Atherosclerosis

Study objectives: We noted clinically that patients with aortic root aneurysms and dissections seemed to have little systemic atherosclerosis. It is our objective to determine whether there is a negative association between ascending thoracic aneurysms and systemic atherosclerosis. Design: Atherosclerosis was quantified by evaluating noncontrast CT images of the chest and scoring the degree of calcifications as a marker for atherosclerosis in the coronary arteries and aorta.

Patients: The degree of calcification was compared in 64 patients with aortic root aneurysm (annuloaortic ectasia, 31 patients; type A dissection, 33 patients) vs 86 control subjects. Multivariable analysis was applied to test for an association between aortic root aneurysms and systemic calcification independent of risk factors for atherosclerosis.

Results: Multivariable analysis revealed that patients with ascending aortic aneurysms of the annuloaortic ectasia type and patients with type A dissections had significantly lower overall calcification scores in their arterial vessels compared to patients in the control group (p = 0.03 and p < 0.0001, respectively). These results were independent of all other risk factors for atherosclerosis. Smoking, dyslipidemia, diabetes, and age were all found to increase the degree of atherosclerosis (p < 0.01 to 0.05).

Conclusions: Aortic root pathology (annuloaortic ectasia or type A dissection) is associated with decreased systemic atherosclerosis. It is possible that a mechanism exists whereby the same genetic mutations predisposing patients to ascending aortic aneurysms also exert a protective effect against systemic atherosclerosis.

Key words: aneurysm; aorta; atherosclerosis; dissection

Abbreviations: LAD = left anterior descending coronary artery; LCA = left circumflex coronary artery; MMP = matrix metalloproteinase; RCA = right coronary artery

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It has been a clinical observation at our institution that patients with annuloaortic ectasia who are undergoing aortic root replacement have a noteworthy absence of atherosclerosis of the aorta and coronary arteries. Often, no atheromas at all are visible in any segment of the aorta, much of which is exposed to direct inspection when the aortic arch is opened under deep hypothermic circulatory arrest. At times, not even a single fatty streak, which are nearly ubiquitous in our cardiac surgical population, can be found. The femoral artery, which is exposed for cannulation in patients undergoing ascending aortic surgery, is also commonly soft and pliable, like that in a young person.

We have previously demonstrated the heritable nature of ascending aortic aneurysms and dissection. (1) It is conceivable that the mutations inherent in the aortic diathesis also play a role in the atherosclerotic process. If patients with certain inheritable aortic pathologies exhibit decreased systemic atherosclerosis, this finding would be important by virtue of providing new insights into the pathophysiology of the most common cause of death in the Western world, heart and blood vessel disease due to atherosclerosis. (2)

Our study compares two patient populations with disease of the ascending aorta, patients with annuloaortic ectasia and patients with type A dissection, to a control group that is representative of the general population (without any aortic pathology). Calcification in the coronary arteries and aorta was used as a marker for atherosclerosis and was quantified by evaluating CT scans of the chest without or prior to IV contrast medium administration.3

MATERIALS AND METHODS

Patient Population

Patients who had undergone surgical repair of the aortic root aneurysm (annuloaortic ectasia or type A dissection) and nonsurgical patients who had undergone aortic root dilatation were extracted from the Yale Center for Thoracic Aortic Disease database4 for study from the period covering 1997 to 2004. Our study population consisted of 31 patients with an aortic root dilatation of the annuloaortic ectasia type and 33 patients with type A dissection, either acute (27 patients) or chronic (6 patients) who were between the ages of 36 and 82 years. Of the patients with annuloaortic ectasia, 25 patients had undergone repair of the aortic root utilizing a composite graft to replace the valve and aorta with reimplantation of the coronary arteries (modified Bentall operation (5)) prior to the date of their CT scans. Of the patients with type A dissection, 19 were evaluated by reading postoperative CT scans. The CT scans of all other patients were performed preoperatively.

As a control group, we retrospectively evaluated 128 trauma patients who had presented to our emergency department and had undergone a CT scan without IV contrast medium as part of a trauma workup between 1997 and 2004. We excluded 21 patients because they were deemed too young to show calcification on their CT scan (using age > 35 years as the criterion for study inclusion). Furthermore, 6 control patients were excluded because of incidental aortic pathology (aortic aueurysms and aortic stenosis), 10 control patients were excluded because they carried the diagnosis of chronic renal failure (which .alters calcium metabolism), and 5 control patients were excluded because of unobtainable cardiac risk factor profiles. A total of 86 patients remained in the control group.

