QT Intervals Correlate with Carotid Artery Intima Media Thickness in a Gender-Specific and Segment-Specific Manner in Asymptomatic Dyslipidemic Patients

AV: Atrioventricular
BMI: Body Mass Index
CC-IMT: Common Carotid-Intima Media Thickness
CV: Cardiovascular
CVD: Cardiovascular Disease
DBP: Diastolic Blood Pressure
ECG: Electrocardiogram
HDL-C: High Density Lipoprotein-Cholesterol
HR: Heart Rate
ICA-IMT: Internal Carotid Intima Media Thickness
IMT: Intima Media Thickness
LDL-C: Low Density Lipoprotein-Cholesterol
QTc QT: Interval Corrected
QT (B) QT: Interval Corrected with Bazett Formula
QT (F) QT: Interval Corrected with Fridericia Formula
QT (H) QT: Interval Corrected with Hodges Formula
QT (K) QT: Interval Corrected with Nomogram-Karjalainen Formula
QT (R) QT: Interval Corrected with Rautaharju Formula
QT (S-F) QT: Interval Corrected with Sagie-Framingham Formula
SBP: Systolic Blood Pressure
TG: Triglycerides
TC: Total Cholesterol

The QT interval is measured from the beginning of the QRS complex to the end of the T-wave and should be corrected for heart rate to enable comparison with reference values. QT interval physiologically differs from women and men, because of hormonal effects and gender differences in autonomic tone [1]. Many studies have suggested a relationship between prolonged QT interval with total and Cardiovascular (CV) mortality [2,3]. A dose-response relationship between longer QTc intervals and the risk of all-cause deaths have been also reported. The association was strongest in men with QTc ≥ 466 ms [HR for CV disease 4.08; 95% Confidence Interval (CI) 2.93-5.69, P<0.001], whereas in women QTc intervals ≤ 379 ms produced a HR of 1.58 (95% CI 1.20-2.09, P=0.001) for Cardiovascular Diseases (CVD) mortality [4].

Carotid artery Intima-Media Thickness (IMT), measured by B-mode ultrasound, is a well recognized subclinical marker of atherosclerosis [5]. In view of the detected correlation between QT interval changes and mortality, the use of this non-invasive marker appears to be of particular interest for the early detection and prevention of cardiovascular diseases. Festa et al., [6] first reported a significant relationship between QT interval duration and atherosclerosis in asymptomatic non-diabetic subjects. QT interval was related to IMT of Common Carotid (CC-IMT), but not to that of the Internal Carotid Arteries (ICA-IMT). The association was stronger in women than in men and was partly associated to the presence of cardiovascular risk factors. A close association between QT corrected (QTc) according to Bazett formula (B) and CC-IMT was also observed in patients with type 2 diabetes [7]. A significant correlation between QTc (B) and the right CC-IMT in obese children was also reported [8].

The influence of gender on the association between carotid IMT variables and QT or QTc intervals was investigated in healthy subjects [9]. An association between QTcs and ICA-IMT was observed in men, whereas in women a statistically significant relationship was found only between QT and CC-IMT [9].

The present study was aimed at investigating the relationship between QT interval duration, with and without correction for Heart Rate (HR) by different formulae, and carotid IMT in a population of dyslipidemic patients without cardio or cerebrovascular disease. In order to assess the role of QT as a marker of subclinical atherosclerosis potentially useful to estimate the cardiovascular risk in a gender-specific manner, all the analyses were stratified by gender.

Subjects and study design

Ultrasound examination

Assessment of cardiac repolarization

Laboratory procedures

Statistical analyses

The descriptive statistics are summarized in table 1. HR was significantly higher in women than men (67.8 ± 10.0 vs. 63.3 ± 8.9 bpm; P<0.001). Non-corrected QT wasn’t different in the two genders, but it resulted higher in women than in men. Using six QT correction formulae, QTcs were far greater in women (P<0.001). Analyzing IMT, we found segment-specific differences in the two genders: l-ICA-IMT and ICA-IMTm were smaller in women compared with men (P=0.017 and 0.031 respectively).

Figure 1: QT and QTc variations depending on carotid IMT in men after adjustment for age, BMI, SBP, DBP, HDL-C, LDL-C.

l-ICA: left Internal Carotid Artery; QTc (B): QTc-Bazett; QTc (F): QTc-Fridericia; QTc (H): QTc-Hodges; QTc (K): QTc-Nomogram-Karjalainen; QTc (R): QTc-Rautaharju; QTc (S-F): QTc-Sagie-Framingham.

