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. 2007 May 25;6(2):65–70. doi: 10.1111/j.1524-6175.2004.03272.x

Aortic Calcification Is Associated With Age and Sex but Not Left Ventricular Mass in Essential Hypertension

Alexandros Tsakiris 1, M Doumas 1, N Nearchos 1, A Mavrokefalos 1, N Mpatakis 1, P Skoufas 1
PMCID: PMC8109369  PMID: 14872143

Abstract

The aim of this study was to investigate the prevalence of aortic calcification in patients with essential hypertension and its relationship with age, sex, and left ventricular hypertrophy. Two hundred ninety consecutive patients with essential hypertension were studied. A chest radiograph and an echocardiograph were performed. Aortic calcification was observed in 74/290 (25.5%) patients. Patients with calcification were mostly female (67.6%) and older (71.8±1.9 years), whereas patients without calcification were younger (59.0±0.79) and of both sexes (51.85% female). Left ventricular mass index in male patients with aortic calcification was 147.3±4.32 g/m2 and without calcification was 132.7±2.28 g/m2 (p=0.023). Female patients' values were 131.9±4.32 g/m2 with calcification and 121.2±2.85 g/m2 without calcification (p=0.025). Left ventricular mass was independently associated with age and sex but not with aortic calcification. The prevalence of aortic calcification in essential hypertension is considerably higher compared to the general population. Essential hypertension and age seem to contribute to the concurrent appearance of aortic calcification and increased left ventricular mass.

In Western countries 15%–25% of the adult population has increased blood pressure. Essential hypertension is considered one of the most common risk factors for cardiovascular disease and results in increased cardiovascular morbidity and mortality, exerting a major socioeconomic impact.

Chest radiography is an extremely useful, non‐invasive screening test that is commonly performed for health risk assessment. It is inexpensive, free of side effects, and is often ordered for patients with essential hypertension because it offers a quick estimation of the heart's dimensions and uncovers lung diseases. In addition, it offers information on calcification of the aortic arch.

Several studies have shown that coronary and extracoronary calcification is related to an increased risk of cardiovascular mortality 1 , 2 , 3 , 4 because calcium deposits in the different arterial beds may indicate the extent of atherosclerosis and serve as a marker for clinical and subclinical cardiovascular disease. 5 , 6 , 7 Two recent reports have further elucidated this issue. According to the first, aortic arch calcification observed on plain chest radiography is associated with coronary artery disease independent of other conventional risk factors, suggesting that it is an important predictor of cardiovascular disease and has a prognostic value beyond other risk factors. 8 The second study confirmed these results using blinded radiologists and coronary angiography findings. 9

Echocardiography represents the most precise noninvasive tool for the determination of left ventricular mass (LVM). LVM is crucially affected by blood pressure level, and the prevalence of left ventricular hypertrophy (LVH) in hypertensive patients is significantly higher compared with that of normotensive subjects. 10 , 11 LVH has been shown to be a strong predictor of morbidity and mortality in patients with essential hypertension. 12 , 13 , 14 Furthermore, LVM is a stronger predictor of cardiovascular morbidity in hypertensive patients than blood pressure itself. 12 , 13

The aim of this study was to evaluate the prevalence of aortic arch calcification in patients with essential hypertension in a Greek population. We also investigated the relationship of aortic calcification with age, sex, and LVM in essential hypertensive patients.

METHODS

The study was conducted in accordance with the principles of Helsinki Declaration and was approved by the Hospital Ethics Committee. The study population consisted of 290 consecutive patients with arterial hypertension from our outpatient clinic. Secondary hypertension was excluded by clinical and laboratory examination. Essential hypertension was defined as the finding of blood pressure higher than 140/90 mm Hg (in accordance with the sixth report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [JNC] and World Health Organization/International Society of Hypertension guidelines, which were not changed by the JNC 7 report or European Society of Hypertension‐European Society of Cardiology guidelines) or current use of antihypertensive drugs. Patients with renal involvement were excluded from the study because renal impairment has been associated with increased frequency of aortic arch calcification. 15

Chest radiography was performed using the standard technique followed in our hospital. Chest radiographs were independently reviewed by two physicians: one radiologist who specializes in chest radiography and one experienced cardiologist who was blinded to the radiologist's opinion. In case of disagreement between observers, films were reviewed by both physicians simultaneously to reach consensus. Both observers were blinded to the results of the echocardiograph. Echocardiography was performed by an experienced cardiologist who specializes in echocardiography and was blinded to the results of the chest x‐ray. Images were obtained from parasternal long and short axis and two‐ and five‐chamber apical and subcostal views. LVM was determined using Devereux's formula (Penn convention):

LVM(g)=1.04(WSd+LVIDd+PWTd)3−LVIDd 3−13.6

where WSd is the end‐diastolic ventricular septum thickness, LVIDd is the left ventricular internal end‐diastolic dimension, and PWTd is the end‐diastolic posterior wall thickness, expressed in centimeters. Left ventricular mass index (LVMI) was determined by correcting LVM to body surface.

