Clinical and Experimental Pharmacology and Physiology (2015) 42, 576–581
doi: 10.1111/1440-1681.12395
ORIGINAL ARTICLE
Increased cardiovascular risk without generalized arterial dilating diathesis in persons who do not have abdominal aortic aneurysm but who are firstdegree relatives of abdominal aortic aneurysm patients Rachel De Basso,*† Thomas Sandgren,‡ Asa Ryden Ahlgren§ and Toste L€anne¶** *Division of Medical Diagnostics, Department of Clinical Physiology, Region J€onk€oping County, †Department of Natural Science and Biomedicine, School of Health Sciences, J€onk€oping University, J€onk€oping, ‡Department of Surgery, Capio Lundby Hospital, Gothenburg, §Clinical Physiology and Nuclearmedicine Unit, Department of Clinical Sciences, Lund University, Malm€ o, ¶Division of Cardiovascular Medicine, Department of Medical and Health Science, Faculty of Health Science, Link€ oping University, Link€ oping, and **Department of Cardiovascular Surgery, Link€oping University Hospital, Link€oping, Sweden
SUMMARY There is a strong genetic predisposition towards abdominal aortic aneurysm (AAA), but it is unknown whether persons without AAA but with first-degree relatives who are AAA patients have a generalized dilating diathesis, defect arterial wall mechanics, or increased cardiovascular risk. The aim of the study was to investigate arterial diameters and wall mechanics at multiple arterial sites in these subjects and compare them with controls without a family history of AAA. This study included 118 first-degree relatives of patients with AAA and 66 controls (age: 40–80 years). The abdominal aorta, common carotid artery, common femoral artery, and popliteal artery were investigated by echo-tracking ultrasound. The relatives had no arterial dilatation, but they did tend to have smaller diameters than controls. Relatives had a higher heart rate, diastolic blood pressure, and mean arterial pressure than controls. The distensibility coefficient and the compliance coefficient were decreased in all arteries in male relatives, adjusted for age and smoking; these coefficients were normalized after adjustment for mean arterial pressure and heart rate. Female relatives had a lower compliance coefficient in the abdominal aorta, adjusted for age and smoking. After adjustment for mean arterial pressure and heart rate, the difference disappeared. No general arterial dilatation in relatives without AAA was found, supporting the hypothesis that the dilating diathesis is linked to the aneurysmal manifestation in the abdominal aorta. Although the threat of aneurysmal dilatation and rupture seems to be lacking in these subjects, heart rate, blood pressure, and arterial wall stiffness
were all increased, which may indicate a higher risk of developing cardiovascular morbidity and mortality. Key words: aneurysmal dilatation, arterial diameter, arterial stiffness, blood pressure.
INTRODUCTION Abdominal aortic aneurysm (AAA) has a strong genetic impact, with 20–30% of close male relatives of patients with AAA also having AAA, after exclusion of genetic connective tissue disorders such as Ehlers–Danlos or Marfan syndrome.1,2 The inheritance trait seems to be polygenic, although there may be a susceptibility locus for AAA on different chromosomes,3,4 which seems to be linked to defective mechanical properties of the abdominal aorta (Ao).5 Abdominal aortic aneurysm seems to be a general defect in the vasculature with focal manifestations in the aorta. Thus, wall mechanics in central elastic arteries have been shown to be defective.6,7 Because increased arterial wall stiffness is an independent predictor of cardiac risk, it may be the cause of the increased cardiac morbidity and mortality in AAA patients.8,9 Whether persons without AAA but with relatives who are AAA patients have a dilating diathesis in the arterial system in general or deranged arterial wall mechanics that affect their cardiovascular risk is unknown at present. The aim of this study was to investigate arterial diameters and wall mechanics at multiple arterial sites in these subjects and to compare them to controls without a family history of AAA.
RESULTS Characteristics of the relatives and controls Correspondence: Dr Rachel De Basso, Department of Clinical Physiology, J€ onk€ oping Hospital, SE 551 85 J€onk€oping, Sweden. Email: rachel. [email protected] Received 9 March 2015; revision 9 March 2015; accepted 27 March 2015. © 2015 Wiley Publishing Asia Pty Ltd
The demographic data of the relatives and controls are presented in Table 1. There were no differences between the male and female relatives and controls regarding age, body surface area (BSA), systolic blood pressure, and pulse pressure. However, the relatives had a higher heart rate (HR) (men, P < 0.001; women,
CV risk in relatives of AAA patients
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Table 1 Demographic data of persons without AAA but with relatives who have AAA and controls Men
Number of subjects Age (years) HR (bpm) BSA (m2) SBP (mmHg) DBP (mmHg) PP (mmHg) MAP (mmHg) Current smoker/former smoker (%) Hypertension (%) Heart disease (%) Hyperlipidaemia (%) Cerebrovascular disease (%) Claudicatio intermittens (%) Diabetes mellitus (%)
Women
Controls
Relatives
Controls
Relatives
29 61 58 2.0 135 81 54 99 0 0 0 0 0 0 0
79 57 69 2.0 142 87 55 105 30 20 9 14 4 4 4
37 60 63 1.7 135 78 57 97 0 0 0 0 0 0 0
39 58 72 1.7 138 84 53 102 24 14 5 3 0 3 3
11 9 0.1 17 7 14 10
6 11‡ 0.1 17 9‡ 13 10†
13 9 0.1 21 9 17 11
5 13‡ 0.1 17 8‡ 12 10†
Values represent mean SD. †P < 0.01. ‡P < 0.001. AAA, abdominal aortic aneurysm; BSA, body surface area; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic blood pressure.
