WG. A critical review of American College of Cardiology/American Heart Association practice guidelines on bicuspid aortic valve with dilated ascending aorta. Am J Cardiol. 2008;102:107–10. 4. Mabuchi H, Koizumi J, Shimizu M, Takeda R. Development of coronary heart disease in familial hypercholesterolemia. Circulation. 1989;79:225–32. 5. Yajima T, editor. An annual report of Japanese peoples of heath and nutrition. Japanese Ministry of Health, Labour and Welfare; 2013. p. 135 (in Japanese). 6. Endo M, Tomizawa Y, Nishida H, Aomi S, Nakazawa M, Tsurumi Y, et al. Angiographic findings and surgical treatments of coronary artery involvement in Takayasu arteritis. J Thorac Cardiovasc Surg. 2002;125:570–7. 7. Ohkawa S, Ueda K, Sugiura M. Valvular disease. Jpn J Geriatrics. 1985;22:317–24 (in Japanese). 8. Yoshimoto G, Moriyama Y, Toyohira H, Shimokawa G, Iguro Y. Congenital bicuspid aortic valve: analysis of 63 surgical cases. J Heart Valve Dis. 1998;7:500–3. 9. Tzemos N, Therrien J, Yip J, Thanassoulis G, Tremblay S, Jamorski MT, et al. Outcomes in adults with bicuspid aortic valves. JAMA. 2008;300:1317–25. 10. Michelens HI, Desjardins VA, Avierinous JA, Russo A, Nkomo VT, Sundt TM, et al. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in community. Circulation. 2008;117:2776–84. 11. Pape LA, Tsai TT, Isselbacher EM, Oh JK, O’Gata PT, Evangelista A, International Registry of Acute Aortic Dissection (IRAD) Investigators, et al. Aortic diameter[or = 5.5 cm is not a
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2007;116:1120–7. Oliver JM, Alonso-Gonzalez R, Gonzalez AE, Gallegp P, Sanchez-Recalde A, Cuesta E, et al. Risk of aortic root or ascending aorta complications on patients with bicuspid aortic valve with and without coarctation of the aorta. Am J Cardiol. 2009;104:1001–6. Iwasa S, Fukushima Y. Moriguchi-Goto S. Acute aortic dissection associated with undetected congenital bicuspid aortic valve and infective endocarditis diagnosed intraoperatively. Interact Cardiovasc Thorac Surg. 2011;12:82–3. Michelena HI, Khanna AD, Mahoney D, Margaryan E, Topilsky Y, Suri BE, et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA. 2011;306:1104–12. Novaro GM, Pearce GL, Sorecher DL, Griffin BP. Comparison of cardiovascular risk and lipid profiles in patients undergoing aortic valve surgery those undergoing coronary artery bypass grafting. J Heart Valve Dis. 2001;10:19–24. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme A reductase inhibitors on the progression of calcific aortic stenosis. Circulation. 2001;104:2205–9. Tanabe N, Iso H, Okada K, Nakamura Y, Harada A, Ohashi Y, Japan Arteriosclerosis Longitudinal Study Group, et al. Serum total and non-high-density lipoprotein cholesterol and the risk prediction of cardiovascular events—the JALS-ECC. Circ J. 2010;74:1346–56. Chan KL, Ghani M, Woodtend K, Burwash G. Case-controlled study to assess risk factors for aortic stenosis in congenital bicuspid aortic valve. Am J Cardiol. 2001;88:690–3. Farivar RD, Cohn LH. Hypercholesterolemia is a risk factor for bioprosthetic valve calcification and explantation. J Thorac Cardiovasc Surg. 2003;126:969–75. Antonini-Canterin F, Zuppiroli A, Popescu BA, Granata G, Cervesato E, Piazza R, et al. Effect of statins on the progression of bioprosthetic aortic valve degeneration. Am J Cardiol. 2003;92:1479–82. Goel SS, Tuzcu EM, Aqarwal S, Aksoy O, Krishnaswamy A, Griffin BP, et al. Comparison of ascending aortic size in patients with severe bicuspid aortic valve stenosis treated with versus without a statin drugs. Am J Cardiol. 2011;108:1458–62. Yasuda H, Nakatani S, Stugaard M, Tsujita-Kuroda Y, Bando K, Kobayashi J, et al. Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve comparison with tricuspid aortic valve. Circulation. 2003;108:II-291–4. Sievers H, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg. 2007;133:126–33. Yoshioka Y, Mitsuno M, Yamamura M, Tanaka H, Ryomoto M, Fukui S, et al. Morphological type and histological features of the dilated ascending aorta in patients with a bicuspid aortic valve. Jpn J Cardiovasc Surg. 2013;42:89–93 (in Japanese). Padang R, Bannon PG, Jeremy R, Richmond DR, Semsarian C, Vallely M, et al. The genetic and molecular basis of bicuspid aortic valve associated thoracic aortopathy: a link to phenotype heterogeneity. Ann Cardiothoracic Surg. 2013;19:83–91.
