Unveiling Cardiovascular Connections between Familial Hypercholesterolemia (FH) and Left Ventricular Hypertrophy (LVH)
Abstract
Abstract Views: 0Left ventricular hypertrophy (LVH), a complex cardiac condition characterized by the enlargement and thickening of the left ventricle, is primarily associated with hypertension and valvular heart disease. Recent studies have identified familial hypercholesterolemia (FH) as a secondary cause of LVH. It is characterized by high low-density lipoprotein cholesterol (LDL-C) in blood. FH is an inherited disorder which involves genetic variations associated with abnormal metabolism of LDL-C. This review article aims to provide a comprehensive overview of the relationship between FH and LVH. It summarizes the current understanding of the pathophysiological mechanisms underlying this association and discusses its implications for clinical practice. Elevated LDL-C levels in FH patients lead to accelerated atherosclerosis and an increased risk of premature cardiovascular events. Animal models and clinical observations provide insights into the mechanistic links between elevated LDL-C levels, oxidative stress, inflammation, and LVH development. Early diagnosis of FH would certainly play a critical role in preventing or delaying the development of LVH and subsequent cardiovascular complications. Preemptive measures emphasize the identification of at risk individuals, in-depth clinical evaluations, and implementation of effective treatments including lifestyle modifications, statins, and adjunctive therapies, such as PCSK9 inhibitors or lipoprotein apheresis. By increasing the awareness of FH as a secondary cause of LVH, healthcare professionals can improve early detection and implement appropriate management strategies to mitigate the cardiovascular burden associated with this inherited disorder.
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Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects. J Am Coll Cardiol. 2020;75(20):2553–2566. https://doi.org/10.1016/j.jacc.2020.03.057
Miname MH, Santos RD. Reducing cardiovascular risk in patients with familial hypercholesterolemia: risk prediction and lipid management. Prog Cardiovasc Dis. 2019;62(5):414–422. https://doi.org/10.1016/j.pcad.2019.10.003
Colbert GB, Szerlip HM. Cardiovascular Impact of Atherosclerotic Renovascular Disease. In: Rangaswami J, Lerma E, McCullough P. eds. Kidney Disease in the Cardiac Catheterization Laboratory. Springer; 2020:69–81. https://doi.org/10.1007/978-3-030-45414-2_4
Kulkarni JD, Bhatia P, Pai SA. Strawberry pink blood. Indian J Hematol Blood Transfus. 2016;32(4):512–513. https://doi.org/ 10.1007/s12288-016-0695-6
Harada-Shiba M, Arai H, Ishigaki Y, et al. Guidelines for diagnosis and treatment of familial hypercholesterolemia 2017. J Atheroscler Thromb. 2018;25(8):751–770. https://doi.org/10.5551/jat.CR003
Mabuchi H. Half a century tales of Familial Hypercholesterolemia (FH) in Japan. J Atheroscler Thromb. 2017;24(3):189–207. https://doi. org/10.5551/jat.RV16008
Durst R, Ibe UK, Shpitzen S, et al. Molecular genetics of familial hypercholesterolemia in Israel–revisited. Atherosclerosis. 2017;257:55–63. https://doi.org/10. 1016/j.atherosclerosis.2016.12.021
Tahmasebi-Birgani M, Zeydooni M, Abolfathi S, et al. Mutation screening of PCSK9 exons in Iranian Arab patients suffering from familial Hypercholesterolemia. SSRN Elect J. 2023:e4333995. http://dx.doi.org/ 10.2139/ssrn.4333995
Guo X, Gao M, Wang Y, et al. LDL receptor gene-ablated hamsters: a rodent model of familial hypercholesterolemia with dominant inheritance and diet-induced coronary atherosclerosis. eBioMedicine. 2018;27:214–224. https://doi.org/10. 1016/j.ebiom.2017.12.013
Moradi A, Maleki M, Ghaemmaghami Z, et al. Mutational spectrum of LDLR and PCSK9 genes identified in Iranian patients with premature coronary artery disease and familial hypercholesterolemia. Front Genet. 2021;12:e625959. https://doi.org/ 10.3389/fgene.2021.625959
Hobbs HH, Russell DW, Brown MS, Goldstein JL. The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet. 1990;24(1):133–170. https://doi.org/ 10.1146/annurev.ge.24.120190.001025