Table 2 The diameter of the Ao, CCA, CFA, and PA of persons without AAA but with relatives who have AAA and controls adjusted for age and body surface area Parameters
Men Controls
Ao (mm) CCA (mm) CFA (mm) PA (mm)
18.5 8.2 10.0 8.2
1.7 1.1 1.0 1.2
Women Relatives
18.7 8.0 9.7 8.2
2.1 0.8 1.0 1.5
Controls 16.1 7.3 8.6 6.8
Mean diameter and predicted diameter
Relatives
2.0 0.6 0.7 0.8
15.7 7.3 8.1 6.6
A number of the relatives reported the presence of hypertension, hyperlipidaemia, heart disease, cerebrovascular events, diabetes mellitus and intermittent claudication (Table 1).
1.5 0.6 0.9* 0.7
Values represent mean SD. *P = 0.031 adjusted for age and BSA. AAA, abdominal aortic aneurysm; Ao, abdominal aorta; CCA, common carotid artery; CFA, common femoral artery; PA, popliteal artery.
P = 0.0005), diastolic blood pressure (DBP) (P < 0.001 in both men and women), and mean arterial blood pressure (MAP) (men, P = 0.004; women, P = 0.04) than the controls. After adjustment of DBP for HR, the difference in DBP was reduced but still significant (men, P = 0.007; women, P = 0.005). The difference in MAP in the relatives was reduced after adjustment for HR, but it was still significant in the male relatives (P = 0.036) but not in the female relatives.
There were no differences in the mean diameter of the Ao, common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA) between relatives and controls after adjustment for age and BSA. However, the female relatives had a slightly decreased CFA diameter compared to the controls (P = 0.031) (Table 2). The predicted diameter based on nomograms of the CFA, with age and BSA taken into account, showed a decreased diameter in male and female relatives (P = 0.032 and P = 0.028, respectively). The predicted diameters of the Ao and PA did not show any differences (Table 3). Distensibility coefficient (DC) and compliance coefficient (CC) Figure 1 shows the DC in the studied arteries after adjustment for age. The male relatives had a lower DC and increased stiffness compared to the controls in the Ao, CCA, and PA but not
Table 3 The predicted diameter of the Ao, CFA, and PA of persons without AAA but with relatives who have AAA and controls Men
Ao (%) CFA (%) PA (%)
Women
Controls
Relatives
Controls
Relatives
96 8 (93–99) 99 10 (95–103) 99 24 (90–108)
97 9 (95–99) 95 9 (92–97)* 98 17 (94–103)
99 12 (95–104) 98 8 (96–101) 102 11 (98–106)
97 9 (94–100) 93 10 (90–96)† 98 10 (94–101)
Values represent mean SD (95% confidence interval). AAA, abdominal aortic aneurysm; Ao, abdominal aorta; CFA, common femoral artery; PA, popliteal artery. *P = 0.032. †P = 0.028.
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R De Basso et al.
in the CFA. After adjustment of the DC for smoking, the male relatives had a lower DC in all four arteries. Finally, after adjustment for HR and MAP, all differences between the male relatives and controls disappeared. There were no differences in DC between the female relatives and controls after adjustment for age, smoking, HR, and MAP. Figure 2 shows the CC in the studied arteries after adjustment for age. The male relatives had a lower CC (decreased arterial buffering capacity) than the controls in all vascular beds, and in female relatives, the CC was reduced in the Ao. After adjustment
Fig. 1 The distensibility coefficient (DC), adjusted for age, of the abdominal aorta (Ao), common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA) of persons without AAA but with relatives who have AAA (black bars) and controls (white bars). Figures are presented as mean SEM. *P < 0.05. †P < 0.01. ‡P < 0.001. M, men; W, women.
Fig. 2 The compliance coefficient (CC) adjusted for age, of the abdominal aorta (Ao), common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA) of persons without AAA but with relatives who have AAA (black bars) and controls (white bars). Figures are presented as mean SEM. *P < 0.05. ‡P < 0.001. M, men; W, women.
of the CC for smoking, the differences remained in both men and women. Finally, after adjustment for HR and MAP, all differences between male and female relatives and controls disappeared, except in the CCA in men (P = 0.046).
