BASIC SCIENCE LECTURE Update on Clinical-Pathologic ...webcast.aats.org/2013/files/Monday/20130506_auditorium_0745_10.00... · Heart Disease 93rd Annual Meeting ... BASIC SCIENCE

©2013 MFMER | 3266944-1

Update on Clinical-Pathologic Correlates of Valvular Heart Disease

93rd Annual Meeting of the

American Association

for Thoracic Surgery

Minneapolis, MN, May 6, 2013

William D Edwards, MD, FACC

Dept of Lab Medicine & Pathology Mayo Clinic, Rochester, MN

BASIC SCIENCE LECTURE

Update on Clin-Path Correlates of VHD Disclosures

Conflicts of interest

None

Relevant financial relationships

None

Off-label usage

None

Update on Clin-Path Correlates of VHD Lecture Outline

Aortic Stenosis

Mitral Stenosis

Mitral Regurgitation

Aortic Regurgitation

Pathogenesis


Aortic Stenosis

Mitral Stenosis



Pathogenesis

0

20

40

60

80

1965 1970 1975 1980 1985 1990 1995 2000

Temporal Changes in Functional State in 1,978 Surgically Excised Aortic Valves

Pure AS

Pure AI

AS + AI

39

27

16 21 14

10 11

13

32

29 25

29 27 23 25 24

16

48

55 52

63 65 64

71

Mayo Clinic Surgical Experience (1965-2000)

%

Pathology: Aortic Stenosis Frequency Among Excised Aortic Valves

Temporal Changes in Etiology in 1,159 Surgically Excised Stenotic Aortic Valves

Degenerative

Bicuspid

49

33

0

46 47

40

34 36

30 31 34

38 33

9 13

7 7 8

51 51 56

61

Postinflammatory

23

13

Pathology: Aortic Stenosis Changing Frequency of Common Types


Condition % M:F Age*

Degenerative 60 1:1 60-90

Bicuspid 30 2:1 50-75

Rheumatic 5 1:1 50-75

Other 5 2:1 50-75

* Age at time of surgery

Pathology: Aortic Stenosis Current Frequency of Common Types

Autopsy Heart (Ao Aspect) Normal AV

Calcification: nodular arches Commissural fusion: none-mild

Pathology: Aortic Stenosis Degenerative Type

Autopsy Heart (Ao Aspect) Surgical

Calcification: nodular arches Commissural fusion: none-mild

Pathology: Aortic Stenosis Degenerative Type

Occurrence

Incidence (%): 1-2

Sex (M:F ratio): 2-3:1

Fate (by age 75) %

Stenosis 85

Regurgitation 10

Infection 3

Dissection 2

Normal 0

Pathology: Aortic Stenosis Congenitally Bicuspid Type

Autopsy Heart (Ao Aspect) Normal

At birth: most are non-stenotic Stenosis: ongoing calcification


Autopsy Heart (Ao Aspect)

Raphe

Normal

Raphe: congenital line of fusion Calcification: first along raphe

(RAY-fee)


Autopsy Heart (Ao Aspect)

Raphe

Surgical

Raphe: congenital line of fusion Calcification: along raphe first

(RAY-fee)

R

R


Autopsy (Ao Aspect) Candle Wax

Fibrosis: cusp, commissure Fusion: commissures (1-3) Calcium: cusp, commissure

Pathology: Aortic Stenosis Rheumatic (Postinflammatory) Type

Autopsy (Ao Aspect) Candle Wax

Fibrosis: cusp, commissure Fusion: commissures (1-3) Calcium: cusp, commissure

Pathology: Aortic Stenosis Rheumatic (Postinflammatory) Type

C

C

Bicuspid Valve

＊ = Shallow Raphe

Obtuse Angle

Acute Angle

Rheumatic Valve

＊ = Tall Commissure

＊＊

Pathology: Aortic Stenosis Congenital vs Acquired Commissural Fusion

Surgical Specimens (Aortic Aspect)

Autopsy Heart (Aortic Aspect)

