Association between cardiovascular risk factors and coronary artery disease assessed using CAD-RADS classification: a cross-sectional study in Romanian population

Loredana Elisabeta Popa; Bianca Petresc; Cristina Cătană; Claudia Gabriela Moldovanu; Diana Sorina Feier; Andrei Lebovici; Călin Schiau; Raluca Alina Rancea; Adrian Molnar; Mircea Marian Buruian

doi:10.1136/bmjopen-2019-031799

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Association between cardiovascular risk factors and coronary artery disease assessed using CAD-RADS classification: a cross-sectional study in Romanian population

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Response letter to Ravnskov U et al "Dyslipidemia is an unlikely cause of atherosclerosis"
Loredana Elisabeta Popa, Bianca Petresc and Raluca Alina Rancea
Published on: 6 February 2020
Dyslipidemia is an unlikely cause of atherosclerosis
Uff'e Ravnskov, David M Diamond and Sherif Sultan
Published on: 22 January 2020

Published on: 6 February 2020
Response letter to Ravnskov U et al "Dyslipidemia is an unlikely cause of atherosclerosis"
- Loredana Elisabeta Popa, Radiologist Department of Radiology, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology of Târgu Mureş,
- Other Contributors:
  Bianca Petresc, Radiologist
  
  Raluca Alina Rancea, Cardiologist
We appreciate the authors’ interest for our paper, and we would like to thank them for the opportunity to discuss the problems raised in their letter (1).

First of all, we would like to emphasize that in our study we didn’t try to investigate the pathophysiology of atherosclerosis, but tried to see how the generally accepted risk factors of atherosclerosis correlate with significant coronary heart disease evaluated by CAD-RADS score in the Romanian population (2). The design of our research was cross-sectional, retrospective, therefore our purpose was not to establish the causality between dyslipidemia and cardiovascular disease. We agree with the authors that there is a difference between causality and association and our current study was based on evaluating the association between the presence of risk factors and the burden of atherosclerotic coronary disease evaluated using CCTA method. We chose dyslipidemia among the atherosclerosis risk factors studied based on the most current guidelines on cardiovascular disease prevention at the time (3).

Regarding the pathophysiology of atherosclerosis, the role of lipids and lipoproteins in the development of atheromatous plaque is proven by many studies (4-7). This complex process, based on an inflammatory response, is initiated by the infiltration of apoB containing lipoproteins into the arterial wall, which cause wall injuries and promote infiltration of monocytes into the subendothelial space. Secondly, the ma...
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We appreciate the authors’ interest for our paper, and we would like to thank them for the opportunity to discuss the problems raised in their letter (1).

First of all, we would like to emphasize that in our study we didn’t try to investigate the pathophysiology of atherosclerosis, but tried to see how the generally accepted risk factors of atherosclerosis correlate with significant coronary heart disease evaluated by CAD-RADS score in the Romanian population (2). The design of our research was cross-sectional, retrospective, therefore our purpose was not to establish the causality between dyslipidemia and cardiovascular disease. We agree with the authors that there is a difference between causality and association and our current study was based on evaluating the association between the presence of risk factors and the burden of atherosclerotic coronary disease evaluated using CCTA method. We chose dyslipidemia among the atherosclerosis risk factors studied based on the most current guidelines on cardiovascular disease prevention at the time (3).

