Objective and design α1-Antitrypsin deficiency (AATD) is a genetic disorder that may be a pathogenic factor in vascular aneurysms and dissection. The aim of this study was to measure the diameters of the Valsalva sinuses (VS), sinotubular junction (STJ), ascending aorta (AA) and aortic arch (AAr) and elastic properties of the AA (distensibility, stiffness and tissue Doppler imaging (TDI strain)) in AATD subjects.
Patients 33 AATD subjects (all Z-homozygous, 17 male, 16 female) were examined. Aortic elastic properties, namely, distensibility and stiffness index, were calculated from the echocardiographically-derived thoracic aortic diameters and TDI strain was measured on the wall of the AA 3 cm above the aortic valve. The results were compared with those obtained in healthy controls matched for age, sex and body mass index.
Results AATD subjects had larger aortic diameters (VS: 3.5±0.5 vs 3.2±0.5 cm, p<0.05; STJ 2.7±0.4 vs 2.4±0.4 cm, p<0.01; AA 3.3±0.5 vs 2.9±0.4 cm, p<0.01; AAr 2.3±0.3 vs 2.1±0.3 cm, p=0.05); greater aortic stiffness 14.9±11.9 versus 7.4±4.4 (pure numbers, p<0.005); and less aortic distensibility 2.4±1.8 versus 4.0±2.6 10−6×cm2×dyne−1, p<0.005. Peak systolic (S) and diastolic (E and A) waves of the aortic wall TDI were similar in patients and controls (S wave: 5.4±1.6 vs 5.9± 2.3 cm/s; E wave: −4.8±2.2 vs −4.5±2.2 cm/s; A wave: −6.1±2.2 vs −6.2±2.4 cm/s) while TDI strain of the aortic wall was lesser in patients than controls (−14.7±8.0% vs −28.3±7.1%, p<0.001).
Conclusions AATD subjects have a larger AA with abnormal elastic properties as compared to controls. The increase in stiffness, decrease in distensibility and abnormal strain of the aortic wall may all reflect pathological changes in its elastic tissue.
- Alpha1-antitrypsin deficiency
- cardiac function
- systolic dysfunction
- diastolic dysfunction
- heart failure
- imaging and diagnostics
- tissue doppler
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- Alpha1-antitrypsin deficiency
- cardiac function
- systolic dysfunction
- diastolic dysfunction
- heart failure
- imaging and diagnostics
- tissue doppler
The most frequent pathological features associated with α1-antitrypsin deficiency (AATD) are panacinar emphysema, often leading to chronic obstructive pulmonary disease, and chronic liver disease. Occasionally, however, the cardiovascular system is involved. Abdominal aortic aneurysm,1 spontaneous dissection of the thoracic aorta,2 coronary artery dissection,3 intracerebral aneurysms4 and cervical artery dissection5 have all been reported as concomitant vascular adverse events. Despite the pathogenesis of the combination of aneurysm and vascular dissection in the presence of AATD being not well established, the reported proportion of mortality accounted for cerebrovascular causes in AATD patients is about 5%.6
α1-Antitrypsin (AAT) is an important glycoprotein that inhibits several proteinases in tissues, especially neutrophil elastase, and its deficiency can promote connective tissue degeneration, mainly in the lung. A reduction in the activity of AAT, however, could also affect the properties of the arterial wall. In fact, elastin, a major component of the elastic lamina that sustains the integrity of the blood vessels, is closely influenced by the elastase levels and the breakdown and reduction of elastic fibres may be important in the loss of vessel tone. Therefore, AATD may be implicated in the development of vascular damage.7
The most common variants of AAT are S and Z, each arising from a single amino acid substitution caused by a mutation. Most homozygotes for the Z allele are affected by lung or liver disease. The very low level of AAT is due to the presence of Z geno/phenotype and possibly may increase the risk of aortic aneurysm. However, the real risk of cardiovascular disease in AATD patients has not been investigated enough to permit firm conclusions.
