Aortic Valvular Disease in Elderly Subjects with Heterozygous Familial Hypercholesterolemia: Impact of Lipid-Lowering Therapy
Abstract
:1. Introduction
2. Methods
2.1. Study Characteristics
2.2. Transthoracic Echocardiography
2.3. Clinical Interview
2.4. Physical Exam
2.5. Laboratory Tests
2.6. Definitions
2.7. Statistical Analysis
3. Results
3.1. Aortic Valve Characterization
3.2. Risk Factors for Valvular Disease
4. Discussion
4.1. Prevalence of AS in HeFH
4.2. Risk Factors for Aortic Valvular Disease
4.3. Statins and Valvular Disease
4.4. Study Limitations
5. Conclusions.
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AoVC | Aortic valve calcification |
AS | Aortic stenosis |
ASc | Aortic sclerosis |
BMI | Body mass index |
GEE | Generalized estimating equations |
HeFH | Heterozygous familial hypercholesterolemia |
HDLc | High-density lipoprotein cholesterol |
LDLc | Low-density lipoprotein cholesterol |
Lp(a) | Lipoprotein(a) |
Vmax | Maximum aortic velocity |
References
- Scriver, C.R. The Metabolic & Molecular Bases of Inherited Disease, 8th ed.; McGraw-Hill: New York, NY, USA, 2001; ISBN 978-0-07-913035-8. [Google Scholar]
- Austin, M.A.; Hutter, C.M.; Zimmern, R.L.; Humphries, S.E. Genetic causes of monogenic heterozygous familial hypercholesterolemia: A HuGE prevalence review. Am. J. Epidemiol. 2004, 160, 407–420. [Google Scholar] [CrossRef] [PubMed]
- de Ferranti, S.D.; Rodday, A.M.; Mendelson, M.M.; Wong, J.B.; Leslie, L.K.; Sheldrick, R.C. Prevalence of Familial Hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation 2016, 133, 1067–1072. [Google Scholar] [CrossRef] [PubMed]
- Civeira, F. International Panel on Management of Familial Hypercholesterolemia Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis 2004, 173, 55–68. [Google Scholar] [CrossRef]
- Nordestgaard, B.G.; Chapman, M.J.; Humphries, S.E.; Ginsberg, H.N.; Masana, L.; Descamps, O.S.; Wiklund, O.; Hegele, R.A.; Raal, F.J.; Defesche, J.C.; et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus statement of the European Atherosclerosis Society. Eur. Heart J. 2013, 34, 3478–3490. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cuchel, M.; Bruckert, E.; Ginsberg, H.N.; Raal, F.J.; Santos, R.D.; Hegele, R.A.; Kuivenhoven, J.A.; Nordestgaard, B.G.; Descamps, O.S.; Steinhagen-Thiessen, E.; et al. Homozygous familial hypercholesterolaemia: New insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur. Heart J. 2014, 35, 2146–2157. [Google Scholar] [CrossRef] [PubMed]
- Palcoux, J.-B.; Atassi-Dumont, M.; Lefevre, P.; Hequet, O.; Schlienger, J.-L.; Brignon, P.; Roussel, B. Low-density lipoprotein apheresis in children with familial hypercholesterolemia: Follow-up to 21 years. Ther. Apher. Dial. 2008, 12, 195–201. [Google Scholar] [CrossRef] [PubMed]
- Raal, F.J.; Santos, R.D. Homozygous familial hypercholesterolemia: Current perspectives on diagnosis and treatment. Atherosclerosis 2012, 223, 262–268. [Google Scholar] [CrossRef] [PubMed]
- Dweck, M.R.; Boon, N.A.; Newby, D.E. Calcific aortic stenosis: A disease of the valve and the myocardium. J. Am. Coll. Cardiol. 2012, 60, 1854–1863. [Google Scholar] [CrossRef] [Green Version]