Regarding the pathophysiology of atherosclerosis, the role of lipids and lipoproteins in the development of atheromatous plaque is proven by many studies (4-7). This complex process, based on an inflammatory response, is initiated by the infiltration of apoB containing lipoproteins into the arterial wall, which cause wall injuries and promote infiltration of monocytes into the subendothelial space. Secondly, the macrophages internalize the apoB, resulting in foam cell formation, which is the hallmark of the fatty streak phase of atherosclerosis. In the process of atherosclerosis, LDL is not involved in its native form, but it has to suffer oxidative modifications in order to facilitate its uptake by the macrophages. The inflammatory cascade lead to proliferation of smooth muscle cells, which produce extracellular matrix, contributing to the formation of a stable fibrous plaque. However, if the inflammation is unresolved, this will result in the formation of a vulnerable plaque.
Pertaining to the role of hypercholesterolemia in the atherosclerotic cardiovascular diseases, the recently published guidelines of the European Society of Cardiology on dyslipidemias and the consensus statement from the European Atherosclerosis Society Consensus Panel confirm that the retention of LDL cholesterol (LDL-C) is the key initiating event of atherosclerosis based on preclinical studies (4-6, 8-10). LDL-C doesn’t only contribute to initiation of atherosclerosis, but also to its progression; the level of LDL-C corelates to the burden of atherosclerotic plaques and progression of atherosclerotic cardiovascular disease in a dose-dependent manner as demonstrated by multiple meta-analysis and Mendelian randomization studies (7,9,12-15). Another proof of the causal link between LDL-C and atherosclerosis are the meta-analysis showing that the LDL-C lowering therapies reduce the risk of cardiovascular events (9,16,17).

The European Atherosclerosis Society based its conclusion that the causal relation between LDL-C and atherosclerosis is certain on a great body of evidence including > 200 studies, with > 2 million participants and > 20 million person-years of follow-up and >150 000 cardiovascular events (9). Our study also showed a positive relation between dyslipidemia and obstructive coronary disease defined as CAD-RADS score ≥ 3 that is in concordance with published literature (2).

Nevertheless, we are aware of the studies which do not support the causality between LDL-cholesterol and cardiovascular disease (18,19). We appreciate the work of the researchers; however we consider that these studies are too few in comparison with the meta-analyses to completely reject this relation.

All in all, we consider that the “universal truth” lies maybe somewhere in between and there is a need for more prospective, long-term studies to research other causes of atherosclerosis besides the presence of dyslipidemia, its dynamics over time with or without lipid-lowering treatment and the progress of coronary artery atherosclerosis assessed using CCTA classification systems.

References
1. Ravnskov U, Diamond DM, Sherif Sultan. Dyslipidemia is an unlikely cause of atherosclerosis. BMJ 22 January 2020
2. Popa LE, Petresc B, Cătană C et al. Association between cardiovascular risk factors and coronary artery disease assessed using CAD-RADS classification: a cross-sectional study in Romanian population. BMJ Open 2020;10:e031799. doi:10.1136/ bmjopen-2019-031799
3. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315–81.
4. Camejo G, Lopez A, Vegas H et al. The participation of aortic proteins in the formation of complexes between low density lipoproteins and intima-media extracts. Atherosclerosis 1975;21:77–91.
5. Skalen K, Gustafsson M, Rydberg EK et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis.Nature 2002;417:750–754
6. Tabas I, Williams KJ, Bore´n J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007;116:1832–1844.
7. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell 2015;161:161–172.
8. Mach F, Baigent C, Catapano AL et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS), European Heart Journal 2020;41:111–188, https://doi.org/10.1093/eurheartj/ehz455
9. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-2472.
10. Schwenke DC, Carew TE. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. Arteriosclerosis 1989;9:908–918.
11. Frank JS, Fogelman AM. Ultrastructure of the intima in WHHL and cholesterolfed rabbit aortas prepared by ultra-rapid freezing and freeze-etching. J Lipid Res 1989;30:967–978.
12.Di Angelantonio E, Gao P, Pennells L, Kaptoge S et al. Lipid-related markers and cardiovascular disease prediction. JAMA 2012;307:2499–2506.
13. Lewington S, Whitlock G, Clarke R et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007;370:1829–1839.
14. Ference BA, Yoo W, Alesh I et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012;60:2631–2639.
15. Holmes MV, Asselbergs FW, Palmer TM et al.Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 2015;36:539–550.
16. Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376:1670–1681.
17. Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532–2561.
18. Ravnskov U, de Lorgeril M, Diamond DM et al LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Expert Rev Clin Pharmacol. 2018;11(10):959-970.
19. Ravnskov U, Diamond DM, Hama R et al Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6(6):e010401
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Conflict of Interest:
None declared.
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Published on: 22 January 2020
Dyslipidemia is an unlikely cause of atherosclerosis
- Uff'e Ravnskov, Independent researcher Not affiliated to any institution
- Other Contributors:
  David M Diamond, Professor Psychology, Molecular Pharmacology & Physiology)
  
