Smooth muscle pharmacology & interventional cardiology

Transcription

1 Smooth muscle pharmacology & interventional cardiology By: Pascal Bernatchez!!!!! LAST LECTURE Classic Vascular pharmacology -chronic -systemic Local Vascular pharmacology -acute -targeted High blood pressure Blood pressure control Atherosclerosis Endothelial Injury Thrombus CABG PTCA Stent Patient burden Restenosis In-sent restenosis Lipid lowering drugs Platelet/SMC pharmacology Drug eluting stents Scaffolds

2 Cath lab patients / surgery blood pressure management lipid management Coagulation Diabetes Macrophage accumulation Formation of necrotic core Formation of fibrous cap CABG

3 PTCA What is PTCA? Restenosis

4 Stenosis and angioplasty Medication? Damage Plaxitaxel Cirrolimus\ Cobalt chromium

5 Restenosis Restenosis: multi step process (lecture X) Angioplasty injury Platelet adhesion

6 Angioplasty injury pdgf Angioplasty injury

7 Stents Stenosis and stenting

8 Restenosis Paclitaxel/Taxol

9 Paclitaxel/Taxol -Anti-cancer agent -Anti-mitotic -As a potent stabilizer of microtubules. Microtubule disassembly is essential for the transition from the G2 to the M phase and migration - less SMC less leukocytes Sirolimus/Rapamycin

10 Sirolimus/Rapamycin -Immunosuppressant possesses anti-proliferative properties -Stent: The metal of the stent has a soft, plastic coating It slowly releases Sirolimus into the artery wall around the stent Eighty percent (80%) of the sirolimus is released during the first 30 days. The rest is released by the end of 90 days Controlled-release, nonresorbable, elastomeric polymer coating A B platform Polymer coating C Arterial injury Paclitaxel C 47 H 51 N 47 MW 854 H Sirolimus C 51 H 79 N 13 MW 914 H H Everolimus C 53 H 83 N 14 MW 958 N N N N Zotarolimus C 52 H 79 N 5 12 MW 966 Activation of vascular smooth-muscle cells NH H H H H H N H H N H H 3 C H N CH 3 H 3 C H Proliferation and migration of vascular smooth-muscle cells and extracellularmatrix formation Binding to β-tubulin subunit of microtubules Binding to FKBP12 Polymerization of tubulin G 0 phase Inhibition of mtr Inhibition of microtubule disassembly Up-regulation of p27kip1 Restenosis G 1 phase M phase (cell division) Cell cycle S phase G 2 phase CLR FIGURE Draft 3 12/17/2012

11 Drug eluting stents -Decrease rate of restenosis by 40-70% compared to BMS -% Stenosis/total lumen diameter: Sirolimus: 3.5% of diameter BMS: 18.5% of diameter Paclitaxel: 3.3% 5100 patients study BMS: 12.2% Delayed restenosis -Work well for a year -Delayed reendothelialization because of taxol/rapamycin affects endoth. -Your vessel is never healed unless your endothelial layer regrows, and becomes functional (not dysfunctional, which is the case mostly) -Thrombosis causes Death or MI so HUGE ANTI PLATELET THERAPY

12 Stent thrombosis Aspirin: should not be interrupted Clopidogrel: no longer that day -5 to day +2 if other surgery Normally a month of clopidogrel after PTCA or stent, now increased at 6 to 12mo Reopro: -ther types of surgeries need cessation of platelet therapy Circulation Circulation February 22, 2011 February 22, 2011 Scaffolds / Resorbable stents -Metal (Mg) -Polymer (polylactic acid) Figure 3. CT and histology at 28 days and 2, 3, and 4 years after stent implan-biggest advantage? tation. At 28 days, CT shows preserved box appearance (A), correspond-biggest ing to the voids not stained by Alcian question marks? Blue (B and C). At 2 years, CT still shows struts as preservedfigure box appear3. CT and histology at 28 days ance (D), but the persistent voids (E) are and (hyaline 2, 3, and 4 years after stent implannow replaced by proteoglycan material), which stained positively tation. with At 28 days, CT shows prealcian Blue (F). At 3 years,served only 2 struts box appearance (A), correspondat 6 o clock remained detectable as preing to the voids not stained by Alcian served box (G). therwise, connective tissue cells are now infiltrated the and strut C). At 2 years, CT still Bluein (B footprints (H, hematoxylin and eosin shows struts as preserved box appearstaining; I, Alcian Blue). At 4 years, struts but the persistent voids (E) are are no longer discernible ance by CT(D), (J); the strut footprints are hardly now detectable in replaced by proteoglycan (hyaline Movat staining (K) and Alcian Blue (L) material), which stained positively with and are characterized by paucity of conalcian Blue (F). At 3 years, only 2 struts nective tissue cells and a small amount of calcification. at 6 o clock remained detectable as pre- expansion was observed in the first 3 months of follow-up. The mean stent cross-sectional area increased from Universitymm of 2 (P"0.086) at 7.42!1.51 mm2 Institute at baseline to 8.18!2.42 Heart + Lung at St. Paul s Hospital mm2 at 6 months.65 A second, larger 3 months and 8.13!2.52 study of 50 elective patients (63 lesions, 84 stents) also showed promising results. IVUS performed at the 3-year follow-up demonstrated the complete absence of stent struts, and angiographic analysis demonstrated a mean diameter stenosis of 25% compared with 38%, 29%, and 26% at 6, 12, served box (G). therwise, connective tissue cells are now infiltrated in the strut footprints (H, hematoxylin and eosin staining; I, Alcian Blue). At 4 years, struts are no longer discernible by CT (J); the strut footprints are hardly detectable in Movat staining (K) and Alcian Blue (L) and are characterized by paucity of connective tissue cells and a small amount of calcification. eluting metallic stent that was later implanted proximal to the previously placed Igaki-Tamai stent. Serial angiographic and CT images of the stent struts out to the 10-year follow-up in 1 anecdotal case are shown in Figure 4. Despite these impressive results, the failure of the stent to progress was related primarily to the use of heat to induce self-expansion. There were concerns that this could cause necrosis of the arterial wall, leading to excessive intimal hyperplasia or increased platelet adhesion, leading to ST.68

13 Endothelial dysfunction and restenosis Endothelial dysfunction and restenosis Flow mediated dilation

14 Diabetes A Primary utcome 60 B Death 60 Death, Myocardial Infarction, or Stroke (%) P=0.005 by log-rank test 5-Yr event rate: 26.6% vs. 18.7% PCI CABG Death from Any Cause (%) P=0.049 by log-rank test 5-Yr event rate: 16.3% vs. 10.9% PCI CABG No. at Risk PCI CABG Years since Randomization No. at Risk PCI CABG Years since Randomization NEJM 367:25, 2012 LAST LECTURE Classic Vascular pharmacology -chronic -systemic Local Vascular pharmacology -acute -targeted High blood pressure Blood pressure control Atherosclerosis Endothelial Injury Thrombus CABG PTCA Stent Patient burden Restenosis In-sent restenosis Lipid lowering drugs Platelet/SMC pharmacology Drug eluting stents

15 Conclusion -Restenosis In-Stent stenosis Delayed restenosis -DES have a fantastic effect on restenosis and revascularization (decreased need of second procedure). -Impaired reendothelialization -Exam? pascal.bernatchez@ubc.ca