Atherosclerosis and HDL Therapy New Virtual Histology Findings M. Pauliina Margolis, MD, PhD

Paulina Margolis, MD, PhD Salary: Volcano Therapeutics, Inc.

Virtual Histology Findings IVUS VH and Lipid profile Total cholesterol, LDL, HDL, and TG Identification of angiographically mild lesions with high risk for a clinical event PROSPECT, VIVA, and Park Preventive Imaging and risk profiling Genetics Other known risk factors Summary and conclusions

IVUS VH and Lipid profile Total cholesterol, LDL, HDL, and TG

IVUS VH and Lipid Profile Forrester JS. Prevention of plaque rupture: a new paradigm of therapy. Ann Intern Med 2002;137:823–833 An increase in serum HDL-C accelerates reverse cholesterol transport, decreasing the NC size potentially stabilizing plaque

Risk factors for sudden coronary death in men (Missel, Mintz, et al, EHJ 2008 The NC/DC ratio was related to both TC/HDL ratio (r = 0.18, P= 0.0008) and low-density lipoprotein cholesterol levels (r = 0.17, P= 0.002); had a negative correlation with HDL-C levels (r = −0.11, P= 0.03); and was higher for smokers [median 1.98 (1.35–3.18)] vs. non-smokers [median 1.70 (1.23–2.53), P= 0.006]. The ratio of NC to calcification detected by VH-IVUS in diseased coronary segments is related to known risk factors for SCD

Identification of angiographically mild lesions with high risk for a clinical event PROSPECT, VIVA, and Park

A Prospective Natural History Study Of Coronary Atherosclerosis Stone GW, Maehara A, Lansky AJ, et. al. "A Prospective Natural History Study Of Coronary Atherosclerosis" N Engl J Med. 2011 Jan 20;364(3):226-35.

Single Center Study confirms PROSPECT data Association Between IVUS Findings and Adverse Outcomes in Patients With Coronary Artery Disease The VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study Patrick A. Calvert al J Am Coll Cardiol Img 2011;4:894–901, 2011 170 patients with stable angina or troponin-positive ACS referred for percutaneous coronary intervention (PCI) were prospectively enrolled and underwent 3-vessel VH-IVUS pre-PCI and also post-PCI in the culprit vessel. 18 MACE occurred in 16 patients (10.6%) over a median follow-up of 1.7 years and 19 lesions resulted in MACE (11.2%, 13 from non-culprit and 6 from culprit lesions). VH-TCFA (HR: 8.16, p 0.007), plaque burden 70% (HR: 7.48, p 0.001), and minimum luminal area 4 mm2 (HR: 2.91, p 0.036) were associated with total MACE. On patient-based analysis, the only factor associated with MACE was 3-vessel non-calcified VH-TCFA (HR: 1.79, p 0.004).

Impact of plaque characteristics analyzed by intravascular ultrasound on long-term clinical outcomes Kim SH Park SJ et al. Impact of plaque characteristics analyzed by intravascular ultrasound On long term clinical outcomes. Am J Cardiol. 2009 May 1:103(9):1221-6. Epub 2009 Mar 4. 183 patients (79 with stable angina pectoris and 104 with acute coronary syndromes) who underwent pre-intervention 3-vessel IVUS and single-vessel stent implantation. The mean follow-up period was 50 +/- 20 months. In the non-target vessels, the long-term critical event-free rate was 8 % lower in patients with vulnerable plaques (88% vs. 96%, p = 0.04). The multiplicity of vulnerable plaques in the non-target vessels was the only independent predictor of long-term critical events.

Genetics Other known risk factors Risk profiling Genetics Other known risk factors

A Higher Peripheral Blood Gene Expression Score is Associated With Larger Plaque Volume and More Vulnerable Plaque Phenotype as Measured by IVUS VH : Results from the ATLANTA Study Josh, Voros et al. Circ. Imagning 2011 Peripheral gene expression score based on quantitative RNA-measurements was prospectively measured in 18 non-diabetic patients and correlated with IVUS VH plaque type analysis In univariate analysis, the score was associated with plaque volume, NC volume, and DC volume Lp-PLA2 and hsCRP also correlated with plaque in univariate analysis but were not additive to gene score in multivariable ANOVA analysis. A gene expression pattern was associated with higher plaque volume and a more vulnerable plaque phenotype as evidenced by more NC and DC on IVUS/VH. This suggests that the composite gene expression score is not only predictive of obstructive coronary artery disease, but also predictive of higher plaque volume and a more vulnerable plaque phenotype.

