J Med Allied Sci 2016; 6(2):46-51 DOI: 10.5455/jmas.228597

Review

Cardiovascular diseases: Traditional and non-traditional risk factors

Chittakath Shaima, Puthamohan Vinayaga Moorthi, Naser Kutty Shaheen

Affiliation(s):

Department of Human Genetics and Molecular Biology, School of Life Sciences, Bharathiar University, Coimbatore-641046, Tamil Nadu, India.

Corresponding author: Dr. Puthamohan Vinayaga Moorthi, Assistant Professor, Department of Human Genetics and Molecular Biology, School of Life Sciences, Bharathiar University, Coimbatore-641046, Tamil Nadu, India.

Phone: +91- 9994809189 Email: vinayputhu@gmail.com

Abstract

Cardiovascular disease (CVD) is responsible for more number of deaths world wide. The muscles and vessels of heart and blood transporting roads become vulnerable portion in most of the CVD. The role of hypertension and cholesterols of different density triglycerides in induction and progression of cardiovascular disease is discussed in this present review. Besides this the potential biomarkers such as homocysteine, fibrinogen, D-dimer and thrombin/anti-thrombin III complex, interleukin and serum amyloid in prognosis is also discussed in this review.

Keywords: Cardiovascular disease, Diabetes, Fibrinogen, HDL, LDL

Introduction

Cardiovascular diseases (CVD) which mainly include coronary heart disease (CHD), stroke, rheumatic heart disease (RHD) and cardiomyopathy represent the leading cause of death worldwide1. In the early 20th century, CVD was responsible for less than 10% of all deaths worldwide, but it increased to 30% by 2001. Countries like low and middle-income have 80% deaths due to CVD.  By 2020, CVD will become the leading cause of death and disability2 in low and middle-income countries. In a year, mortality of CVD accounts ~ 9%3. CVD includes a wide range of disorders which includes diseases of the cardiac muscle and of the vascular systems. Potential risk factors for CVD include hypertension, tobacco use, physical inactivity, elevated low-density lipoprotein cholesterol, diabetes and a cluster of interrelated metabolic risk factors4. Framingham Heart Study in 1961 was the first to introduce the concept of risk factors which links the presence of high cholesterol, tobacco usage, hypertension and diabetes mellitus to future CVD5. Mostly CVDs are due to atherosclerosis as well as due to infections.

Traditional risk factors

Although earliest research has recognized hypertension, diabetes and hypercholesterolemia as traditional CVD risk factors, several researchers have reported their absence in a considerable portion of individuals experience clinical vascular events. Indeed, up to half of those having their first clinical vascular events does not have traditional CVD risk factors6. However, these findings may not be relevant to all populations, researchers from the FHS report that 50% of the patients with CHD had levels of total cholesterol (TC) ≤240 mg/dl and 20% had TC <200 mg/dl7.

Data from the Women’s Health Study (WHS) confirmed those three quarters of coronary events happen in 27,939 women without a high level of LDL cholesterol (<160 mg/dl) and 45% happen in women with normal LDL cholesterol (<130 mg/dl)8. When numerous large studies of CVD were reviewed, as one would expect, most individuals had one or more traditional risk factors9. Conversely, one fifth had none of the traditional risk factors. In addition, among cohort individuals who did not suffered CHD, the rates of traditional cardiovascular risk factors were also relatively high10. Given these findings, new research has focused on ways of enhancing our ability to predict CVD. However, many of these show promise and most widely used in routine clinical practice. 

Hypertension and cardiovascular disease

In its Sixth Report, the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (1997) defines categorical hypertension as a BP ≥140 mmHg systolic or ≥90 mmHg diastolic or current use of antihypertensive drugs. Several observational studies have confirmed clearly a powerful relationship between high BP and CHD11-13. This relationship holds for both men and women and younger and older persons. Occasionally those with high BP are at higher risk of CHD14.