DISCUSSION Recent reports have indicated that AAA is not only a localized disease in the Ao, but it may also be a general defect in the vasculature with focal manifestations in the aorta. Mechanical properties as well as dimensions of central arteries not affected by aneurysmal disease have been shown to be defective,6,7 while peripheral muscular arteries have no dilating diathesis. Being a systemic disorder, AAA seems to have different features in central and peripheral arteries.10 Genetic influence affects 20–30% of near male relatives of patients with AAA who also have AAA as well as disturbances of the connective tissue (e.g. type I and III collagen, inflammatory cell-derived matrix metalloproteinases and their inhibitors, autoimmune components, and components related to atherosclerosis, elastin, and fibrillin-1 genotype).11,12 The inheritance trait seems to be polygenic, and no specific locus has been found to be solely responsible, although there may be susceptibility loci for AAA on chromosomes 19q13 and 4q31.13 The diameter of the Ao increases by 25–30% in healthy subjects between 20 and 70 years of age,14 but smaller central arteries such as the CCA and peripheral muscular arteries (e.g. CFA and PA) do not increase as much in size.15,16 This is due to degeneration and remodelling of the arterial wall.17–20 Furthermore, the arterial diameter is dependent on age, body size, and gender. Nomograms have been created to predict the diameters of the Ao, CFA, and PA, and these may be used to determine the pathological dilatation or narrowing of arteries.15,16,20 In our study, no dilating diathesis was found in relatives in either the central elastic arteries or the peripheral muscular arteries, but a tendency towards narrowing was found (Tables 2,3). We used an echo-tracking technique to measure the luminal interfaces of the B-mode image and found that an increased intima media thickness due to incipient atherosclerosis might lead to an underestimation of the diameter, which explains the narrower arteries in the relatives.21 Peripheral vascular occlusive disease affects 10– 30% of AAA patients,10 and it seems likely that their relatives also have an increased frequency of peripheral vascular occlusive disease (Table 1). Several studies have indicated that a high HR is related to the development of coronary atherosclerosis, cardiovascular events, and death.22–24 We observed a higher resting HR in the relatives than in controls, and this may alter cardiovascular regulation in several ways (Table 1). Firstly, it may affect blood pressure due to an increase in diastolic decay and reduced diastolic time. Secondly, an elevated HR is often accompanied by an increase in sympathetic tone, leading to increased peripheral resistance. This, in turn, may result in changed pressure amplification between central and peripheral arteries due to modifications in reflection sites; as a consequence, central aortic pressure may be overestimated when only the peripheral blood pressure is measured, as in this study.25,26 Arterial stiffness was increased in all measured regions (Figs 1,2). However, when adjusted for HR and MAP, the
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CV risk in relatives of AAA patients increase in arterial stiffness remained, but it disappeared in male relatives after adjustment for age and smoking. Furthermore, the increase in diastolic pressure was reduced, although it still reached significance. The increased HR thus affected both blood pressure and arterial stiffness in the relatives. These findings indicate that relatives not affected by aneurysm may have a higher risk of developing cardiovascular events. Also, a high frequency of cardiovascular disease was reported among the relatives (Table 1). Aortic stiffness has an independent predictive value for allcause and cardiovascular mortality, fatal and non-fatal coronary events, and fatal strokes in patients with uncomplicated hypertension,27,28 type 2 diabetes,29 and end-stage renal disease,30 in elderly subjects,31 and in the general population.32 Patients with AAA have augmented stiffness in the Ao and CCA.7 In the Strong Heart Family Study, carotid stiffness heritability was assessed. Although classical covariates accounted for about half of the variance, the proportion of residual phenotypic variance caused by the additive effects of genes was 23%.33 The augmentation index (in which arterial stiffness is included) and the inheritance of arterial stiffness were studied in monozygotic and dizygotic twins. Up to 37% of the variance was determined to be caused by genetic factors.34 Because arterial stiffness seems to be increased in patients with AAA, an underlying genetic predisposition to aneurysmal disease could to some extent explain the increased arterial stiffness in their relatives (Figs 1,2).7,8 Another important factor may be blood pressure. The pressure–diameter curve is non-linear, with reduced changes in diameter for a given pressure change at higher distending pressures rather than at lower pressures. Because arterial compliance is defined as the change in arterial volume for a given change in distending pressure, it has a functional response and decreases as blood pressure increases. The increased arterial stiffness found in the relatives was normalized after correction for MAP and HR, indicating that genetic influence on arterial stiffness is minor and that the increase in arterial stiffness is functional rather than structural. In conclusion, we found no sign of a dilating diathesis in either central elastic arteries or peripheral muscular arteries in persons without AAA but with first-degree relatives who have AAA; rather, we found a tendency towards narrowing arteries, which supports the hypothesis that the dilating diathesis in the arterial tree is linked to the aneurysmal manifestation in the Ao. However, HR, blood pressure, and arterial wall stiffness were all increased in the relatives, which may indicate a higher risk of developing cardiovascular morbidity and mortality.
METHODS Study subjects Persons without AAA but with first-degree relatives who have AAA and controls This study included 131 subjects (90 men, 41 women) without AAA but with first-degree relatives (siblings and offspring) who have AAA; subjects were consecutively recruited from a parish registration, identified, and invited to participate in the study. Subjects and controls underwent blood pressure and
579
ultrasound examinations. Subjects were excluded for the following reasons: (i) AAA (6 men); (ii) abdominal aortic graft (1 man); (iii) low ultrasound quality (4 men); and (iv) inability to confirm that they were first-degree relatives of AAA patients (2 women). The study ultimately had 118 subjects, including 79 men (age: 41–70 years) and 39 women (age: 51–70 years). An aneurysmal dilatation of the Ao was defined according to a previously established standard as a localized dilatation and/ or aortic diameter ≥ 3.0 cm.35 Sixty-six controls were recruited from hospital staff. Inclusion criteria for the controls were as follows: (i) no family history of AAA; (ii) non-smokers; (iii) no prescribed drugs; and (iv) no heart disease, hypertension, peripheral occlusive disease, or cerebral vascular disease. The controls included 29 men (age: 40– 78 years) and 37 women (age: 40–80 years). All subjects and controls answered a questionnaire regarding their former or present smoking habits, prescribed drugs, heart disease, hypertension, peripheral occlusive disease, and cerebralvascular disease. All subjects gave informed consent to participate, and the Ethics Committee at Lund University approved the study. Examination An experienced ultrasound technician performed all measurements in a darkened and quiet room. Auscultatory blood pressure was measured with a sphygmomanometer on both upper arms to exclude differences in blood pressure. The subjects rested at least 15 min before the ultrasound measurements. The arteries were visualized in the longitudinal section, and care was taken to minimize pressure from the transducer on the skin. All arterial sites were measured in a plaque-free area. After these measurements, brachial pressure was recorded. The Ao was studied between the origin of the renal arteries and the aortic bifurcation about 3 cm proximal to the aortic bifurcation. The right CCA was examined 1–2 cm proximal to the bifurcation. The right CFA was measured at the site of the inguinal fossa, with the patient in supine position and the hip joint as a landmark. The right PA was measured at the site of the popliteal fossa, with the patient in prone position and the patella as a landmark. Arterial diameter, predicted arterial diameter, and arterial stiffness measurements An ultrasound echo-tracking system (Diamove; Teltec, Lund, Sweden) interfaced with a 3.5- or 5-MHz B-mode real-time linear scanner (EUB 240; Hitachi, Tokyo, Japan) was used to measure pulsatile changes in vessel diameter during the cardiac cycle.36 The repetition frequency of the echo-tracking loop was 870 Hz, the time resolution was 1.2 ms, and the smallest detectable movement was less than 10 lm. A personal computer and a 12-bit analogue-to-digital converter (Analog Devices, Norwood, MA, USA) were used to sample the measurements. All arteries were examined three times, and the mean diameter was calculated from the systolic and diastolic diameter: (Dmax + Dmin)/2. Furthermore, the predicted diameter was calculated based on nomograms on healthy subjects corrected for age, gender, and BSA.15,16,20
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R De Basso et al.