- Osnabrugge, R.L.J.; Mylotte, D.; Head, S.J.; Van Mieghem, N.M.; Nkomo, V.T.; LeReun, C.M.; Bogers, A.J.J.C.; Piazza, N.; Kappetein, A.P. Aortic stenosis in the elderly: Disease prevalence and number of candidates for transcatheter aortic valve replacement: A meta-analysis and modeling study. J. Am. Coll. Cardiol. 2013, 62, 1002–1012. [Google Scholar] [CrossRef] [Green Version]
- Nishimura, R.A.; Otto, C.M.; Bonow, R.O.; Carabello, B.A.; Erwin, J.P.; Guyton, R.A.; O’Gara, P.T.; Ruiz, C.E.; Skubas, N.J.; Sorajja, P.; et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2014, 63, 2438–2488. [Google Scholar] [CrossRef] [Green Version]
- Rossebø, A.B.; Pedersen, T.R.; Boman, K.; Brudi, P.; Chambers, J.B.; Egstrup, K.; Gerdts, E.; Gohlke-Bärwolf, C.; Holme, I.; Kesäniemi, Y.A.; et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N. Engl. J. Med. 2008, 359, 1343–1356. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Greve, A.M.; Bang, C.N.; Boman, K.; Egstrup, K.; Kesäniemi, Y.A.; Ray, S.; Pedersen, T.R.; Wachtell, K. Relation of Lipid-Lowering Therapy to Need for Aortic Valve Replacement in Patients With Asymptomatic Mild to Moderate Aortic Stenosis. Am. J. Cardiol. 2019, 124, 1736–1740. [Google Scholar] [CrossRef] [PubMed]
- Banach, M.; Serban, C.; Sahebkar, A.; Mikhailidis, D.P.; Ursoniu, S.; Ray, K.K.; Rysz, J.; Toth, P.P.; Muntner, P.; Mosteoru, S.; et al. Impact of statin therapy on coronary plaque composition: A systematic review and meta-analysis of virtual histology intravascular ultrasound studies. BMC Med. 2015, 13, 229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lindroos, M.; Kupari, M.; Heikkilä, J.; Tilvis, R. Prevalence of aortic valve abnormalities in the elderly: An echocardiographic study of a random population sample. J. Am. Coll. Cardiol. 1993, 21, 1220–1225. [Google Scholar] [CrossRef] [Green Version]
- Vongpromek, R.; Bos, S.; Ten Kate, G.-J.R.; Yahya, R.; Verhoeven, A.J.M.; de Feyter, P.J.; Kronenberg, F.; Roeters van Lennep, J.E.; Sijbrands, E.J.G.; Mulder, M.T. Lipoprotein(a) levels are associated with aortic valve calcification in asymptomatic patients with familial hypercholesterolaemia. J. Intern. Med. 2015, 278, 166–173. [Google Scholar] [CrossRef] [PubMed]
- Perak, A.M.; Ning, H.; de Ferranti, S.D.; Gooding, H.C.; Wilkins, J.T.; Lloyd-Jones, D.M. Long-Term Risk of Atherosclerotic Cardiovascular Disease in US Adults With the Familial Hypercholesterolemia Phenotype. Circulation 2016, 134, 9–19. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ten Kate, G.-J.R.; Bos, S.; Dedic, A.; Neefjes, L.A.; Kurata, A.; Langendonk, J.G.; Liem, A.; Moelker, A.; Krestin, G.P.; de Feyter, P.J.; et al. Increased Aortic Valve Calcification in Familial Hypercholesterolemia: Prevalence, Extent, and Associated Risk Factors. J. Am. Coll. Cardiol. 2015, 66, 2687–2695. [Google Scholar] [CrossRef] [Green Version]