Patients with Marfan syndrome were excluded from this investigation. This investigation looked specifically at patients with non-Martian annuloaortic ectasia. Our study was approved by the Human Investigation Committee at Yale University School of Medicine.

Risk Factor Analysis

All patients were evaluated for the presence or absence of the following risk factors for atherosclerosis and calcification, which were included as multiple dichotomous independent variables in our analysis:

1. Hypertension, as documented in the chart or defined by antihypertensive treatment;

2. Diabetes mellitus, as documented in the chart or defined by hypoglycemic treatment;

3. Tobacco use (past or present);

4. Illicit drug use (past or present);

5. Dyslipidemia, defined by history or by a fasting LDL level of > 160, an HDL level of < 40, a triglyceride level of > 150, or a total cholesterol value of > 200;

6. Gender; and

7. Obesity, defined as a calculated body mass index of > 30.

The two study groups were encoded as multiple dichotomous variables as well. Age at the time of the CT scan was included as an interval-independent variable.

Calcification Scoring

CT scans of the chest performed without IV contrast in all patients were read by an experienced chest radiologist in a blinded fashion and were analyzed for the degree of calcification in the coronary arteries and aorta. The three coronary arteries, the right coronary artery (RCA), left anterior descending (LAD) artery, and the left circumflex coronary artery (LCA), were analyzed separately. Similarly, the aorta was divided into four segments, and each segment was evaluated separately, as follows:

1. Ascending aorta, defined by the aortic annulus proximally and the brachiocephalic artery distally;

2. Aortic arch, defined as the segment between the brachiocephalic artery proximally and the left subclavian artery distally;

3. Descending thoracic aorta, defined by the left subclavian artery proximally and the diaphragm distally; and

4. Abdominal aorta, defined by the diaphragm proximally and the renal arteries distally.

A calcification score was allocated to each coronary artery and aortic segment, with 0 points to denote the absence of calcium, 1 point to denote a small number (three or fewer) of minimal flecks (flecks were < 1 mm in greatest dimension), 2 points for more than three minimal flecks or larger noncircumferential calcification ranging from 1 to 3 mm in its greatest extent, and 3 points for any calcification > 3 mm in greatest extent or circumferential calcification.

The total score for a given patient could therefore range from 0 points for no calcifications to 21 points for a 3-point calcium score in each of the seven segments of vasculature that were analyzed. Patients who had received a prosthetic graft in place of their ascending aorta (as was the case in all patients operated on) or whose CT scan did not include the abdominal aorta were not scored for those specific parts. Since almost all patients in the annuloaortic ectasia study group had undergone a Bentall operation, we decided to disregard all calcification scores of the ascending aorta for all patients in our statistical analysis.

Statistical Analysis

We used [chi square] statistics for categoric variables and t tests for continuous variables. Multivariate linear regression analysis was performed for the overall degree of calcification, and logistic regression analysis was applied for the individual arterial segments evaluated. We used a statistical software package (SAS, version 8.2; SAS Institute; Cary, NC). The p values were two-tailed, and a p value of < 0.05 was considered to be significant.

Because the majority of the individual artery segments that were positive for calcification had a score of 3, we decided to convert each outcome score to a dichotomous variable for the calcification that Was present (calcification scores 1, 2, and 3) or absent (calcification score 0). [chi square] analysis was performed to test for significant differences in the patients' baseline characteristics using the Mantel-Haenszel [chi square] test. For observations with calcification scores [less than or equal to] 3, we used the Fisher exact test. There were no statistically significant differences between the groups for the independent variables obesity and illicit drug use. Moreover, preliminary statistical analyses did not suggest that either factor was an independent predictor of calcification. Hence, we excluded them from the analysis to increase the overall power of the study. For the overall calcification score, 28 observations were missing for calcification in file abdominal aorta. In these eases, we imputed the abdominal calcification score. More specifically, for subjects with a dissection for whom no abdominal calcification score was observed, we used the average abdominal calcification score among those subjects with dissections for whom such scores were observed. A similar procedure was followed for annuloaortic ectasia subjects and control subjects. In addition to the multiple linear regression results reported herein, we also performed a regression analysis, which added a binary variable indicating whether or not the abdominal value had been imputed. This variable was highly insignificant. Furthermore, including this variable had virtually no effect on the other variables in the model. Finally, we estimated the values for the model excluding the 28 subjects for whom abdominal measures were missing. This also yielded results similar to those reported in the text.