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ORIGINAL ARTICLE
Differing relationship between hypercholesterolemia and a bicuspid aortic valve according to the presence of aortic valve stenosis or aortic valve regurgitation Masahiro Endo1 • Akihiro Nabuchi1 • Hiroshi Okuyama1 • Yasushi Muto1 • Susumu Hiranuma1 • Takuya Miyazaki1 • Joji Hosokawa2 • Yoshihisa Enjoji2 Yumi Shimura2 • Osamu Hashimoto2
•
Received: 5 October 2013 / Accepted: 16 May 2015 Ó The Japanese Association for Thoracic Surgery 2015
Abstract Objectives To assess the difference in hyperlipidemia between patients with bicuspid aortic valve (BAV) and those with a normal aortic valve (NAV), and to compare aortic valve stenosis (AS), with aortic valve regurgitation (AR). Methods Among 32 patients with BAV and 142 patients with NAV who underwent aortic valve replacement, 81 patients had AR and 91 patients had AS. The preoperative clinical characteristics were compared between the BAV and NAV patients. Patients with replacement of the ascending aorta were included, and those who underwent combined valvular surgery, coronary artery bypass grafting, or statin treatment were excluded. Results The proportions of females patients (p = 0.42), patients with diabetes (p = 0.26) and patients on dialysis (p = 0.69) were similar in the two groups. Mean age was significantly lower, the mean diameter of the ascending aorta was significantly larger, and the rate of surgical intervention for the ascending aorta was significantly higher in the BAV group than in the NAV group (all p \ 0.0001). The mean levels of low-density lipoprotein cholesterol (LDL) (p \ 0.0001) and total cholesterol (TC) (p = 0.0003) were significantly higher in the BAV group than in the NAV group, in the analysis of only patients with AS, whereas these levels did not differ significantly between the groups, when only patients with AR were considered.
& Masahiro Endo [email protected] 1
Department of Cardiovascular Surgery, Tokyo Heart Center, 5-4-12 Kitashinagawa, Shinagawa-ku, Tokyo 140-0001, Japan
2
Department of Cardiology, Tokyo Heart Center, Tokyo, Japan
Conclusion BAV with AS is associated with hypercholesterolemia. However, BAV with AR was not associated with hypercholesterolemia. Keywords Bicuspid aortic valve LDL cholesterol Aortic valve replacement
Introduction Bicuspid aortic valve (BAV) disease is a common congenital cardiac abnormality with an estimated prevalence of 0.46–2 % [1, 2]. Aortic valvular stenosis (AS) is mainly attributed to degenerative (i.e., valve calcification), congenital (i.e., BAV disease), or rheumatic diseases. Factors contributing to aortic stenosis progression include advanced age, diabetes mellitus (DM), hyperlipidemia (HL), hypertension (HT), smoking, male sex, and concomitant coronary artery disease [3]. Although HL often results from dietary and other lifestyle factors, it can be caused by genetic factors; for example, heterozygous familial hypercholesterolemia is a disorder that affects 1 in 500 people [4]. According to annual report (2013) from the Japanese Ministry of Health, Labour and Welfare, the incidence rates of an increased low-density lipoprotein (LDL) level ([140 mg/dL) among Japanese individuals who did not take related medication undergoing health examination were 34.4 % (166/482) (for those aged 50–59 years), 34.0 % (166/482) (for those aged 60–69 years) and 22.2 % (177/797) (for those aged [70 years) [5]. We investigated the prevalence and severity of higher level of LDL cholesterol, total cholesterol (TC), and triglyceride (TG) in patients who underwent aortic valve replacement (AVR) by comparing patients with BAV to those with a normal aortic valve (NAV), and
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by further comparing patients with aortic valve stenosis (AS) to those with aortic valve regurgitation (AR).