Diabetes and cardiovascular disease

Risk for all forms of CVD, is increased significantly in patients with type 1 and type 2 diabetes mellitus15,16. The mortality rate in non-diabetic patients was less compared to diabetic patients who experienced CHD17,18. Hyperglycemia is considered to be the potential risk factor while it is not dependant on the normally observed characters in diabetics like obesity and dyslipidemia. Good glycemic control decreases risk for microvascular complications of diabetes. However, in diabetic patients, significant control of glucose has not been reducing the macrovascular disease (CHD), although a trend toward benefit has been observed19. 

Total cholesterol, low-density lipoprotein cholesterol and cardiovascular disease

Cholesterol is synthesized almost in all cells and considerable amounts of it can be absorbed from the diet. According to the lipid hypothesis, unusually high cholesterol levels (hypercholesterolemia), or higher concentrations of LDL cholesterol have been recognized as principle lipid risk factors20. Various studies have confirmed that blood TC levels have an exponential role on cardiovascular and total mortality, with the association more evident in younger subjects. In old age people, the effect of higher cholesterol on health is indeed larger21.

Several studies have consistently confirmed that CHD risk and TC had a dose-response relationship. The Multiple Risk Factor Intervention Trial (MRFIT) screened >300,000 men and established a curvilinear relation between TC and age-adjusted CHD death rate; in MRFIT screeners with a TC level of ≥240 mg/dL, relative risk (RR) for CHD, compared with those with TC <182 mg/dL, the death rate was 3.422. Conversely, except TC, there are factors influencing the risk of CHD risk was clearly established by studies of 25 years of follow-up in the Seven Countries Study (SCS)23, in which a dose-response association between TC and CHD mortality rate was observed.

Studies across different populations demonstrate that those with higher cholesterol levels have more atherosclerosis and CHD than do those who having lower levels (Keys et al., 1984). The positive association between proportion of serum cholesterol and onset of first or consequent CHD attack, due to elevated LDL cholesterol, was observed; the higher the level, the greater the risk24. Prospective data recommended that the risk of CHD at lower cholesterol levels and this evident has disappeared in larger studies24,25. Population with very low serum cholesterol e.g. TC <150 mg/dL (or LDL cholesterol <100 mg/dL) witness the almost absence of clinical CHD throughout the life26,27.

The association between the elevated LDL cholesterol to the onset of CHD observed to be a multi-step process28. Atherogenesis, the fatty streak, having macrophages filled with cholesterol, is the first stage and most of them derived from LDL cholesterol. The fibrous plaques, scar tissue over lipid rich core, are the second stage. Other risk factors also contribute to plaque growth. The third stage is demonstrated the onset of plagues, prone to rupture and luminal thrombosis formation, of unstable. Plaque rupture is responsible for most acute coronary syndromes (ACS) 29,30 .

Triglycerides, very low-density lipoprotein cholesterol and cardiovascular disease

Triglyceride (TG) is an ester formed from a glycerol molecule, provided OH group each with and make up the majority of fats, which was later properly utilized by digestion. Lipids cannot be absorbed by the duodenum in TG form and it is absorbed as fatty acids, monoglycerides and some diglycerides, once the TG have been digested. In the human body, high levels of TG in the bloodstream have been linked to atherosclerosis and CHD.

Several observational studies and analysis published in the earlier years largely support TG as an independent risk factor for CHD. These studies have been performed in populations over a wide spectrum of ages in a number of countries with quite different rates of CVD31-34. Traditionally, CHD events due to elevated TG were predicted in univariate analysis, after adjustment for other covariates, including plasma glucose and HDL cholesterol, to which it is strongly and inversely correlated35. Yet, even after adjustment for HDL cholesterol, detailed assessment of population-based prospective studies has disclosed an independent effect of TG on CHD events36.  Coupled with the knowledge that combined hyperlipidemia promotes CHD to a significantly greater extent than either high LDL cholesterol or TG alone37.

Very low-density lipoprotein (VLDL) cholesterol is a type of lipoprotein formed by the liver, which enable movement of fats and cholesterol within blood stream. It is accumulated in the liver from cholesterol and apolipoproteins, which converted in the bloodstream to LDL cholesterol. VLDL cholesterol transports endogenous products (such as TG, phospholipids, cholesterol and cholesteryl esters) where chylomicrons transport exogenous (dietary) products.

