COI Disclosure I have no conflict of interest to disclose I have no conflict of interest to disclose

Calcium is Strongly Correlated with Necrotic Core in Human Coronary Arteries: Insights from the Multicenter VH-IVUS Registry Eduardo Missel, Gary S. Mintz, Stephane G. Carlier, Koichi Sano, Joanna Lui, Roxana Mehran, Jeffrey Moses, Gregg W. Stone, and Martin B. Leon Cardiovascular Research Foundation Columbia University Medical Center New York – NY - USA European Society of Cardiology Congress 2007 Vienna - Austria

I - Background Unstable and/or ruptured plaques: Unstable and/or ruptured plaques: - Larger necrotic core content (Histopathology) - Less quantitative calcium with a “spotty” pattern (IVUS) when compared to stable/non-ruptured plaques, HOWEVER… Calcification in the coronary tree is a predictor of coronary events (EBCT) Calcification in the coronary tree is a predictor of coronary events (EBCT) The “coronary calcification paradox”

II- Methods Allows spectral analysis of radiofrequency (RF) ultrasound backscatter; Allows spectral analysis of radiofrequency (RF) ultrasound backscatter; 80-92% ex-vivo and % in vivo accuracy for characterization of basic plaque components 80-92% ex-vivo and % in vivo accuracy for characterization of basic plaque components Virtual Histology Fibrous tissue (FI) Fibro-fatty (FF) Dense calcium (DC) Necrotic core (NC)

II - Methods Study protocol Study protocol Between August 2004 to July patients in 42 centers were enrolled in the prospective, multi-center, non-randomized VH- IVUS registry Between August 2004 to July patients in 42 centers were enrolled in the prospective, multi-center, non-randomized VH- IVUS registry We identified 625 patients with a de novo coronary lesion who were studied with either diagnostic or pre-interventional VH-IVUS. We identified 625 patients with a de novo coronary lesion who were studied with either diagnostic or pre-interventional VH-IVUS.

II - Methods VH-IVUS imaging protocol A phased-array, 20MHz, 3.2Fr IVUS catheter was placed at a branch distal to the lesion A phased-array, 20MHz, 3.2Fr IVUS catheter was placed at a branch distal to the lesion A motorized pull-back through the diseased segment was performed at 0.5mm/s to a point proximal to the lesion site A motorized pull-back through the diseased segment was performed at 0.5mm/s to a point proximal to the lesion site Grey-scale IVUS was recorded, raw RF data was captured at the top of the R wave, and a color-coded VH-IVUS map was generated Grey-scale IVUS was recorded, raw RF data was captured at the top of the R wave, and a color-coded VH-IVUS map was generated

II - Methods Data Analysis Off-line volumetric reconstruction of the four tissue types along the whole diseased segment was performed using pcVH 2.1 software Off-line volumetric reconstruction of the four tissue types along the whole diseased segment was performed using pcVH 2.1 software The four VH-IVUS plaque components were measured in every recorded frame, and expressed as The four VH-IVUS plaque components were measured in every recorded frame, and expressed as - Mean analysis segment CSA (mm2) - Absolute volume (mm3) - Percentages of total plaque volume (%)

III - Results Baseline patients characteristics (n=625) Age (years)62±11 Male gender, # (%)473 (76) Current smoker, # (%)157 (25) Lipid disorder, # (%)426 (68) Hypertension, # (%)401 (64) Family history of CHD, # (%)241 (39) Diabetes mellitus, # (%)146 (23) Prior myocardial infarction, # (%)150 (24) Prior bypass surgery, # (%)39 (6) Congestive heart failure, # (%)38 (6) Acute Coronary Syndrome, # (%)273 (44) Unstable Angina, # (%)164 (26) Non-Q-wave MI, # (%)62 (10) Acute MI, # (%)48 (8)

III - Results Target Vessel

III - Results Grey-scale IVUS parameters (n=625) Pullback length (mm)48.6±20.9 Mean lumen CSA (mm 2 )8.60±2.87 Mean EEM CSA (mm 2 )15.40±4.71 Average P&M CSA (mm 2 )6.80±2.79 Lumen volume (mm 3 )412.87± EEM volume (mm 3 )741.97± Plaque volume (mm 3 )329.10± Mean plaque burden (%)43.57±9.33

