Smooth muscle pharmacology & interventional cardiology · Smooth muscle pharmacology & interventional cardiology LAST LECTURE Providence Heart + Lung Institute at St. Paul’s Hospital

10/9/14

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By: Pascal Bernatchez

Providence!Heart + Lung Institute!at St. Paul’s Hospital!

University of!British Columbia!

Smooth muscle pharmacology & interventional cardiology

LAST LECTURE

Providence Heart + Lung Institute at St. Paul’s Hospital

University of British Columbia

High blood pressure

Blood pressure control

Atherosclerosis Endothelial Injury

Thrombus

CABG

PTCA

Stent

Drug eluting stents Scaffolds

Classic Vascular pharmacology -chronic -systemic

Local Vascular pharmacology -acute -targeted

Patient burden

Restenosis

In-sent restenosis

Lipid lowering drugs Platelet/SMC pharmacology

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Cath lab patients / surgery



blood pressure management lipid management Coagulation Diabetes Macrophage

accumulation Formation of necrotic core

Formation of fibrous cap

CABG

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PTCA

What is PTCA?

Restenosis

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Stenosis and angioplasty



Medication?

Damage



Plaxitaxel Cirrolimus\ Cobalt chromium

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Restenosis

Restenosis: multi step process (lecture X)

Angioplasty injury



Platelet adhesion

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Angioplasty injury



pdgf

Angioplasty injury



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Stents

Stenosis and stenting



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Restenosis

Paclitaxel/Taxol



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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

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-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

Sirolimus/Rapamycin

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 368;3 nejm.org january 17, 2013256

stenosis, which is manifested as myocardial in-farction in 10 to 20% of patients.28,29

Everolimus-Eluting StentsIn randomized trials, everolimus-eluting stents improved clinical outcomes as compared with paclitaxel-eluting stents, reducing the risks of re-

peat revascularization, myocardial infarction, and stent thrombosis.30,31 Randomized comparisons showed similar outcomes for stents releasing everolimus and those releasing sirolimus with respect to rates of death, myocardial infarction, and repeat revascularization.32-34 A large trial showed lower rates of stent thrombosis with

Bare-metal stent

Inhibition

Binding toFKBP12

Inhibition ofmTOR

Binding to !-tubulinsubunit of microtubules

Polymerizationof tubulin

Up-regulation ofp27Kip1

Inhibition of microtubuledisassembly

Drug-eluting stent

Cell cycle

G0 phase

S phase

G2 phase

M phase(cell division)

G1 phase

Stentplatform

Stentplatform

Polymer coating

Antiproliferative

Drug release Polymer coating

biodegradation

PaclitaxelC47H51NO47

MW 854

SirolimusC51H79NO13

MW 914

EverolimusC53H83NO14

MW 958

ZotarolimusC52H79N5O12

MW 966

OOO OOO

OO

OOOOOOO

OOO

OOOOOO

OH

OHOHOH

OHOHOO

OHOHOH

NHNHNHNH

OH OOOO OOOOO OHHH

NNN

HOHO

OOOOOO

OO

OOOOOOO

OOOOOOOOO

OOOOOOOO

OHOH

OOOOO

OO

HOHO

NNN

HOHO

OOOOOO

OO

OOOOOOO

OOOOOOOOO

OOOOOOOO

OHOH

OOOOO

OO

HOHOHO

OH

NNN

HOHO

OOOOOO

OO

OOOOOOO

OOOOOOOOO

OOO

OHOH

NNNNNNN

NNNNNNN

H3CO

H3COCO

OCHOCH3

C

A B

Polymer coatingPolymer coating

platform

Restenosis

Arterial injury

Activation of vascularsmooth-muscle cells

Proliferation and migrationof vascular smooth-muscle

cells and extracellular-matrix formation

12/17/2012

1/17/2013

AUTHOR PLEASE NOTE:Figure has been redrawn and type has been reset

Please check carefully

AuthorFig #Title

DEMEArtistPub Date

COLOR FIGURE

Draft 3

Drug-Eluting CoronaryArtery Stents

1

NameWilliams

Holmes ra1210816

Ingelfinger

The New England Journal of Medicine Downloaded from nejm.org by Pascal Nicolas Bernatchez on January 17, 2013. For personal use only. No other uses without permission.

Copyright © 2013 Massachusetts Medical Society. All rights reserved.