- Rosenhek, R.; Binder, T.; Porenta, G.; Lang, I.; Christ, G.; Schemper, M.; Maurer, G.; Baumgartner, H. Predictors of outcome in severe, asymptomatic aortic stenosis. N. Engl. J. Med. 2000, 343, 611–617. [Google Scholar] [CrossRef]
- Coffey, S.; Cox, B.; Williams, M.J.A. The prevalence, incidence, progression, and risks of aortic valve sclerosis: A systematic review and meta-analysis. J. Am. Coll. Cardiol. 2014, 63, 2852–2861. [Google Scholar] [CrossRef] [Green Version]
- Mundal, L.J.; Hovland, A.; Igland, J.; Veierød, M.B.; Holven, K.B.; Bogsrud, M.P.; Tell, G.S.; Leren, T.P.; Retterstøl, K. Association of Low-Density Lipoprotein Cholesterol With Risk of Aortic Valve Stenosis in Familial Hypercholesterolemia. JAMA Cardiol. 2019, 4, 1156–1159. [Google Scholar] [CrossRef]
- Pohle, K.; Mäffert, R.; Ropers, D.; Moshage, W.; Stilianakis, N.; Daniel, W.G.; Achenbach, S. Progression of aortic valve calcification: Association with coronary atherosclerosis and cardiovascular risk factors. Circulation 2001, 104, 1927–1932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nkomo, V.T.; Gardin, J.M.; Skelton, T.N.; Gottdiener, J.S.; Scott, C.G.; Enriquez-Sarano, M. Burden of valvular heart diseases: A population-based study. Lancet 2006, 368, 1005–1011. [Google Scholar] [CrossRef]
- Cosmi, J.E.; Kort, S.; Tunick, P.A.; Rosenzweig, B.P.; Freedberg, R.S.; Katz, E.S.; Applebaum, R.M.; Kronzon, I. The risk of the development of aortic stenosis in patients with “benign” aortic valve thickening. Arch. Intern. Med. 2002, 162, 2345–2347. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Supino, P.G.; Borer, J.S.; Preibisz, J.; Bornstein, A. The epidemiology of valvular heart disease: A growing public health problem. Heart Fail. Clin. 2006, 2, 379–393. [Google Scholar] [CrossRef]
- Rallidis, L.; Naoumova, R.P.; Thompson, G.R.; Nihoyannopoulos, P. Extent and severity of atherosclerotic involvement of the aortic valve and root in familial hypercholesterolaemia. Heart 1998, 80, 583–590. [Google Scholar] [CrossRef] [PubMed]
- Sprecher, D.L.; Schaefer, E.J.; Kent, K.M.; Gregg, R.E.; Zech, L.A.; Hoeg, J.M.; McManus, B.; Roberts, W.C.; Brewer, H.B. Cardiovascular features of homozygous familial hypercholesterolemia: Analysis of 16 patients. Am. J. Cardiol. 1984, 54, 20–30. [Google Scholar] [CrossRef]
- Civeira, F.; Ros, E.; Jarauta, E.; Plana, N.; Zambon, D.; Puzo, J.; Martinez de Esteban, J.P.; Ferrando, J.; Zabala, S.; Almagro, F.; et al. Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia. Am. J. Cardiol. 2008, 102, 1187–1193. [Google Scholar] [CrossRef]
- Talmud, P.J.; Shah, S.; Whittall, R.; Futema, M.; Howard, P.; Cooper, J.A.; Harrison, S.C.; Li, K.; Drenos, F.; Karpe, F.; et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: A case-control study. Lancet 2013, 381, 1293–1301. [Google Scholar] [CrossRef] [Green Version]
- Khera, A.V.; Won, H.-H.; Peloso, G.M.; Lawson, K.S.; Bartz, T.M.; Deng, X.; van Leeuwen, E.M.; Natarajan, P.; Emdin, C.A.; Bick, A.G.; et al. Diagnostic Yield and Clinical Utility of Sequencing Familial Hypercholesterolemia Genes in Patients With Severe Hypercholesterolemia. J. Am. Coll. Cardiol. 2016, 67, 2578–2589. [Google Scholar] [CrossRef]