frequency or mean ± standard deviation (SD). The characteristics of the patient groups were compared by using the v2 test or Fisher’s exact probability test. Two-tailed values of p \ 0.05 were considered to indicate a statistically significant difference.
Methods Ethics Participants Inclusion criteria The subjects were patients who underwent primary and isolated AVR at our institution between January 2006 and June 2013. Patients undergoing emergent surgery, chronic dialysis, concomitant ascending aorta replacement for aortic aneurysm or dilatation, and/or the Bentall operation were included. Concomitant aortic surgery was performed according to the size of the ascending aorta: replacement for a diameter of [45 mm in patients with BAV and for a diameter of [50 mm in patients with NAV [3]. The study included 172 subjects consisting 30 patients with BAV and 142 with NAV. Exclusion criteria Seven patients who were administered statins and/or other lipid lowering drugs preoperatively were excluded from the study. Patients were also excluded from the study if they had concomitant mitral valve surgery and/or tricuspid valvular surgery, coronary artery bypass grafting, recent percutaneous coronary intervention, annuloaortic ectasia/aortic valve regurgitation (AAE/AR) due to Marfan syndrome or Takayasu disease [6]. Laboratory measurements We compared age, sex, height, weight, maximum ascending aortic diameter, incidence of concomitant surgery involving the ascending aorta, TC level, LDL, high-density lipoprotein (HDL) level, TG level and the proportion of patients with hyper LDL ([140 mg/dL) between patients with BAV and those with NAV. We further compared patients with AS and these with AR, the diagnoses of which were determined on the basis of the operative findings, irrespective of the presence of BAV or NAV. Whether BAV or NAV, final diagnosis was decided due to the operation findings. Statistical analysis The analyses were performed using the SAS System (SAS Institute Inc, Cary, NC, USA). The data are presented as
123
The study design was approved by the institutional review board and all patients provided written informed consent.