Epidemiological studies have shown that arterial stiffness is associated with an increased risk of cardiovascular morbidity and mortality.8–12 Arterial stiffness is due to degeneration of elastic fibres, hypertrophy of the vascular smooth muscle cells and increase in collagenous material.12–15 A decreased compliance of the central vasculature alters arterial pressure transmission and flow dynamics and influences cardiac performance and coronary perfusion. In addition, arterial stiffness is independently associated with emphysema severity in patients with chronic obstructive pulmonary disease16 (the main AATD-related lung disorder).
Aortic distensibility can be measured by a non-invasive method such as echocardiography with the same degree of accuracy as direct invasive measurements.17 Aortic function has been assessed by two-dimensional guided M-mode echocardiography of the aortic root combined with simultaneous sphygmomanometry of the brachial artery.18 New echocardiographic technologies such as tissue Doppler imaging (TDI) have been used more recently for assessing aortic function in different clinical settings.19–22
The aim of the study was to measure the ascending aorta (AA) and assess its elastic properties in patients with AATD (all Z homozygotes), compared with sex- and age-matched healthy controls, and also using TDI to investigate the functional characteristics of the aortic root.
Materials and methods
After the approval of the study by the local Ethics Committee (Spedali Civili, Brescia and University of Brescia, Brescia, Italy), we enrolled 33 consecutive subjects with AATD (all Z homozygotes) who were compared with 33 normal consecutive subjects with similar age and gender without AATD (all resulted M homozygotes). All subjects gave written consent to participate in the study. AATD was diagnosed on the basis of the AAT serum level, measured using an immune-nephelometric method (Dade Behring, Deerfield, Illinois, USA; normal range 90–200 mg/dl). Genetic analysis for AAT mutations was done using PCR-mediated site-directed mutagenesis followed by restriction fragment length polymorphism analysis. The subjects and controls received a clinical examination, 12-lead electrocardiography and two-dimensional and Doppler trans-thoracic echocardiography. ECGs were done using Vivid 7 (General Electric Medical Systems, Milwaukee, Wisconsin, USA) equipment with a 3.5 MHz transducer, with the patients in the left lateral decubitus position, in accordance with the standardisation of the American Society of Echocardiography.23 The individuals performing and interpreting ECGs were unaware of whether the subjects belonged to the AATD or control group.
All conventional and TDI measurements were taken in five consecutive cycles and respective means were used for statistical comparison. Systolic and diastolic arterial blood pressure (BP), measured with a conventional sphygmomanometer, and heart rate were recorded during the echocardiographic study.
Aortic size was assessed at four levels: Valsalva sinus (VS), sinotubular junction (STJ), AA and aortic arch at the end of diastole. Aortic elasticity was assessed on the basis of a two-dimensional guided M-mode recording of systolic (AoS) and diastolic (AoD) aortic diameters, 3 cm above the aortic valve. AoD was obtained at the peak of the R wave at the simultaneously recorded electrocardiography, and AoS was measured at the maximal anterior motion of the aortic wall; five measurements were averaged for each diameter.
The following indexes of aortic elasticity were calculated: aortic distensibility =(2(AoS-AoD)/AoD(PP)) (10−6×cm2×dyne−1); aortic stiffness index (SI) = ln(SBP/DBP)/((AoS - AoD)/AoD) (pure number) where systolic blood pressure (SBP) and diastolic blood pressure (DBP) refer to brachial systolic and diastolic arterial BP in mm Hg, respectively; pulse pressure was calculated as SBP-DBP and ln(SBP/DBP) refers to the natural logarithm of the relative pressures ratio.24
Parasternal long-axis recordings of the aortic anterior wall were done using Vivid-7 technology (General Electric Medical Systems) with activated TDI. Two-dimensional tissue velocity images of the aortic wall were obtained at 130±15 frames/s, which implies a temporal resolution of approximately 16 ms. The velocity scale was modified to avoid aliasing. A sample volume was placed in the region of interest on the anterior aortic wall (3 cm above the aortic valve at the same position as in M-mode measurements). TDI wall velocities during systole (Sm), early relaxation (Em) and atrial systole (Am) were measured in both groups. Velocity data sets were analysed off line using a dedicated software (EchoPac; GE Healthcare, Waukesha, Wisconsin, USA), and peak systolic strain was measured from the resulting deformation curves.