RESULTS

Patient Characteristics

Table 1 lists all of the baseline characteristics for both groups. In both study groups, we observed a higher prevalence of hypertension (87% of annuloaortic ectasia patients and 85% of type A dissection patients vs 59% of control patients). Similarly, there were more dyslipidemic patients in the study groups (45% of annuloaortic ectasia patients and 48% of type A dissection patients vs 24% of control group patients). [chi square] analysis indicated that both study groups were significantly more likely to have hypertension and dyslipidemia compared to the control group (dissection patients, p = 0.009 and p = 0.012, respectively; annuloaortic ectasia patients, p = 0.005 and p = 0.031, respectively). Whereas the fraction of patients in the annuloaortic ectasia group with a history of smoking (48%) was comparable to that of the control group (41%), we found that the majority of patients with type A dissections were present or past smokers (70%). Again, this difference reached statistical significance (p = 0.005). Even though control group patients were more likely to be diabetic (21%) than patients in either the annuloaortic ectasia group (10%) or the type A dissection group (6%), this difference did not reach statistical significance (p = 0.186 and p = 0.059, respectively).

Outcome Analysis

We found more patients with calcifications in the control group than in the two study groups for all of the three coronary arteries evaluated. The same results were noted for the different aortic segments analyzed (ie, aortic arch, thoracic aorta, and abdominal aorta) [Table 2].

Based on the logistic regression analyses, we found a negative association between atherosclerosis and either of the two study groups (aneurysm and dissection) for each coronary artery and aortic segment. This is illustrated in Figure 1, by odds ratios for calcification at each segment of the vasculature being smaller than 1 in both study groups. Importantly, these odds ratios (Table 3) were calculated independently from all other risk factors for atherosclerosis.

[FIGURE 1 OMITTED]

We also investigated the overall calcification score, which was defined as the sum of calcification scores of each aortic segment for each patient. Multivariable regression analysis revealed that patients with ascending aortic aneurysms of the annuloaortic ectasia type and patients with type A dissections have significantly lower overall calcification scores in their arterial vessels compared to patients in the control group (p = 0.03 and p < 0.0001, respectively). Specifically, patients with type A dissection had the strongest negative association with atherosclerosis, exhibiting overall calcification scores that were 3.7 points (regression coefficient, -3.73) less than those for the control group (Table 3). Patients with annuloaortic ectasia had calcification scores that were almost 2 points lower (regression coefficient, -1.84). Again, these results were independent of all other risk factors, such as diabetes mellitus or hypertension. Figure 2 illustrates these negative associations of an ascending aortic aneurysm and type A dissection with calcification. The independent effects of the other risk factors are depicted as well.

[FIGURE 2 OMITTED]

All other independent variables were associated with an increased risk for calcification. The average increase of calcium among hypertensive patients (regression coefficient, 0.94) and male patients (regression coefficient, 0.42) did not reach statistical significance (p = 0.21 and p = 0.51, respectively). However, a history of diabetes mellitus (p = 0.03), smoking (p = 0.004), or dyslipidemia (p = 0.008) and age (p < 0.0001) all posed a highly significant risk for increased calcification. The corresponding regression coefficients are displayed in Table 3.

DISCUSSION

The results of this study were consistent with our prior clinical impression that aortic root disease (ie, annuloaortic ectasia or type A dissection) is associated with a lower prevalence of systemic atherosclerosis. We found a lower prevalence of calcification (a marker for atherosclerosis) in our study groups independent of the major risk factors for atherosclerosis (ie, age, gender, dyslipidemia, hypertension, diabetes mellitus, and smoking history).

Although the study groups and control group differed in the prevalence of the various risk factors for atherosclerosis, our multivariable analyses allowed us to calculate the association of aortic disease independent of the effects of each risk factor for atherosclerosis (eg, diabetes mellitus or hypertension).

Supporting Evidence From the Literature

Our findings are consistent with related studies in the literature. A lower incidence of coronary artery disease was found among patients with thoracic aortic dilatation compared to those with the same pathology in the abdominal aorta. (6,7) Furthermore, autopsied cases revealed a lower incidence of atherosclerosis in type A dissections compared to type B dissections, (8) and in type A dissections compared to abdominal aortic aneurysms. (9) However, the literature is deficient in systematic comparisons between the degree of atherosclerosis in patients with thoracic aortic aneurysms and the general population.