Results Among overall 172 patients who underwent AVR, no patients died. However, 1 patient with NAV (0.6 %) died due to multiple organ failure on 75 days postoperatively. The patients with BAV were, on average, 14.9 years younger than those with NAV (p \ 0.0001). Specifically, the mean age (43.8 ± 8.8 years old) of patients with the BAV and AR was significantly lower than that (69.0 ± 11.6 years old) of patients with NAV and AR (p \ 0.0001). The mean age (61.4 ± 9.3 years old) of patients with AS was significantly higher than that (43.8 ± 8.8 years old) of the patient with AR in the BAV group (p \ 0.0001). No significant differences were found in the male/female ratio (p = 0.42), height (p = 0.23), weight (p = 0.47), prevalence of DM (p = 0.26) or end-stage renal dysfunction on hemodialysis (p = 0.69) between the two groups. The mean ascending aortic diameters were 44.6 ± 13.2 mm in the BAV group and 36.7 ± 7.1 mm in the NAV group, and the difference was significant (p \ 0.0001). The frequency of concomitant surgery of the ascending aorta was significantly higher in the BAV group than in the NAV group (p \ 0.0001). The mean sizes of the prosthetic valve were 22.9 ± 2.1 mm in the BAV group and 22.2 ± 2.1 mm in the NAV group, although this difference was not statistically significant (p = 0.13). Mechanical valves were used in 33.3 % of patients in the BAV group and in 13 % of patients in the NAV group, and this difference was significant (p = 0.009). Preoperative laboratory tests showed that the mean levels of LDL (p \ 0.0001), TC (p = 0.0003), and TG (p \ 0.0001) and the proportion of patients with a higher LDL ([140 mg/ dL) (p \ 0.0001) were significantly higher in the BAV group than in the NAV group. The HDL level was almost different, but not statistically significant (p = 0.06) (Table 1). The mean values of LDL in patients with AS were significantly higher than those in patients with AR in the NAV group (p \ 0.0001). However, the mean values of LDL in the patients with AS were not significantly higher
Gen Thorac Cardiovasc Surg Table 1 Preoperative parameters
BAV (n = 30)
NAV (n = 142)
p value
Height (cm)
161.1 ± 9.4
158.9 ± 9.1
0.23
Weight (kg)
59.4 ± 10.6
57.8 ± 11.3
0.47
Body mass index
23.1 ± 3.4
22.9 ± 2.9
0.61
Age (years)
56.7 ± 12.0
71.6 ± 11.2
\0.0001
Female/male ratio
12/18
71/71
0.42
Diabetes mellitus
2 (6.7 %)
22 (15.5 %)
0.26
Dialysis
1 (3.3 %)
10 (7.0 %)
0.69
LDL [140 mg/dL
19 (63.3 %)
25 (17.6 %)
\0.0001
LDL (mg/dL)
140 ± 30.6
112.3 ± 31.6
\0.0001
HDL (mg/dL)
52.8 ± 11.1
59.1 ± 17.2
0.06
LDL/HDL ratio
2.83 ± 0.9
2.11 ± 0.87
\0.0001
Total cholesterol (mg/dL)
222.3 ± 38.7
196.1 ± 34.9
0.0003
Triglyceride (mg/dL)
146.2 ± 65.0
102.1 ± 49.0
\0.0001
Maximal diameter of ascending aorta (mm)
44.6 ± 13.2
36.7 ± 7.1
\0.0001
Required aortic surgery Size of prosthesis (mm)
16 (53.3 %) 22.9 ± 2.1
14 (9.9 %) 22.2 ± 2.1
\0.0001 0.13
Mechanical prosthesis
10 (33.3 %)
13 (9.2 %)
0.009
Values are expressed as mean ± standard deviation NAV normal cuspid aortic valve, BAV bicuspid aortic valve, LDL low-density lipoprotein cholesterol, HDL high-density-lipoprotein cholesterol
Table 2 Preoperative lipid value of study patients with BAV or NAV, and patients with AR or AS
BAV (n = 30)
NAV (n = 142)
p value
Total (n = 172)
140.7 ± 30.6
112.3 ± 31.6
\0.0001
AR (n = 81)
127.0 ± 37.6 (n = 8)
119.1 ± 32.8 (n = 73)
0.52
AS (n = 91)
145.7 ± 26.9 (n = 22)
105.9 ± 28.8 (n = 69)
\0.0001
Total (n = 172)
222.3 ± 38.7
196.1 ± 34.9
AR (n = 81)
205.1 ± 50.5
202.8 ± 39.1
0.87
AS (n = 91)
228.5 ± 32.6
188.8 ± 28.3
\0.0001
Total (n = 172)
146.2 ± 65.0
102.1 ± 49.0
\0.0001
AR (n = 81)
168.4 ± 90.2
104.7 ± 50.2
0.003
AS (n = 91)
138.1 ± 47.3
99.3 ± 47.8
0.0013
Total (n = 172)
52.8 ± 13.1
59.1 ± 17.2
0.06
AR (n = 81) AS (n = 91)
55.0 ± 15.7 52.0 ± 12.3
59.1 ± 17.2 57.8 ± 16.6
0.42 0.14
LDL (mg/dL)
TC (mg/dL) 0.0003
Triglyceride (mg/dL)
HDL (mg/dL)
Value are expressed as mean ± standard deviation AR aortic valve regurgitation, AS aortic valve stenosis, BAV bicuspid aortic valve, NAV normal aortic valve, TC total cholesterol, LDL low-density lipoprotein cholesterol, HDL high-density lipoprotein cholesterol
than those in patients with AR in the BAV group (p = 0.52; Table 2). The mean values of TG were significantly higher in the BAV group than that in the NAV group, in patients with AS (p = 0.003) and in those with AR (p = 0.0013).