Pathology: Aortic Stenosis Unicommissural Valve, Mild Stenosis

Surgical Specimens (Aortic Aspect)

R R

Pathology: Aortic Stenosis Unicommissural Valves, Severe Stenosis

R R

Fibrotic Calcific

Comparison of Surgical Specimens (Ao Aspect)

Degenerative 60%

Bicuspid 30%

Rheumatic 5%

Pathology: Aortic Stenosis Three Most Common Types

Common Denominator: Extensive Calcification

RV

LV LA

Aorta SVC

RPA

Age-Related Subaortic Septal Bulge

Pathology: Aortic Stenosis Subaortic Septal Myectomy in Elderly

Autopsy Heart (Long-Axis View)

>65 Yrs, Get Stain for Amyloid


Aortic Stenosis

Mitral Stenosis



Pathogenesis


Aortic Stenosis

Mitral Stenosis



Pathogenesis

Condition % M:F Age * Rheumatic >95 1:3 40-80

Non-rheumatic † <5 1:1 Any


† Congenital, autoimmune, vegetation, storage, iatrogenic (drugs, radiation)

Stenosis of Cardiac Valves Mitral Stenosis – Causes

Autopsy Heart (Opened Valve, LA Aspect)

Posterior

AL PM

LV

Pathology: Mitral Stenosis Normal Valve for Comparison

Anterior

LA

Post

Autopsy Heart (Opened Valve) Candlewax

Anterior

LA

LV

Post Post

PM PM

Pathology: Mitral Stenosis Rheumatic (Post-Inflammatory Type)

Fibrosis, Fusion & Calcification

Autopsy, Short-Axis Surgical Valve


Fishmouth Deformity

Autopsy, Short-Axis Catfish


Fishmouth Deformity

Serotonin-Like Migraine Medications

Serotonin Methysergide Ergotamine

5-Hydroxy-Tryptamine

Pathology: Mitral Stenosis Non-Rheumatic Type

Serotonin-Like Migraine Medications

Serotonin Methysergide Ergotamine

5-Hydroxy-Tryptamine

Pathology: Mitral Stenosis Non-Rheumatic Type

SSRI Medications for Depression Do Not Cause Valvular Disease

LA Aspect LV Aspect

Pathology: Mitral Stenosis Non-Rheumatic Cause

Surgical Specimen (LA & LV Aspects)


Aortic Stenosis

Mitral Stenosis



Pathogenesis


Aortic Stenosis

Mitral Stenosis



Pathogenesis

0

10

20

30

40

50

60

70

80

90

1965 1970 1975 1980 1985 1990 1995 2000

Temporal Changes in Functional State in 1,238 Surgically Excised Mitral Valves

%

MS + MR

Pure MR

61

Pure MS

44 39 38

57 58

79 78

21

18 21

29 29

17 17

8 8

14 13

25

26

33 32 35


Pathology: Mitral Regurgitation Frequency Among Excised Mitral Valves

Temporal Changes in Etiology in 694 Surgically Excised Regurgitant Mitral Valves

0

20

40

60

80

1965 1970 1975 1980 1985 1990 1995 2000

%

Degenerative (Two Types)

Postinflammatory

Iatrogenic Ischemic

Endocarditis

45 43

17

33 36

32

57

44 49

78 71

0, 3 8

7

15

11

12

2 4

22 17

15

16, 13

9

9 4, 0

4 2

9 8


Pathology: Mitral Regurgitation Changing Frequency of Common Types

Cause % M:F Age *

Degenerative † 80 1.5:1 40-80

Rheumatic 5 1:2 40-80

Ischemic 5 2:1 60-80

Endocarditis 5 4:1 60-80

Other 5 1:1 Any

* Age at time of surgery † Includes two types of MV prolapse

Pathology: Mitral Regurgitation Current Frequency of Common Types

Pathology: Mitral Regurgitation Degenerative Disease (MV Prolapse)*

Barlow’s disease

Classic MVP

Myxomatous MV

<60 yrs, F>M

Years to decades

Occasionally

Xq28; 16p11.2-p12.1

Multi-segmental

Diffuse

Often

Yes

Common

Fibroelastic deficiency

Non-classic MVP

Fibroelastic dysplasia

>60 yrs, F=M

Months

No

No mutations

Focal (often P2)