STATISTICAL ANALYSIS

Results are expressed as mean value±standard deviation (SD) or standard error (SE), as indicated. Statistical analyses were carried out using the Student t test to compare means and χ2 to compare proportions. Multiple regression analysis was used to evaluate the independent associations of LVMI with different variables. Changes were considered statistically significant if p<0.05. Data were processed using the STATISTICA (version 5.0, Statsoft, Inc., Tulsa, OK) statistical program for Windows.

RESULTS

Essential hypertension patients were 30–90 years old (62.3±12.6 [SD]) and mostly female (162/290 or 55.9%). Calcification of the aortic arch was observed in 74 out of the 290 patients with essential hypertension (25.52%) whereas no signs of calcification were found in the remaining 216 subjects (Figure 1). The age of patients with aortic calcification was 71.8±1.19 (SE) years, ranging from 46 to 90 years, while patients without calcification tended to be much younger (59.0±0.8 years [SE]), ranging from 30 to 82 years, p=0.0001. Patients with calcification of the aorta, apart from being older, were mostly female (67.57% vs. 32.43%), while patients without calcium deposition were almost equally of both sexes (51.85% female vs. 48.15% male), χ2=5.52; p=0.019 (Figure 2). All chest radiographs were read independently by both observers. The agreement between the two observers regarding the presence or absence of calcification reached 94%, a high inter‐reader reliability.

Figure 1.

Figure 1

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Aortic calcification (AC) in patients with essential hypertension by prevalence and age

Figure 2.

Figure 2

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Female predominance of aortic calcification (AC) in patients with essential hypertension

The ratio of LVM to body surface area (BSA) was 136.9±3.62 g/m2 in patients with aortic calcification, while patients without calcification of the aortic arch had a ratio of 126.8±1.88 g/m2; the difference was statistically significant (p=0.009). In male patients with aortic calcification, LVM/BSA was 147.3±4.32 g/m2, while in patients without calcification LVM/BSA was significantly lower: 132.7+2.28 g/m2 (p=0.023, Figure 3). Female patients with calcification had a ratio of 131.9±4.32 g/m2, while patients without calcification had a significantly lower ratio of 121.2±2.85 g/m2 (p=0.025, Figure 4). There were no statistically significant differences between patients with and without calcification regarding the use of antihypertensive medication, the different classes of drugs, and the percentage of patients on monotherapy or combination therapy (factors that could influence LVM).

Figure 3.

Figure 3

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Left ventricular mass index in male hypertensive patients with and without aortic calcification (AC)

Figure 4.

Figure 4

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Left ventricular mass index in female hypertensive patients with and without aortic calcification (AC)

Although essential hypertensive patients with aortic calcification had greater LVMI, when multiple regression analysis was used evaluating the dependence of LVMI on aortic calcification, age, and sex, it was found that only age and sex were independently associated with LVMI; aortic calcification was not. Specifically, multiple regression analysis (F [11.21]; p<0.000001) revealed that LVMI was independently associated with age (β=0.215; R 2=0.216; t=3.41; p=0.0007) and sex β=−0.246; R 2=0.045; t=−4.31; p=0.00002), whether or not an independent association was found with aortic calcification β=−0.093; R 2=0.196; t=−1.48; p=0.14). Figure 5 shows in scatterplot diagram the relationship between LVMI and sex, age, and aortic calcification.

Figure 5.

Figure 5

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Association of left ventricular mass index (LVMI) with age, sex, and aortic calcification in patients with essential hypertension. White circle=men without calcification; black circle=men with calcification; white triangle=women without calcification; black triangle=women with calcification

DISCUSSION

Aortic arch calcification was observed in 26% of patients with essential hypertension in our study. This prevalence was extremely higher compared with that found in the general population in a previous large‐scale retrospective study (1.9% of men and 2.6% of women). 8 However, even in that study patients with calcification of the aortic arch were more likely to have hypertension than those without such calcification. The prevalence of aortic arch calcification may be extremely high in high‐risk patients, such as patients undergoing coronary angiography. In a recent study by Li et al., 9 360 out of 654 (55%) consecutive patients undergoing coronary angiography at their institution were found to have calcification of the aortic arch. In patients with hypertension compared with normotensive subjects, a higher prevalence of coronary calcification was found and a larger amount of coronary calcium deposit was observed. 16 This observation, along with the findings of our study, suggests that high blood pressure predisposes to calcification of the aortic arch and coronary arteries.

