Assessment of cardiovascular risk in post-menopausal women in Ghana

Introduction

Menopause is a permanent physiological state with cessation of menstruation attributable to the loss of ovarian function and reduction in the production of estrogen¹. The average age of menopause is reported to be 51 years² but the age of natural menopause may vary from 40 to 58 years. This phase is characterized by variety of changes in socio-cultural, physiological and psychological states. These changes culminate into myriad of symptoms including insomnia, sweating, hot flashes, depressive mood, vaginal dryness and general discomfort³.

Cardiovascular diseases (CVD) are the major cause of death among post-menopausal women⁴. Studies have shown that pre-menopausal women have a low risk of CVD as compared to men but after menopause the level of risk increases⁵. Epidemiological data have revealed elevated risk of CVD in post-menopausal females compared to men of the same age⁶. Estrogen is the major female hormone that regulates many aspects of a female’s development. Reduced circulating estrogen levels impeded ovulation as results of under stimulation of the hypothalamus to release follicle stimulating hormones^7,8. Estrogen is known to possess both anti-atherogenic and cardioprotective effect by maintaining high levels of high-density lipoprotein (HDL-C) coupled with decreasing low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG)⁹. Several factors, including diabetes, hypertension, and atherosclerosis among others can lead to CVD in women. The World Health Organization (WHO) has ranked CVDs as the number one cause of death, with global estimation of about 17.7 million deaths in 2015¹⁰.

Current data have shown that Castelli risk index I and II which are estimated as TC/HDL-C and LDL/HDL-C ratios respectively predict cardiovascular risk accurately than conventional lipid profile indices such as serum TC and serum triglycerides^11,12. Similarly, comparison of individual lipid ratios in subjects of the Framingham Heart Study unarguably indicates that lipid ratios are significantly more useful predictors of CVD than the individual levels of LDL or HDL¹². Many clinical studies have also made efforts to introduce better markers of atherogenic dyslipidemia that can predict the risk of CVD to be useful for evaluating response to treatment instead of the classical ratios¹³. Notable among these markers is the atherogenic index of plasma, which has proven to be a strong marker for the prediction of atherosclerosis and coronary heart disease risk¹⁴.

Menopausal health has received little attention due to high illiteracy rate, poverty and a possible lack of understanding of the clinical dynamics associated with it, irrespective of the fact that menopause is a key risk factors for dyslipidemia which affects cardiovascular health of women. Compared with men, the diagnosis of CVD in women is difficult due to hormone-related changes and difference in sex in the clinical manifestation of CVD. Such limitations and challenges present the need for an increased consciousness of the significance of CVD as a major public health issue for older women. This study therefore sought to assess the cardiovascular risk between pre and post-menopausal woman in the Cape Coast municipality by comparing the lipid profiles and other emerging biomarkers of CVD such as atherogenic index of plasma visceral adiposity index and basal adiposity index.

Methods

Results

Cardiovascular and atherogenic markers

Serum TC, TG and NON-HDL-C were significantly increased in post-menopausal women compared to pre-menopausal women (p<0.0001). In addition, there was an observed significant increase in LDL-C (p<0.0001) and VLDL (p=0.0021) levels in the post-menopausal women. In comparison with pre-menopausal women, atherogenic markers (AIP, VAI, BAI and CRI-I) were significantly elevated in post-menopausal women (p<0.0001) (Table 2).

Table 2. Comparison of Lipid profile and other atherogenic biomarkers among pre and post-menopausal women.

Variable	Pre-Menopause	Post-Menopause	P-value
TC (mmol/L)	4.130±0.4758	5.889±0.6545	< 0.0001
HDL-C (mmol/L)	1.941±0.5831	1.111±0.2106	< 0.0001
LDL-C (mmol/L)	3.036±0.6797	4.449±0.7094	< 0.0001
VLDL (mmol/L)	0.3381±0.4217	0.5043±0.1803	0.0021
TG (mmol/L)	0.576±0.2869	1.087±0.3612	< 0.0001
NON-HDL (mmol/L)	2.189±0.8091	4.778±0.7299	< 0.0001
AIP	-0.5333±0.2251	-0.02147±0.1839	< 0.0001
VAI	0.6431±0.9652	1.907±1.907	< 0.0001
BAI	28.31±6.576	31.08±4.847	0.0038
CRI-I	2.366±1.009	5.523±1.318	< 0.0001

TC, total cholesterol; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; VLDL, very low-density lipoprotein; TG, triglycerides; AIP, atherogenic index of plasma; BAI, body adiposity index; CRI-I, Castelli index I.

