In middle-aged women, estrogen deficiency and the high prevalence of traditional risk factors such as obesity, sedentary behavior and hypertension can cause significant changes in the cardiovascular risk profile.^{1 , 2} Although approximately 90% of these women are classified as “low risk” based on the Framingham Risk Score (FRS), events such as acute myocardial infarction and sudden death are common in this group,^{3 , 4} suggesting that traditional cardiovascular risk scores may not be accurate.^{3 , 5 - 7} Thus, variables not included in the traditional scores, such as a premature family history of cardiovascular events,^{3 , 4} exercise testing variables,^{4 , 5 - 10} and subclinical atherosclerosis markers have been considered for risk reclassification in women.^{8 , 9 , 11 , 12} In addition, a history of infarction or death from cardiovascular disease in first-degree male relatives before 55 years of age and female relatives before 60 years of age has been considered in this regard.^{1 , 10 , 13} The prevalence of subclinical atherosclerosis is found to be high in women with a family history of cardiovascular events, even in those at low risk according to the FRS.^{12 , 13}

Among the markers of subclinical atherosclerosis, coronary calcium score has been of increasing interest, especially in asymptomatic individuals deemed to be at intermediate risk by the FRS,^{3 , 14 , 15} since it is able to detect coronary calcifications that correlate with disease extent and cardiovascular events.^{16 , 17} Another marker of subclinical atherosclerosis, carotid intima-media thickness (CIMT), assessed by ultrasonography, is associated with the presence and extent of disease in both men and women, and a predictor of myocardial infarction and stroke.^{11 , 18 , 19}

Exercise testing, a non-invasive functional method established in the field of cardiology, is not only of high diagnostic value, but also of prognostic value, including in asymptomatic women.^{20 - 23} In this sense, valuable information can be obtained regarding the prediction of cardiovascular risk when exercise parameters – functional capacity, chronotropic response, chronotropic index, heart rate (HR) recovery, and ventricular ectopy after exercise – are assessed.^{24 - 30}

Studies have demonstrated the prognostic role of imaging and functional tests, alone but especially in combination, to identify which women are at greatest risk for cardiovascular events.^{31 - 33} Thus, markers of subclinical atherosclerosis and exercise testing variables may contribute to the adoption of earlier and more effective preventive measures,^{8 , 9 , 18 , 33 , 34} especially in those initially classified as low or intermediate risk by the FRS.

In this context, the purpose of this study was to reclassify the risk estimated by the FRS in asymptomatic middle-aged women with the incorporation of a premature family history of cardiovascular events, exercise testing variables, and subclinical atherosclerosis markers.

More than one-third of the middle-aged women participating in the study (mean age, 56.4 ± 4.8 years; body mass index, 27.8 ± 4.9 kg/m²) had systemic arterial hypertension, dyslipidemia, and obesity ( Table 1 ). Among them, 11.2% were diabetic and 7.7% reported smoking. Approximately 11.0% were using HR-reducing medication to control systemic arterial hypertension. In the exercise testing ( Table 1 ), mean values of maximal HR, exercise time, and VO₂ were adequate for test interpretation.

Table 1

Variable	Value (n = 509)
Age group [n (%)], years
46-55	231 (46.1%)
56-60	147 (29.3%)
61-65	123 (24.6%)
Age (mean ± SD), years	56.4 ± 4.8
BMI (mean ± SD), kg/m2	27.8 ± 4.9
Obesity [n (%)]	158 (31.1%)
Diabetes [n (%)]	57 (11.2%)
Systemic arterial hypertension [n (%)]	247 (48.5%)
Dyslipidemia [n (%)]	211 (41.5%)
Smoking [n (%)]	39 (7.7%)
Coronary calcium score (mean ± SD)	21.4 ± 89.7
CIMT (mean ± SD)], mm	0.6 ± 0.1
HR-lowering medication [n (%)]	57 (11.2%)
Exercise testing
HR response (mean ± SD), bpm	74.4 ± 13.3
Maximum HR (mean ± SD), bpm	152.5 ± 19.6
HR recovery at 1 minute (mean ± SD), bpm	130.7 ± 19.3
Chronotropic index (mean ±SD),%	88.4 ± 20.8
Decreased HR recovery at 1 minute (mean ± SD), bpm	21.8 ±9.1
Functional capacity (mean ± SD), %	104.1 ± 26.9
Exercise time, (mean ±SD), minutes	7.4 ± 2.1
VO2 (mean ± SD), METs	7.6 ± 2.0
Arrhythmia [n (%)]	43 (9.9%)