The proportion of patients with higher level of LDL ([140 mg/dL) was significantly higher in the BAV group (19/30) than in Japanese individual, aged 50–59 years (166/433; p = 0.0015) as reported by the Japanese Ministry of Health, Labour and Welfare in 2013 [5].
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The macro-morphology of the aortic valve was evaluated by inspecting of the valve during surgery. Based on appearance, the valve was classified according to number of cusps and commissures. Three cusps and three commissures denoted a tricuspid valve: while two cusps and two commissures denoted a bicuspid valve.
Discussion The BAV sketched by Leonardo Da Vinci (1452–1519) approximately 500 years ago is featured on the home page of the Bicuspid Aortic Foundation. To the best of our knowledge, no studies have yet examined the relationship between aortic valvular disease and hypercholesterolemia by comparing subjects with BAV and those with NAV, and further comparing subgroups of patients with AS and those with AR. We assessed patients with aortic valvular disease who underwent AVR, and compared patients with BAV to those with NAV. No significant differences were found between the two groups with respect to the male/female ratio, or the prevalence of DM, or chronic dialysis. However, patients with BAV were significantly younger than those with NAV. The proportions of patients using a mechanical valve and those undergoing concomitant surgery were significantly higher in the BAV group than in NAV group, but there was no significant difference in the sizes of prosthetic valves used. The mean values of TC, LDL cholesterol, TG, and the proportion of patients with hyper LDL [140 mg/dL were significantly higher in the BAV group than in the NAV group. Additionally, the levels of hypercholesterolemia were not significantly different between the BAV group and in the NAV group when the analysis was limited to patients with AR. The mean values of TG in the BAV group were significantly higher than those in the NAV group, both in patients with AS and in those with AR. In the present study, 30 of 172 (17.2 %) patients with AVR had BAV, consistent with the findings of previous studies [8]. For example, Tutar et al. assessed 567 male neonates and 508 female neonates using echocardiography and reported the prevalence of BAV to be 0.46 % [1]. In a consecutive autopsy series of 4000 cases of patients [60 years of age, Ohkawa and colleagues found that 9 of 458 patients (2 %) with valvular disease had BAV [7]. Yoshimoto and co-workers reported that 63 of 375 (16.8 %) patients with AVR had BAV [8]. The main purpose of AVR in patients with BAV was the prevention of rupture or dissection of the ascending aorta rather than clinical symptoms. The concomitant diseases reported were dilatation of the ascending aorta [9, 10], aortic aneurysm [11], dissecting aortic aneurysm [12], and infective
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endocarditis [13, 14]. These reports are also consistent with the present findings. Novaro et al. investigated lipid profiles of 2356 patients undergoing aortic valve replacement at the Cleveland Clinic Foundation. They reported that AS was more strongly associated with HL than AR [15]. Additionally, statins were effective in slowing the progression of AS [16]. Tanabe and colleagues compared the predictive values of LDL and non-HDL cholesterol for myocardial infarction (MI) and stroke. Both LDL and non-HDL cholesterol levels were significantly associated with the incidence of MI. However, there was no relationship between the incidence of stroke and levels either LDL or non-HDL cholesterol [17]. Several studies have investigated the relationship between AS and