Parental Longevity, Carotid Atherosclerosis, and Aortic Arterial Stiffness in Adult Offspring
Background and Purpose— We examined the associations of parental longevity with carotid intima-media thickness, carotid plaques, and aortic arterial stiffness in adult offspring.
Methods— A population of 1117 volunteers who participated in the SUVIMAX Vascular Study (mean age, 59.7 years; 49.0% women) were included. Carotid-femoral pulse-wave velocity (PWV) was used to assess aortic stiffness. Carotid B-mode ultrasound examination included measurements (at sites free of plaque) of intima-media thickness at the common carotid arteries and assessment of atherosclerotic plaques in the extracranial carotid arteries.
Results— The prevalence of carotid plaques in subjects whose fathers had died at <65 years, in those whose fathers were alive at 65 years but who had died by 80 years, and in those whose fathers were alive at 80 years was 40.4%, 30.4%, and 28.9%, respectively (P<0.001). The multivariate odds ratios of carotid plaques in the 3 groups of paternal longevity, adjusted for conventional cardiovascular risk factors, were 1, 0.68 (95% CI, 0.48 to 0.96), and 0.69 (95% CI, 0.49 to 0.98), respectively. The mean common carotid arteries intima-media thickness was higher in subjects with premature paternal death in univariate (P<0.007) but not in multivariate (P=0.39) analyses. Mean PWV decreased with increasing paternal longevity in both univariate and multivariate analyses. The multivariate-adjusted means of PWV in the 3 groups of paternal longevity were 11.9±0.14, 11.7±0.12, and 11.0±0.12 m/s (P<0.0001), respectively. In contrast, neither B-mode ultrasound measurements nor PWV measurements were associated with maternal longevity.
Conclusion— These results may indicate that there are modifications of structure and function of large arteries according to paternal longevity.
Afamily history of premature coronary heart disease (CHD) is a well-known risk factor for subsequent coronary disease in the offspring.1 Less attention has been paid to study the effects of parental longevity on cardiovascular and all-cause mortality in sons and daughters, but the results of studies that have assessed this issue have suggest that longevity predicts CHD in offspring.2,3 However, the underlying mechanisms are not known. Vascular alterations, including atherosclerosis and arterial stiffness, might be involved.
Atherosclerosis is obviously the main underlying pathology of ischemic cardiovascular diseases. B-mode ultrasound of carotid arteries is a noninvasive, valid, and reproducible method for directly visualizing and assessing carotid structure (intima-media thickness [IMT] and focal atherosclerosis plaques).4,5
The arterial system serves as a “cushion” to buffer the pulsatile pressure and flow from the heart. The viscoelastic properties of large arterial walls are a major determinant of the speed of propagation of the arterial pressure wave, of the timing of wave reflection, and of cardiovascular hemodynamics.6,7 In a previous article, we reported an accelerated progression over time of systolic blood pressure (SBP) and pulse pressure in the offspring of fathers with premature death, suggesting that the age at death of fathers might predict in the offspring the degree of large-artery stiffness.8 It has been shown that the noninvasive measurement of carotid-femoral pulse-wave velocity (PWV) is an easy, safe, and reproducible method of assessing aortic arterial stiffness.9
In the present report based on cross-sectional data from the SUpplémentation en VItamines et Minéraux AntioXydants (SUVIMAX) Vascular Study, we assessed the associations of parental longevity with carotid IMT, carotid plaques, and aortic stiffness in a population of 1117 middle-aged subjects.
Subjects and Methods
The design and methods of the SUVIMAX Vascular Study as well as characteristics of the participants have been described in detail elsewhere.10 In brief, this study is a substudy of the SUVIMAX Study, which is a randomized, double-blind, placebo-controlled, primary prevention trial undertaken to determine whether supplementation with antioxidant vitamins and minerals can reduce the incidence of cancers and cardiovascular diseases, with a follow-up of 7.2±0.3 years.11
The SUVIMAX Vascular Study took place during the end-trial visit (between January and July 2002). The eligible subjects for this specific substudy were participants living in the Paris area, aged >50 years in 2002, whose end-trial visit was schedule to take place at 1 facility (CNAM Center). These subjects were blindly examined according to their assigned intervention group (supplementation or placebo). Detailed cardiovascular risk factor assessment, carotid ultrasound examination, and PWV measurement of this substudy protocol were added to the standard measurements performed during the end-trial visit. All subjects gave their informed, written consent to the study, which was approved by the local medical ethics committee, Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale. All data shown in this report were cross-sectional and obtained from the end-trial visit.
