Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3752_Библиотеки_им_академика_М_И_Перельмана

Coronary artery calcium has long been known to be associ­ated with atherosclerotic plaque and its development is due to an active process resembling bone formation. Similarly, aortic valve degeneration and calcifi cation appear to follow a pathophysiologic process very similar to atherosclerosis. With non-contrast CT it is possible to detect and accurately quantify the extent of calcifi cation of vessels and cardiac valves offering an opportunity to monitor progression of dis­ease. While interventions have generally failed to slow pro­gression of calcifi cation, it has become apparent that continued progression of coronary artery calcium (CAC) is associated with an increased risk of myocardial infarction and cardiac death, suggesting that there might be some util-

typical plaques with a lipid-rich core and scattered calcifi c granules. As plaques expanded the calcifi c deposits grew. After exposing the animals to a diet severely restricted in cholesterol, the plaques became more fi brotic, with a lower cholesterol content and the calcium deposits stopped growing [ 14 ]. In another experiment Williams et al. [ 15 ] used a monkey model of atherosclerosis to study the effect of medical therapy in addition to diet on atherosclerosis progression and regression. Thirty-two adult (7–10 years of age) male cynomolgus monkeys were fed an atherogenic diet for 2 years (progression phase). During the subsequent 2-year a low cholesterol diet was begun (treatment phase). Additionally, 14 monkeys received pravastatin (20 mg/kg body weight per day), while the diet of the other 18 monkeys was adjusted to maintain equal plasma LDL levels between groups over time. At the end of the treatment phase the total, low density and high-density lipoprotein cholesterol levels were similar in the two animal groups. However, histological analysis of the coronary, carotid and iliac arteries revealed important differences between treatment groups. While the lumen area was not different, pravastatin treated animals showed a reduction in intimal neovascularization, plaque macrophage infi ltration and a decrease in calcifi cation of early as well as advanced plaques. These fi ndings suggested that statins might benefi t the arterial wall in ways that differ from simple lipoprotein lowering. However, Stary [ 16 ], Daoud [ 17 ] and Clarkson [ 18 ] did not fi nd any reduction in calcium deposition in the atherosclerotic plaque with interventions in experiments conducted in swine and monkeys. Hence, although attractive, the histological proof that arterial calcifi cation may regress remains very controversial.

The severity of calcifi cation is assessed by means of quantitative calcium-scores. The fi rst score was developed by Agatston et al. [ 19 ]; this score holds a good correlation with the underlying atherosclerotic plaque burden [ 20 ] and has been used widely in research and clinical trials. The Agatston score is derived by multiplying the area of a calcifi ed plaque by a density coeffi cient rated 1 through 4. This scoring method was shown to have a limited inter-scan reproducibility, especially when used with the older EBCT technology, and new scoring methods were therefore introduced for the purpose of performing reliable sequential studies [ 21 – 23 ]. The calcium volume score (measured in picoliters) is derived using an isotropic interpolation principle and it represents the volume of matter denser than 130 Hounsfi eld units (i.e. calcium) contained in an atherosclerotic plaque. The inter-scan reproducibility of this score is signifi cantly higher than that of the Agatston method [ 21 ].

The mass score was the third and last score to be introduced [ 22 , 23 ]. Though reportedly more reliable and reproducible than the other two scores, to date this measurement has not yet been employed extensively. Another important technical consideration is the method used to report change and the numerous imaging platforms currently available with the various brands and models of CT scanners present on the market. The change in absolute score tends to minimize while a change in percent score exaggerates the difference at follow-up in the presence of small baseline scores (the reverse is true for large baseline scores). A novel method was therefore introduced by Hokanson based on the difference between the square root of the follow-up and the square root of the baseline calcium volume score [ 24 ]. This score is not affected by the baseline score and an increase ≥2.5 is consid­ered a reliable indication of true change. A fi nal word of cau­tion should be reserved for the type of scanner and imaging protocol utilized for sequential imaging; it is unlikely that an Agatston score measured with an original EBCT scanner can be compared with a follow-up scan obtained years later with a high-resolution MDCT. If possible, a patient should be re­scanned with the same equipment and with the same param­eters (slice thickness, voltage, electrocardiographic gating etc.)