dyslipidemia [15–17]. Chan et al. reported that TC and HT were associated with progression in patients with BAV and AS without AVR; however, there is a lack of data on patients with BAV and AR [18]. In this study, the proportion of mechanical prosthetic valves for patients with BAV was significantly higher than that for patients with NAV. Our surgical strategy, mechanical prosthetic valve should be selected in patients with BAV, even patient is not younger age. Additionally, increased serum cholesterol level may be risk factor for bioprosthetic valve calcification requiring explantation [19]. Although total management of the risk factors such as HT, DM, and smoking is important for the prevention of bioprosthetic valve degeneration, the management of dyslipidemia may be the most important. The effect of statin treatment on bioprosthetic valve degeneration found a beneficial effect of statin in slowing bioprosthetic degeneration [20]. Goel and associates compared ascending aortic diameters between patients with BAV taking statins and those not taking statin. They reported that patients with statin-treated BAV stenosis have a smaller ascending aortic size than those with statin-untreated BAV [21]. Yasuda et al. examined the ascending aortic dilatation rate after AVR. They found that the annual dilatation rate in patients with BAV tended to exceed the rate in patients with NAV [22]. Sievers and co-workers identified three major classification of BAV: type 0 (no raphe), type 1 (one raphe), and type 2 (two raphes) in the patients with BVA [23]. Yoshioka et al. reported that type 1 of the Sievers classification was the most common in patients with BAV [24]. According to Padang and colleagues, the genetic and molecular backgrounds of BAV patients are associated with aortic complications [25]. Unfortunately, we do not have the genetic data of patients with BAV and hyper LDL cholesterol, or the postoperative long-term results of BAV patients with or without statin treatment.
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Study limitation This study was subject to the limitations inherent to a retrospective design, and no genetic data were available.
Conclusion
13.
Our results suggest that BAV with AS was significantly associated with hyper TC and LDL. However, BAV with AR was not associated with hyper TC and LDL. These findings may be helpful in guiding the decision-making process for the application of prosthetic valves, delay in aortic valve replacement and postoperative management. Conflict of interest interest.
12.
All the authors have declared no competing
References 1. Tutar E, Ekici F, Atalay S, Nacar N. The prevalence of bicuspid aortic valve in newborns by echocardiographic screening. Am Heart J. 2005;150:513–5. 2. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;19:1890–900. 3. Guntheroth WG. A critical review of American College of Cardiology/American Heart Association practice guidelines on bicuspid aortic valve with dilated ascending aorta. Am J Cardiol. 2008;102:107–10. 4. Mabuchi H, Koizumi J, Shimizu M, Takeda R. Development of coronary heart disease in familial hypercholesterolemia. Circulation. 1989;79:225–32. 5. Yajima T, editor. An annual report of Japanese peoples of heath and nutrition. Japanese Ministry of Health, Labour and Welfare; 2013. p. 135 (in Japanese). 6. Endo M, Tomizawa Y, Nishida H, Aomi S, Nakazawa M, Tsurumi Y, et al. Angiographic findings and surgical treatments of coronary artery involvement in Takayasu arteritis. J Thorac Cardiovasc Surg. 2002;125:570–7. 7. Ohkawa S, Ueda K, Sugiura M. Valvular disease. Jpn J Geriatrics. 1985;22:317–24 (in Japanese). 8. Yoshimoto G, Moriyama Y, Toyohira H, Shimokawa G, Iguro Y. Congenital bicuspid aortic valve: analysis of 63 surgical cases. J Heart Valve Dis. 1998;7:500–3. 