Risk Factor Assessment
Participants were asked through a standardized questionnaire to provide information about demographic background, occupation, medical history, and personal habits. The body mass index (BMI) was computed as weight (in kilograms) divided by height (in meters) squared. Subjects were classified as never-smokers, former smokers, or current smokers.
BP was measured with a digital electronic tensiometer (model CP750, Omron), and the average of 2 measurements was used in the statistical analyses. Subjects who reported having a medical history of using antihypertensive drugs or subjects who had an SBP ≥140 mm Hg or a diastolic BP ≥90 mm Hg were considered hypertensive. Mean arterial pressure and pulse pressure were calculated according to the following formula: Mean arterial pressure= 2/3BP+1/3 SBP, and pulse pressure=SBP−diastolic BP. Hypercholesterolemia and diabetes were defined as previously reported.10
At the end-trial visit, subjects were also administered a standardized questionnaire about parental history. The subjects were asked, in separate questions, whether their mothers and fathers were still alive and their ages. If the parents were deceased, the subjects were asked at which ages they had died.8 It was found that 84.6% of the fathers and 59.1% of the mothers were deceased. The mean age at death for fathers was 70.7 (±13.8) years, and the mean age of those still living was 84.0 (±5.6) years. The corresponding figures for mothers were 74.3 (±14.5) years and 83.1 (±5.5) years, respectively.
For the present analysis, we classified the subjects into 3 groups according to the ages of their parents (at death or current age). Paternal and maternal longevity classes were analyzed separately. Premature death of parents was defined as a paternal (or a maternal) death at an age <65 years. A paternal (or maternal) current age or death at an age >80 years was considered to represent increased paternal (or maternal) longevity. The intermediate group included subjects whose fathers (or mothers) were alive at 65 years but deceased by 80 years. The subjects whose parents were still alive and aged between 65 and 80 years (52 fathers and 126 mothers) were excluded from the analyses, because their parents might live longer than 80 years and therefore could not be classified in the intermediate group.
Carotid Ultrasound Examination
Ultrasound examinations were performed by 2 technicians with the use of an Aloka SSD-650, with a transducer frequency of 7.5 MHz. Acquisition, processing, and storage of B-mode images were computer assisted with the new version of specific software (M’ATHS).12 The protocol involved scanning of the common carotid arteries (CCAs), the carotid bifurcations, and the origin (first 2 cm) of the internal carotid arteries. The presence of plaques was defined as previously reported.10,12
For IMT measurements, the far and near walls of the right and left CCAs 2 to 3 cm proximal to the bifurcation were imaged. For each side, at least 3 optimal longitudinal images with the best visualization of far and near walls were frozen, transferred to a computer (IBM PC), digitized into 640×580 peak cells with 256 gray levels, and stored for off-line analysis.
All measurements were performed by 1 experienced sonographer. The IMT was measured at a site free of any discrete plaques along a 10-mm-long segment of the far wall of the CCA and measured as the distance between the lumen-intima interface and the media-adventitia interface with use of an automated edge-detection algorithm. A mean of 50 measurements was automatically performed on each image (3 images per side) and on each side (left and right). The mean of the 6 right and left CCA-IMT measurements was used in the analysis.
Two pressure waves were recorded transcutaneously at the base of the neck for the right CCA and over the right femoral artery. PWV was determined as the foot-to-foot velocity. Pulse transit time was determined as the average of 10 consecutive beats. The distance traveled by the pulse wave was measured over the body surface as the distance between the 2 recording sites. Aortic PWV was calculated with an automatic device (Complior, Colson) as the ratio of distance to transit time. The results of the reproducibility study of carotid ultrasound and carotid-femoral PWV, conducted in 80 subjects, were acceptable.10
Standard procedures from the Statistical Analysis System (SAS, Cary, NC) were used for univariate and multivariate analyses. The associations of carotid plaques (presence/absence) with parental longevity groups were assessed by χ2 for univariate analysis and by multiple logistic-regression models for multivariate analysis. The associations of PWV and CCA-IMT (used as continuous variables) with parental longevity groups were assessed by ANOVA for univariate analysis and ANCOVA for multivariate analysis. Multivariate associations were adjusted for the variables listed in the footnotes to Tables 2 and 3⇓. Of the 1162 subjects included in the SUVIMAX Vascular Study, complete data on parental longevity and cardiovascular risk factors were available for 1117 subjects.