Bea AM, Lamiquiz-Moneo I, Marco-Benedí V, et al. Lipid-lowering response in subjects with the p.(Leu167del) mutation in the APOE gene. Atherosclerosis. 2019;282:143–147. https://doi.org/10.1016/j. atherosclerosis.2019.01.024
Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111(12):1795–1803. https://doi. org/10.1172/JCI18925
Alves AC, Chora JR, Bourbon M. Genomics of familial hypercholesterolaemia. Curr Opin Lipidol. 2019;30(2):148–150. https:// doi.org10.1097/MOL.0000000000000584
Blanco-Vaca F, Martin-Campos JM, Beteta-Vicente Á, et al. Molecular analysis of APOB, SAR1B, ANGPTL3, and MTTP in patients with primary hypocholesterolemia in a clinical laboratory setting: Evidence supporting polygenicity in mutation-negative patients. Atherosclerosis. 2019;283:52–60. https://doi.org/10. 1016/j.atherosclerosis.2019.01.036
Los B, Ferreira GM, Borges JB, et al. Effects of PCSK9 missense variants on molecular conformation and biological activity in transfected HEK293FT cells. Gene. 2023;851:e146979. https://doi.org/10.1016/j.gene.2022.146979
Sun D, Zhou BY, Li S, et al. Genetic basis of index patients with familial hypercholesterolemia in Chinese population: mutation spectrum and genotype-phenotype correlation. Lipids Health Dis. 2018;17(1):e252. https://doi.org/10.1186/s12944-018-0900-8
Truong TH, Do DL, Kim NT, Nguyen MN, Le TT, Le HA. Genetics, screening, and treatment of familial hypercholesterolemia: Experience gained from the implementation of the Vietnam familial hypercholesterolemia registry. Front Genet. 2020;11:e914. https://doi.org/ 10.3389/fgene.2020.00914
Reeskamp LF, Venema A, Pereira JPB, et al. Differential DNA methylation in familial hypercholesterolemia. eBioMedicine. 2020;61:e103079. https://doi.org/ 10.1016/j.ebiom.2020.103079
Khan MR, Batool M, Amir RM, et al. Ameliorating effects of okra (Abelmoschus esculentus) seed oil on hypercholesterolemia. Food Sci Technol. 2020;41(1):113–119. https://doi.org/10.1590/fst.38919
Katzmann JL, Gouni-Berthold I, Laufs U. PCSK9 inhibition: insights from clinical trials and future prospects. Front Physiol. 2020;11:e595819. https://doi.org/10.3389/fphys.2020.595819
Yao YS, Li T Di, Zeng ZH. Mechanisms underlying direct actions of hyperlipidemia on myocardium: an updated review. Lipids Health Dis. 2020;19(1):e23. https://doi.org/ 10.1186/s12944-019-1171-8
Zhang Z, Wu H, Wang T, Liu Y, Meng C. Mechanisms of myocardial damage due to hyperlipidemia: a review of recent studies. Med Sci Monit. 2022;28:e937051. https://doi.org/ 10.12659%2FMSM.937051
Peluso I, Urban L, Ioannone F, Serafini M. Oxidative stress in atherosclerosis development: the central role of LDL and Oxidative Burst. Endocr Metab Immune Disord Drug Targets. 2012;12(4):351–360. https://doi.org /10.2174/187153012803832602
Tousoulis D, Kampoli A-M, Tentolouris Nikolaos Papageorgiou C, Stefanadis C. The role of nitric oxide on endothelial function. Curr Vasc Pharmacol. 2012;10(1):4–18. https:// doi.org/10.2174/157016112798829760
Filippi A, Constantin A, Alexandru N, et al. Integrins α4β1 and αVβ3 are reduced in endothelial progenitor cells from diabetic dyslipidemic mice and may represent new targets for therapy in aortic valve disease. Cell Transplant. 2020;29:1–8. https://doi. org/10.1177/0963689720946277
Choi B, Shin M-K, Kim E-Y, et al. Elevated neuropeptide Y in endothelial dysfunction promotes macrophage infiltration and smooth muscle foam cell formation. Front Immunol. 2019;10:e1701. https://doi.org/10. 3389/fimmu.2019.01701
Singh S, Changkija S, Mudgal R, Ravichandiran V. Bioactive components to inhibit foam cell formation in atherosclerosis. Mol Biol Rep. 2022;49:2487–2501. https://doi. org/10.1007/s11033-021-07039-9
Yari Z. Review of isoflavones and their potential clinical impacts on cardiovascular and bone metabolism markers in peritoneal dialysis patients. Prev Nutr Food Sci. 2022;27(4):347–353. https://doi.org/10.3746%2Fpnf. 2022.27.4.347
Libby P, Buring JE, Badimon L, et al. Atherosclerosis (Primer). Nat Rev Dis Prim. 2019;5:e56. https://doi.org/10. 1038/s41572-019-0106-z
Safian RD. Renal artery stenosis. Prog Cardiovasc Dis. 2021;65:60–70.