  Sherif Sultan, Professor, Cardiac surgery
The study by Popa et al. (1) is potentially of value in identifying adverse influences on cardiovascular health. Their study, however, suggests that dyslipidemia causes cardiovascular disease (CVD). We feel compelled to show that the broader literature is not consistent with this perspective and that their finding of an association between dyslipidemia and CVD is influenced by a methodological flaw in their design.

First, there is no evidence that dyslipidemia causes atherosclerosis. Already in 1936 Lande ́ and Sperry found that when corrected for age, healthy people with low total cholesterol (TC) were just as atherosclerotic as healthy people with high TC (2) and their finding has been verified and replicated later by many research groups (2). A strong contradiction has also been documented by sixteen angiographic trials where the authors had calculated exposure-response, which was present in only two of them (2). Furthermore, a study of the coronary arteries of 304 asymptomatic women by Hecht and Superco showed that the role of high LDL-cholesterol (LDL-C) is questionable as well. By using electron beam tomography, they found that neither the calcium percentile or the calcium score were associated with LDL-C (3). Also contradictory is, that In five studies of people with familial hypercholesterolemia there were no association between degree of atherosclerosis and LDL-C (4).

Second, numerous observations and experiments have shown that dyslipidemia does no...
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The study by Popa et al. (1) is potentially of value in identifying adverse influences on cardiovascular health. Their study, however, suggests that dyslipidemia causes cardiovascular disease (CVD). We feel compelled to show that the broader literature is not consistent with this perspective and that their finding of an association between dyslipidemia and CVD is influenced by a methodological flaw in their design.

First, there is no evidence that dyslipidemia causes atherosclerosis. Already in 1936 Lande ́ and Sperry found that when corrected for age, healthy people with low total cholesterol (TC) were just as atherosclerotic as healthy people with high TC (2) and their finding has been verified and replicated later by many research groups (2). A strong contradiction has also been documented by sixteen angiographic trials where the authors had calculated exposure-response, which was present in only two of them (2). Furthermore, a study of the coronary arteries of 304 asymptomatic women by Hecht and Superco showed that the role of high LDL-cholesterol (LDL-C) is questionable as well. By using electron beam tomography, they found that neither the calcium percentile or the calcium score were associated with LDL-C (3). Also contradictory is, that In five studies of people with familial hypercholesterolemia there were no association between degree of atherosclerosis and LDL-C (4).

Second, numerous observations and experiments have shown that dyslipidemia does not cause CVD (5). The strongest contradiction is that several follow-up studies including more than 600 000 individuals of all ages have shown that people with high TC or high LDL-C live just as long or longer than people with normal or low values, whether they are on statin treatment or not (6-9). These findings are most likely due to the anti-infectious role played by LDL (10).

It is correct, as mentioned by Popa et al. (1). that many studies have shown an association between dyslipidemia and CVD. However, most of them have only included young and middle-aged people, and association is not the same as causation. Many studies have shown that mental stress may cause atherosclerosis and CVD and mental stress is most likely more common among young and middle-aged people than among retired citizens. Mental stress may raise cholesterol (11,12) but it may cause CVD by other ways, for instance by hypercoagulation (13).

An explanation of the findings by Popa et al. may be that they have defined the presence of dyslipidemia as high TC or the presence of cholesterol-lowering treatment. It is a fact that long-time statin-treatment increases the degree of arterial calcification (14,15). Such treatment may therefore have contributed to the degree of atherosclerosis.

