Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant disorder that affects 1 in 250 people. Aortic stiffness, measured by pulse wave velocity (PWV), is an independent predictor for cardiovascular events. Young FH patients are a unique group with early vessel wall disease that may serve to elucidate the determinants of aortic stiffness. We hypothesized that young FH patients would have early changes in aortic stiffness compared to healthy, age- and sex-matched reference values. Thirty-three FH patients ( ≥ 7 years age; mean age 14.6 ± 3.3 years; 26/33 on statin therapy) underwent cardiac MRI. PWV was determined using propagation of flow waveform from aortic arch phase contrast images. Distensibility and aortic wall thickness (AWT) were measured at the ascending, proximal descending, and diaphragmatic aorta. Ventricular volumes and left ventricular (LV) myocardial mass were measured from 2D cine images. These parameters were compared to age- and sex-matched reference values. FH patients had significantly higher PWV (4.5 ± 0.8 vs. 3.5 ± 0.3 m/s; p < 0.001), aortic distensibility, and ascending aortic wall thickness (1.37 ± 0.18 vs. 1.30 ± 0.02 mm; p < 0.05) compared to reference. There was no difference in aortic area or descending aortic wall thickness between groups. Young FH patients had aortic changes with increased aortic pulse wave velocity in the setting of increased aortic distensibility, accompanied by increased thickness of the ascending aortic wall. Presence of these early findings in young patients despite the majority being on statin therapy support enhanced screening and aggressive treatment of familial hypercholesterolemia to prevent potential future cardiovascular events.
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de Ferranti SD, Rodday AM, Mendelson MM, Wong JB, Leslie LK, Sheldrick RC (2016) Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation 133(11):1067–1072. https://doi.org/10.1161/CIRCULATIONAHA.115.018791
Scientific Steering Committee on behalf of the Simon Broome Register Group (1999) Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Atherosclerosis 142(1):105–112
Perak AM, Ning H, de Ferranti SD, Gooding HC, Wilkins JT, Lloyd-Jones DM (2016) Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype. Circulation 134(1):9–19. https://doi.org/10.1161/CIRCULATIONAHA.116.022335
Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P, Seed M, Humphries SE (2008) Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J 29(21):2625–2633. https://doi.org/10.1093/eurheartj/ehn422
Urbina EM, de Ferranti SD (2016) Lipid screening in children and adolescents. JAMA 316(6):589–591. https://doi.org/10.1001/jama.2016.9671
de Ferranti SD, Rodday AM, Parsons SK, Cull WL, O'Connor KG, Daniels SR, Leslie LK (2017) Cholesterol screening and treatment practices and preferences: a survey of United States pediatricians. J Pediatr 185(99–105):e102. https://doi.org/10.1016/j.jpeds.2016.12.078
Schmitz SA, O'Regan DP, Fitzpatrick J, Neuwirth C, Potter E, Tosi I, Hajnal JV, Naoumova RP (2008) Quantitative 3T MR imaging of the descending thoracic aorta: patients with familial hypercholesterolemia have an increased aortic plaque burden despite long-term lipid-lowering therapy. JVIR 19(10):1403–1408. https://doi.org/10.1016/j.jvir.2008.06.020
Mohrschladt MF, Westendorp RG, Gevers Leuven JA, Smelt AH (2004) Cardiovascular disease and mortality in statin-treated patients with familial hypercholesterolemia. Atherosclerosis 172(2):329–335. https://doi.org/10.1016/j.atherosclerosis.2003.11.007
O'Leary DH, Bots ML (2010) Imaging of atherosclerosis: carotid intima-media thickness. Eur Heart J 31(14):1682–1689. https://doi.org/10.1093/eurheartj/ehq185
Mattace-Raso FUS, Van Der Cammen TJM, Hofman A, Van Popele NM, Bos ML, Schalekamp MADH, Asmar R, Reneman RS, Hoeks APG, Breteler MMB, Witteman JCM (2006) Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam study. Circulation 113(5):657–663. https://doi.org/10.1161/CIRCULATIONAHA.105.555235
Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Ducimetiere P, Benetos A (2001) Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37(5):1236–1241. https://doi.org/10.1161/01.HYP.37.5.1236
Wentland AL, Grist TM, Wieben O (2014) Review of MRI-based measurements of pulse wave velocity: a biomarker of arterial stiffness. Cardiovasc Diagn Ther 4(2):193–206. https://doi.org/10.3978/j.issn.2223-3652.2014.03.04
