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No correlation and low agreement of imaging and inflammatory atherosclerosis’ markers in familial hypercholesterolemia

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Lilton R.C. Martinez MD, Marcio H. Miname MD, Luiz A. Bortolotto MD, Ana P.M. Chacra MD, Carlos E. Rochitte MD, Andrei C. Sposito MD, Raul D. Santos MD,PhD.

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  • 1. No correlation and low agreement of imaging and inflammatory atherosclerosis’ markers in familial hypercholesterolemia Lilton R.C. Martinez MD, Marcio H. Miname MD, Luiz A. Bortolotto MD, Ana P.M. Chacra MD, Carlos E. Rochitte MD, Andrei C. Sposito MD, Raul D. Santos MD,PhD. Lipid Clinic Heart Institute InCor-University of Sao Paulo Medical School Hospital Sao Paulo, Brazil Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 2. Background
    • Familial hypercholesterolemia (FH) is the most frequent
    • monogenic hereditary disorder in the general population.
    • If left untreated, 85% of males and 50% of females with
    • FH will suffer a premature coronary heart disease (CHD)
    • event, and as many as 30% of these patients will not survive
    • their first myocardial infarction.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 3. Background
    • However, there is evidence indicating that the clinical course of CHD in FH is variable in its onset and severity, with some patients developing clinical manifestations earlier than others despite elevated LDL-C levels.
    • The use of inflammatory biomarkers, as well as imaging markers of subclinical atherosclerosis has been proposed as tools to improve CHD risk stratification in FH subjects.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 4. Background
    • So far the relation between inflammatory biomarkers like high sensitivity C-reactive protein (CRP), white blood cell count (WBC) and imaging markers of carotid and coronary subclinical atherosclerosis e.g. carotid intima media thinckness (IMT), coronary artery calcification (CAC) and markers of aortic stiffness such as carotid-femoral pulse wave velocity was not yet explored concomitantly in FH subjects.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 5. Objective
    • Our purpose was to study the determinants of coronary and carotid subclinical atherosclerosis as well as aortic stiffness and their relation in FH subjects.
    • Furthermore, the agreement degree of imaging and inflammatory biomarkers’ severity used to predict CHD risk was evaluated.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 6. Methods
    • 89 FH (34 males, mean age 39 ± 14 years, range 14-69 years) and 31 normal subjects (NL) (16 males, 40 ± 12years) were studied.
    • Coronary calcium score quantification was performed with the AquillionR 16-64 multiple detector computerized tomography (MDCT) scanner ( Toshiba Medical Systems Corporation, Otawara, Japan).
    • Calcium scores were calculated by the Agatston’s method.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 7. Methods
    • Aortic stiffness was evaluated by carotid-femoral pulse wave velocity (PWV) with Complior (Colson, Garges les Gonesses, France).
    • Carotid intima media thickness (IMT) was determined on the right common carotid artery with an automated ultrasonographic “echotracking” device, Wall-Track System2 (PIE MEDICAL, Maastricht, Netherlands), with a probe of 7.5 MHz.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 8. Methods
    • Clinical CHD risk stratification: CHD risk was calculated by 2 methods
    • 1-Total 10-year CHD risk was calculated by Framingham risk scores (FRS).
    • 2-Clinical and laboratory risk factors, proposed by Civiera et al. for FH subjects:
      • age >30 years for men, and >45 years for women,
      • smoking, high blood pressure, diabetes,
      • early history of CHD in the family,
      • HDL-C <40 mg/dl,
      • LDL-C >330 mg/dl,
      • Lp(a) >60 mg/dl.
    • FH patients were considered at high risk for CHD if had >2 risk factors.
    . Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 9. Methods
    • Imaging and inflammatory markers severity:
    • CCS >75th% for age and sex
    • IMT >900 μ m
    • PWV >12 m/s
    • CRP levels >3 mg/l
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 10. Methods
    • Statistical analysis
    • The determinants of IMT, CAC and PWV were evaluated by multivariate analysis.