BMI: body mass index; CIMT: carotid intima-media thickness; HR: heart rate; METs: metabolic equivalents; SD: standard deviation; VO ₂ : oxygen uptake

Among the variables incorporated into the FRS for cardiovascular risk reclassification ( Table 2 ), premature family history of acute myocardial infarction and/or sudden death was the most frequent (more than one-third of participants), followed by chronotropic index, with almost one-third of participants with values below 80% or 62% (in users of HR-lowering drugs). The lowest frequency was related to ST-segment depression, observed in 22 women (4.4%), of whom only 11 (2.2% of the total sample) had a horizontal or descending pattern (>1 mm), suggestive of myocardial ischemia. According to the FRS strata, differences ( p <0.05) were observed only in the distribution of the chronotropic index and carotid calcium score.

Table 2

Variable	Framingham Risk Score*										p†
	Low		Intermediate		High		Total
	N	%	N		%	N	%	N	%
Premature family history of AMI and/or sudden death
Yes	146	37.0	13		41.9	25	37.9	184	37.4	0.856
Not	249	63.0	18		58.1	41	62.1	308	62.6
Chronotropic index
Altered (<62%‡/<80%)	104	25.9	14		45.2	22	32.4	140	28.0	0.049
Normal	297	74.1	17		54.8	46	67.6	360	72.0
Decreased HR recovery at 1 minute
Altered ( < 12 bpm)	52	12.9	5		16.7	12	17.6	69	13.8	0.520
Normal	350	87.1	25		83.3	56	82.4	431	86.2
Functional capacity
Altered (<85%)	90	22.4	8		25.8	20	29.4	118	23.6	0.430
Normal	312	77.6	23		74.2	48	70.6	383	76.4
ST-segment depression
Yes	15	3.7	1		3.2	6	8.8	22	4.4	0.157
Not	387	96.3	30		96.8	62	91.2	479	95.6
Coronary calcium score
Zero	264	76.5	13		52.0	41	71.9	318	74.5	0.022
1-99	68	19.7	8		32.0	9	15.8	85	19.9
> 100	13	3.8	4		16.0	7	12.3	24	5.6
CIMT
< 1 mm	360	89.6	27		87.1	55	80.9	442	88.2	0.120
>1 mm and/or carotid plaque	42	10.4	4		12.9	13	19.1	59	11.8

AMI: acute myocardial infarction; HR: heart rate; CIMT: carotid intima-media thickness.

As shown in Figure 1 , about 6% of the women were classified as intermediate risk by the FRS. After the variables of interest were added, the percentage of women at this stratum increased, with the highest increment (to 33.3%) after the addition of premature family history of cardiovascular events, followed by low chronotropic index (24.2%) and impairment in functional capacity (22.2%) ( Figure 1 ). Regarding the percentage of women at high risk based on the FRS (13.6% of the women), after reclassification, it increased to 14.4% with the addition of one-minute HR recovery ≤12 bpm and to 17.1% with the addition of a calcium score >0. The percentage of women at low risk based on the FRS (80.2%) decreased due to the migration of women to the strata of higher risk, from 80.2% to 50.6% when considering a premature family history of a cardiovascular event, and to 77.2% when considering the ST-segment depression.

Figure 1

FRS: Framingham Risk Score; AMI: acute myocardial infarction; HR: heart rate; CIMT: carotid intima-media thickness.

*History of acute myocardial infarction (AMI) and/or sudden death in parents and/or siblings younger than 55 years (men) or 60 years (women); †Chronotropic index <62% if using heart rate-lowering medication.

This study demonstrated that adding the variables premature family history of cardiovascular events, exercise test parameters, and markers of subclinical atherosclerosis to the FRS provided a cardiovascular risk reclassification in asymptomatic, middle-aged women. Among the seven variables used, ST-segment depression contributed to the smallest increase (3%) in cardiovascular risk when added to the FRS, while other variables like premature family history of cardiovascular events (about 30%) and altered chronotropic index (about 21%) contributed to the largest increases.