The main characteristics of the participants are presented in Table 1. The mean age of the participants was 59.7 years (±4.7). The mean CCA-IMT was 0.71±0.08 mm for men and 0.69±0.07 mm for women (P<0.001); mean PWV was 12.0±2.7 and 10.9±2.2 m/s (P<0.0001), respectively; and the proportions of subjects with plaques were 41.4% and 22.5% (P<0.0001), respectively. CCA-IMT, PWV, and carotid plaques were positively associated with age, BMI, SBP, and pulse pressure and negatively associated with HDL. Hypertensive subjects had a higher mean PWV than did subjects without hypertension (12.3±2.8 versus 10.8±2.1 m/s, P<0.0001). Subjects with carotid plaques had a higher mean CCA-IMT (0.73±0.08 versus 0.69±0.07 mm, P<0.0001) and a higher mean PWV (12.1±2.7 versus 11.2±2.4 m/s, P<0.001) than did subjects without plaques.
After the exclusion of subjects whose parents were still alive and aged between 65 and 80 years (52 fathers and 126 mothers), statistical analyses were performed on 1065 subjects for paternal longevity and on 991 for maternal longevity. In a recent article, we reported that premature paternal death was associated with higher values of SBP and pulse pressure and a higher frequency of hypertension.8 Premature paternal death was also associated with a lower educational level and a higher level of plasma triglycerides. For maternal longevity, age, a lower educational level, and a higher BMI were significantly associated with premature maternal death.8 Neither paternal longevity nor maternal longevity was associated with smoking habits.
The relations of paternal longevity with B-mode ultrasound and PWV measurements are shown in Table 2. The percentage of subjects with plaques was higher in those with premature paternal death compared with the others (P for trend=0.003). In the multivariate analysis, the odds ratios of carotid plaques in subjects whose fathers had died before 65 years, in those whose fathers were alive at 65 years but who had died by 80 years of age, and in those whose fathers were alive at 80 years were 1, 0.68 (95% CI, 0.48 to 0.96), and 0.69 (95% CI, 0.49 to 0.98), respectively. In the multivariate analyses, the substitution of pulse pressure (or hypertension) for SBP did not alter the results. CCA-IMT was higher in subjects with paternal premature death in univariate but not in multivariate analyses (Table 2).
PWV decreased with increasing paternal longevity in both univariate and multivariate analyses. The multivariate-adjusted means of PWV in the 3 groups of paternal longevity were 11.9, 11.7, and 11.0 m/s, respectively (P<0.001). In the multivariate analyses, the substitution of pulse pressure (or hypertension) for SBP did not alter the results. Adding carotid plaques and/or CCA-IMT to the multivariate model also did not modify these results. Analyses repeated separately for several subgroups according to age, hypertension status, and the presence of carotid plaques also yielded similar patterns of results (Table 3). Neither B-mode ultrasound measurements nor PWV measurements were associated with maternal longevity (Table 4).
Paternal premature death was associated with a higher prevalence of carotid atherosclerosis and aortic arterial stiffness in adult offspring in this large-scale, population-based study conducted in middle-aged subjects. In contrast, no independent relations between maternal longevity and ultrasound measurements and arterial stiffness were observed. To our knowledge, the present study is the first to simultaneously report the relations of structure and function of large arteries with parental longevity.
Several studies have suggested that longevity has a familial pattern. Inherited susceptibility and/or shared environmental exposures could be involved in this phenomenon.13 Twin studies have shown some higher similarities in age at death for identical (monozygotic) twins.14 The structure and function of large arteries also have a familial component.15,16 Nevertheless, it is not clear whether the familial resemblance in longevity could be partly explained by the familial resemblance of large-artery vascular alterations or by some unidentified familial factors.
Differential associations of paternal longevity with carotid plaques and CCA-IMT were observed. The association of CCA-IMT with paternal longevity disappeared once BP variables were introduced into the models, suggesting that BP may link the etiological pathway. In contrast, the association between carotid plaque and paternal longevity cannot be explained by established risk factors such as BP.