- Rajamannan, N.M. Calcific Aortic Stenosis: Lessons Learned from Experimental and Clinical Studies. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 162–168. [Google Scholar] [CrossRef] [Green Version]
- Lindman, B.R.; Clavel, M.-A.; Mathieu, P.; Iung, B.; Lancellotti, P.; Otto, C.M.; Pibarot, P. Calcific aortic stenosis. Nat. Rev. Dis. Primers 2016, 2, 16006. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- O’Brien, K.D.; Reichenbach, D.D.; Marcovina, S.M.; Kuusisto, J.; Alpers, C.E.; Otto, C.M. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of “degenerative” valvular aortic stenosis. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 523–532. [Google Scholar] [CrossRef] [PubMed]
- Chan, K.L.; Teo, K.; Dumesnil, J.G.; Ni, A.; Tam, J. ASTRONOMER Investigators Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: Results of the aortic stenosis progression observation: Measuring effects of rosuvastatin (ASTRONOMER) trial. Circulation 2010, 121, 306–314. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Moura, L.M.; Ramos, S.F.; Zamorano, J.L.; Barros, I.M.; Azevedo, L.F.; Rocha-Gonçalves, F.; Rajamannan, N.M. Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis. J. Am. Coll. Cardiol. 2007, 49, 554–561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saremi, A.; Bahn, G.; Reaven, P.D. VADT Investigators Progression of vascular calcification is increased with statin use in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 2012, 35, 2390–2392. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mundy, G.; Garrett, R.; Harris, S.; Chan, J.; Chen, D.; Rossini, G.; Boyce, B.; Zhao, M.; Gutierrez, G. Stimulation of bone formation in vitro and in rodents by statins. Science 1999, 286, 1946–1949. [Google Scholar] [CrossRef]
- Kwon, O.; Kang, S.-J.; Kang, S.H.; Lee, P.H.; Yun, S.-C.; Ahn, J.-M.; Park, D.-W.; Lee, S.-W.; Kim, Y.-H.; Lee, C.W.; et al. Relationship Between Serum Inflammatory Marker Levels and the Dynamic Changes in Coronary Plaque Characteristics After Statin Therapy. Circ. Cardiovasc. Imaging 2017, 10, e005934. [Google Scholar] [CrossRef] [Green Version]
- Cho, K.I.; Sakuma, I.; Sohn, I.S.; Jo, S.-H.; Koh, K.K. Inflammatory and metabolic mechanisms underlying the calcific aortic valve disease. Atherosclerosis 2018, 277, 60–65. [Google Scholar] [CrossRef]
- Al Kindi, M.; Bélanger, A.M.; Sayegh, K.; Senouci, S.; Aljenedil, S.; Sivakumaran, L.; Ruel, I.; Al Rasadi, K.; Al Waili, K.; Awan, Z.; et al. Aortic Calcification Progression in Heterozygote Familial Hypercholesterolemia. Can. J. Cardiol. 2017, 33, 658–665. [Google Scholar] [CrossRef]
- Greve, A.M.; Bang, C.N.; Boman, K.; Egstrup, K.; Forman, J.L.; Kesäniemi, Y.A.; Ray, S.; Pedersen, T.R.; Best, P.; Rajamannan, N.M.; et al. Effect Modifications of Lipid-Lowering Therapy on Progression of Aortic Stenosis (from the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] Study). Am. J. Cardiol. 2018, 121, 739–745. [Google Scholar] [CrossRef]