The most likely candidates for atherogenic TG-rich lipoproteins (TGRLP) are remnant lipoproteins. These lipoproteins include small VLDL cholesterol and lipoproteins of intermediate-density i.e., IDL. The atherogenicity of remnants was well supported by several reviews38-40. In several clinical studies elevation as well as their specific identification of remnants was noticed to be strong predictors of CHD41-42.

High-density lipoprotein cholesterol and cardiovascular disease

HDL cholesterol is one of the 5 major groups of lipoproteins cholesterol, which enable lipids like cholesterol and TG to be transported within the water based blood stream. In healthy persons, about thirty percent of blood cholesterol is carried by HDL cholesterol. An increased level of HDL cholesterol protect against CVD while lowering which cause enhanced heart disease risk. When measuring cholesterol, some contained in HDL particles is considered as guardians of the cardiovascular health of the body, in contrast to "bad” LDL cholesterol.

Strong epidemiological evidence links low serum HDL to increased CHD morbidity and mortality43,44. High HDL cholesterol levels conversely convey reduced risk. Various epidemiological data taken as a whole suggest that a 1 percent decrease in HDL cholesterol is associated with a 2–3 percent increase in CHD risk44. Low HDL cholesterol, based on epidemiology studies, to be an independent risk factor for CHD and it holds after correction for other risk variables in multivariate analysis.

In fact, in prospective studies45,46, HDL cholesterol usually the risk factor of CHD risk having high correlation with CHD risk. Adult Treatment Panel II (ATP II) at <35 mg/dL were noticed as a low HDL cholesterol, one of several major risk factors used to modify the therapeutic goal for LDL cholesterol. The definition of low-HDL cholesterol was set to be the same for both genders because the level of HDL cholesterol would impart the same risk for men and women.

Non-traditional risk markers

The epidemiological and basic science search for better understanding of the etiology of CVD has produced numerous serum markers as candidates for representing “nontraditional” risk.  Several are part of the progression of inflammation - a process, now understood to be central to atherosclerotic disease47. Candidates have included homocysteine, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, D-dimer and thrombin/antithrombin III complex; and various inflammatory markers such as CRP, interleukin (IL), serum amyloid A (SAA), MMP and adhesion molecule. However, many of these markers show promise, most are not used in routine clinical practice and the predictive power of many has not been confirmed.

Homocysteine

It was clearly understood from the literatures48,49 that the role of homocysteine as oxidative stress indicator. As a mediator of one carbon metabolism, homocysteine, levels are associated with CVD50-52. It was suggested53 (Humphrey et al., 2008) that, the level of homocysteine moderately increase the risk of CVD by 20%. Ueland et al.54 and Van Guldener et al.55 reported that, the one type of CVDs, like stroke and deep vein thrombosis can be reduced by reducing the level of homocysteine by 3-5 mol/L in serum.

Plasminogen activator inhibitor-1 (PAI-1)

PAI-1 is the key fibrinolysis regulator. Jugo et al.56 based on the bivariate analysis, stated that, the PAI-1 was directly correlated with carotid intima-media thickness, BP, Body Mass Index (BMI), LDL and total cholesterol, glomerular filtration and triglycerides. Zhuang et al.57 reported that, the patients with acute ischemic stroke had significant amount of t-PA, while level of PAI-1 was reduced significantly. Existence of negative correlation between t-PA and PAI-1 was revealed and significant difference in activities of t-PA and PAI-1 was observed in control group, acute, convalescent and chronic groups. Tofler et al.58 revealed that, those with CVD have higher level of PAI-1 (29.1 ng/ml) compared to those without (22.1 ng/ml) CVD.  It was also observed from his experiment that, an antigen level of PAI-1 and t-PA was in strong linear relationship with CVD incidence.