Higher levels of TC, LDL-C, AIP, BAI and CRI-I, as well as low levels of HDL-C, were all crudely associated with post-menopausal women (p<0.0001). However when the data was adjusted for age and BMI, only elevated levels of TC [aOR=76.58 (95%CI=5.880-2439.396), P=0.0032], LDL-C [aOR=11.76 (95%CI=1.934-90.816), P=0.011], BAI [aOR=41.19 (95%CI=6.7511-321.0692), P=0.0001], CRI-1 [aOR=818.824 (95%CI=51.900-29515.961), P=0.0001] as well as low levels of HDL-C [aOR=11.76 (95%CI=1.934-90.816), P=0.011] were significantly associated with post-menopausal women (Table 3).

Table 3. Crude and adjusted odds ratios of lipid variable and markers of atherogenicity associated with menopausal status of study participants.

Variable	Crude OR (95%CI)		aOR (95%CI)	P-value
TC
LOW	0.4286(0.01635 to 11.23)	0.7115	NA
Normal	*reference
High	474.5(59.09 to 3810)	<0.0001	76.58(5.880-2439.396)	0.0032
HDL-C
Low	24.65(7.277 to 78.69)	<0.0001	11.76(1.934-90.816)	0.011
Normal	*reference
LDL-C
LOW	6.83(0.3596 to 129.7)	0.0855	1.164×10-5(0.162- 2.022×104)	0.996
Normal	*reference
High	29.06(3.793 to 222.6)	<0.0001	16.86(1.641-433.443)	0.0343
VLDL
Normal	*reference
High	0.7396(0.1597 to 3.425)	0.6987	4.32×107(1.992×10-60-1.789×1040)	0.993
TG
Low	9.65×10-9(NA to 2.67×1071)	0.933	4.73×10-8 (2.5×10-9, 1.379×1071)	0.993
Normal	*reference
High	1.808(0.1601 to 20.42)	0.6272	15.77(0.122-15974.386)	0.336
AIP
low	0.005(0.001 to 0.02)	0.0001	0.262(0.020-3.046)	0.2885
normal	*reference
high	4.103(1.372 to 11.76)	0.0218	2.61(0.363-18.652)	0.334
BAI
low	0.4(0.07202 to 2.246)	0.2949	0.16(0.0045-39194)	0.27
normal	*reference
high	54.17(19.46 to 133)	<0.0001	41.19(6.7511-321.0692)	0.0001
CRI-I
low	0.5039(0.02176 to 11.67)	0.6654	7.02×10-6(NA-8.35×10112)	0.9965
normal	*reference
high	467.2(87.58 to 2492)	<0.0001	818.824(51.900-29515.961)	<0.0001

NA, odds ratio value not given by R statistical package; aOR, age- and BMI-adjusted odds ratio; CI, confidence interval; TC, total cholesterol; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; VLDL, very low-density lipoprotein; TG, triglycerides; AIP, atherogenic index of plasma; BAI, body adiposity index; CRI-I, Castelli index I.

In post-menopausal women, we report a positive correlation of TC with all the cardiovascular and atherogenic markers except HDL-C whilst HDL-C on the other hand showed a significant negative correlation with all the atherogenic and cardiovascular markers with the exception of BAI, which wasn’t significant (Figure 1).

Figure 1. Scatter plot and correlation matrix between lipid profile and atherogenic markers among Post-menopausal women.

Discussion

Although CVD is the major cause of death and disability in women, it usually starts about 10 years late in men of the same age. It is also true that CVD are the major cause of mortality in post-menopausal women⁴. The patterns of dyslipidemia that leads to CVD and its associated complications have been linked with hormonal changes associated with menopause. Estrogen is known to possess both anti-atherogenic and cardioprotective effect by maintaining an acceptable balance between pro/anti-atherogenic and cardiovascular risk markers⁹. We therefore sought to assess cardiovascular and atherogenic risk among pre and post-menopausal women in the Cape-Coast municipality.

In comparison to pre-menopausal women, we report elevated levels of TC (p<0.0001), VLDL, TG (p<0.0001), LDL-C (p<0.0001) and NON-HDL cholesterol (p<0.0001) in post-menopausal women. This is in line with earlier findings by Pardhe et al., who also reported significantly increased levels of TG, TC, LDL-C and reduced levels of HDL-C among Nepalese women⁴. Adverse changes in lipids and lipoprotein independent of age has been linked to mmenopause²⁰. Among all the risk factors for CVD, the major indication suggests an association of estrogen with the observed discrepancies in lipids and lipoproteins¹². Earlier studies have reported an increase in the release of free fatty acids into circulation due to high-fat accumulation leading to elevated hepatic triglycerides synthesis²¹. In addition, a reduction in estrogen after menopause increases plasma lipoprotein lipase (LPL) and hepatic TG lipase activity thereby causing accumulation of plasma LDL-C²². However, HDL-C was significantly decreased in post-menopausal women which is in tandem with the findings of previous studies^23,24. Available evidence shows that as HDL-C increases by 0.026 mmol/ml, there is a reduction in risk of cardiovascular diseases, with a 4.7% decrease in mortality rate of CVD²⁵. Changes in plasma lipid is known to partly increase the incidence of cardiovascular disease following menopausal transition^20,24.