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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

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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:

-Other types of surgeries need cessation of platelet therapy

Scaffolds / Resorbable stents



-Metal (Mg) -Polymer (polylactic acid) -Biggest advantage? -Biggest question marks?

expansion was observed in the first 3 months of follow-up.The mean stent cross-sectional area increased from7.42!1.51 mm2 at baseline to 8.18!2.42 mm2 (P"0.086) at3 months and 8.13!2.52 mm2 at 6 months.65 A second, largerstudy of 50 elective patients (63 lesions, 84 stents) alsoshowed promising results. IVUS performed at the 3-yearfollow-up demonstrated the complete absence of stent struts,and angiographic analysis demonstrated a mean diameterstenosis of 25% compared with 38%, 29%, and 26% at 6, 12,and 24 months, respectively. Clinical outcomes at 4-yearfollow-up showed rates of overall and MACE-free survivalrates of 97.7% and 82.0%, respectively.66

At the 10-year clinical follow-up, freedom from cardiacdeath, noncardiac death, and MACEs was 98%, 87%, and48%, respectively.67 In the limited cases with serial angio-graphic follow-up, the minimum lumen diameter was stable:the mean minimum lumen diameter was 2.01 mm at 1 yearand 2.06 mm at 10 years. There were 2 ST events: 1 subacuteevent occurring at day 5 possibly as a result of inadequateheparinization at the time of percutaneous coronary interven-tion and 1 very late ST event occurring in the sirolimus-

eluting metallic stent that was later implanted proximal to thepreviously placed Igaki-Tamai stent. Serial angiographic andOCT images of the stent struts out to the 10-year follow-up in1 anecdotal case are shown in Figure 4.

Despite these impressive results, the failure of the stent toprogress was related primarily to the use of heat to induceself-expansion. There were concerns that this could causenecrosis of the arterial wall, leading to excessive intimalhyperplasia or increased platelet adhesion, leading to ST.68

None of these concerns were substantiated in the initialstudies; however, only low-risk patients were enrolled. Aftercompletion of the Biodegradable peripheral Igaki-Tamaistents PERSEUS study,69 the stent became available in Europefor peripheral use; however, there are plans to review itsuse in coronary arteries. At present, the stent has no drugelution, although preclinical studies of the polymeric stenteluting the tyrosine kinase antagonist ST 638 showedpromising results.52

Magnesium AlloyMagnesium (Mg) is the fourth-most-common cation withinthe human body; the total body content is #20 g, with 350 mg

Figure 3. OCT and histology at 28 daysand 2, 3, and 4 years after stent implan-tation. At 28 days, OCT shows pre-served box appearance (A), correspond-ing to the voids not stained by AlcianBlue (B and C). At 2 years, OCT stillshows struts as preserved box appear-ance (D), but the persistent voids (E) arenow replaced by proteoglycan (hyalinematerial), which stained positively withAlcian Blue (F). At 3 years, only 2 strutsat 6 o’clock remained detectable as pre-served box (G). Otherwise, connectivetissue cells are now infiltrated in the strutfootprints (H, hematoxylin and eosinstaining; I, Alcian Blue). At 4 years, strutsare no longer discernible by OCT (J); thestrut footprints are hardly detectable inMovat staining (K) and Alcian Blue (L)and are characterized by paucity of con-nective tissue cells and a small amountof calcification.

784 Circulation February 22, 2011

by guest on September 18, 2014http://circ.ahajournals.org/Downloaded from

expansion was observed in the first 3 months of follow-up.The mean stent cross-sectional area increased from7.42!1.51 mm2 at baseline to 8.18!2.42 mm2 (P"0.086) at3 months and 8.13!2.52 mm2 at 6 months.65 A second, largerstudy of 50 elective patients (63 lesions, 84 stents) alsoshowed promising results. IVUS performed at the 3-yearfollow-up demonstrated the complete absence of stent struts,and angiographic analysis demonstrated a mean diameterstenosis of 25% compared with 38%, 29%, and 26% at 6, 12,and 24 months, respectively. Clinical outcomes at 4-yearfollow-up showed rates of overall and MACE-free survivalrates of 97.7% and 82.0%, respectively.66

At the 10-year clinical follow-up, freedom from cardiacdeath, noncardiac death, and MACEs was 98%, 87%, and48%, respectively.67 In the limited cases with serial angio-graphic follow-up, the minimum lumen diameter was stable:the mean minimum lumen diameter was 2.01 mm at 1 yearand 2.06 mm at 10 years. There were 2 ST events: 1 subacuteevent occurring at day 5 possibly as a result of inadequateheparinization at the time of percutaneous coronary interven-tion and 1 very late ST event occurring in the sirolimus-

eluting metallic stent that was later implanted proximal to thepreviously placed Igaki-Tamai stent. Serial angiographic andOCT images of the stent struts out to the 10-year follow-up in1 anecdotal case are shown in Figure 4.