Fibrinogen

Fibrinogen (Fg), the precursor of fibrin, coagulation factor described first in 1836 by Buchanan. The hematological changes such as increase in viscosity of plasma, aggregation of erythrocytes, thrombogenesis of platelets are due to increase in level of Fg59. Meade et al.60, based on the epidemiological studies, stated that the risk of CVD such as ischaemic heart disease, thromboembolism and stroke increase with respect to the increase in concentration of plasma Fg.

D-dimer

The fibrin degradation marker, D-dimer, one of the important marker associated with CVD. Lind et al.61 in his longitudinal cohort study on 719 patients with oral anticoagulant revealed the association of CVD with higher level of D-dimer. Fruchter et al.62, based on data from clinical and laboratory, proposed D-dimer as prominent prognostic marker of short and long term survivors subjected to acute exacerbation. He also noticed the changes in the mean D-dimer level in non-survivors (3.18 mg/L and survivors (1.45 mg/L).

Interleukin

Interleukin-6, the potent prognosis indicator in serum, used as a tool for the early diagnosis of CVD based on clinical trials63. Reichert et al.64 suggested from his study with 942 coronary heart disease (CHD) revealed that the polymorphism in IL-6 c.-174 CC genotype was found to be the independent risk marker of CHD.  Similarly, Buraczynska et al.65 provided an information that, the patients with diabetic (Type-2) having an allele of C IL-6 G(-174)C are highly susceptible to CVD.

Conclusion

Studies implicate urbanization, westernization of diet and increasing rates of smoking, obesity, and diabetes contributes to disease pathogenesis. The steps taken towards the control of CVD during the past decades reduced mortality related to CVD. Potential risk factors for CVD include hypertension, tobacco use, physical inactivity, elevated low-density lipoprotein cholesterol, diabetes and a cluster of interrelated metabolic risk factors4. However, many patients never acquired adequate control over the CVD risk factors even when these factors have been identified. Besides the growing prevalence of obesity and type 2 diabetes mellitus (Type -2 DM) threatens to decline the improvements in CVD that have been achieved. The increased incidence of obesity has contributed to significant increase in the prevalence of other important CVD risk factors, including hypertension, dyslipidemia, insulin resistance, and type 2 DM4. Various studies have confirmed that blood cholesterol are primarily important component that leads to CVD and its associated mortality evidenced in younger subjects. A high level of HDL cholesterol seems to protect against CVD and low HDL cholesterol levels increase the risk for heart disease. Non-traditional risk markers  includes homocysteine, coagulation markers such as plasminogen activator inhibitor-1 (PAI-1), fibrinogen, D-dimer and thrombin/anti-thrombin III complex; and various inflammatory markers such as CRP, interleukin (IL), serum amyloid A (SAA), MMP and adhesion molecule. Pharmacologic therapies are now available to address individual CVD risk factors and are being evaluated, including endo-cannabinoid receptor antagonists, peroxisome proliferator inhibitor are regulating the activity of glucagon-like peptide-14.

Acknowledgements: Authors thank Dr. A. Vijaya Anand, Head of the department of Human Genetics and Molecular Biology, Bharathiar Univeristy, Coimbatore for his valuable suggestion and correction.

Conflict of interest: None

References

1.    Celermajer DS, Chow CK, Marijon E, Anstey NM, Woo KS. Cardiovascular disease in the developing world: prevalences, patterns and the potential of early disease detection. J Am Coll. Cardiol. 2012; 60(14):1207-1216.

2.    Murray CJL, Lopez AD. Global burden of disease and injury series. Vols. I and II, Global Health Statistics. Boston: Harvard School of Public Health 1996; p.4.

3.    Foley RN, Parfrey PS, Sarnak MJ. Epidemiology of cardiovascular disease in chronic renal disease. J Am Soc Nephrol 1998; 9(12 Suppl):16-23.

4.    Cannon CP. Cardiovascular disease and modifiable cardiometabolic risk factors. Clin Cornerstone 2007; 8(3):11-28.

5.    Mahmood SS, Levy D, Vasan RS, Wang TJ. The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet 2014; 383(9921):999-1008.

