THE RELATIONSHIP BETWEEN VASCULAR RISK FACTORS, CALCIFICATIONS AND DEGENERATIVE VALVULAR LESIONS IN WOMEN
Received for publication: 11th of December, 2005
Revised: 21st of February, 2006
SUMMARY: (Hide the summary)
It is well known that the rate of cardiovascular diseases in women is high in Romania. Therefore, in the Cardiology Clinic we studied the classic risk factors in women (hypertension, diabetes mellitus, menopause, hypercholesterolemia, obesity, depression) and their relationship with degenerative aortic and mitral lesions, especially calcifications, considered as markers of atherosclerosis. These parameters were studied in 403 women with vascular pathology - coronary artery disease (n=355) (CAD) and in 48 women with CAD associated with cerebrovascular disease or peripheral arterial disease. We found a high rate of occurrence of aortic ectasia (18,75%) in the group aged 40-54, aortic root calcification (21,6% between 45-49 years and 33% over 70 years) and aortic or mitral valve sclerosis (13,12% over 75 years). Metabolic abnormalities were more frequent between in hypertensive women aged 55-59; cholesterol level and family history represented high risk factors until the age of 75..
risk factors, aortic calcifications, women
The importance of atherosclerosis risk factors is indisputable. On the one hand the evidence of a systemic disease is given by studies about the association of coronary and vascular pathology proved sometimes by very simple diagnosis tests (e.g. ankle-arm index in asymptomatic patients) (1). On the other hand, the presence of degenerative lesions, like aortic valves sclerosis, mitral annulus calcification or aortic root atheromatosis has been associated with aortic atheromatosis, with significant sensibility, specificity and predictive value, especially in men (2).
The vascular pathology has increased the mortality rate in women with 46% over the last years and the mortality rate is still high in our geographic area (3). This fact determined us to study women with vascular pathology, to examine the associated risk factors and their relationship with echocardiographic lesions..
Matherial and method
We studied 712 women hospitalized during the last 12 mWe studied 712 women hospitalized over the last 12 months in Cardiology Clinic. Among the 403 women with vascular pathology, 355 were diagnosed with coronary heart disease (CAD) and 48 women had associated vascular determinations: neurological - 35 cases (72,9%), peripheral vascular pathology - 10 cases (20,8%) and 3 patients (6,25%) had plurivascular disease.
The female patients were grouped by age. We studied the following risk factors:
- anamnesis factors: family history, onset of menopause, presence of depression or anxiety, previous and current smoking;
- objective factors: body mass index (BMI), systolic (SBP) and diastolic blood pressure (DBP)
- biological factors: the cholesterol level (COL), triglycerides (TG), serum glucose (SG), leucocytes count.
We measured aortic root diameter, noticed the presence of aortic root calcifications, degenerative valvular lesions and calcifications of mitral annulus, using VINGMED CFM-800 echocardiography unit. Two echo cardiologists read the TTE studies. We defined aortic root calcification as a focal area of increased echogenity and thickening in the aortic root, in the parasternal long-axis view, aortic valve sclerosis as a focal area of increased echogenicity and thickening of the aortic valve leaflets. Mitral annulus calcification was defined as an intense echo-producing structure located at the junction of atrioventricular groove with posterior mitral valve leaflet, in the parasternal axis or apical four chambers. Mitral valve sclerosis was defined as a focal area of increased echogenity and thickening of the mitral leaflets.
Differences in the distribution of continuous variables were assessed with the t test. Comparisons between categorical variables were made using c2 test; differences were significant at p<0.5. Stepwise regression techniques were used to investigate the effects of risk factors.
The analysis was performed with Graph Pad InStat Software.
In CAD patients group we found an incidence peak at 50-54 years group followed by a decrease and then by a progressive increase to another peak over 75 years. Family history as a risk factor was noticed in 25-68,75% cases and it seems to be important for the patients aged under 50 (see table I). Menopause started in women in the age interval 40-55 and it was earlier in women with coronary heart disease under 49 (even if the data has no statistical significance). Incidence of diabetes mellitus increased with ageing. Anxiety or depression was diagnosed in a higher proportion in women aged fewer than 49.
5% of the female patients were current smokers and 2,5% were previous smokers.
Blood pressure was increased in all groups and it had two frequency peaks, SBP in 70-74 years group and both SBP and DBP in 45-54 years group. (see table 2).
Glucose levels are not excessively high, but cholesterol was increased, particularly over 40 years and the peak incidence of triglycerides was in the age interval 45-64.
In spite of the fact that triglycerides and SBP levels were higher there were no particular findings in women with plurivascular pathology, except old age women. Statistical data could not find significant correlation between studied parameters (see Table 3).