    • CAC was explored as both continuous Log(CCS+1) and categorical variables (CAC>0 vs CAC=0)
    • The agreement degree of markers’ severity was determined by kappa statistics.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 11. Results
    • Table 1: Clinical characteristics of FH patients and NL subjects
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014 0.001 3 (9.6 %) 80 (89.9 %) Family history of early CHD 0.001 0 (0%) 26 (29.2 %) Xanthomas, n (%) 0.0003 0 (0%) 28 (31.5%) Previous statin use, n (%) 0.18 1 (3 %) 12 (13.5 %) Metabolic Syndrome, n (%) 0.002 3.2 ± 2.9 6.7 ± 5.7 FRS (% 10 years) 0.54 76 ± 6 77 ± 9 DBP (mmHg) 0.14 117 ± 8 121 ± 14 SBP (mmHg) 0.18 1 (3.2 %) 12 (13.5 %) Hypertension, n (%) 0.22 3(9.6 %) 13(14.6 %) Smoking habit, n (%) 0.024 0.95 ± 0.05 0.92 ± 0.06 Waist/hip 0.1 91 ± 12 95 ± 10 Hip (cm) 0.8 87 ± 11 88 ± 12 Waist (cm) 0.14 24.7 ± 3.5 25.9 ± 4.9 BMI (kg/m 2 ) 1.0 24 (77.4 %) 68 (76.4 %) Caucasians n (%) 0.19 16 (51.6 %) 34 (38.2 %) Male, n (%) 0.85 40 ± 12 (19-69) 39 ± 14 (14-69) Age, years (ranges) P NL (n=31) FH (n=89)
  • 12. Results
    • Table 2: Laboratorial characteristics of the FH patients and NL subjects
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014 < 0.001 4,089 ± 1,673 10,736 ± 4,809 LYS (LDL-c x age) 0.046 6,452 ± 1,546 7,198 ± 2,083 White blood cells 10 3 /mm 3 0.39 1.3( 0.2-8) 1.7 (0.2-34) CRP (mg/l) median (range) < 0.001 11 (1-127) 39 (1-282) Lp(a) (mg/dl) median (range) < 0.001 0.5 ± 0.2 1.3 ± 0.5 Apolipoprotein B/Apolipoprotein A-I < 0.001 0.8 ± 0.2 1.6 ± 0.5 Apolipoprotein B (g/l) 0.008 1.48 ± 0.2 1.33 ± 0.3 Apolipoprotein A-I (g/l) 0.14 88 ± 11 94 ± 29 Glucose (mg/dl) < 0.001 1.6 ± 1.1 2.9 ± 1.7 TG/HDL-cholesterol < 0.001 83 ± 36 133 ± 58 TG (mg/dl) < 0.001 119 ± 29 309 ± 99 Non HDL-cholesterol (mg/dl) < 0.001 2.0 ± 0.8 6.0 ±2.8 LDL-cholesterol/HDL-cholesterol < 0.001 102 ± 26 279 ± 97 LDL -cholesterol (mg/dl) 0.08 55 ± 13 50 ± 13 HDL - cholesterol (mg/dl) < 0.001 174 ± 27 359 ± 97 TC (mg/dl) P NL (n=31) FH (n=89)
  • 13. Results
    • In comparison with NL FH patients presented
    • (see table 3):
    • almost three times more CAC than NL (p = 0.024),
    • almost six times more subjects with CCS > 75 th % for age and gender (p = 0.041),
    • higher CCS than NL (p = 0.026).
    • higher Carotid IMT (p = 0.027),
    • higher aortic PWV values (p = 0.007)
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 14. Table 3: CAC, IMT and PWV in FH patients and NL subjects. Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014 0.026 0.02 0 (0-54) 4.5 ± 13 0 (0-798) 46 ± 140 CCS Agatston units median (ranges) mean ± SD 0.87 6623 ± 796 6596 ± 772 Carotid diameter (μm) 0.99 460 ± 178 461 ± 194 Carotid distension (μm) 0.027 593 ± 111 653 ± 160 Carotid IMT (μm) 0.007 8.5 ± 1 9.2 ± 1.5 PWV (m/s) 0.041 1 (4%) 21 (23%) CCS ≥ 75 th % 0.024 3 (12%) 30 (34%) CAC prevalence n (%) P NL (n=31) FH (n=89)
  • 15. Table 4: Univariate determinants of CAC as continuous and dichotomous variable, IMT and PWV in FH patients 0.08 - - - - - Male gender CAC dichotomous p= p = Log(CCS+1) r = p = PWV r = p = IMT r = Determinants 0.001 0.002 0.33 - - 0.0001 0.55 Carotid diameter (μm) 0.014 0.007 0.29 - - - - PWV (m/s) - 0.02 0.26 0.0008 0.35 - - IMT (μm) - - - 0.003 0.32 0.02 0.26 Log (CCS+1) - 0.04 0.23 - - Apolipoprotein A-I (g/l) 0.0036 0.008 0.28 0.02 0.26 - - Lp(a) (mg/dl) - - - - 0.05 0.22 Apolipoprotein B (g/l) - - - - 0.01 0.28 CRP (mg/l) - - - 0.01 0.26 0.02 0.26 Glucose (mg/dl) 0.024 0.02 0.25 - - 0.03 0.24 TG / HDL- cholesterol 0.02 0.01 0.27 0.03 0.24 0.03 0.23 TG (mg/dl) - 0.04 0.22 - - - - LDL-cholesterol /HDL- cholesterol 0.044 0.02 0.25 - - - - LDL-cholesterol (mg/dl) 0.02 0.25 - - - - Total cholesterol (mg/dl) <0.001 0.0001 0.51 0.0001 0.52 0.003 0.32 LYS <0.001 0.0001 0.48 0.0002 0.39 0.006 0.29 Civiera (high risk) <0.001 0.0001 0.54 0.0001 0.44 0.0001 0.40 FRS - - - - 0.005 0.31 PP (mmHg) - - 0.01 0.27 0.009 0.28 DBP. (mmHg) - - 0.02 0.26 0.0003 0.39 SBP (mmHg) 0.04 - - - - - - Xanthoma 0.001 - - - - - - Metabolic Syndrome <0.001 0.0001 0.43 0.0001 0.62 0.002 0.33 Age (years)
  • 16. Carotid IMT determinants
    • Parameters associated with carotid IMT in univariate analyses are shown in table 4.