580 The DC was defined as follows:37 DC ¼
2Ddiastolic DD þ DD2 DP Ddiastolic2
University (Link€ oping, Sweden) and the Swedish Heart-Lung Foundation. ð1Þ
DISCLOSURE
The CC was defined as follows:37 CC ¼
pð2Ddiastolic DD þ DD2 Þ 4DP
The authors declare no conflicts of interest. ð2Þ
ΔP is the blood pressure change (systolic – DBP (kPa)) during the heart cycle. The unit for DC is 103/kPa, and for CC mm2/kPa. Distensibility characteristics of large arteries depend on the extent to which they are expanded. For example, a vessel that is distensible at low pressures and small diameters may gradually get stiffer with increasing pressure and diameter. Thus, there is a non-linear pressure–diameter relationship of the arterial wall.8 The DC is the change in arterial diameter in relation to a given increase in pressure; the lower DC, the higher arterial stiffness. The CC is the absolute increase in cross-sectional area for a given increase in arterial pressure; it is assumed that the vessel length is constant during the pulse wave. A lower CC indicates a reduced buffering capacity for the heart. The intra-observer variability coefficient is 4–5% in measurements of the arterial diameter in Ao, CCA, CFA, and PA and 10–16% for pulsatile diameter change in Ao, CCA, CFA, and PA when the echo-tracking system is used.38 The calculated stiffness values are based on the assumption that intra-arterial pressure is equal to the pressure in the brachial artery when measured by the auscultatory method. When blood pressure is measured, it is favourable to measure it invasively in situ because the blood pressure undergoes transformation in the arterial tree.18 Comparisons between intra-arterial pressure in the brachial artery, Ao, and CFA using auscultatory blood pressure in the upper arm show only slight differences.39 Mean arterial blood pressure was defined as DBP plus one-third of the pulse pressure. Body surface area was estimated in m2 according to Du Bois’s formula:40 weight0.425 9 height0.725 9 71.84, with weight measured in kilograms and height measured in metres. Statistical analysis Men and women were studied separately. Variance analysis was used to compare relatives and controls regarding arterial wall mechanics and was adjusted for age, smoking, MAP, and HR. Variance analysis was used in the calculation of mean arterial diameter and adjusted for age and BSA. Nomograms were used to express the diameter as predicted diameter.15,16,20 The data are presented as mean SD and mean SEM, and P < 0.05 was considered as a significant difference. Statistical analysis was performed with SPSS V.15.0 statistical package (SPSS, Chicago, IL, USA).
ACKNOWLEDGEMENTS The study was supported by grants from Futurum – the Academy for Healthcare (Region, J€onk€oping County, Sweden), the Swedish Research Council (No. 12161), and the funds of Link€ oping
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CV risk in relatives of AAA patients 18. Nichols W, O’Rourke M. Properties of the arterial wall: Theory. In: Nichols W, O’Rourke M (eds). McDonald’s Blood Flow in Arteries Theoretical, Experimental and Clinical Principles, 4th edn. Edward Arnold, London, 1998; 54–72. 19. Sonesson B, Lanne T, Vernersson E, Hansen F. Sex difference in the mechanical properties of the abdominal aorta in human beings. J. Vasc. Surg. 1994; 20: 959–69. 20. Sonesson B, Lanne T, Hansen F, Sandgren T. Infrarenal aortic diameter in the healthy person. Eur. J. Vasc. Surg. 1994; 8: 89–95. 21. Simons PC, Algra A, Bots ML, Banga JD, Grobbee DE, van der Graaf Y. Common carotid intima-media thickness in patients with peripheral arterial disease or abdominal aortic aneurysm: The SMART study. Second Manifestations of ARTerial disease. Atherosclerosis 1999; 146: 243–8. 22. Gillman MW, Kannel WB, Belanger A, D’Agostino RB. Influence of heart rate on mortality among persons with hypertension: The Framingham Study. Am. Heart J. 1993; 125: 1148–54. 23. Palatini P, Julius S. Heart rate and the cardiovascular risk. J. Hypertens. 1997; 15: 3–17. 24. Thomas F, Bean K, Provost JC, Guize L, Benetos A. Combined effects of heart rate and pulse pressure on cardiovascular mortality according to age. J. Hypertens. 2001; 19: 863–9. 25. Albaladejo P, Copie X, Boutouyrie P et al. Heart rate, arterial stiffness, and wave reflections in paced patients. Hypertension 2001; 38: 949–52. 26. Wilkinson IB, Mohammad NH, Tyrrell S et al. Heart rate dependency of pulse pressure amplification and arterial stiffness. Am. J. Hypertens. 2002; 15: 24–30. 27. Boutouyrie P, Tropeano AI, Asmar R et al. Aortic stiffness is an independent predictor of primary coronary events in hypertensive patients: A longitudinal study. Hypertension 2002; 39: 10–5. 28. Laurent S, Katsahian S, Fassot C et al. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003; 34: 1203–6. 29. Cruickshank K, Riste L, Anderson SG, Wright JS, Dunn G, Gosling RG. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: An integrated index of vascular function? Circulation 2002; 106: 2085–90.