6.    Braunwald E. Shattuck lecture--cardiovascular medicine at the turn of the millennium:  triumphs, concerns, and opportunities. N Engl J Med. 1997; 337(19):1360-1369.

7.    Kannel WB.  Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol. 1995; 76(9):69C-77C.

8.    Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C–reactive protein and low–density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347(20):1557-1565.

9.    Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM, Brener SJ, Ellis SG, Lincoff AM, Topol EJ. Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003; 290(7):898-904.

10.  Greenland P, Knoll MD, Stamler J, Neaton JD, Dyer AR, Garside DB, Wilson PW. Major risk factors as antecedents of fatal and nonfatal coronary heart disease events. JAMA. 2003; 290(7):891-897.

11.  Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk factors, and 12–yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.  Diabetes Care.1993; 16(2):434-444.

12.  Franklin SS, Khan SA, Wong ND, Larson MG, Levy D.  Is pulse pressure useful in predicting risk for coronary heart disease? The Framingham Heart Study. Circulation.  1999; 100(4):354-360.

13.  van den Hoogen PCW, Feskens EJ, Nagelkerke NJ, Menotti A, Nissinen A, Kromhout D. The relation between blood pressure and mortality due to coronary heart disease among men in different parts of the world.  Seven Countries Study Research Group. N Engl J Med. 2000; 342(1):1-8.

14.  Rodgers A, MacMahon S. Blood pressure and the global burden of cardiovascular disease.  Clin Exp Hypertens. 1999; 21(5-6): 543-552.

15.  Wingard DL, Barrett–Connor E. Heart disease and diabetes. In: Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, and Bennett PH, eds. Diabetes in America, 2nd edition. Bethesda, MD: U.S. Department of Health and Human Services, pp. 429-448, 1995.

16.  Bierman EL. George Lyman Duff Memorial Lecture. Atherogenesis in diabetes. Arterioscler Thromb. 1992; 12(6):647-656.

17.  Herlitz J, Karlson BW, Edrardsson N, Emanuelsson H, Hjalmarson A. Prognosis in diabetics with chest pain or other symptoms suggestive of acute myocardial infarction. Cardiology. 1992;  80(3-4):237-245.

18.  Miettinen H, Lehto S, Salomaa V, Mahonen M, Niemela M, Haffner SM, Pyorala K, Tuomilehto J. Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group. Diabetes Care. 1998; 21(1):69-75.

19.  The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long–term complications in insulin–dependent diabetes mellitus. N Engl J Med. 1993; 329(14):977-986.

20.  Durrington. P. Dyslipidaemia. Lancet 2003; 362(9385):717-731.

21.  Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J, Qizilbash N, Peto R, Collins R. 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(9602):1829-1839.

22.  Neaton JD, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men. Multiple Risk Factor Intervention Trial Research Group. Arch Intern Med. 1992; 152(1):56-64.

23.  Verschuren WM, Jacobs DR, Bloemberg BP, Kromhout D, Menotti A, Aravanis C, Blackburn H, Buzina R, Dontas AS, Fidanza F, et al. Serum total cholesterol and long-term coronary heart disease mortality in different cultures: Twenty-five-year follow-up of the seven countries study. JAMA. 1995; 274(2):131-136.

24.  Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986; 256(20):2823-2828.

25.  Law MR. Lowering heart disease risk with cholesterol reduction: evidence from observational studies and clinical trials. Eur Heart J 1999; 1(Suppl S):S3-S8.

26.  People’s Republic of China–United States Cardiovascular and Cardiopulmonary Epidemiology Research Group. An epidemiological study of cardiovascular and cardiopulmonary disease risk factors in four populations in the People's Republic of China. Baseline report from the P.R.C.–U.S.A. Collaborative Study.  Circulation.  1992; 85(3):1083-1096.

27.  Law MR, Wald NJ, Wu T, Hackshaw A, Bailey A. Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study.  BMJ.  1994; 308(6925):363-366.

28.  Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation. 1995; 92(5):1355-1374.