Figure 2: QT and QTc variations depending on carotid IMT in women after adjustment for age, BMI, SBP, DBP, HDL-C, LDL-C.

l-CC: left-Common Carotid artery; QTc (B): QTc-Bazett; QTc (F): QTc-Fridericia; QTc (H): QTc-Hodges; QTc (K): QTc-Nomogram-Karjalainen; QTc (R): QTc-Rautaharju; QTc (S-F): QTc-Sagie-Framingham.

Covariate analysis was performed using QT and QTc as dependent variables, while carotid IMT and gender as independent variables after adjustment for age, BMI, SBP, DBP, HDL-C and LDL-C.

Significant interaction were found between l-CC-IMT, CC-IMTm and gender for QT, while l-ICA-IMT and gender for QTc (F,K,R,S-F) (Table 4). These results confirm the gender linked differences reported in the linear model analyses.

Prolonged QT interval and increased carotid IMT have been both associated with cardiovascular morbidity and mortality in epidemiological studies [5,14-20] with significant gender related differences. This was underlined in the report by Nielsen et al., where, in women, a very short QTc interval has an equivalent risk as a moderately prolonged QTc interval. A recent meta-analysis [18] showed consistent associations between prolonged QT interval and increased risk of total, cardiovascular, coronary, and sudden death mortality in the general population; not providing, however, specific gender-related comparisons. In a follow up study of a larger population of both genders [19], the same authors reported an increased mortality risk associated with both the longest and the shortest QT intervals, thus suggesting that the presence of a significant number of women may bring to light the risk of very short QTc intervals.

Besides the association with clinical outcomes, a number of studies have evaluated the association of QT intervals (corrected or uncorrected) and subclinical atherosclerosis. Strohmer et al., [9] showed crude correlations between QT or QTcs (Bazett, Fridericia, Hodges, Rautaharju and Sagie-Framingham) and ICA-IMT in healthy men, as well as a significant crude correlation between QTcs and CC-IMT. In our series of dyslipidemic patients, we observed similar results but only for QT in women (Tables 2,3(a,b)) whereas our findings confirm the correlations between QT or QTc and ICA-IMT in men (Table 2). Differently from other authors [9], we did not find any correlation between QT or QTc and CC-IMT in men. After adjusting for age (Model 1, Table 3a), in men correlations were similar to those reported by Strohmer [9], while after adjusting for other clinical and laboratory parameters (Model 2, Table 3b), we found correlations between ICA-IMT and QTc calculated according to some formulas (F,K,R,S-F), but not for QTc calculated with others (B, H) or for uncorrected QT.

Differently from Strohmer et al., [9], in the present study the two genders were more uniformly represented. In addition, we analyzed separately both right and left CC-IMT and ICA-IMT, not only the mean value of the two [9]. Finally, for the assessment of cardiac repolarization we used six correction formulae, not five.

Taken together, all of these findings indicate that the relationship between QT or QTc intervals and carotid IMT may differ between genders. The present findings, appear thus to indicate a different association between altered QT or QTc and specific arterial segments [9]. Previous data from our group indicated that the carotid IMT is best correlated to coronary IMT, as assessed by intravascular ultrasound [5]. In a recent large European study, Baldassarre et al., [20] evaluated the performance of several carotid IMT markers as predictors of cardiovascular events. They observed that CC-IMT is a better predictor of coronary events vs. ICA-IMT. In contrast, in the same study ICA-IMT was better correlated to combined or cerebrovascular events. In an earlier study by O’Leary et al., [21], on the other hand, there was the indication that, compared to CC-IMT, ICA-IMT may be a better predictor of cardiovascular but not of cerebrovascular events.

A review of several epidemiological studies has recently shown that in all eight studies reviewed CC-IMT by itself or combined with the ICA-IMT, was an independent predictor of cardiovascular events [22]. More recently Polak et al., [23] showed both CC-IMT and ICA-IMT are independent predictors of cardiovascular outcomes.

QT intervals, that reflect total duration of ventricular myocardial depolarization and repolarization, are associated with carotid IMT, thus confirming that also these variables are markers of subclinical atherosclerosis. The fact that QT intervals correlate better with common carotid IMT in women and with internal carotid arteries IMT in men suggest that gender-specific differences exist regarding carotid segment involvement. Whether these differences imply also differences in the capacity of QT intervals to predict vascular events in men and in women remains to be determined.

Log equations[RR interval (s) = 60/HR]
Bazett [QTc (B) = QT/RR interval 1/2] 
Fridericia [QTc (F) = QT/RR interval 1/3] 

Linear equations: Hodges [QTc (H) = QT + 1.75(HR-60)] 
Sagie-Framingham [QTc (S-F) = QT + 154 (1-60/HR)] 

Other equations: Rautaharju QT(R) = QT+ [410-656/ (1+HR/100)] 
Nomogram-Karjalainen QTc (N) = QT+ Nomogram correction factor

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