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doi: 10.1111/1440-1681.12395
ORIGINAL ARTICLE
Increased cardiovascular risk without generalized arterial dilating diathesis in persons who do not have abdominal aortic aneurysm but who are firstdegree relatives of abdominal aortic aneurysm patients Rachel De Basso,*† Thomas Sandgren,‡ Asa Ryden Ahlgren§ and Toste L€anne¶** *Division of Medical Diagnostics, Department of Clinical Physiology, Region J€onk€oping County, †Department of Natural Science and Biomedicine, School of Health Sciences, J€onk€oping University, J€onk€oping, ‡Department of Surgery, Capio Lundby Hospital, Gothenburg, §Clinical Physiology and Nuclearmedicine Unit, Department of Clinical Sciences, Lund University, Malm€ o, ¶Division of Cardiovascular Medicine, Department of Medical and Health Science, Faculty of Health Science, Link€ oping University, Link€ oping, and **Department of Cardiovascular Surgery, Link€oping University Hospital, Link€oping, Sweden
SUMMARY There is a strong genetic predisposition towards abdominal aortic aneurysm (AAA), but it is unknown whether persons without AAA but with first-degree relatives who are AAA patients have a generalized dilating diathesis, defect arterial wall mechanics, or increased cardiovascular risk. The aim of the study was to investigate arterial diameters and wall mechanics at multiple arterial sites in these subjects and compare them with controls without a family history of AAA. This study included 118 first-degree relatives of patients with AAA and 66 controls (age: 40–80 years). The abdominal aorta, common carotid artery, common femoral artery, and popliteal artery were investigated by echo-tracking ultrasound. The relatives had no arterial dilatation, but they did tend to have smaller diameters than controls. Relatives had a higher heart rate, diastolic blood pressure, and mean arterial pressure than controls. The distensibility coefficient and the compliance coefficient were decreased in all arteries in male relatives, adjusted for age and smoking; these coefficients were normalized after adjustment for mean arterial pressure and heart rate. Female relatives had a lower compliance coefficient in the abdominal aorta, adjusted for age and smoking. After adjustment for mean arterial pressure and heart rate, the difference disappeared. No general arterial dilatation in relatives without AAA was found, supporting the hypothesis that the dilating diathesis is linked to the aneurysmal manifestation in the abdominal aorta. Although the threat of aneurysmal dilatation and rupture seems to be lacking in these subjects, heart rate, blood pressure, and arterial wall stiffness
were all increased, which may indicate a higher risk of developing cardiovascular morbidity and mortality. Key words: aneurysmal dilatation, arterial diameter, arterial stiffness, blood pressure.
INTRODUCTION Abdominal aortic aneurysm (AAA) has a strong genetic impact, with 20–30% of close male relatives of patients with AAA also having AAA, after exclusion of genetic connective tissue disorders such as Ehlers–Danlos or Marfan syndrome.1,2 The inheritance trait seems to be polygenic, although there may be a susceptibility locus for AAA on different chromosomes,3,4 which seems to be linked to defective mechanical properties of the abdominal aorta (Ao).5 Abdominal aortic aneurysm seems to be a general defect in the vasculature with focal manifestations in the aorta. Thus, wall mechanics in central elastic arteries have been shown to be defective.6,7 Because increased arterial wall stiffness is an independent predictor of cardiac risk, it may be the cause of the increased cardiac morbidity and mortality in AAA patients.8,9 Whether persons without AAA but with relatives who are AAA patients have a dilating diathesis in the arterial system in general or deranged arterial wall mechanics that affect their cardiovascular risk is unknown at present. The aim of this study was to investigate arterial diameters and wall mechanics at multiple arterial sites in these subjects and to compare them to controls without a family history of AAA.