Caballero P, Alonso R, Rosado P, Mata N, Fernández-Friera L, Jiménez-Borreguero LJ, Badimon L, Mata P (2012) Detection of subclinical atherosclerosis in familial hypercholesterolemia using non-invasive imaging modalities. Atherosclerosis 222(2):468–472. https://doi.org/10.1016/j.atherosclerosis.2012.02.043
Soljanlahti S, Autti T, Vuorio AF, Keto P, Turtola H, Lauerma K (2008) Aorta of young and middle-aged heterozygous familial hypercholesterolemia patients shows no functional or morphological impairment assessed by MRI. Vasc Health Risk Manage 4(4):923–929
Buechel EV, Kaiser T, Jackson C, Schmitz A, Kellenberger CJ (2009) Normal right- and left ventricular volumes and myocardial mass in children measured by steady state free precession cardiovascular magnetic resonance. J Cardiovasc Magn Resonance 11:19–19. https://doi.org/10.1186/1532-429X-11-19
Mensel B, Quadrat A, Schneider T, Kuhn JP, Dorr M, Volzke H, Lieb W, Hegenscheid K, Lorbeer R (2014) MRI-based determination of reference values of thoracic aortic wall thickness in a general population. Eur Radiol 24(9):2038–2044. https://doi.org/10.1007/s00330-014-3188-8
Kawel-Boehm N, Maceira A, Valsangiacomo-Buechel ER, Vogel-Claussen J, Turkbey EB, Williams R, Plein S, Tee M, Eng J, Bluemke DA (2015) Normal values for cardiovascular magnetic resonance in adults and children. J Cardiovasc Magn Reson 17(1):29–29. https://doi.org/10.1186/s12968-015-0111-7
Voges I, Jerosch-Herold M, Hedderich J, Pardun E, Hart C, Gabbert DD, Hansen JH, Petko C, Kramer H-H, Rickers C (2012) Normal values of aortic dimensions, distensibility, and pulse wave velocity in children and young adults: a cross-sectional study. J Cardiovasc Magn Reson 14:77–77. https://doi.org/10.1186/1532-429X-14-77
Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG (2009) Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 42(2):377–381. https://doi.org/10.1016/j.jbi.2008.08.010
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18(6):499–502. https://doi.org/10.1177/107424840501000106
Hoeg JM, Feuerstein IM, Tucker EE (1994) Detection and quantitation of calcific atherosclerosis by ultrafast computed tomography in children and young adults with homozygous familial hypercholesterolemia. Arterioscler Thromb 14(7):1066–1074
van Engelen A, Silva Vieira M, Rafiq I, Cecelja M, Schneider T, de Bliek H, Figueroa CA, Hussain T, Botnar RM, Alastruey J (2017) Aortic length measurements for pulse wave velocity calculation: manual 2D vs automated 3D centreline extraction. J Cardiovasc Magn Reson 19(1):32–32. https://doi.org/10.1186/s12968-017-0341-y
Gaddum NR, Alastruey J, Beerbaum P, Chowienczyk P, Schaeffter T (2013) A technical assessment of pulse wave velocity algorithms applied to non-invasive arterial waveforms. Ann Biomed Eng 41(12):2617–2629. https://doi.org/10.1007/s10439-013-0854-y
Markl M, Harloff A, Bley TA, Zaitsev M, Jung B, Weigang E, Langer M, Hennig J, Frydrychowicz A (2007) Time-resolved 3D MR velocity mapping at 3T: improved navigator-gated assessment of vascular anatomy and blood flow. J Magn Reson Imaging 25(4):824–831. https://doi.org/10.1002/jmri.20871
Markl M, Wallis W, Brendecke S, Simon J, Frydrychowicz A, Harloff A (2010) Estimation of global aortic pulse wave velocity by flow-sensitive 4D MRI. Magn Reson Med 63(6):1575–1582. https://doi.org/10.1002/mrm.22353
Hussain T, Clough RE, Cecelja M, Makowski M, Peel S, Chowienczyk P, Schaeffter T, Greil G, Botnar R (2011) Zoom imaging for rapid aortic vessel wall imaging and cardiovascular risk assessment. J Magn Reson Imaging 34(2):279–285. https://doi.org/10.1002/jmri.22617
Burkhardt BEU, Velasco Forte MN, Durairaj S, Rafiq I, Valverde I, Tandon A, Simpson J, Hussain T (2017) Timely pulmonary valve replacement may allow preservation of left ventricular circumferential strain in patients with tetralogy of fallot. Front Pediatrics 5:1–7. https://doi.org/10.3389/fped.2017.00039
Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, de Ferranti SD, Dionne JM, Falkner B, Flinn K, Gidding SS, Goodwin C, Leu MG, Powers ME, Rea C, Samuels J, Simasek M, Thaker VV, Urbina EM (2017) Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 140(3):1–72. https://doi.org/10.1542/peds.2017-1904
Farrar DJ, Bond MG, Riley WA, Sawyer JK (1991) Anatomic correlates of aortic pulse wave velocity and carotid artery elasticity during atherosclerosis progression and regression in monkeys. Circulation 83(5):1754–1763