Intravascular ultrasound measures of coronary atherosclerosis are associated with the Framingham risk score Marso SP, et al Intra-Vascular ultrasound measures of coronary atherosclerosis are associated with the Framingham risk score: an analysis from a global IVUS registry. EuroIntervention 2009:5:1-00. Among 531 patients, plaque volume of the most diseased 10mm segment increased with increasing FRS (P=0.0006) Patients with higher FRS estimates of CHD risk had a higher proportion of plaque classified as thin cap fibroatheroma compared with patients in the middle or lower risk score categories (P=0,008)

Lesion in Stable and Unstable Patients. Clin Cardiol 2009 May 19. Plaque Characteristics of the Coronary Segment Proximal to the Culprit Lesion in Stable and Unstable Patients Nakamura T et alPlaque Characteristics of the Coronary Segment Proximal to the Culprit Lesion in Stable and Unstable Patients. Clin Cardiol 2009 May 19. ACS patients showed significantly higher ratio of dense calcium and necrotic core plaque compared with SA patients. VH-IVUS-derived thin-cap fibroatheroma (VH-TCFA) was more frequently observed in ACS patients compared with SA patients Among ACS patients, plasma high sensitivity C-reactive protein (hs-CRP) levels were significantly higher in patients with VH-TCFA than in patients without VH-TCFA (p = 0.004).

The Relationship Between Volumetric Plaque Components And Classical Cardiovascular Risk Factors And The Metabolic Syndrome Zheng M, Choi SY, Tahk SJ, et. al. “The Relationship Between Volumetric Plaque Components And Classical Cardiovascular Risk Factors And The Metabolic Syndrome” JACC Cardiovasc Interv. 2011 May;4(5):503-10. "Whole vessel" VH IVUS analysis was performed in 189 vessels of 63 patients. Three-vessel VH IVUS analysis showed that DM and MS patients had a larger plaque-plus-media burden, larger amount of NC, and more frequent IVUS VH derived TCFAs in coronary arterial trees, implying greater plaque vulnerability in DM and MS patients.

The American journal of cardiology 103(9):1210-4, 2009 Impact of Gender and Age on In Vivo Virtual Histology Imaging Plaque Characterization Qian J, et al.Impact of Gender and Age on In Vivo Virtual Histology Imaging Plaque Characterization The American journal of cardiology 103(9):1210-4, 2009 both women and men had an increase in plaque with increasing age; at any age, men had more plaque than women; percentages of dense calcium and necrotic core increased with increasing patient age in both men and women; and gender differences were lowest in the oldest tercile (>68 years).

170 stable and ACS referred for PCI underwent 3-vessel IVUS VH Leukocyte Telomere Length Is Associated With High-Risk Plaques on Virtual Histology Intravascular Ultrasound and Increased Proinflammatory Activity Calvert et al Arterioscler Thromb Vasc Biol. 2011;31:00-00.) Leukocyte telomere length (LTL) is inversely associated with cardiovascular events. Mean LTL in patients with CAD either before MI or with premature MI have been shown to be 0.3 Kb shorter than in controls, corresponding to a biological age of 11 years older. 170 stable and ACS referred for PCI underwent 3-vessel IVUS VH LTL was not associated with plaque volume but was associated with calcified thin-capped fibroatheroma (OR, 1.24; CI, 1.01–1.53; P0.039) and total fibroatheroma numbers (OR, 1.19; CI, 1.02–1.39; P0.027). Shorter LTL is associated with high-risk plaque morphology on IVUS VH but not total 3-vessel plaque burden suggesting that telomere shortening promotes high-risk plaque subtypes by increasing proinflammatory activity.

In Summary and as Basil Lewis and David Halon so elegantly stated – More Progression Toward Regression? Beyond Low- Density Lipoprotein Cholesterol Lowering Although plaques that rupture and cause an acute event are almost always large , specific plaque characteristics may have greater predictive value. Recent evidence from studies using VH-IVUS shows that characteristics of plaque are related to the major risk factors diabetes, hypertension, and serum LDL-C and HDL-C levels , and that the ratio of necrotic core to dense calcium seems to correlate with LDL-C and the total cholesterol/HDL-C ratio. It appears that plaque characteristics by IVUS VH may indeed relate to outcome events. In the PROSPECT trial, the combination of a large non-culprit plaque burden, small luminal area (4 mm2) and large necrotic core without visible cap (combination found in 15% of this acute coronary syndrome population) was associated with an almost 10-fold increase in major adverse cardiovascular events We need more in vivo information if we are to piece together the missing links in the chain between plaque volume and a clinically relevant event. We appear to be at least somewhat on track in our fight to halt and perhaps reverse the pathology and progression of atherosclerotic vascular disease. JACC 55;2743-2744, 2011