Despite these encouraging results, other observational studies [ 34 – 36 ] and several randomized trials [ 37 – 39 ] failed to confi rm an association between LDL lowering and pro­gression of CAC. The BELLES trial (Beyond Endorsed Lipid Lowering With EBT Scanning) was a prospective, ran­domized study of post-menopausal and dyslipidemic women with a minimal calcium volume score of 30 at baseline [ 37 ]. After the initial EBCT scan, the 615 women enrolled were randomized to treatment with atorvastatin 80 mg/day or pravastatin 40 mg/day; a follow-up scan was performed 12 months after randomization (Fig. 6.2 ). The mean LDL cholesterol level was signifi cantly lower with atorvastatin (94 mg/dl) than pravastatin (129 mg/dl). Nonetheless, the median percent change of the calcium volume score was not different between the two treatment arms (15.1 % and 14.3 % for atorvastatin and pravastatin respectively, P = NS). The St. Francis Heart Study [ 38 ] was a prospective, randomized study of 1005 healthy individuals with a CAC score above the 80th percentile for age and sex at screening. The study compared the effect of 20 mg/daily of atorvastatin along with vitamin C and E versus placebo on progression of CAC. At the end of a mean follow-up of 4.3 years the progression was similar among treatment arms (~20 %/year). Schmermund

4.5 years of follow-up the mortality of calcium treated patients was double that of sevelamer treated subjects (haz­ard ratio: 3.2; p < 0.02) [ 63 ]. In contrast with these 2 studies, the investigators of the CARE-2 study were unable to con­fi rm that sevelamer and calcium-acetate phosphate binders affect CAC progression differently and showed an approxi­mate 30 % progression at the end of 1 year for both treatment arms [ 64 ]. In this protocol the investigators meant to ascer- tain whether the effect of sevelamer on CAC progression is due to its lipid lowering ability; therefore they planned to randomize patients to sevelamer or a combination of calcium salts and statins. However, 80 % of the sevelamer treated patients also received statins and this may have caused CAC progression in both arms as shown in the general population (see above). Furthermore, the PTH level of sevelamer treated patients was double that of prior studies [ 58 , 62 ], suggesting a very poor control of mineral metabolism. In a more recent trial cinacalcet and vitamin D, both used to reduce the PTH levels in secondary hyperparathyroidism, were compared as far as their ability to slow CAC progression [ 65 ]. At the end of 1 year of follow-up cinacalcet showed a non-signifi cant

tion of traditional risk factors and HIV-specifi c risk factors, such as chronic infl ammation, proliferation of pro­infl ammatory lymphocytes, endothelial damage and dys­function and global activation of the immune system. HIV infected patients have been demonstrated to have a higher prevalence and larger than expected deposits of CAC [ 69 – 71 ] and CAC seems to progress rapidly in HIV infected patients [ 72 , 73 ]. In addition to traditional risk factors, immunological factors have been associated with the preva­lence and progression of CAC such as nadir CD4 count [ 69 ], HIV infection per se [ 72 ], volume of epicardial fat [ 73 ], and circulating CD16+ monocytes [ 74 ].

The current epidemic of obesity, insulin resistance and dia­betes mellitus in western countries, has generated a strong interest in the potential role of visceral adipose tissue in the development of atherosclerosis and its complications. The intra-abdominal and epicardial adipose tissues (EAT) (Fig. 6.5 ) are highly infl amed in obese patients, patients with the metabolic syndrome and in those with established coronary artery disease; large quantities of pro-infl ammatory

dial infarction was estimated in a cohort of 495 asymptom-

atic individuals submitted to sequential EBCT scanning while undergoing treatment with statins. The mean follow­up was 3 years, men and women were enrolled in equal pro­portions and the mean age of the enrolled subjects was 57 ± 8 years. In spite of an identical average LDL level on treatment (~120 mg/dl in each group), the 41 patients who suffered a myocardial infarction showed a much greater yearly CAC score progression than the 454 event-free survi­vors (42 ± 23 % vs 17 ± 25 %, P < 0.001, Fig. 6.6 ). The inves- tigators further applied a threshold of 15 %/year increase in CAC score to differentiate a true score change from a mea­surement reproducibility error [ 21 ]. Independent of the base- line CAC score patients with an increase smaller than 15 %/ year (i.e no progression from baseline) suffered very few events (N = 5) and the events occurred late during follow-up. On the contrary, the majority of events (N = 36) occurred in patients showing a CAC score progression >15 %/year and the events occurred early during follow-up. Figure 6.7 shows an example of rapid progression of CAC and the occurrence of an acute coronary event in a 64 year old man. In the MESA study [ 81 ] 5862 patients had a baseline and follow-up CAC scan at approximately 2.5 year interval while the median clinical follow-up time was 7.5 years. Progression of CAC was a predictor of incident cardiovascular events both in patients without and those with CAC at baseline. An increase of ≥300 Agatston score units in patients with CAC at base­line was associated with a hazard ratio of 6.3 of developing hard cardiovascular events. In an observational study of 4609 asymptomatic patients, Budoff et al. [ 82 ] performed sequential CT scans an average of 3.5 years from baseline. The intent was to test whether CAC progression measured by three different methods (absolute change, increase >15 %/ year and square root) predicted mortality and which method was the most predictive. During follow-up there were 288 all-cause deaths and CAC progression measured by any of the three methods was predictive of an event, although the square root method was the best model. Finally, three