Riggio S, Mandraffino G, Sardo MA, Iudicello R, Camarda N, Imbalzano E, Alibrandi A, Saitta C, Carerj S, Arrigo T, Saitta A (2010) Pulse wave velocity and augmentation index, but not intima-media thickness, are early indicators of vascular damage in hypercholesterolemic children. Eur J Clin Invest 40(3):250–257. https://doi.org/10.1111/j.1365-2362.2010.02260.x
Lehmann ED, Watts GF, Fatemi-Langroudi B, Gosling RG (1992) Aortic compliance in young patients with heterozygous familial hypercholesterolaemia. Clinical Science (London, England: 1979) 83 (6):717–721
Newman DL, Gosling RG, Bowden NL (1971) Changes in aortic distensibility and area ratio with the development of atherosclerosis. Atherosclerosis 14(2):231–240
Ribeiro P, Shapiro LM, Gonzalez A, Thompson GR, Oakley CM (1983) Cross sectional echocardiographic assessment of the aortic root and coronary ostial stenosis in familial hypercholesterolaemia. Heart 50(5):432–437. https://doi.org/10.1136/hrt.50.5.432
Summers RM, Andrasko-Bourgeois J, Feuerstein IM, Hill SC, Jones EC, Busse MK, Wise B, Bove KE, Rishforth BA, Tucker E, Spray TL, Hoeg JM (1998) Evaluation of the aortic root by MRI: insights from patients with homozygous familial hypercholesterolemia. Circulation 98(6):509–518. https://doi.org/10.1161/01.CIR.98.6.509
Awan Z, Alrasadi K, Francis GA, Hegele RA, McPherson R, Frohlich J, Valenti D, de Varennes B, Marcil M, Gagne C, Genest J, Couture P (2008) Vascular calcifications in homozygote familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 28(4):777–785. https://doi.org/10.1161/ATVBAHA.107.160408
Brandts A, Westenberg JJM, van Elderen SGC, Kroft LJM, Roes SD, Tamsma JT, van der Geest RJ, Lamb HJ, Doornbos J, Putter H, Stuber M, de Roos A (2013) Site-specific coupling between vascular wall thickness and function: an observational MRI study of vessel wall thickening and stiffening in hypertension. Invest Radiol 48(2):86–91. https://doi.org/10.1097/RLI.0b013e31827f6410
Liu CY, Chen D, Bluemke DA, Wu CO, Teixido-Tura G, Chugh A, Vasu S, Lima JAC, Hundley WG (2015) Evolution of aortic wall thickness and stiffness with atherosclerosis: long-term follow up from the multi-ethnic study of atherosclerosis. Hypertension 65(5):1015–1019. https://doi.org/10.1161/HYPERTENSIONAHA.114.05080
Junyent M, Gilabert R, Zambon D, Pocovi M, Mallen M, Cofan M, Nunez I, Civeira F, Tejedor D, Ros E (2008) Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect. Arterioscler Thromb Vasc Biol 28(3):580–586. https://doi.org/10.1161/ATVBAHA.107.153841
Berberich AJ, Hegele RA (2019) The complex molecular genetics of familial hypercholesterolaemia. Nat Rev Cardiol 16(1):9–20. https://doi.org/10.1038/s41569-018-0052-6
Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, Ose L, Averna M, Boileau C, Boren J, Bruckert E, Catapano AL, Defesche JC, Descamps OS, Hegele RA, Hovingh GK, Humphries SE, Kovanen PT, Kuivenhoven JA, Masana L, Nordestgaard BG, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AF, Steinhagen-Thiessen E, Stroes ES, Taskinen MR, Tybjaerg-Hansen A, Wiklund O, European Atherosclerosis Society Consensus P (2015) Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 36(36):2425–2437. https://doi.org/10.1093/eurheartj/ehv157
Alrasadi K, Alwaili K, Awan Z, Valenti D, Couture P, Genest J (2009) Aortic calcifications in familial hypercholesterolemia: potential role of the low-density lipoprotein receptor gene. Am Heart J 157(1):170–176. https://doi.org/10.1016/j.ahj.2008.08.021
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We thank Dr. Sadia Malik for her research guidance and writing support.
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Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR001105 and CTSA NIH Grant UL1-RR024982. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Further support was provided by the Pogue Family Distinguished Chair in Pediatric Cardiology, University of Texas Southwestern Medical Center and the Millennium Science Initiative of the Ministry of Economy, Development, and Tourism of Chile—Nucleus for Cardiovascular Magnetic Resonance grant.
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Tran, A., Burkhardt, B., Tandon, A. et al. Pediatric heterozygous familial hypercholesterolemia patients have locally increased aortic pulse wave velocity and wall thickness at the aortic root. Int J Cardiovasc Imaging 35, 1903–1911 (2019). https://doi.org/10.1007/s10554-019-01626-5
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DOI: https://doi.org/10.1007/s10554-019-01626-5