All 33 subjects (17 male) had the ZZ genotype with serum AAT serum level amounting to 22.6±5.9 mg/dl. Twenty were ‘index cases’, meaning they had been diagnosed because they had AATD-related disease. Eleven had emphysema, five AATD-related liver disease, one cirrhosis and emphysema, one cirrhosis, one bronchiectasis, and one suffered from cervical artery dissection. Thirteen were ‘not index’ cases, that is to say, they had no AATD-related disease and had been diagnosed because they were related to an index case or because a low level of α1globulin had been detected at electrophoresis. The medical history of control subjects did not reveal any pulmonary disease.
All data were expressed as mean ± SD. Differences between continuous variables were analysed using Student t test and the χ2 test was used for categorical variables. A regression analysis was performed and Spearman's test was employed to analyse correlations between variables. Statistical significance was accepted at p<0.05. MedCalc Statistical Software (Broekstraat, Mariakerke, Belgium) was used for statistical analysis.
The main clinical features of the AATD subjects and controls are shown in table 1. There were no appreciable differences in age, sex, anthropometric measurements, arterial BP or cardiovascular risk factors between the two groups.
Compared with age, body mass index and sex matched controls, the AATD subjects had greater left ventricular (LV) posterior wall and interventricular septum thickness with a greater LV mass than controls. No difference in terms of LV end-diastolic/end-systolic diameter or ejection fraction was observed (table 2). AATD subjects showed larger diameters than controls in all segments of the AA (figure 1, panels A, B, C and D), lower aortic distensibility and greater aortic stiffness (figure 2, panels A and B). Peak systolic (S) and diastolic (E and A) waves of the aortic wall tissue Doppler were similar in AATD subjects and controls (table 2), but tissue strain of the aortic wall was reduced in AATD subjects (figure 2, panel C). LV mass index was significantly increased in AATD subjects (figure 2, panel D). LV mass showed a significant—albeit weak—inverse correlation with aortic distensibility in the AATD subjects (r =−0.31; p<0.05) (figure 3). No different correlation between single parameters of aorta elasticity and LV mass was found looking only at AATD patients with pulmonary emphysema.
The main findings of this study are: (1) subjects with AATD (Z homozygotes) have enlarged aortic diameters (VS, STJ, AA and aortic arch) and abnormal elastic properties of the aorta (increased arterial stiffness and lower distensibility and strain) than controls and (2) AATD subjects also have an increased LV mass. Our results may give a physio-pathological support to several reports of ruptured mesenteric aneurysm and cerebral, carotid or coronary artery dissection in patients with AATD, suggesting that these lesions might result from damage of the elastic fibres of the arterial walls due to an unopposed elastase activity.2–4 25–28
In fact, AAT is an important glycoprotein that inhibits the activity of a number of proteinases in tissues, and its deficiency may play a fundamental role in the spontaneous arterial dissection or aneurysm. By inhibiting proteolytic enzymes like neutrophil elastase, AAT is essential for maintaining the integrity of connective tissue, including the vascular extracellular matrix. Shift in this balance between proteolytic enzymes and their inhibitors could result in breakdown of elastic fibres of the arterial wall. This theory was substantiated in a study that showed an increase of elastase and decrease of AAT activity in aortic tissue from patients with multiple aneurysm and ruptured aortic abdominal aneurysm in comparison with similar tissue from patients undergoing elective repair of aortic abdominal aneurysm or with occlusive aortic disease.29 The available data, however, are controversial. Ahlgren30 and coworkers found lower distensibility in men with AATD and no significant difference in aortic diameter, while another study31 found increased aortic stiffness with AATD supporting our observations. Furthermore, previous studies suggest that individuals with AATD have lower arterial BP and reduced risk of cardiovascular disease,32 while others have observed the opposite.33