29.  Libby P. Atherosclerosis: the new view. Sci Am. 2002; 286(5):46-55.

30.  Fuster V. Elucidation of the role of plaque instability and rupture in acute coronary events. Am. J. Cardiol. 1995; 76(9):24C-33C.

31.  Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998; 81(4A):7B-12B.

32.  Avins AL, Neuhaus JM. Do triglycerides provide meaningful information about heart disease risk? Arch Intern Med. 2000; 160(13):1937-1944.

33.  Simons LA, Simons J, Friedlander Y, McCallum J. Cholesterol and other lipids predict coronary heart disease and ischemic stroke in the elderly, but only in those below 70 years. Atherosclerosis. 2001; 159(1):201-208.

34.  Sharett AB, Ballantyne CM, Coady SA. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein (a), apolipoproteins A–1 and B, and HDL density subfractions. The Atherosclerosis Risk (ARIC) in Communities Study. Circulation 2001; 104:1108-1113.

35.  Criqui MH, Heiss G, Cohn R, Cowan LD, Suchindran CM, Bangdiwala S, Kritchevsky  S, Jacobs DR, O'Grady HK, Davis CE. Plasma triglyceride level and mortality from coronary heart disease. N Engl J Med. 1993; 328(17):1220-1225.

36.  Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, Boekholdt SM, Khaw KT, Gudnason V. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation 2007; 115(4):450-458.

37.  Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP,  Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment.  Circulation. 1992; 85(1):37-45.

38.  Havel RJ. Role of triglyceride–rich lipoproteins in progression of atherosclerosis. Circulation. 1990; 81(2):694-696.

39.  Grundy SM. Low–density lipoprotein, non–high–density lipoprotein, and apolipoprotein B as targets of lipid–lowering therapy. Circulation. 2002; 106(20):2526-2529.

40.  Krauss RM. Atherogenicity of triglyceride–rich lipoproteins. Am J Cardiol. 1998; 81(4A):13B-17B.

41.  Takeichi S, Yukawa N, Nakajima Y, Osawa M, Saito T, Seto Y, Nakano T, Saniabadi AR, Adachi M, Wang T, Nakajima K. Association of plasma triglyceride-rich lipoprotein remnants with coronary atherosclerosis in cases of sudden cardiac death. Atherosclerosis. 1999; 142(2):309-315.

42.  Karpe F, Boquist S, Tang R, Bond GM, de Faire U, Hamsten A. Remnant lipoproteins are related to intima-media thickness of the carotid artery independently of LDL cholesterol and plasma triglycerides. J Lipid Res 2001; 42(1):17-21.

43.  Abbott RD, Donahue RP, Kannel WB, Wilson PW. The impact of diabetes on survival following myocardial infarction in men vs women. The Framingham Study. JAMA. 1988; 260(23):3456-3460.

44.  Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr, Bangdiwala S, Tyroler HA. High–density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation. 1989; 79(1):8-15.

45.  Wilson PW, Garrison RJ, Castelli WP, Feinleib M, McNamara PM, Kannel WB. Prevalence of coronary heart disease in the Framingham Offspring Study: role of lipoprotein cholesterols. Am J Cardiol. 1980; 46(4):649-654.

46.  Assmann G, Schulte H, von Eckardstein A, Huang Y. High–density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis.  1996; 124(Suppl):S11-S20.

47.  Libby P, Schoenbeck U, Mach F, Selwyn AP, Ganz P. Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization. Am J Med.  2002; 104(2A):14S-8S.

48.  Stanger O, Fowler B, Piertzik K, Huemer M, Haschke-Becher E, Semmler A, Lorenzl S, Linnebank M. Homocysteine, folate and vitamin B12 in neuropsychiatric diseases: review and treatment recommendations. Expert Rev Neurother. 2009; 9(9):1393-1412.

49.  Hoffman M. Hypothesis: hyperhomocysteinemia is an indicator of oxidant stress.  Med. Hypotheses. 2011; 77(6):1088-1193.