Considering the many contradictions mentioned above, we hypothesize that one of the main causes of atherosclerosis and CVD is hypercoagulation, either inborn as in familial hypercholesterolemia (4) or induced by stress. There is also much evidence that infections, which may increase LDL-C as a component of an immune response, may contribute to atherosclerosis and CVD (10).

References

1. Popa LE, Petresc B, Cătană C et al. Association between cardiovascular risk factors and coronary artery disease assessed using CAD-RADS classification: a cross-sectional study in Romanian population. BMJ Open 2020;10:e031799. doi:10.1136/ bmjopen-2019-031799
2. Ravnskov U. Is atherosclerosis caused by high cholesterol? QJM 2002;95:397–403. doi.org/10.1093/qjmed/95.6.397
3. Hecht HS, Superko HR. Electron beam tomography and National Cholesterol Education Program guidelines in asymptomatic women. J Am Coll Cardiol 2001;37:1506-11. doi.org/10.1016/s0735-1097(01)01211-6
4. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM. Inborn coagulation factors are more important cardiovascular risk factors than high LDL- cholesterol in familial hypercholesterolemia. Med Hypotheses 2018;121:60-3. doi: 10.1016/j.mehy.2018.09.019.
5. Ravnskov U, de Lorgeril M, Diamond DM et al. LDL-C does not cause cardiovascular disease: a comprehensive review of current literature. Expert Rev Clin Pharmacol 2018;11:959-70. doi.org/10.1080/17512433.2018.1519391
6. Ravnskov U, Diamond DM, Hama R, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 2016;6: e010401. doi:10.1136/ bmjopen-2015-010401
7. Charlton J, Ravindrarajah R, Hamada S et al. Trajectory of total cholesterol in the last years of life over age >80 years: cohort study of 99,758 participants. J Gerontol A Biol Sci Med Sci 2018;73:1083-9. doi: 10.1093/gerona/glx184.
8. Sung KC, Huh JH, Ryu S et al. Low levels of low-density lipoprotein cholesterol and mortality outcomes in non-statin users. J Clin Med 2019;8. pii: E1571. doi: 10.3390/jcm8101571.
9. Gnanenthiran SR, Ng ACC, Cumming R et al. Low total cholesterol is associated with increased major adverse cardiovascular events in men aged >70 years not taking statins. Heart 2019 pii: heartjnl-2019-315449. doi: 10.1136/heartjnl-2019-315449.
10. Ravnskov U, McCully KS. Infections may be causal in the pathogenesis of atherosclerosis. Am J Med Sci 2012;344:391-94. doi.org/10.1097/MAJ.0b013e31824ba6e0
11. Rosenman RH. Relationships of neurogenic and psychological factors to the regulation and variability of serum lipids. Stress Med 1993;9:133-40.
12. Dimsdale JE, Herd A. Variability of plasma lipids in response to emotional arousal. Psychosom Med 1982;44:413-30. doi.org/10.1097/00006842-198211000-00004
13. Thrall G, Lane D, Carroll D, Lip GY. A systematic review of the effects of acute psychological stress and physical activity on haemorheology, coagulation, fibrinolysis and platelet reactivity: Implications for the pathogenesis of acute coronary syndromes. Thromb Res 2007;120:819-47. doi.org/10.1016/j.thromres.2007.01.004
14. Saremi A, Bahn G, Reaven PD, et al. Progression of vascular calcification is increased with statin use in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 2012;35:2390-2. doi: 10.2337/dc12-0464.
15. Nakazato R, Gransar H, Berman DS, et al. Statins use and coronary artery plaque composition: results from the International Multicenter CONFIRM Registry. Atherosclerosis 2012;225:148-53. doi.org/10.1016/j.atherosclerosis.2012.08.002
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Conflict of Interest:
None declared.
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