We chose to use trauma patients as representative of the general population, because these patients did not have any known aortic pathology but had undergone CT scans of the chest. Assuming that the degree of calcification is a true marker of the degree of atherosclerosis, (3) our results indicate that patients with ascending aortic aneurysms and those with type A dissections exhibit significantly less atherosclerosis than may be found in the general population.

Limitations of the Study

Our study does have inherent limitations. A problem with our method of evaluating the CT scans for calcification is that the CT scans cannot be analyzed 2in a totally blinded fashion. The CT scans of some study group patients could be identified as such by noting the aortic aneurysm or prosthetic graft in the ascending aorta. Nevertheless, we feel the calcification scores were accurately determined since they had been performed by an expert chest radiologist who was impartial with regard to study outcome. Calcification is a late finding in atherosclerosis. In future investigations, we plan to look at additional indexes of atherosclerosis, such as carotid artery thickness. Another limitation of our study is that we probably overestimated the prevalence of hypertension in the study groups by classifying ,all patients receiving BP-lowering medication as hypertensive. Some patients with aneurysms, however, might be receiving BP-lowering medications for the sole purpose of preventing future rupture or dissection of their aneurysms.

Possible Mechanism for Our Findings

We can think of three possible mechanisms to explain our observations:

1. Arterial calcification hinders aneurysmal dilatation of the aorta. If indeed calcification of the arterial vasculature would prevent aneurysmal dilation of the aorta, one would expect an absence of calcification in patients with abdominal aortic aneurysms. However, this is clearly not the case.

2. A hemodynamic effect exerted by the morphologic change of the ascending aorta reduces the incidence of atherosclerosis. Several studies (10,11) have found decreased aortic wall compliance in aortic aneurysms. Such a decrease in compliance and Windkessel properties should lead to an increase in systolic BP, a decrease in diastolic BP, and consequent pulse pressure widening. (12,13) However, an increase in pulse pressure is thought to increase the risk of atherosclerosis rather than to exert a protective effect. (14)

3. A genetic effect caused by the same mutations that render these patients susceptible to aneurysms protects them from systemic atherosclerosis. Gene mutations are thought to be responsible for the progressive loss and destruction of elastic fibers, smooth muscle cells, and ground substance in the aortic media, thereby causing thoracic aortic aneurysms and dissections. (1,15) Dissections can be regarded as the end point in this disease process. (16) If the same gene mutations would exert a protective effect against atherosclerosis, one might expect a higher degree of protection in patients with dissections. This was indeed observed in our study.

We and others have found an altered balance of matrix metalloproteinases (MMPs), which are proteolytic enzymes that degrade extracellular matrix components, such as collagen and elastin, in our aneurysm and dissection patients. (17) A hypothesis has been described (18,19) that some MMPs are actually proaneurysmal and antiatherogenic at the same time. Consistent with this hypothesis is the observation that polymorphisms in the human MMP-3 promoter leading to decreased expression of this gene have been correlated with a more rapid progression of angiographically documented coronary atherosclerosis. (20,21) Interestingly, the gene for MMP-3 maps to chromosome 11q23; a very similar region was identified as a locus to harbor mutations that are responsible for familial aortic aneurysms (11q23.3-q24). (22) In close proximity (11@2.3) are also located the genes for MMP-1, MMP-7, MMP-8, MMP-10, MMP-12, and MMP-13. (23) It is conceivable that mutations in either of these genes could not only predispose the patient to the development of aortic aneurysms but also could decrease the propensity for the formation and progression of atherosclerotic lesions.

CONCLUSION

We conclude that ascending aortic aneurysms (annuloaortic ectasia and type A dissection) are associated with decreased systemic atherosclerosis. While the mechanism of a genetic protection against atherosclerosis in patients with thoracic aneurysms remains speculative, we think that a genetic mechanism is the most compelling cause.

REFERENCES

(1) Coady MA, Davies RR, Roberts M, et al. Familial patterns of thoracic aortic aneurysms. Arch Surg 1999; 134:361-367

(2) Hoyert DL, Arias E, Smith BL, et al. Deaths: final data for 1999. Natl Vital Stat Rep 2001; 49:1-113

(3) Allison MA, Criqui MH, Wright CM. Patterns and risk factors for systemic calcified atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24:331-336

(4) Rizzo JA, Coady MA, Elefteriades JA. Interpreting data on thoracic aortic aneurysms: statistical issues. Cardiol Clin 1999; 17:797-805, x

(5) Hagl C, Strauch JT, Spielvogel D, et al. Is the Bentall procedure for ascending aorta or aortic valve replacement the best approach for long-term event-free survival? Ann Thorac Surg 2003; 76:698-703