Regarding echocardiography findings in CAD women belonging to the age interval 50-59, increased aortic root diameter was reported; aortic root calcifications were noticed especially in the 45-59-age interval. Valvular degenerative lesions and calcifications of mitral annulus increased progressively with ageing (see Table 4). Degenerative lesions were predominant (45,38%) in women with plurivascular pathology; aortic root calcifications (20,8%) were as frequent as those present in CAD patients. In the same time the aortic root exceeded 30 mm in diameter in 4% of patients with plurivascular pathology, and it was less frequent than in isolated CAD women (Fig.1).
Statistically speaking, Romania is placed among countries with important mortality caused by cardiovascular diseases 734,0%o, in comparison with Poland (506,2), Russia (662,1) and Hungary (727,9). (3). We raise the following matter: are there any particularities and if there are any, can we modify them?
Age seems to be one of the most important risk factors. Old age particularities were at least partially connected with women's hormonal status. The possible connection between morbidity peak in women aged 50 and early onset of menopause is a debatable issue.
The 17-beta-estradiol vasoprotector effect irrespective of expression inducible oxide synthase has been demonstrated for carotid artery (4) or on vascular endothelium by Fas-ligand expression regulation. (5).
Obesity seems to be important especially under the age of 59 (28,1-41,66%); however diet improvement could reduce morbidity (although the data is contradic-tory)(18).
Elevated systolic and diastolic blood pressure levels do not seem to be a particularity; the Framingham study has shown an increase of the cardiovascular risk with 1,68, respectively 1,83 (6).
Hypercholesterolemia has a high rate of occurrence starting with the age of 40. The mechanism of hypercholesterolemia seems to induce an irreversible vascular dysfunction by soluble guanylyl cyclase (sGC)(7) or by small particles of LDL cholesterol that can alter endothelial function independently by HDL and total cholesterol level, as described in men (8). The relationship between LDL cholesterol and aortic atheromatous lesions was also described (9). A systematic assessment is necessary in order to treat hypercholesterolemia and the low HDL cholesterol level. In female patients with hypercholesterolemia and early menopause, lipid-lowering therapy (statines) is indicated, and as for estrogen replacement therapy, it is still a debatable recommendation. Statines could neutralize the increase of inflammatory parameters induced by estrogen. (11) Hypertrygliceridemia seems to be specific for vascular pathology in women, taking into account that demographical studies had established an increased risk by 76% in women, in comparison to 31% in men (12).
The high rate of incidence of the three important risk factors: high blood pressure, dislipidemia and obesity can be explained by a rich in fats and salt diet and also by the daily stress (despite that declared psychic disorders are not frequent).
Diabetes mellitus is considered a major parameter irrespective of other risk factors (13), which affects endothelium; in our statistic its incidence is directly proportional to age.
Unlike some medical findings (15), leukocytes count, as an inflammatory parameter was not correlated with the severity of pathology.
Smoking and documented depression incidence in our patients was low: 5%, respectively 6%, so we cannot take into account smoking (16) and depression effects in coronary artery disease progression. (17).
Echocardiography results seem to confirm studies showing the specificity of calcium deposits for the severity of vascular lesions especially in women (57% women vs. 46% men) (19).
Degenerative aortic and mitral valve lesions are more frequent in plurivascular pathology (in Jeon Doo-Soo opinion these could be a marker in plurivascular lesions.)
(20). The presence of aortic root calcifications in a large group of patients suggests their role in producing complications. (21). Aortic root diameter is frequently increased in women with CAD and there is a strong correlation between aortic root diameter, brachial artery diameter and CAD (22).
- Age and increased systolic and diastolic blood pressure values are essential factors in isolated coronary artery disease or in associated vascular disorders.
- The coronary pathology of studied women has two morbidity peaks: a) in the age interval 50-54, characterized by high diastolic blood pressure, high body mass index and high number of triglycerides and b) over the age of 75 characterized by aortic ectasia, when age itself seems to be an isolated risk factor.
- Cholesterol values and family history are high risk factors until the age of 74.
- Degenerative valve lesions are more frequent in older age patients and in those with associated vascular pathology.
- Aortic diameter over 30 mm is more frequent in patients suffering from coronary artery disease.
- Correct control of blood pressure in women with family history, statines associated or no with substitutive hormonal therapy could be a solution for decreasing the incidence of clinical and sub clinical coronary artery disease in women from our geographic region.
1. Pearson TA. New Tools for Coronary Risk Assessment-what are their Advantages and Limitations. Circulation 2002; 105;886-892.
2. Kirsten Tolstrup, Carlos A Roldan, Clifford R Quarls, Michael H Crawford. Aortic valve sclerosis, mitral annular calcium and aortic root sclerosis, as markers of atherosclerosis in men. Am J Cardiol 2002; 89; 1030-1034.