Despite these impressive results, the failure of the stent toprogress was related primarily to the use of heat to induceself-expansion. There were concerns that this could causenecrosis of the arterial wall, leading to excessive intimalhyperplasia or increased platelet adhesion, leading to ST.68

None of these concerns were substantiated in the initialstudies; however, only low-risk patients were enrolled. Aftercompletion of the Biodegradable peripheral Igaki-Tamaistents PERSEUS study,69 the stent became available in Europefor peripheral use; however, there are plans to review itsuse in coronary arteries. At present, the stent has no drugelution, although preclinical studies of the polymeric stenteluting the tyrosine kinase antagonist ST 638 showedpromising results.52

Magnesium AlloyMagnesium (Mg) is the fourth-most-common cation withinthe human body; the total body content is #20 g, with 350 mg

Figure 3. OCT and histology at 28 daysand 2, 3, and 4 years after stent implan-tation. At 28 days, OCT shows pre-served box appearance (A), correspond-ing to the voids not stained by AlcianBlue (B and C). At 2 years, OCT stillshows struts as preserved box appear-ance (D), but the persistent voids (E) arenow replaced by proteoglycan (hyalinematerial), which stained positively withAlcian Blue (F). At 3 years, only 2 strutsat 6 o’clock remained detectable as pre-served box (G). Otherwise, connectivetissue cells are now infiltrated in the strutfootprints (H, hematoxylin and eosinstaining; I, Alcian Blue). At 4 years, strutsare no longer discernible by OCT (J); thestrut footprints are hardly detectable inMovat staining (K) and Alcian Blue (L)and are characterized by paucity of con-nective tissue cells and a small amountof calcification.

784 Circulation February 22, 2011

by guest on September 18, 2014http://circ.ahajournals.org/Downloaded from

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Endothelial dysfunction and restenosis



Endothelial dysfunction and restenosis



Flow mediated dilation

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Diabetes



NEJM 367:25, 2012


n engl j med 367;25 nejm.org december 20, 20122380

tients with myocardial infarction in that group). All the procedural myocardial infarctions in the trial were non–Q-wave events. Myocardial in-farctions that occurred more than 30 days after the index procedures were reported in 81 of 99 patients (82%) in the PCI group and in 29 of 48 patients (60%) in the CABG group.

There were fewer strokes in the PCI group than in the CABG group (P = 0.03) (Table 2, and Fig. 2B in the Supplementary Appendix). The

5-year rates were 2.4% in the PCI group and 5.2% in the CABG group. Of these strokes, the major-ity (87%) were ischemic and 13% were hemor-rhagic. In the first 30 days after the procedure, 3 patients in the PCI group and 16 in the CABG group had a stroke (Table 3). The excess of strokes in the CABG group occurred in the first 30 days after randomization. An NIH Stroke Scale score of more than 4 (severely disabling) at the time of the event was reported in 27% of patients in the PCI group, as compared with 55% of those in the CABG group. A score on the Rankin scale of more than 1 at the time of the stroke was re-ported in 60% of patients in the PCI group, as compared with 70% in the CABG group.

Secondary OutcomesRates of cardiovascular death (63.7% of all deaths) did not differ significantly between the two study groups (P = 0.12 by the log-rank test), nor did rates of major adverse cardiovascular and cerebrovas-cular events at 30 days (P = 0.68 by the log-rank test). However, at 1 year after the procedure, there was a significant difference in rates of major ad-verse cardiovascular and cerebrovascular events, with 16.8% in the PCI group versus 11.8% in the CABG group (P = 0.004) (Table 3, and Fig. 2C in the Supplementary Appendix). This difference was attributed largely to the preponderance of repeat revascularization events by 1 year in the PCI group, as compared with the CABG group, with repeat events in 12.6% and 4.8% of patients in the two groups, respectively (hazard ratio, 2.74; 95% CI, 1.91 to 3.89; P<0.001) (Fig. 2D in the Supplemen-tary Appendix).

Prespecified Subgroup AnalysesThe greater benefit of CABG versus PCI was con-sistent across all prespecified subgroups (Fig. 2). The analysis according to the category of SYNTAX score showed no significant subgroup interac-tion (P = 0.58). At 5 years, the absolute difference in the rate of the primary outcome in the PCI group, as compared with the CABG group, was similar in the three SYNTAX subgroups (6 percentage points for a low SYNTAX score, 10 percentage points for an intermediate score, and 8 percentage points for a high score). The hazard ratios for the PCI group, as compared with the CABG group, according to SYNTAX subgroup were 1.14, 1.46, and 1.46, re-spectively. Similarly, for the rate of major adverse cardiovascular and cerebrovascular events at 1 year,

Dea

th, M

yoca

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ion,

or S

trok

e (%

)60

40

30

10

50

20

00 1 2 3 4 5

Years since Randomization

B Death

A Primary Outcome

P=0.005 by log-rank test5-Yr event rate: 26.6% vs. 18.7%

No. at RiskPCICABG

953947

848814

788758

625613

416422

219221

PCI

CABG

Dea

th fr

om A

ny C

ause

(%)

60

40

30

10

50

20

00 1 2 3 4 5



No. at RiskPCICABG

953947

897855

845806

685655

466449

243238

PCI

CABG

Figure 1. Kaplan–Meier Estimates of the Composite Primary Outcome and Death.