Atherosclerotic vascular disease is a diffuse process, which explains the association between aortic and coronary artery atherosclerosis. Several studies have demonstrated an association between atherosclerosis of the aorta and coronary heart disease. 17 , 18 Furthermore, aortic atherosclerosis was predictive of obstructive coronary artery disease, even after adjustment for conventional coronary heart disease risk factors. 17 , 18 Finally, atherosclerosis of the aorta has been found to be associated with cerebrovascular ischemic events in autopsy, 19 case‐control, 20 and prospective echocardiographic studies, 21 and more importantly this association is related to the presence of risk factors such as age and hypertension. 22 , 23

The observation that hypertension promotes vascular calcium deposits, an anatomic marker of atherosclerosis, indicates that hypertension plays a crucial role in the pathogenesis of cardiovascular disease. There seems to be a complex interrelationship between hypertension, calcification, and vascular atherosclerosis. Atherosclerosis may be induced by arterial wall trauma caused by the rise of arterial pressure and shear stress alterations. 24 In addition, atheroma calcification represents an active process with several substances interacting and contributing to the final result. Osteopontin, a protein involved in bone metabolism and mineralization, holds an important place in the calcification process 25 and extensive expression of its gene may be induced by arterial wall trauma and the subsequent mediators. 26

Calcification of the aortic arch was found to be age and sex related in our study because it was more common in women than in men and more frequent in older than younger patients with essential hypertension. This finding is in line with prior studies that reported similar results in different groups of patients. 8 , 27 , 28 Several hypotheses can be made to explain the sex relationship. First, essential hypertensive men with aortic arch calcification may have died at an earlier age than women with such calcification, offering a selective survival to female patients, or the sex association may be due to technical aspects of chest radiography testing, because it could be easier to observe aortic arch calcification in women than in men due to different body composition. However, this doesn't seem very likely because radiologists are aware of this issue and make the necessary adjustments. Finally, it can be suggested that aortic arch calcification reflects a redistribution of calcium metabolism from bone to vessel wall. Osteoporosis is commonly found in elderly women, and coronary and aortic calcification are related to menopause 29 and metacarpal bone loss during menopause. 30

Bone mineralization and atherosclerotic calcification have striking similarities. Hydroxyapatite is the mineral found within calcified atherosclerotic plaques and in bones, 31 while matrix vesicles (the initial nucleation sites for hydroxyapatite mineral in bones) are also present in atherosclerotic lesions. 32 Osteoblasts show significant similarities with calcifying vascular cells, 33 and several peptides involved in bone formation have been found within atherosclerotic plaques. Several factors are involved in arterial calcification, such as bone matrix proteins (type‐I collagen, 34 osteopontin, 31 and osteocalcin 35 ), whereas within lesions the morphogenetic protein 2a (a bone differentiation factor) has been demonstrated. 36

Aortic calcification and osteoporosis during menopause may result from a common etiologic factor, such as estrogen deficiency, parathyroid hormone, oxidized lipids, or inflammation. Bones and arteries represent target organs for estrogen, and estrogen receptors have been found on osteo‐blasts and osteoclasts in bones 37 , 38 and on arterial smooth muscle and endothelial cells in vessels, 39 suggesting that estrogen exerts a direct effect on bone and vascular cells. Parathyroid hormone is involved in calcium metabolism and its levels increase with age. 40 Hyperparathyroidism may contribute to bone loss 41 and result in arterial calcification through calcium deposition to soft tissues. Oxidized lipids may be another contributing factor, since it is known that they inhibit the differentiation and the mineralization of bone cells 42 and promote atherogenesis as well. 43 Cytokines and inflammatory agents (interleukin‐1, interleukin‐6 and tumor necrosis factor) may be produced by estrogen deficiency, 44 and inflammation may contribute to bone resorption 45 , 46 and play an important role in the atherosclerotic process. 47

LVH is believed to be a compensatory phenomenon in response to an increased cardiac workload imposed by hypertension. LVH is now considered an independent risk factor for coronary heart disease. There appears to be a continuous, graded relationship between LVM and the development of cardiovascular disease, with no discernible critical cut‐off point separating postulated compensatory from pathologic hypertrophy. 12

In our study, LVM was age and sex dependent in patients with essential hypertension, as expected based on the results of previous studies. The prevalence of LVH increases progressively with age. In the Framingham study, LVH prevalence increased from 7% in subjects under age 30 years to 40% in persons over age 70 years. 10 The upward trend of LVH with age persists even after adjustment for blood pressure and weight, but is markedly influenced by these variables.

In our study of essential hypertensive patients, those with aortic calcification tended to have greater LVM. However, LVM was independently associated with age but not with aortic calcification. This finding underlines that aging and hypertension may be the common underlying mechanisms for the development of aortic atherosclerosis and LVH because both aging and hypertension promote atherosclerosis and the increase of LVM. It seems that calcification of the aorta and LVH follow a parallel process, which leads to their concurrent occurrence, due to the same underlying factors.

The results of our study are in contrast to a recently published report that stated that aortic calcification was independently associated with LVH in patients on maintenance hemodialysis. 48 This discordance could be explained by different study populations because the independent association was found in patients with chronic renal failure on hemodialysis, while our study group consisted of patients with essential hypertension without renal impairment. LVH in chronic renal failure may be developed through pressure and flow/volume overload by overhydration, anemia, and the arteriovenous shunt (in addition to age and hypertension). 49

The prevalence of aortic calcification in patients with essential hypertension is considerably higher when compared with the general population and is age and sex (female) dependent. Essential hypertensive patients with aortic calcification tend to have greater LVM, and LVH may, at least in part, contribute to the increased risk for coronary heart disease in patients with aortic calcification. Essential hypertension and age seem to be the underlying factors for the concurrent occurrence of aortic calcification and increased LVM.

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