3. *** Epidemiological essential descriptive data of cardiovascular diseases in Romania. Romanian Ministry of Health-Cardiology Committee.
4. Tolbert Todd, Thompson A, Bouchrd P, Oparel S. Estrogen induced vasoprotection is independent of inducible nitric oxide synthesis expression. Circulation; 2002; 104; 2740-2745
5. Amant Carole, Holm P., Xu Shu-Hua, Tritman M., Kearney M., Losardo DW. Estrogen receptor-mediated, nitric oxide-dependent modulation of the immunologic barrier, function of the endothelium. Circulation; 2001; 104; 2576-2581
6. Vasan RS, Massaro JM, Nelson PW, Seshandri S, Wolf PA, Levy D, D’Agosto RB. Antecedent blood pressure and risk of cardiovascular disease-The Framingham Study. Circulation; 2002; 105; 48-53
7. Laser Ute, Koser T, Schmitz V, Schrammel A, Meyer W, Mayer B, Weser M, Kojda G. Effect of hypercholesterolemia on expression and function of vascular soluble guanylyl cyclase. Circulation; 2002; 105; 855-860
8. Vakkilainen Juha, Makimattila S, Seppalla-indroos A, Vehkavaara S, Lahdenpera S, Groop PH. Endothelial dysfunction in men with small LDL particles. Circulation; 2000; 102; 716-721
9. Trisouilloy CM, Pettier M, Iannetta-Pettier MC, Zhu Z, Andrejak M, Leshire JP. Relation between low-density lipoprotein cholesterol and thoracic aortic atherosclerosis. Am J Cardiol; 1999; 84,1; 603-605
10. Rader Daniel J. Pathophysiology and management of low high-density lipoprotein cholesterol. Am J Cardiol; 1999; 83; 22F-24F
11. Kon Koh Kwang, Schenke WH, Waclawiw MA, Csako G, Cannon RO. Statin attenuates increase in C-reactive protein during estrogen replacement therapy in postmenopausal women. Circulation; 2002; 105; 1531-1533
12. Austin Melissa A. Epidemiology of hypertriglyceridemia and cardiovascular disease. Am J Cardiol 1999; 83; 13F-16F
13. Hoogwerf BJ, Sprecher DL, Pearce GL, Acevedo M, Frolkis JP, Foody JM, Cross JA, Pashkow FJ, Robinson K, Vidt DG. Blood glucose concentrations£125 mg/dl and coronary heart disease risk. Am J Cardiol; 2002; 89; 1; 596-598
14. Kawano H, Motoyama T, Hirashima O, Hirai M, Miyao Y, Sakamoto t, Kugiyama K, Ogawa H, Yasyue H. Hyperglycemia rapidly suppresses flow-mediated endothelium-dependent vasodilatation of brachial artery. J Am Coll Cardiol; 1999; 34; 146-154
15. Bickel C, Rupprecht HJ, Blankenberg S, Espiniola-Klein C, Schlitt A, Roppin G, Hafner G, Treude R, Oshman H, Hoffman KP, Meyer J. Relation of markers of inflammation (C-protein, fibrinogen, von Willebrand factor and leukocyte count) and statin therapy to long-term mortality in patients with angiographicaly proven coronary artery disease. Am J Cardiol; 2002; 89; 901-908
16. Santo-Tomas M, Lopez-Jimenez F, Machado H, Aldrich HR, Lamas GA, Liebermann EH. Effect of cigar smoking on endothelium-dependent brachial artery dilation in healthy young adults. Am Heart J; 2002; 143; 83-86
17. O’Connor CM, Gruisel PA, Serebruany VL. Depression and ischemic heart disease. Am Heart J; 2000; 140; S63-9
18. Hu FB, Stamper MJ, Manson JE, Grodstein F, Colditz GA, Speizer FE, Willett W. Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women. N.Engl.J.Med; 2000; 343; 8; 530
19. Budoff MJ, Shokooh S, Shavelle RM, Kim T, French WJ. Electron beam tomography and angiography: sex differences. Am Heart J; 2002; 143; 877-82
20. Jeon Doo-Soo, Atar S, Brach AV, Luo H, Mirocha J, Magvi TZ, Kraus R, Berman DS, Siegel RJ. Association of mitral annulus calcification with abnormal myocardial perfusion single photon emission topography in subjects age£65 years old. J Am Coll Cardiol; 2001; 38; 1988-93
21. Tunnick PA, Konzon I. Atheromas of the thoracic aorta clinical and therapeutic update. J Am Coll Cardiol; 2000; 35; 545-54
22. Holubkov R, Karas RH, Rickens CR, Reichek M, Rogers WJ, Sharaf BI, Sapko G, Merz CM, Kelsey SF. Large brachial artery diameter is associated with angiographic coronary artery disease in women. Am Heart J; 2002; 143; 802-7