9. Tzemos N, Therrien J, Yip J, Thanassoulis G, Tremblay S, Jamorski MT, et al. Outcomes in adults with bicuspid aortic valves. JAMA. 2008;300:1317–25. 10. Michelens HI, Desjardins VA, Avierinous JA, Russo A, Nkomo VT, Sundt TM, et al. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in community. Circulation. 2008;117:2776–84. 11. Pape LA, Tsai TT, Isselbacher EM, Oh JK, O’Gata PT, Evangelista A, International Registry of Acute Aortic Dissection (IRAD) Investigators, et al. Aortic diameter[or = 5.5 cm is not a
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
good predictor of type A aortic dissection: observations from the International Registry of Acute Aortic Dissection (IRAD). Circulation. 2007;116:1120–7. Oliver JM, Alonso-Gonzalez R, Gonzalez AE, Gallegp P, Sanchez-Recalde A, Cuesta E, et al. Risk of aortic root or ascending aorta complications on patients with bicuspid aortic valve with and without coarctation of the aorta. Am J Cardiol. 2009;104:1001–6. Iwasa S, Fukushima Y. Moriguchi-Goto S. Acute aortic dissection associated with undetected congenital bicuspid aortic valve and infective endocarditis diagnosed intraoperatively. Interact Cardiovasc Thorac Surg. 2011;12:82–3. Michelena HI, Khanna AD, Mahoney D, Margaryan E, Topilsky Y, Suri BE, et al. Incidence of aortic complications in patients with bicuspid aortic valves. JAMA. 2011;306:1104–12. Novaro GM, Pearce GL, Sorecher DL, Griffin BP. Comparison of cardiovascular risk and lipid profiles in patients undergoing aortic valve surgery those undergoing coronary artery bypass grafting. J Heart Valve Dis. 2001;10:19–24. Novaro GM, Tiong IY, Pearce GL, Lauer MS, Sprecher DL, Griffin BP. Effect of hydroxymethylglutaryl coenzyme A reductase inhibitors on the progression of calcific aortic stenosis. Circulation. 2001;104:2205–9. Tanabe N, Iso H, Okada K, Nakamura Y, Harada A, Ohashi Y, Japan Arteriosclerosis Longitudinal Study Group, et al. Serum total and non-high-density lipoprotein cholesterol and the risk prediction of cardiovascular events—the JALS-ECC. Circ J. 2010;74:1346–56. Chan KL, Ghani M, Woodtend K, Burwash G. Case-controlled study to assess risk factors for aortic stenosis in congenital bicuspid aortic valve. Am J Cardiol. 2001;88:690–3. Farivar RD, Cohn LH. Hypercholesterolemia is a risk factor for bioprosthetic valve calcification and explantation. J Thorac Cardiovasc Surg. 2003;126:969–75. Antonini-Canterin F, Zuppiroli A, Popescu BA, Granata G, Cervesato E, Piazza R, et al. Effect of statins on the progression of bioprosthetic aortic valve degeneration. Am J Cardiol. 2003;92:1479–82. Goel SS, Tuzcu EM, Aqarwal S, Aksoy O, Krishnaswamy A, Griffin BP, et al. Comparison of ascending aortic size in patients with severe bicuspid aortic valve stenosis treated with versus without a statin drugs. Am J Cardiol. 2011;108:1458–62. Yasuda H, Nakatani S, Stugaard M, Tsujita-Kuroda Y, Bando K, Kobayashi J, et al. Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve comparison with tricuspid aortic valve. Circulation. 2003;108:II-291–4. Sievers H, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg. 2007;133:126–33. Yoshioka Y, Mitsuno M, Yamamura M, Tanaka H, Ryomoto M, Fukui S, et al. Morphological type and histological features of the dilated ascending aorta in patients with a bicuspid aortic valve. Jpn J Cardiovasc Surg. 2013;42:89–93 (in Japanese). Padang R, Bannon PG, Jeremy R, Richmond DR, Semsarian C, Vallely M, et al. The genetic and molecular basis of bicuspid aortic valve associated thoracic aortopathy: a link to phenotype heterogeneity. Ann Cardiothoracic Surg. 2013;19:83–91.
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