RESULTS Characteristics of the relatives and controls Correspondence: Dr Rachel De Basso, Department of Clinical Physiology, J€ onk€ oping Hospital, SE 551 85 J€onk€oping, Sweden. Email: rachel. [email protected] Received 9 March 2015; revision 9 March 2015; accepted 27 March 2015. © 2015 Wiley Publishing Asia Pty Ltd
The demographic data of the relatives and controls are presented in Table 1. There were no differences between the male and female relatives and controls regarding age, body surface area (BSA), systolic blood pressure, and pulse pressure. However, the relatives had a higher heart rate (HR) (men, P < 0.001; women,
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Table 1 Demographic data of persons without AAA but with relatives who have AAA and controls Men
Number of subjects Age (years) HR (bpm) BSA (m2) SBP (mmHg) DBP (mmHg) PP (mmHg) MAP (mmHg) Current smoker/former smoker (%) Hypertension (%) Heart disease (%) Hyperlipidaemia (%) Cerebrovascular disease (%) Claudicatio intermittens (%) Diabetes mellitus (%)
Women
Controls
Relatives
Controls
Relatives
29 61 58 2.0 135 81 54 99 0 0 0 0 0 0 0
79 57 69 2.0 142 87 55 105 30 20 9 14 4 4 4
37 60 63 1.7 135 78 57 97 0 0 0 0 0 0 0
39 58 72 1.7 138 84 53 102 24 14 5 3 0 3 3
11 9 0.1 17 7 14 10
6 11‡ 0.1 17 9‡ 13 10†
13 9 0.1 21 9 17 11
5 13‡ 0.1 17 8‡ 12 10†
Values represent mean SD. †P < 0.01. ‡P < 0.001. AAA, abdominal aortic aneurysm; BSA, body surface area; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; PP, pulse pressure; SBP, systolic blood pressure.
Table 2 The diameter of the Ao, CCA, CFA, and PA of persons without AAA but with relatives who have AAA and controls adjusted for age and body surface area Parameters
Men Controls
Ao (mm) CCA (mm) CFA (mm) PA (mm)
18.5 8.2 10.0 8.2
1.7 1.1 1.0 1.2
Women Relatives
18.7 8.0 9.7 8.2
2.1 0.8 1.0 1.5
Controls 16.1 7.3 8.6 6.8
Mean diameter and predicted diameter
Relatives
2.0 0.6 0.7 0.8
15.7 7.3 8.1 6.6
A number of the relatives reported the presence of hypertension, hyperlipidaemia, heart disease, cerebrovascular events, diabetes mellitus and intermittent claudication (Table 1).
1.5 0.6 0.9* 0.7
Values represent mean SD. *P = 0.031 adjusted for age and BSA. AAA, abdominal aortic aneurysm; Ao, abdominal aorta; CCA, common carotid artery; CFA, common femoral artery; PA, popliteal artery.
P = 0.0005), diastolic blood pressure (DBP) (P < 0.001 in both men and women), and mean arterial blood pressure (MAP) (men, P = 0.004; women, P = 0.04) than the controls. After adjustment of DBP for HR, the difference in DBP was reduced but still significant (men, P = 0.007; women, P = 0.005). The difference in MAP in the relatives was reduced after adjustment for HR, but it was still significant in the male relatives (P = 0.036) but not in the female relatives.
There were no differences in the mean diameter of the Ao, common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA) between relatives and controls after adjustment for age and BSA. However, the female relatives had a slightly decreased CFA diameter compared to the controls (P = 0.031) (Table 2). The predicted diameter based on nomograms of the CFA, with age and BSA taken into account, showed a decreased diameter in male and female relatives (P = 0.032 and P = 0.028, respectively). The predicted diameters of the Ao and PA did not show any differences (Table 3). Distensibility coefficient (DC) and compliance coefficient (CC) Figure 1 shows the DC in the studied arteries after adjustment for age. The male relatives had a lower DC and increased stiffness compared to the controls in the Ao, CCA, and PA but not
Table 3 The predicted diameter of the Ao, CFA, and PA of persons without AAA but with relatives who have AAA and controls Men
Ao (%) CFA (%) PA (%)
Women
Controls
Relatives
Controls
Relatives
96 8 (93–99) 99 10 (95–103) 99 24 (90–108)
97 9 (95–99) 95 9 (92–97)* 98 17 (94–103)
99 12 (95–104) 98 8 (96–101) 102 11 (98–106)
97 9 (94–100) 93 10 (90–96)† 98 10 (94–101)
Values represent mean SD (95% confidence interval). AAA, abdominal aortic aneurysm; Ao, abdominal aorta; CFA, common femoral artery; PA, popliteal artery. *P = 0.032. †P = 0.028.
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R De Basso et al.
in the CFA. After adjustment of the DC for smoking, the male relatives had a lower DC in all four arteries. Finally, after adjustment for HR and MAP, all differences between the male relatives and controls disappeared. There were no differences in DC between the female relatives and controls after adjustment for age, smoking, HR, and MAP. Figure 2 shows the CC in the studied arteries after adjustment for age. The male relatives had a lower CC (decreased arterial buffering capacity) than the controls in all vascular beds, and in female relatives, the CC was reduced in the Ao. After adjustment
Fig. 1 The distensibility coefficient (DC), adjusted for age, of the abdominal aorta (Ao), common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA) of persons without AAA but with relatives who have AAA (black bars) and controls (white bars). Figures are presented as mean SEM. *P < 0.05. †P < 0.01. ‡P < 0.001. M, men; W, women.
Fig. 2 The compliance coefficient (CC) adjusted for age, of the abdominal aorta (Ao), common carotid artery (CCA), common femoral artery (CFA), and popliteal artery (PA) of persons without AAA but with relatives who have AAA (black bars) and controls (white bars). Figures are presented as mean SEM. *P < 0.05. ‡P < 0.001. M, men; W, women.
of the CC for smoking, the differences remained in both men and women. Finally, after adjustment for HR and MAP, all differences between male and female relatives and controls disappeared, except in the CCA in men (P = 0.046).