    • The following parameters were independently associated with IMT in multivariate linear regression analyses:
      • FRS (r 2 = 0.36 p = 0.0001),
      • Apo B (r2 = 0.032, p = 0.02)
      • systolic blood pressure (r2 = 0.26, p = 0.0045).
    • Considered these three variables explained only one third of IMT variability in FH subjects (r 2 = 0.33, p = 0.001).
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 17. Aortic stiffness determinants
    • Parameters associated with PWV in univariate analyses are shown in table 4.
    • Multivariate linear regression analyses:
    • only age was independently correlated with PWV
    • (r 2 = 0.37, p = 0.0001), explaining 37% of its variability.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 18. CAC determinants Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
    • Parameters associated with presence of CAC as dichotomous in univariate analyses (table 4).
    • Multivariate logistic analyses:
    • FRS (p = 0.0027),
      • FRS > 5.5% had an odds ratio = 6.15 (95% CI: 2.28-6.56)
      • (sensitivity = 74% and specificity = 69%).
    • LYS (LDL x year score) (p = 0.0228)
      • LYS > 10,797 (in a mean age of 38.5 years correspond a LDL-C of 280 mg/dl, for example) had an odds ratio = 9.86 (95% CI: 3.48–27.89)
    • ROC analysis, showed areas under the curve for
      • LYS 0.82
      • FRS 0.80
  • 19. CAC Intensity
    • Parameters associated with intensity of CAC e.g. log (CCS + 1) as a continuous variable in univariate analyses (table 4).
    • Multivariate regression analyses,
    • male gender (r 2 = 0.29, p = 0.0001)
    • LYS (r2 = 0.36, p = 0.0027).
    • Considering these two variables,
    • it was possible to explain 31% of the CAC intensity variability (r 2 = 0.31, p = 0.0009).
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 20. Table 5: Agreement degree of imaging and inflammatory markers severity in FH subjects Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014 With exception of moderate agreement between IMT and PWV severity (kappa = 0.517) all other markers of severity presented only a slight agreement (kappa < 0.1). 0.031 CRP > 3 (mg/l) PWV > 12 (m/s) 0.064 CRP > 3 (mg/l) IMT > 900 (μm) 0.517 PWV > 12 (m/s) IMT > 900 (μm) 0.16 CRP > 3 (mg/l) CCS > 75 th % 0.004 PWV > 12 (m/s) CCS > 75 th % 0.109 IMT > 900 (μm) CCS > 75 th % kappa
  • 21. Conclusions
    • To our knowledge, this is the first study evaluating simultaneously subclinical coronary and carotid atherosclerosis,
    • aortic stiffness and inflammatory biomarkers in FH subjects.
    • Notwithstanding that CAC, PWV, and IMT values were higher in FH subjects than in NL, these markers poorly correlated among each other in univariate analysis and this correlation disappeared after adjustment for confounders.
    • Furthermore inflammatory markers did not correlate with IMT, CAC or PWV.
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014
  • 22. Conclusions (cont)
    • With exception of moderate agreement between severity of IMT and PWV all other markers of severity presented only a slight agreement.
    • The poor or absent correlation among imaging markers and the low agreement degree of their severity might have prognostic implications
    Martinez LRC et al . Atherosclerosis (2008), doi:10.1016/j.atherosclerosis.2007.12.014