Despite the recognized importance of the FRS, studies^{3 , 27 , 29} have drawn attention to the use of some variables for reclassification of the cardiovascular risk in middle-aged women, since although most of them are classified as low risk by the FRS, some are affected by acute myocardial infarction, even without previous symptoms. Thus, for women at low or intermediate risk based on the FRS, with one or more risk factors or a positive family history, the addition of other variables to the risk score may identify and benefit those most vulnerable to cardiovascular events.³⁹

Several variables have been proposed for reclassification of cardiovascular risk estimated by the FRS,^{3 , 27 , 29} varying from simple clinical history to more complex methods that are expensive or require advanced technology, such as cardiac imaging tests. The variables analyzed in the present study were previously shown to be associated with severe outcomes,^{3 , 11 , 16 - 18 , 23 , 26 , 29} including death, acute myocardial infarction, and stroke. Five of the seven variables showed a homogeneous distribution between the FRS strata, which reinforces the possible benefit of their addition to this traditional risk score.

A premature family history of cardiovascular events in parents and siblings has been independently associated with a higher incidence of cardiovascular events, even in women classified as low risk by the FRS.^{1 , 13 , 40 , 41} This is a class I variable in asymptomatic individuals¹⁰ obtained during the initial evaluation, regardless of other exams and at no additional cost.

The predictive factors of mortality, although easily assessed in exercise testing, are not always considered important in the interpretation of the test results, including in asymptomatic women,^{26 , 29 , 42} and are not considered for primary prevention. As noted in this study, about one-fifth of asymptomatic middle-aged women would be more closely monitored for their cardiovascular risk if abnormalities in the chronotropic index or functional capacity were added to the FRS. A low functional capacity is potentially reversible by physical activity programs aimed to reduce cardiovascular risk.^{26 , 33 , 34 , 43 , 44} On the other hand, a good functional capacity is indicative of better prognosis, even in the presence of ischemia, elevated calcium score, or anatomical coronary disease.^{34 , 45 , 46} Also, the finding of a good functional capacity, can avoid the overvaluation of eventual ST-segment depression and the subsequent performance of unnecessary or even harmful exams.

In relation to the coronary calcium score and CIMT, studies^{3 , 11 , 12} have shown that they add independent prognostic information to the FRS. In the present study, the increment in cardiovascular risk by the addition of CIMT >1 mm and/or carotid plaque to the FRS was lower than that observed with the addition of a carotid calcium score >0. However, access to both tests may be costly and not possible in clinical practice. In this case, we consider the CIMT due to the higher feasibility and lack of radiation exposure.

Among the strengths of the study, our study population consisted of middle-aged women whose complaints may go unmonitored and uninvestigated, despite the increase in the prevalence and severity of cardiovascular diseases in this group.^{3 , 4 , 40} Middle-aged women have relatively low participation rates in clinical trials and scientific guidelines.^{47 , 48} In addition, we analyzed variables that are easily measured by exercise testing but not always valued in clinical practice.^{21 - 23 , 49} It should be emphasized that exercise testing is a widespread, low-cost method, that does not involve radiation, with proven accuracy in different populations, including asymptomatic women.^{20 , 24 , 30} In this study, exercise testing was symptom-limited, rather than by maximal HR, which could have underestimated functional capacity.^{29 , 30}

In the present study, we evaluated whether the addition of certain variables to the FRS would improve risk classification in asymptomatic middle-aged women, and propose that premature family history of cardiovascular events should be the first factor to be evaluated by clinicians in women classified at low or intermediate risk based on the FRS. Then, after risk reclassification, these women would undergo exercise testing and carotid artery ultrasound for assessment of markers of subclinical atherosclerosis, including the CIMT, and calcium score testing. In each stage, stricter recommendations for periodic follow-up and primary prevention strategies are recommended to early identify those women at higher risk of cardiovascular events.

This study was limited by its cross-sectional design, and the absence of monitoring the effect of adding family history, exercise testing parameters and subclinical atherosclerosis markers on cardiovascular outcomes of these women over time. However, the selection of variables for risk reclassification was based on cohort studies that evaluated severe outcomes such as death, acute myocardial infarction, and stroke.^{3 , 11 , 16 - 18 , 26 , 29} It is also worth noting that all variables used in the present study to reclassify cardiovascular risk in asymptomatic middle-aged women are currently recommended in national and international guidelines as factors for consideration in risk assessments.^{4 , 9 , 10 , 20}

In asymptomatic middle-aged women, the study revealed an increase of 3.0-29.7% in cardiovascular risk estimated by the FRS with the addition of premature family history of acute myocardial infarction and/or sudden death, mortality predictive factors assessed by exercise testing, and subclinical atherosclerosis markers. This enabled risk reclassification of women classified as low or intermediate risk based on the FRS, and the possibility for a more effective control and reduction of the risk for cardiovascular events in this group of asymptomatic women.