Baran J, Kleczyński P, Niewiara Ł, et al. Importance of increased arterial resistance in risk prediction in patients with cardiovascular risk factors and degenerative aortic stenosis. J Clin Med. 2021;10(10):e2109. https://doi. org/10.3390/jcm10102109
Gomez JA. Renin Angiotensin Aldosterone System Functions in Renovascular Hypertension. London, United Kingdom. Intechopen; 2021:79–116.
Ma N, Wang SY, Sun YJ, Ren JH, Guo FJ. Diagnostic value of contrast-enhanced ultrasound for accessory renal artery among patients suspected of renal artery stenosis. Zhonghua Yi Xue Za Zhi. 2019;99(11):838–840. https://doi.org/10.3760/cma.j.issn.0376-2491.2019.11.008
Akar EM, Aydın F, Tüzüner A, et al. Renal Autotransplantation in a Patient with Bilateral Renal Artery Stenosis Secondary to Takayasu Arteritis. Int J Organ Transplant Med. 2020;11(1):37–41.
Stein EJ, Fearon WF, Elmariah S, et al. Left ventricular hypertrophy and biomarkers of cardiac damage and stress in aortic stenosis. J Am Heart Assoc. 2022;11(7):e023466. https:// doi.org/10.1161/JAHA.121.023466
Nakagawa K, Nakashima Y. Pathologic intimal thickening in human atherosclerosis is formed by extracellular accumulation of plasma-derived lipids and dispersion of intimal smooth muscle cells. Atherosclerosis. 2018;274:235–242. https://doi.org/10. 1016/j.atherosclerosis.2018.03.039
Bobryshev Y V. Monocyte recruitment and foam cell formation in atherosclerosis. Micron. 2006;37(3):208–222. https://doi.org /10.1016/j.micron.2005.10.007
Bec J, Vela D, Phipps JE, et al. Label-free visualization and quantification of biochemical markers of atherosclerotic plaque progression using intravascular fluorescence lifetime. Cardiovasc Imaging. 2021;14(9):1832–1842. https://doi.org/10.1016/j.jcmg.2020.10.004
Xiang P, Blanchard V, Francis GA. Smooth muscle cell—macrophage interactions leading to foam cell formation in atherosclerosis: Location, location, location. Front Physiol. 2022;13:e921597. https://doi.org /10.3389/fphys.2022.921597
Farahi L, Sinha SK, Lusis AJ. Roles of macrophages in atherogenesis. Front Pharmacol. 2021;12:e785220. https://doi.org/10.3389/fphar.2021.785220
Yeo KP, Lim HY, Thiam CH, et al. Efficient aortic lymphatic drainage is necessary for atherosclerosis regression induced by ezetimibe. Sci Adv. 2020;6(50):eabc2697. https://doi. org/10.1126/sciadv.abc2697
Yalçin F, Kucukler N, Cingolani O, et al. Evolution of ventricular hypertrophy and myocardial mechanics in physiological and pathological hypertrophy. J Appl Physiol. 2019;126(2):354–362. https:// doi.org/10.1152/japplphysiol.00199.2016
Budzyń M, Gryszczyńka B, Boruczkowski M, et al. The potential role of circulating endothelial cells and endothelial progenitor cells in the prediction of left ventricular hypertrophy in hypertensive patients. Front Physiol. 2019;10:e1005. https://doi.org/10.3389/fphys.2019.01005
Igbekele AE, Jia G, Hill MA, Sowers JR, Jia G. Mineralocorticoid receptor activation in vascular insulin resistance and dysfunction. Int J Mol Sci. 2022;23(16):e8954. https://doi.org/ 10.3390/ijms23168954
Braam B, Lai CF, Abinader J, Bello AK. Extracellular fluid volume expansion, arterial stiffness and uncontrolled hypertension in patients with chronic kidney disease. Nephrol Dial Transplant. 2020;35(8):1393–1398. https://doi.org/10.1093/ndt/ gfz020
Lavenniah A, Luu TDA, Li YP, et al. Engineered circular RNA sponges act as miRNA inhibitors to attenuate pressure overload-induced cardiac hypertrophy. Mol Ther. 2020;28(6):1506–1517. https://doi.org /10.1016/j.ymthe.2020.04.006
Bornstein AB, Rao SS, Marwaha K. Left Ventricular Hypertrophy. StatPearls Publishing; 2024.