DISCUSSION Recent reports have indicated that AAA is not only a localized disease in the Ao, but it may also be a general defect in the vasculature with focal manifestations in the aorta. Mechanical properties as well as dimensions of central arteries not affected by aneurysmal disease have been shown to be defective,6,7 while peripheral muscular arteries have no dilating diathesis. Being a systemic disorder, AAA seems to have different features in central and peripheral arteries.10 Genetic influence affects 20–30% of near male relatives of patients with AAA who also have AAA as well as disturbances of the connective tissue (e.g. type I and III collagen, inflammatory cell-derived matrix metalloproteinases and their inhibitors, autoimmune components, and components related to atherosclerosis, elastin, and fibrillin-1 genotype).11,12 The inheritance trait seems to be polygenic, and no specific locus has been found to be solely responsible, although there may be susceptibility loci for AAA on chromosomes 19q13 and 4q31.13 The diameter of the Ao increases by 25–30% in healthy subjects between 20 and 70 years of age,14 but smaller central arteries such as the CCA and peripheral muscular arteries (e.g. CFA and PA) do not increase as much in size.15,16 This is due to degeneration and remodelling of the arterial wall.17–20 Furthermore, the arterial diameter is dependent on age, body size, and gender. Nomograms have been created to predict the diameters of the Ao, CFA, and PA, and these may be used to determine the pathological dilatation or narrowing of arteries.15,16,20 In our study, no dilating diathesis was found in relatives in either the central elastic arteries or the peripheral muscular arteries, but a tendency towards narrowing was found (Tables 2,3). We used an echo-tracking technique to measure the luminal interfaces of the B-mode image and found that an increased intima media thickness due to incipient atherosclerosis might lead to an underestimation of the diameter, which explains the narrower arteries in the relatives.21 Peripheral vascular occlusive disease affects 10– 30% of AAA patients,10 and it seems likely that their relatives also have an increased frequency of peripheral vascular occlusive disease (Table 1). Several studies have indicated that a high HR is related to the development of coronary atherosclerosis, cardiovascular events, and death.22–24 We observed a higher resting HR in the relatives than in controls, and this may alter cardiovascular regulation in several ways (Table 1). Firstly, it may affect blood pressure due to an increase in diastolic decay and reduced diastolic time. Secondly, an elevated HR is often accompanied by an increase in sympathetic tone, leading to increased peripheral resistance. This, in turn, may result in changed pressure amplification between central and peripheral arteries due to modifications in reflection sites; as a consequence, central aortic pressure may be overestimated when only the peripheral blood pressure is measured, as in this study.25,26 Arterial stiffness was increased in all measured regions (Figs 1,2). However, when adjusted for HR and MAP, the
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CV risk in relatives of AAA patients increase in arterial stiffness remained, but it disappeared in male relatives after adjustment for age and smoking. Furthermore, the increase in diastolic pressure was reduced, although it still reached significance. The increased HR thus affected both blood pressure and arterial stiffness in the relatives. These findings indicate that relatives not affected by aneurysm may have a higher risk of developing cardiovascular events. Also, a high frequency of cardiovascular disease was reported among the relatives (Table 1). Aortic stiffness has an independent predictive value for allcause and cardiovascular mortality, fatal and non-fatal coronary events, and fatal strokes in patients with uncomplicated hypertension,27,28 type 2 diabetes,29 and end-stage renal disease,30 in elderly subjects,31 and in the general population.32 Patients with AAA have augmented stiffness in the Ao and CCA.7 In the Strong Heart Family Study, carotid stiffness heritability was assessed. Although classical covariates accounted for about half of the variance, the proportion of residual phenotypic variance caused by the additive effects of genes was 23%.33 The augmentation index (in which arterial stiffness is included) and the inheritance of arterial stiffness were studied in monozygotic and dizygotic twins. Up to 37% of the variance was determined to be caused by genetic factors.34 Because arterial stiffness seems to be increased in patients with AAA, an underlying genetic predisposition to aneurysmal disease could to some extent explain the increased arterial stiffness in their relatives (Figs 1,2).7,8 Another important factor may be blood pressure. The pressure–diameter curve is non-linear, with reduced changes in diameter for a given pressure change at higher distending pressures rather than at lower pressures. Because arterial compliance is defined as the change in arterial volume for a given change in distending pressure, it has a functional response and decreases as blood pressure increases. The increased arterial stiffness found in the relatives was normalized after correction for MAP and HR, indicating that genetic influence on arterial stiffness is minor and that the increase in arterial stiffness is functional rather than structural. In conclusion, we found no sign of a dilating diathesis in either central elastic arteries or peripheral muscular arteries in persons without AAA but with first-degree relatives who have AAA; rather, we found a tendency towards narrowing arteries, which supports the hypothesis that the dilating diathesis in the arterial tree is linked to the aneurysmal manifestation in the Ao. However, HR, blood pressure, and arterial wall stiffness were all increased in the relatives, which may indicate a higher risk of developing cardiovascular morbidity and mortality.