50.  Lok A, Mocking RJ, Assies J, Koeter MW, Bockting CL, deVries GJ, Visser I, Derks EM, Kayser M, Schene AH. The one-carbon-cycle and methylenetetrahydrofolatereductase (MTHFR) C677T polymorphism in recurrent major depressive disorder; influence of antidepressant use and depressive state? J. Affect. Disord. 2014; 166:115-123.

51.  Nabi H, Bochud M, Glaus J, Lasserre AM, Waeber G, Vollenweider P, Preisig M. Association of serum homocysteine with major depressive disorder: results from a large population-based study. Psychoneuroendocrinology. 2013; 38(10):2309-2318.

52.  Wang ZM, Zhou B, Nie ZL, Gao W, Wang YS, Zhao H, Zhu J, Yan JJ, Yang ZJ, Wang LS. Folate and risk of coronary heart disease: a meta-analysis of prospective studies. Nutr. Metab. Cardiovasc. Dis. 2012; 22(10):890-899.

53.  Humphrey LL, Fu R, Rogers K, Freeman M, Helfand M. Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis. Mayo Clin Proc. 2008; 83(11):1203-1212.

54.  Ueland PM, Refsum H, Beresford SA, Vollset SE. The controversy over homocysteine and cardiovascular risk. Am J Clin Nutr. 2000; 72(2):324-332.

55.  van Guldener C, Nanayakkara PW, Stehouver CD. Homocysteine and blood pressure. Curr Hypertens Rep. 2003; 5(1):26-31.

56.  Raiko JR,  Oikonen M, Wendelin-Saarenhovi M,  Siitonen N,  Kähönen M, Lehtimäki T, Viikari J, Jula A, Loo BM, Huupponen R, Saarikoski L, Juonala M, Raitakari OT. Plasminogen activator inhibitor-1 associates with cardiovascular risk factors in healthy young adults in the Cardiovascular Risk in Young Finns Study. Atherosclerosis. 2012; 224(1):208-212.

57.  Zhuang P,  Wo D,  Xu ZG,  Wei W,  Mao HM. Dynamic changes in plasma tissue plasminogen activator, plasminogen activator inhibitor-1 and beta- thromboglobulin content in ischemic stroke. J Clin Neurosci. 2015; 22(7):1123-1127.

58.  Tofler GH, Massaro J, O'Donnell CJ, Wilson PW, Vasan RS, Sutherland PA, Meigs JB, Levy D, D'Agostino RB Sr. Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study. Thrombosis Res. 2016; 140: 30-35.

59.  Lominadze D, Dean WL, Tyagi SC, Roberts AM. Mechanisms of fibrinogen-induced microvascular dysfunction during cardiovascular disease. Acta Physiologica (Oxf). 2010; 198(1):1-13. 

60.  Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986; 2(8506):533-537. 

61.  Lind M, Boman K, Johansson L, Nilsson TK, Järvholm LS, Jansson JH. D-dimer predicts major bleeding, cardiovascular events and all-cause mortality during warfarin treatment. Clin Biochem. 2014; 47(7-8):570-573.

62.  Fruchter O, Yigla M, Kramer MR.  D-dimer as a prognostic biomarker for mortality in chronic obstructive pulmonary disease exacerbation. Am J. Med. Sci. 2015; 349(1):29-35.

63.  Nishida H,  Horio T,  Suzuki Y,  Iwashima Y,  Tokudome T,  Yoshihara F, Nakamura S, Kawano Y. Interleukin-6 as an independent predictor of future cardiovascular events in high-risk Japanese patients: comparison with C-reactive protein. Cytokine. 2011; 53(3):342-346.

64.  Reichert S, Schlitt A, Benten AC, Hofmann B, Schaller HG, Schulz S. The interleukin 6 c.-174 CC genotype is a predictor for new cardiovascular events in patients with coronary heart disease within three years follow-up. Cytokine. 2016; 83:136-138.

65.  Buraczynska M, Zukowski P,  Drop B,  Baranowicz-Gaszczyk I, Ksiazek A. Effect of G(-174)C polymorphism in interleukin-6 gene on cardiovascular disease in type 2 diabetes patients. Cytokine. 2016; 79:7-11.