Poredos P, Poredos AV, Gregoric I. Endothelial dysfunction and its clinical implications. Angiology. 2021;72(7):604–615. https://doi.org/ 10.1177/0003319720987752
Oliveira e Silva VR, Stringuetta Belik F, Hueb JC, et al. Aerobic exercise training and nontraditional cardiovascular risk factors in hemodialysis patients: results from a prospective randomized trial. Cardiorenal Med. 2019;9(6):391–399. https://doi.org/10.1159/000501589
Chen Y, Freedman ND, Albert PS, et al. Association of cardiovascular disease with premature mortality in the United States. JAMA Cardiol. 2019;4(12):1230–1238. https://doi. org/10.1001/jamacardio.2019.3891
Zhang D, Li L, Chen Y, et al. Syndecan-1, an indicator of endothelial glycocalyx degradation, predicts outcome of patients admitted to an ICU with COVID-19. Mol Med. 2021;27(1):e151. https://doi.org/ 10.1186/s10020-021-00412-1
Barone Gibbs B, Hivert M-F, Jerome GJ, et al. Physical activity as a critical component of first-line treatment for elevated blood pressure or cholesterol: who, what, and how?: a scientific statement from the American Heart Association. Hypertension. 2021;78(2):e26–e37. https://doi.org /10.1161/HYP.0000000000000196
Selva-O’Callaghan A, Alvarado-Cardenas M, Pinal-Fernández I, et al. Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations. Expert Rev Clin Immunol. 2018;14(3):215–224. https://doi.org/10.1080/1744666X.2018.1440206
Liu Z, Neuber S, Klose K, et al. Relationship between epicardial adipose tissue attenuation and coronary artery disease in type 2 diabetes mellitus patients. J Cardiovasc Med. 2023;24(4):244–252. https://doi.org/ 10.2459/JCM.0000000000001454
Watts GF, Sullivan DR, Hare DL, et al. Integrated guidance for enhancing the care of familial hypercholesterolaemia in Australia. Hear Lung Circ. 2021;30(3):324–349. https://doi.org/10.1016/j.hlc.2020.09.943
Moors J, Krishnan M, Sumpter N, et al. A polynesian-specific missense CETP variant alters the lipid profile. Hum Genet Genomics Adv. 2023;4(3):e100204. https://doi.org /10.1016/j.xhgg.2023.100204
Rhainds D, Brodeur MR, Tardif J-C. Lipoprotein (a): when to measure and how to treat? Curr Atheroscler Rep. 2021;23:1–14. https://doi.org/10.1007 /s11883-021-00951-2
Tang Z, Li T, Peng J, et al. PCSK9: a novel inflammation modulator in atherosclerosis? J Cell Physiol. 2019;234(3):2345–2355. https://doi. org/10.1002/jcp.27254
Yehuda H, E. LN. PCSK9 Inhibitors in lipid management of patients with diabetes mellitus and high cardiovascular risk: a review. J Am Heart Assoc. 2018;7(13):e008953. https://doi.org/10.1161/JAHA.118.008953
Hong D-Y, Lee D-H, Lee J-Y, et al. Relationship between brain metabolic disorders and cognitive impairment: LDL receptor defect. Int J Mol Sci. 2022;23(15):e8384. https://doi.org /10.3390/ijms23158384
A Romero C, Mathew S, Wasinski B, et al. Angiotensin‐converting enzyme inhibitors increase anti‐fibrotic biomarkers in African Americans with left ventricular hypertrophy. J Clin Hypertens. 2021;23(5):1008–1016. https://doi.org/10.1111/jch.14206
Park S-J. The role of systolic blood pressure reduction in diastolic dysfunction: RAAS inhibition versus Non-RAAS blood pressure lowering. J Cardiovasc Imaging. 2020;28(3):183–185. https://doi.org/10.4250%2Fjcvi. 2020.0083
Pugliese NR, Masi S, Taddei S. The renin-angiotensin-aldosterone system: a crossroad from arterial hypertension to heart failure. Heart Fail Rev. 2020;25(1):31–42. https://doi.org /10.1007/s10741-019-09855-5
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