Thus, despite data indicating a potential role of AATD in vascular disease, no systematic study has been done on the aortic wall in subjects with AATD. To the best of our knowledge, the present study is the first to investigate the dimensions and elastic proprieties of the AA in AATD subjects assessed by a two-dimensional guided M-mode echocardiography and with the TDI technique. Our observations of abnormal elastic properties of the aorta are consistent with previous studies reporting an abnormal stiffness of the abdominal aortic wall due to a reduction of elastic fibres in rats34 and a significant reduction of AAT in the vascular wall of acutely dissected AA in humans, respectively.2
Aortic distensibility can be recorded by a non-invasive method such as echocardiography with the same degree of accuracy as direct invasive measurements17 and also arterial stiffness can be assessed non-invasively using relating changes in aortic size to distending pressure.24
The findings of reduced aortic distensibility and increased aortic stiffness in the present study indicate that elastic properties of the aortic wall are likely impaired in AATD subjects. Hence, a single routine conventional echocardiographic examination offers multiple advantages, allowing the assessment of LV function, LV mass, pulmonary systolic pressure, valve function and the analysis of the elastic properties of the aortic wall. These measurements may help in the evaluation of the individual risk of AATD subjects.
Another novelty of this study is that we used TDI to examine the aortic wall. The only other studies in which this technique was adopted for studying the aortic wall were those by Vitarelli et al and Harada et al in Marfan syndrome.19 ,20 Strain represents the difference between the reference state of the wall and the state of deformation and is expressed as a percentage of end-systolic aortic wall length. Changes in strain might reflect dynamic tissue alterations in the AA of ZZ phenotype AATD subjects, suggesting early histopathological abnormalities in the vessel wall.
An increased stiffness and a reduced distensibility and TDI strain of the aortic wall might just be a functional consequence of the enlargement of AA, so that an impairment of its elastic properties could be mainly due to geometric factors (ie, aortic dilatation). The correlations, however, among the ascending aortic size parameters, such as VS, STJ and TT diameters, and distensibility, stiffness and TDI strain showed determination coefficients (r2) ranging between 0.30 and 0.13. Hence, the poor relationships we found among distensibility, stiffness and aortic wall strain and different diameters of AA strongly suggest an intrinsic abnormality of the aortic wall rather than a mere effect of its enlarged dimension.
In the absence of cardiovascular risk factors, the increase in LV mass in AATD subjects, as compared with controls, cannot be entirely explained by their decreased aortic distensibility. In fact, although a significant relationship between LV mass and aortic distensibility was present (p<0.05), such correlation was too weak (r =−0.31) and probably other factors must be involved in the heart tissue remodelling in ATTD to explain this finding.
On the basis of these results, a strict control of systemic arterial hypertension and other cardiovascular risk factors in subjects with AATD may be desirable to lower their risk of aortic dissection.
One limitation of this study might be represented by the fact that BP was not recorded continuously and simultaneously with diameter nor was it assessed in the aorta.
In conclusion, this study provides the first demonstration that AATD subjects with ZZ genotype had enlarged aortic diameters and abnormal elastic properties of the aortic wall. Future longitudinal studies are required to investigate the predictive value of these findings.
Considering that α1-antitrypsin deficiency is a genetic disorder that may be a pathogenic factor in vascular aneurysms and dissection, the aim of this study was to measure the diameters of the Valsalva sinuses, sinotubular junction, ascending aorta and aortic arch and elastic properties of the ascending aorta in α1-antitrypsin deficient subjects. We observed that α1-antitrypsin deficient subjects have a larger ascending aorta, with abnormal elastic properties as compared with controls. The increase in stiffness, decrease in distensibility and abnormal strain of the aortic wall may reflect pathological changes in its elastic tissue. To our knowledge, it is the first demonstration that Z-homozygous α1-antitrypsin deficient subjects had enlarged aortic diameters and abnormal elastic properties of the aortic wall.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; internally peer reviewed.
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