III - Results VH-IVUS parameters (n=625) Mean fibrous plaque CSA (mm 2 )2.16±1.45 Mean fibro-fatty plaque CSA (mm 2 )0.73±0.62 Mean necrotic core CSA (mm 2 )0.43±0.41 Mean dense calcium CSA (mm 2 )0.29±0.34 Fibrous plaque volume (mm 3 )104.99±87.75 Fibro-fatty plaque volume (mm 3 )34.79±33.18 Necrotic core volume (mm 3 )20.42±20.03 Dense calcium volume (mm 3 )13.86±17.65 % Fibrous volume28.81±9.68 % Fibro-fatty volume9.59±5.54 % Necrotic core volume5.74±3.78 % Calcified volume3.83±3.49

III - Results Relationship between NC and DC (n=625) Relationship between NC and DC (n=625) r=0.81 r 2 =0.68 P<0.0001

III - Results Lipid Profile ParametersNC/DC ratiop MedianIQR Male GenderYes1.79[ ]0.04 No1.60[ ] DiabetesYes1.63[ ]0.08 No1.58[ ] SmokingYes1.96[ ]0.007 No1.65[ ] HypertensionYes1.86[ ]0.06 No1.65[ ] Family history of CHD Yes1.82[ ]0.51 No1.70[ ] NC/DC ratio and risk factors (n=625) NC/DC ratio and risk factors (n=625)

III - Results Lipid Profile ParametersNC/DC ratiop MedianIQR Male GenderYes1.79[ ]0.04 No1.60[ ] DiabetesYes1.63[ ]0.08 No1.58[ ] SmokingYes1.96[ ]0.007 No1.65[ ] HypertensionYes1.86[ ]0.06 No1.65[ ] Family history of CHD Yes1.82[ ]0.51 No1.70[ ] NC/DC ratio and risk factors (n=625) NC/DC ratio and risk factors (n=625)

III - Results Lipid Profile ParametersNC/DC ratiop MedianIQR Total Cholesterol>200mg/dl1.83[ ]0.08 ≤200mg/dl1.68[ ] LDL-C≥100mg/dl1.79[ ]0.003 <100mg/dl1.58[ ] HDL-C<50mg/dl1.78[ ]0.22 ≥50mg/dl1.63[ ] TC/HDL ratio≥51.98[ ]0.006 <51.67[ ] Triglycerides≥150mg/dl1.92[ ]0.005 <150mg/dl1.66[ ] NC/DC ratio and serum lipid cutoffs (n=625) NC/DC ratio and serum lipid cutoffs (n=625)

III - Results Lipid Profile ParametersNC/DC ratiop MedianIQR Total Cholesterol>200mg/dl1.83[ ]0.08 ≤200mg/dl1.68[ ] LDL-C≥100mg/dl1.79[ ]0.003 <100mg/dl1.58[ ] HDL-C<50mg/dl1.78[ ]0.22 ≥50mg/dl1.63[ ] TC/HDL ratio≥51.98[ ]0.006 <51.67[ ] Triglycerides≥150mg/dl1.92[ ]0.005 <150mg/dl1.66[ ] NC/DC ratio and serum lipid cutoffs (n=625) NC/DC ratio and serum lipid cutoffs (n=625)

III - Results Independent predictors of p-Value NC/DC ratio: Admission hs-CRP p=0.007 LDL-C p=0.03 -Age, smoking, hypertension p=NS -Stepwise regression was performed -HDL-C, TG, previous history of CHD and diabetes were dropped from the analysis

III - Results NC/DC ratio and LDL-C Quartiles (n=625) NC/DC ratio and LDL-C Quartiles (n=625) p=0.005

III - Results NC/DC ratio and TC/HDL Quartiles (n=625) NC/DC ratio and TC/HDL Quartiles (n=625) p=0.003

IV - Conclusions Calcium has a strong correlation with necrotic core in human coronary arteries Calcium has a strong correlation with necrotic core in human coronary arteries The NC/DC ratio has a significant positive association with an adverse lipid profile, and smoking The NC/DC ratio has a significant positive association with an adverse lipid profile, and smoking

IV - Conclusions Even though calcium is not prominent within lesions of ACS patients, more calcium indicates larger and/or more numerous necrotic cores Even though calcium is not prominent within lesions of ACS patients, more calcium indicates larger and/or more numerous necrotic cores These findings are consistent with the concept that an EBCT calcium score is able to predict further coronary events These findings are consistent with the concept that an EBCT calcium score is able to predict further coronary events