(6) Islamoglu F, Atay Y, Can L, et al. Diagnosis and treatment of concomitant aortic and coronary disease: a retrospective study and brief review. Tex Heart Inst J 1999; 26:182-188

(7) Agmon Y, Khandheria BK, Meissner I, et al. Is aortic dilatation an atherosclerosis-related process? Clinical, laboratory, and transesophageal echocardiographic correlates of thoracic aortic dimensions in the population with implications for thoracic aortic aneurysm formation. J Am Coll Cardiol 2003; 42:1076-1083

(8) Nakashima Y, Kurozumi T, Sueishi K, et al. Dissecting aneurysm: a clinicopathologic and histopathologic study of 111 autopsied cases. Hum Pathol 1990; 21:291-296

(9) Kojima S, Suwa S, Fujiwara Y, et al. Incidence and severity of coronary artery disease in patients with acute aortic dissection: comparison with abdominal aortic aneurysm and arteriosclerosis obliterans. J Cardiol 2001; 37:16.5-171

(10) Wilson K, Whyman M, Hoskins P, et al. The relationship between abdominal aortic aneurysm wall compliance, maximum diameter and growth rate. Cardiovasc Surg 1999; 7:208-213

(11) Koullias GJ, Modak R, Tranquilli M, et al. Mechanical deterioration underlies malignant behavior of aneurysmal human ascending aorta. J Thorac Cardiovasc Surg 2005 (in press)

(12) Nagai Y, Helwegen J, Fleg JL, et al. Associations of aortic Windkessel function with age, gender and cardiovascular risk factors. Ultrasound Med Biol 2001; 27:1207-1210

(13) Maeta H, Hori M. Effects of a lack of aortic "Windkessel" properties on the left ventricle. Jpn Circ J 1985; 49:232-237

(14) Dart AM, Kingwell BA. Pulse pressure: a review of mechanisms and clinical relevance. J Am Coil Cardiol 2001; 37:975-984

(15) Guo D, Hasham S, Kuang SQ, et al. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation 2001; 103: 2461-2468

(16) Muller BT, Modlich O, Prisack HB, et al. Gene expression profiles in the acutely dissected human aorta. Eur J Vasc Endovasc Surg 2002; 24:356-364

(17) Koullias GJ, Ravichandran P, Korkolis DP, et al. Increased tissue microarray matrix metalloproteinase expression favors proteolysis in thoracic aortic aneurysms and dissections. Ann Thorac Surg 2004; 78:2106-2110

(18) Bendeck MP. Matrix metalloproteinases: are they antiatherogenic but proaneurysmal? Circ Res 2002; 90:836-837

(19) Silence J, Collen D, Lijnen HR. Reduced atherosclerotic plaque but enhanced aneurysm formation in mice with inactivation of the tissue inhibitor of metalloproteinase-1 (TIMP-1) gene. Circ Res 2002; 90:897-903

(20) Ye S, Watts GF, Mandalia S, et al. Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J 1995; 73:209-215

(21) Humphries SE, Luong LA, Talmud PJ, et al. The 5A/6A polymorphism in the promoter of the stromelysin-1 (MMP-3) gene predicts progression of angiographically determined coronary artery disease in men in the LOCAT gemfibrozil study: Lopid Coronary Angiography Trial. Atherosclerosis 1998; 139:49-56

(22) Vaughan CJ, Casey M, He J, et al. Identification of a chromosome 11q23.2-q24 locus for familial aortic aneurysm disease, a genetically heterogeneous disorder. Circulation 2001; 103:2469-2475

(23) Pendas AM, Santamaria I, Alvarez MV, et al. Fine physical mapping of the human matrix metalloproteinase genes clustered on chromosome 11q22.3. Genomics 1996; 37:266-268

* From the Section of Cardiothoraeic Surgery (Drs. Achneck, Modi, Albornoz, Fusco, and Elefteriades), and the Department of Diagnostic Imaging (Dr. Shaw), Yale University School of Medicine, New Haven CT. and the Division of Evaluative Sciences (Dr. Rizzo), Department of Preventive Medicine at Stony Brook University School of Medicine, Stony Brook, NY. Manuscript received March 10, 2005; revision accepted March 17, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: John A. Elefteriades, MD, Section of Cardiothoracic Surgery, Yale University School of Medicine, 333 Cedar St, 121 FMB, New Haven, CT, 06520; e-mail: john.elefteriades@ yale.edu

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