- Rajamannan, N.M.; Greve, A.M.; Moura, L.M.; Best, P.; Wachtell, K. SALTIRE-RAAVE: Targeting calcific aortic valve disease LDL-density-radius theory. Expert Rev. Cardiovasc. Ther. 2015, 13, 355–367. [Google Scholar] [CrossRef] [PubMed]
- Alskaf, E.; Kardos, A. The mystery of defining aortic valve area: What have we learnt from three-dimensional imaging modalities? J. Echocardiogr. 2018, 16, 130–138. [Google Scholar] [CrossRef] [PubMed]
Mean (SD) / proportion (n = count) | Controls | Cases | |||
---|---|---|---|---|---|
n | Mean/% | n | Mean/% | p-value | |
Age (years) | 93 | 70.0 (7.3) | 112 | 71.8 (6.5) | 0.038 |
Sex, women % (n = count) | 93 | 51.6 (n = 48) | 112 | 66.1 (n = 74) | 0.050 |
Weight (Kg) | 92 | 75.9 (14.3) | 110 | 72.1 (13.5) | 0.054 |
Height (cm) | 92 | 161.7 (8.5) | 110 | 159.4 (9.9) | 0.075 |
Systolic blood pressure (mmHg) | 92 | 136.7 (14.9) | 110 | 134.1 (16.9) | 0.199 |
Diastolic blood pressure (mmHg) | 92 | 79.5 (9.7) | 110 | 77.1 (9.7) | 0.089 |
Body mass index (Kg/m2) | 92 | 29.0 (4.7) | 110 | 28.3 (4.0) | 0.265 |
Tendon xanthomas, % (n = count) | 93 | 0.0 (n = 0) | 102 | 39.2 (n = 40) | <0.001 |
Hypertension, % (n = count) | 93 | 55.9 (n = 52) | 112 | 54.5 (n = 61) | 0.769 |
Type 2 diabetes, % (n = count) | 93 | 14.0 (n = 13) | 112 | 21.4 (n = 24) | 0.139 |
Previous cardiovascular disease, % (n = count) | 93 | 16.1 (n = 15) | 112 | 27.7 (n = 31) | 0.036 |
Family history of premature cardiovascular disease, % (n = count) | 89 | 25.8 (n = 23) | 100 | 45.0 (n = 45) | <0.001 |
Packages/day × number of years smoking | 90 | 15.2 (25.3) | 108 | 9.8 (21.6) | 0.120 |
Lipid-lowering treatment, % (n = count) | 93 | 51.6 (n = 48) | 112 | 100.0 (n = 112) | <0.001 |
Statin treatment (years) | 48 | 8.3 (7.2) | 110 | 22.5 (8.7) | <0.001 |
Ezetimibe treatment, % (n = count) | 68 | 8.8 (n = 6) | 112 | 83.0 (n = 93) | <0.001 |
Untreated total cholesterol (mg/dL) | 93 | 223.8 (43.3) | 111 | 395.9 (73.0) | <0.001 |
Untreated triglycerides (mg/dL) | 93 | 145.7 (119.0) | 112 | 139.7 (76.3) | 0.669 |
Untreated HDLc (mg/dL) | 91 | 56.9 (15.3) | 112 | 55.7 (13.6) | 0.621 |
Untreated LDLc (mg/dL) | 90 | 138.0 (31.7) | 111 | 314.2 (71.4) | <0.001 |
Mean (SD)/proportion (n = count) | Controls | Cases | |||||
---|---|---|---|---|---|---|---|
n | mean/% | n | mean/% | p-value * | p-value ** | p-value *** | |
Mean aortic valve pressure gradient (mm) | 92 | 5.0 (2.8) | 111 | 7.4 (7.3) | 0.002 | 0.003 | 0.626 |
Maximum aortic velocity (Vmax) (m/s) | 92 | 1.5 (0.4) | 111 | 1.7 (0.7) | 0.004 | 0.011 | 0.959 |
Aortic valve area (cm2) | 92 | 2.4 (0.6) | 107 | 2.0 (0.7) | <0.001 | <0.001 | 0.771 |
Left ventricular ejection fraction (%) | 93 | 67.2 (7.0) | 111 | 65.7 (9.5) | 0.167 | 0.056 | 0.285 |
Aortic valve velocity ratio | 61 | 0.73 (0.11) | 61 | 0.70 (0.14) | 0.244 | 0.138 | 0.321 |
Calcification of the aortic valve leaflets (score) | 92 | 0.7 (0.9) | 110 | 1.1 (1.0) | 0.002 | 0.008 | 0.723 |
Valvular thickening >3 mm, % (n = count) | 93 | 12.9 (n = 12) | 112 | 27.7 (n = 31) | 0.006 | 0.004 | 0.600 |
Aortic stenosis, % (n = count) | 93 | 11.8 (n = 11) | 112 | 20.5 (n = 23) | 0.107 | 0.171 | 0.842 |