Shown are rates of the composite primary outcome of death, myocardial infarction, or stroke (Panel A) and death from any cause (Panel B) truncated at 5 years after randomization. The P value was calculated by means of the log-rank test on the basis of all available follow-up data.

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF BRITISH COLUMBIA on August 16, 2013. For personal use only. No other uses without permission.



n engl j med 367;25 nejm.org december 20, 20122380

tients with myocardial infarction in that group). All the procedural myocardial infarctions in the trial were non–Q-wave events. Myocardial in-farctions that occurred more than 30 days after the index procedures were reported in 81 of 99 patients (82%) in the PCI group and in 29 of 48 patients (60%) in the CABG group.

There were fewer strokes in the PCI group than in the CABG group (P = 0.03) (Table 2, and Fig. 2B in the Supplementary Appendix). The

5-year rates were 2.4% in the PCI group and 5.2% in the CABG group. Of these strokes, the major-ity (87%) were ischemic and 13% were hemor-rhagic. In the first 30 days after the procedure, 3 patients in the PCI group and 16 in the CABG group had a stroke (Table 3). The excess of strokes in the CABG group occurred in the first 30 days after randomization. An NIH Stroke Scale score of more than 4 (severely disabling) at the time of the event was reported in 27% of patients in the PCI group, as compared with 55% of those in the CABG group. A score on the Rankin scale of more than 1 at the time of the stroke was re-ported in 60% of patients in the PCI group, as compared with 70% in the CABG group.

Secondary OutcomesRates of cardiovascular death (63.7% of all deaths) did not differ significantly between the two study groups (P = 0.12 by the log-rank test), nor did rates of major adverse cardiovascular and cerebrovas-cular events at 30 days (P = 0.68 by the log-rank test). However, at 1 year after the procedure, there was a significant difference in rates of major ad-verse cardiovascular and cerebrovascular events, with 16.8% in the PCI group versus 11.8% in the CABG group (P = 0.004) (Table 3, and Fig. 2C in the Supplementary Appendix). This difference was attributed largely to the preponderance of repeat revascularization events by 1 year in the PCI group, as compared with the CABG group, with repeat events in 12.6% and 4.8% of patients in the two groups, respectively (hazard ratio, 2.74; 95% CI, 1.91 to 3.89; P<0.001) (Fig. 2D in the Supplemen-tary Appendix).

Prespecified Subgroup AnalysesThe greater benefit of CABG versus PCI was con-sistent across all prespecified subgroups (Fig. 2). The analysis according to the category of SYNTAX score showed no significant subgroup interac-tion (P = 0.58). At 5 years, the absolute difference in the rate of the primary outcome in the PCI group, as compared with the CABG group, was similar in the three SYNTAX subgroups (6 percentage points for a low SYNTAX score, 10 percentage points for an intermediate score, and 8 percentage points for a high score). The hazard ratios for the PCI group, as compared with the CABG group, according to SYNTAX subgroup were 1.14, 1.46, and 1.46, re-spectively. Similarly, for the rate of major adverse cardiovascular and cerebrovascular events at 1 year,

Dea

th, M

yoca

rdia

l Inf

arct

ion,

or S

trok

e (%

)

60

40

30

10

50

20

00 1 2 3 4 5


B Death

A Primary Outcome


No. at RiskPCICABG

953947

848814

788758

625613

416422

219221

PCI

CABG

Dea

th fr

om A

ny C

ause

(%)

60

40

30

10

50

20

00 1 2 3 4 5



No. at RiskPCICABG

953947

897855

845806

685655

466449

243238

PCI

CABG

Figure 1. Kaplan–Meier Estimates of the Composite Primary Outcome and Death.

Shown are rates of the composite primary outcome of death, myocardial infarction, or stroke (Panel A) and death from any cause (Panel B) truncated at 5 years after randomization. The P value was calculated by means of the log-rank test on the basis of all available follow-up data.

The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF BRITISH COLUMBIA on August 16, 2013. For personal use only. No other uses without permission.


LAST LECTURE



High blood pressure

Blood pressure control

Atherosclerosis Endothelial Injury

Thrombus

CABG

PTCA

Stent

Drug eluting stents

Classic Vascular pharmacology -chronic -systemic

Local Vascular pharmacology -acute -targeted

Patient burden

Restenosis

In-sent restenosis

Lipid lowering drugs Platelet/SMC pharmacology

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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? [email protected]

Documents

Smooth muscle pharmacology & interventional cardiology · Smooth muscle pharmacology & interventional cardiology LAST LECTURE Providence Heart + Lung Institute at St. Paul’s Hospital