Newly emerging atherogenic markers such as AIP, VAI, BAI and CRI-I have been used to assess cardiovascular risk and atherogenicity among various disease states including hypertension²⁶, diabetics²⁷ and among HIV patients¹¹. Our results revealed that, markers of atherogenicity including AIP (p<0.0001), VAI (p<0.0001), BAI (p<0.0038) and CRI-I (p<0.0001) were significantly increased in post-menopausal women. This is in line with a study by Nwagha et al., which reported a significantly reduced AIP levels among pre-menopausal women confirming the alteration of lipid profile in menopause²⁶. The use of lipid ratios as prognosticators of cardiovascular risk cannot be overemphasized. In fact, variations in lipid ratios such as CRI-I and CRI-II have been reported to be better predictors of risk reduction in coronary heart disease compared to the absolute lipoproteins or lipids²⁸.

Higher levels of TC, LDL-C, AIP, BAI and CRI-I as well as low levels of HDL-C were all crudely associated with post-menopausal women; however, after correction for age and BMI, AIP was not significantly associated to postmenopausal status with a marked reduction in the significance levels of the other parameters (Table 3). This confirms the significant intersection between cardiovascular risk and aging²⁹. We also report a positive correlation of TC, TG, and VLDL with atherogenic markers AIP, VAI and CRI-1 in post-menopausal women. Upsurge in the levels of TG in isolation has been shown to increase AIP in women than in men but its influence can be neutralized by the levels of HDL³⁰. Others have reported an association of CVD progression with the size of LDL-C and HDL-C, with the lesser size showing great atherogenic potential³¹. There is indeed a strong relationship between cholesterol etherification rate in HDL plasma (FERHDL) and lipoprotein particle sizes, which is considered as a risk marker of coronary artery diseases. Lately, VAI has demonstrated to be a potent marker of adipose distribution and function indirectly conveying cardiometabolic risk³². Among post-menopausal women, VAI was shown to predict cardiometabolic risk in association with visceral fat³³ while positively correlating with peripheral glucose usage during euglycemic hyperinsulinemic clamp³². Among our study population, post-menopausal women showed increased body adiposity with a high percentage of body fat than pre-menopausal counterparts. An easy but effective determination of adiposity is needed to assess the magnitude of cardiovascular disease for the development of suitable management and preventive strategies. Confirmatory studies in different ethnicities have consistently revealed the overestimation and underestimation of adiposity at low and higher body fat percentages, respectively, by BAI³⁴. Therefore, it is important to carefully interpret BAI values along with other anthropometric and cardiovascular markers.

Our results also indicated there was a significant increase in BMI, blood pressure and fasting blood sugar in post-menopausal women in contrast with pre-menopausal women. The increase may be attributed to the reduction in the production of estrogen, which may be associated with amplified cardiovascular risk in post-menopausal women. Surgical or naturally induced menopause increases the risk of CVD³⁵ and the changeover may be associated with changes in body composition, with a considerable increase in the waist-to-hip ratio during menopause coupled to a possible increase in BMI³⁶. Research has demonstrated the upsurge in the release of nitric oxide and the production of prostacyclin within the arterial endothelial cells by estrogen, culminating into the induction of a vasodilatory effect leading to a drop in BP³⁷. Furthermore, estrogen again reduces the synthesis of thromboxane A₂ by platelets with vasoconstriction properties³⁸. Hence the absence or a reduction in the estrogen levels during menopause may increase blood pressure due to an increase in peripheral resistance. Also, when estrogen production is low, there is reduced stimulation of the liver to synthesize renin. This is a rate-limiting step in the renin-angiotensin-aldosterone system leading to vasoconstriction with subsequent increase in blood pressure³⁹. On the other hand, urbanization, affluence, changing dietary habits and sedentary lifestyles can also be implicated for the above findings⁴⁰. Even though a significant association of increased cardiovascular risk with post-menopausal status was found in this study, our findings may be limited by the smaller sample size used and hence a larger sample size would have provided more stability to our conclusions.

Conclusion

Menopause could lead to changes in lipid profile in the direction of atherogenicity and increase the risk of CVDs. Atherogenic markers such as AIP, VAI, BAI, and CR can serve as potential biomarkers for predicting CVD and can be used together with other markers.

Data availability