Aortic stenosis moderate or severe, % (n = count) | 93 | 1.1 (n = 1) | 112 | 7.1 (n = 8) | 0.067 | 0.031 | 0.187 |
Aortic sclerosis, % (n = count) | 92 | 34.8 (n = 32) | 111 | 49.5 (n = 55) | 0.046 | 0.061 | 0.337 |
Morphological and hemodynamic parameters | Cases | |||
---|---|---|---|---|
Per each 10 year of age Difference/OR (95% CI) | p-value | Per each 10 year of lipid-lowering use Difference/OR (95% CI) | p-value | |
Mean aortic valve pressure gradient (mm) | 4.623 (2.518, 6.728) | <0.001 | 0.214 (−1.304, 1.732) | 0.783 |
Maximum aortic velocity (Vmax) (m/s) | 0.394 (0.185, 0.603) | <0.001 | 0.012 (−0.139, 0.162) | 0.881 |
Aortic valve area (cm2) | −0.373 (−0.562, −0.185) | <0.001 | 0.001 (−0.133, 0.135) | 0.990 |
Left ventricular ejection fraction (%) | −1.924 (−4.634, 0.787) | 0.167 | −2.877 (−4.827, −0.927) | 0.005 |
Calcification of the aortic valve leaflets (score) | 0.698 (0.418, 0.979) | <0.001 | −0.034 (−0.233, 0.165) | 0.737 |
Valvular thickening >3 mm, OR | 1.36 (0.69, 2.63) | 0.359 | 0.86 (0.52, 1.41) | 0.549 |
Aortic stenosis, OR | 2.11 (1.04, 4.37) | 0.038 | 0.94 (0.52, 1.65) | 0.817 |
Aortic stenosis moderate or severe, OR | 2.95 (1.07, 8.26) | 0.032 | 0.82 (0.29, 2.15) | 0.687 |
Aortic sclerosis, OR | 1.23 (0.67, 2.32) | 0.510 | 1.03 (0.66, 1.62) | 0.883 |
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Marco-Benedí, V.; Laclaustra, M.; Casado-Dominguez, J.M.; Villa-Pobo, R.; Mateo-Gallego, R.; Sánchez-Hernández, R.M.; Blanco Nuez, M.; Ortega-Martínez de Victoria, E.; Sitges, M.; Pedro-Botet, J.; et al. Aortic Valvular Disease in Elderly Subjects with Heterozygous Familial Hypercholesterolemia: Impact of Lipid-Lowering Therapy. J. Clin. Med. 2019, 8, 2209. https://doi.org/10.3390/jcm8122209
Marco-Benedí V, Laclaustra M, Casado-Dominguez JM, Villa-Pobo R, Mateo-Gallego R, Sánchez-Hernández RM, Blanco Nuez M, Ortega-Martínez de Victoria E, Sitges M, Pedro-Botet J, et al. Aortic Valvular Disease in Elderly Subjects with Heterozygous Familial Hypercholesterolemia: Impact of Lipid-Lowering Therapy. Journal of Clinical Medicine. 2019; 8(12):2209. https://doi.org/10.3390/jcm8122209
Chicago/Turabian StyleMarco-Benedí, Victoria, Martin Laclaustra, Juan M. Casado-Dominguez, Rosa Villa-Pobo, Rocío Mateo-Gallego, Rosa M. Sánchez-Hernández, Marta Blanco Nuez, Emilio Ortega-Martínez de Victoria, Marta Sitges, Juan Pedro-Botet, and et al. 2019. "Aortic Valvular Disease in Elderly Subjects with Heterozygous Familial Hypercholesterolemia: Impact of Lipid-Lowering Therapy" Journal of Clinical Medicine 8, no. 12: 2209. https://doi.org/10.3390/jcm8122209
APA StyleMarco-Benedí, V., Laclaustra, M., Casado-Dominguez, J. M., Villa-Pobo, R., Mateo-Gallego, R., Sánchez-Hernández, R. M., Blanco Nuez, M., Ortega-Martínez de Victoria, E., Sitges, M., Pedro-Botet, J., Puzo, J., Villarroel, T., & Civeira, F. (2019). Aortic Valvular Disease in Elderly Subjects with Heterozygous Familial Hypercholesterolemia: Impact of Lipid-Lowering Therapy. Journal of Clinical Medicine, 8(12), 2209. https://doi.org/10.3390/jcm8122209