METHODS Study subjects Persons without AAA but with first-degree relatives who have AAA and controls This study included 131 subjects (90 men, 41 women) without AAA but with first-degree relatives (siblings and offspring) who have AAA; subjects were consecutively recruited from a parish registration, identified, and invited to participate in the study. Subjects and controls underwent blood pressure and
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ultrasound examinations. Subjects were excluded for the following reasons: (i) AAA (6 men); (ii) abdominal aortic graft (1 man); (iii) low ultrasound quality (4 men); and (iv) inability to confirm that they were first-degree relatives of AAA patients (2 women). The study ultimately had 118 subjects, including 79 men (age: 41–70 years) and 39 women (age: 51–70 years). An aneurysmal dilatation of the Ao was defined according to a previously established standard as a localized dilatation and/ or aortic diameter ≥ 3.0 cm.35 Sixty-six controls were recruited from hospital staff. Inclusion criteria for the controls were as follows: (i) no family history of AAA; (ii) non-smokers; (iii) no prescribed drugs; and (iv) no heart disease, hypertension, peripheral occlusive disease, or cerebral vascular disease. The controls included 29 men (age: 40– 78 years) and 37 women (age: 40–80 years). All subjects and controls answered a questionnaire regarding their former or present smoking habits, prescribed drugs, heart disease, hypertension, peripheral occlusive disease, and cerebralvascular disease. All subjects gave informed consent to participate, and the Ethics Committee at Lund University approved the study. Examination An experienced ultrasound technician performed all measurements in a darkened and quiet room. Auscultatory blood pressure was measured with a sphygmomanometer on both upper arms to exclude differences in blood pressure. The subjects rested at least 15 min before the ultrasound measurements. The arteries were visualized in the longitudinal section, and care was taken to minimize pressure from the transducer on the skin. All arterial sites were measured in a plaque-free area. After these measurements, brachial pressure was recorded. The Ao was studied between the origin of the renal arteries and the aortic bifurcation about 3 cm proximal to the aortic bifurcation. The right CCA was examined 1–2 cm proximal to the bifurcation. The right CFA was measured at the site of the inguinal fossa, with the patient in supine position and the hip joint as a landmark. The right PA was measured at the site of the popliteal fossa, with the patient in prone position and the patella as a landmark. Arterial diameter, predicted arterial diameter, and arterial stiffness measurements An ultrasound echo-tracking system (Diamove; Teltec, Lund, Sweden) interfaced with a 3.5- or 5-MHz B-mode real-time linear scanner (EUB 240; Hitachi, Tokyo, Japan) was used to measure pulsatile changes in vessel diameter during the cardiac cycle.36 The repetition frequency of the echo-tracking loop was 870 Hz, the time resolution was 1.2 ms, and the smallest detectable movement was less than 10 lm. A personal computer and a 12-bit analogue-to-digital converter (Analog Devices, Norwood, MA, USA) were used to sample the measurements. All arteries were examined three times, and the mean diameter was calculated from the systolic and diastolic diameter: (Dmax + Dmin)/2. Furthermore, the predicted diameter was calculated based on nomograms on healthy subjects corrected for age, gender, and BSA.15,16,20
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R De Basso et al.
580 The DC was defined as follows:37 DC ¼
2Ddiastolic DD þ DD2 DP Ddiastolic2
University (Link€ oping, Sweden) and the Swedish Heart-Lung Foundation. ð1Þ
DISCLOSURE
The CC was defined as follows:37 CC ¼
pð2Ddiastolic DD þ DD2 Þ 4DP
The authors declare no conflicts of interest. ð2Þ
ΔP is the blood pressure change (systolic – DBP (kPa)) during the heart cycle. The unit for DC is 103/kPa, and for CC mm2/kPa. Distensibility characteristics of large arteries depend on the extent to which they are expanded. For example, a vessel that is distensible at low pressures and small diameters may gradually get stiffer with increasing pressure and diameter. Thus, there is a non-linear pressure–diameter relationship of the arterial wall.8 The DC is the change in arterial diameter in relation to a given increase in pressure; the lower DC, the higher arterial stiffness. The CC is the absolute increase in cross-sectional area for a given increase in arterial pressure; it is assumed that the vessel length is constant during the pulse wave. A lower CC indicates a reduced buffering capacity for the heart. The intra-observer variability coefficient is 4–5% in measurements of the arterial diameter in Ao, CCA, CFA, and PA and 10–16% for pulsatile diameter change in Ao, CCA, CFA, and PA when the echo-tracking system is used.38 The calculated stiffness values are based on the assumption that intra-arterial pressure is equal to the pressure in the brachial artery when measured by the auscultatory method. When blood pressure is measured, it is favourable to measure it invasively in situ because the blood pressure undergoes transformation in the arterial tree.18 Comparisons between intra-arterial pressure in the brachial artery, Ao, and CFA using auscultatory blood pressure in the upper arm show only slight differences.39 Mean arterial blood pressure was defined as DBP plus one-third of the pulse pressure. Body surface area was estimated in m2 according to Du Bois’s formula:40 weight0.425 9 height0.725 9 71.84, with weight measured in kilograms and height measured in metres. Statistical analysis Men and women were studied separately. Variance analysis was used to compare relatives and controls regarding arterial wall mechanics and was adjusted for age, smoking, MAP, and HR. Variance analysis was used in the calculation of mean arterial diameter and adjusted for age and BSA. Nomograms were used to express the diameter as predicted diameter.15,16,20 The data are presented as mean SD and mean SEM, and P < 0.05 was considered as a significant difference. Statistical analysis was performed with SPSS V.15.0 statistical package (SPSS, Chicago, IL, USA).
ACKNOWLEDGEMENTS The study was supported by grants from Futurum – the Academy for Healthcare (Region, J€onk€oping County, Sweden), the Swedish Research Council (No. 12161), and the funds of Link€ oping
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![[The abdominal aortic aneurysm].](/assets/img/hold.png)