Thickening of the carotid intima-media is generally considered to be an early marker of generalized atherosclerosis. However, its pathophysiological significance with regard to the atherosclerotic process is questionable because of the inability of B-mode ultrasonography to differentiate the intimal from the medial layer; the anatomic structure involved in arterial wall thickening cannot be determined. In this study, we used a methodological approach for carotid imaging that clearly differentiates between diffuse intima-media thickening and plaque. The IMT was measured in the mid and distal portions of the CCA on a segment free of any focal atherosclerotic lesion. We have previously reported in the Etude du vieillissement artériel (EVA study) that the 2 types of lesions were interrelated,12 but some factors could be specifically associated with increased IMT alone or with plaques alone. Interestingly, a parental history of premature death from CHDs was strongly related to carotid plaques but not to CCA-IMT, suggesting that familial transmission of cardiovascular risk does not seem to be specifically mediated by diffuse arterial wall thickening.17 The results of a recent article suggest that parental longevity is associated with lower IMT values of the extracranial carotid arteries.18 Measurements of IMT were made whether a focal atherosclerotic lesion was present or not. Because the carotid arteries frequently contained atheromatous plaques in this population of patients attending a lipid clinic, atherosclerosis rather than wall hypertrophy may be implied in the association between carotid wall thickness and parental longevity. Neither carotid plaques nor arterial stiffness were assessed in this study.18 In our study, consistent associations have been observed between PWV and paternal longevity. Aortic arterial stiffness has been shown to be a predictor of cardiovascular events in the general population.19
One can argue that the relations of arterial stiffness with paternal longevity may reflect the associations of hypertension and atherosclerosis with paternal longevity. However, the results of multivariate analyses, which took those factor into account, did not support that hypothesis. The magnitude of the association between paternal longevity and PWV is relatively important and may be considered clinically relevant. Subjects with premature paternal death had an excess of PWV of ≈0.9 m/s over subjects whose fathers were alive at 80 years. This magnitude represents more than half the difference between hypertensive and normotensive subjects.
Our present data suggest that the paternal age at death might predict in the offspring the degree of large-artery stiffness. Such hemodynamic changes may be modulated by genetic or environmental factors or a combination of both. The role of genetic polymorphisms, such as those of the renin-angiotensin system, has been recently emphasized20,21 and even could by triggered through changes in telomere length.22 The present data not only suggest the role of genetic factors but also do not exclude the concept that environmental factors may be involved.
The reasons for the differential associations of B-mode ultrasound and PWV measurements with paternal and maternal longevity are unclear. Women have a longer life span than men, and 1 explanation for the discrepancy between paternal and maternal results is that longevity in women might be a more heterogeneous phenotype involving many different genetic and environmental factors. This heterogeneity may lead to the “dilution” of its eventual association with carotid ultrasound and arterial stiffness measurements. Another plausible and complementary explanation is that paternal premature death from cardiovascular diseases is more frequent than maternal premature death from cardiovascular diseases. This may explain why some cardiovascular risk markers, such as aortic stiffness, are more strongly and inversely associated with paternal longevity. This hypothesis is partially supported by our results. In fact, subjects were also administered a standardized questionnaire that gave the cause of death (cardiovascular causes: sudden death, myocardial infarction and stroke, cancer, and other causes). Eighty-eight paternal premature cardiovascularly related deaths (paternal death age at <65 years) but only 34 maternal premature cardiovascular-related deaths (maternal death age at <65 years) were reported. For paternal history, the highest PWV measurements were observed in subjects with paternal premature cardiovascular mortality (12.1±3.0 m/s), followed by those with paternal premature noncardiovascular mortality (11.9±2.5 m/s) and then by the other subjects (11.2±2.3 m/s; P<0.001). For maternal history, the subjects with maternal premature cardiovascular mortality did not have a significantly higher PWV than did those with maternal premature noncardiovascular mortality or the others subjects. However, because of the low number of subjects with maternal premature cardiovascularly related deaths, these results should be interpreted with caution.
Our population consisted of volunteers recruited from an urban area with a relatively high proportion of subjects with a high level of education. However, similar patterns of associations between parental longevity and vascular parameters were observed when analyses were conducted after adjusting and/or stratifying for education level.
In conclusion, this study suggests that paternal premature death is associated with a higher frequency of carotid plaques and increased aortic arterial stiffness. These results may indicate that there are modifications of structure and function of large arteries according to paternal longevity. Our data may suggest that paternal longevity can provide an easily accessible parameter for a more accurate definition of cardiovascular risk profile in individual subjects. Subjects with premature paternal death may warrant more aggressive cardiovascular risk monitoring and intervention.
- Received March 24, 2006.
- Revision received June 2, 2006.
- Accepted July 5, 2006.
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