Focal (often P2)

Often

No

No

Name

Synonyms

Age, sex

Duration

Familial

Mutations

Prolapse

Involvement

Cordal rupture

Thick fused cords

Annular calcium

* Mixed forms may occur

Modified from Anyanwu & Adams, Semin Thorac CV Surg 2007;19:90

Autopsy Heart (Opened Valve, LA Aspect)

P3

AL PM LV

Pathology: Mitral Regurgitation Commissures vs Clefts

Minor Commissure

P2 P1

Minor Pap M

* * Anterior

Pap M Pap M

Major Commissure

Major Commissure

Normal Mitral Valve

True Commissure (Arrow)

(Opened RA and RV)

Congenital Cleft (Arrows)

(Opened LA and LV)

ASD

ASD

Autopsy Heart (R & L Aspects)

FO

RV LV

LA RA

Pathology: Mitral Regurgitation Commissures vs Clefts

Partial Atrioventricular Septal Defect

Autopsy Heart (Cardiac Base)

Post Ant

Dilated annulus Thick leaflets Billowing Hooding

Pathology: Mitral Regurgitation Degenerative (Barlow’s Disease) Type

Diffuse Prolapse

Autopsy Heart (LA View)

Anterior

Posterior

Pathology: Mitral Regurgitation Degenerative (Fibroelastic Deficiency) Type

Prolapse of A2 Segment

Autopsy Heart (Long-Axis View)

LA

LV

RV Ao

Leaflet Prolapse

Pathology: Mitral Regurgitation Degenerative (Barlow’s Disease) Type

Ruptured Cord with

Prolapse of P2

Autopsy Heart (Left Atrial View)

P2

A1

Cordal Rupture P1

P3

A2 A3

Anterolateral Commissure Posteromedial

Commissure

Pathology: Mitral Regurgitation Degenerative (Mixed) Type

P4

Surgical Specimen (Gross & Microscopy)

Pad

Fibrous

Spongy

Pad

Proliferative Fibrous Pad

H&E

VVG

P2 Segment

Pathology: Mitral Regurgitation Degenerative Type, Not Otherwise Specified

Autopsy Heart (Base)

TV

PV

Fibrosis with Scar Retraction

Mild Cordal & Comm Fusion

Normal Annular Dimension

Pathology: Mitral Regurgitation Rheumatic (Postinflammatory) Type

Surgical Specimen

Comparison of Surgical Specimens (LA Aspect)

Degenerative (Barlow’s) Rheumatic

Mitral Regurgitation Mitral Annular Dilatation

No Annular Dilatation

Annular Dilatation

May Be Striking

Risk factors Female, >60 yr MV prolapse Renal dialysis LV pressure

Gross Appearance Posterior leaflet Along LV free wall C- or J-shaped O-shaped (rare)

CS

LV

MAC

MV

Involves Both MV Annulus & Post Leaflet

Calcium

Inflammation

Collagen

Autopsy Heart (X-ray & Slice) Microscopy

H&E

TV

MV

AV

PV

LA

Pathology: Mitral Regurgitation Annular Calcification

Core Inflammation Acute or chronic May seem necrotic, caseous, abscess Rarely infected

Gross Appearance Posterior leaflet Along LV free wall C- or J-shaped O-shaped (rare)

CS

LV

MAC

MV

Involves Both MV Annulus & Post Leaflet

Calcium

Inflammation

Collagen

Autopsy Heart (X-ray & Slice) Microscopy

H&E

TV

MV

AV

PV

LA

Pathology: Mitral Regurgitation Annular Calcification


Aortic Stenosis

Mitral Stenosis



Pathogenesis


Aortic Stenosis

Mitral Stenosis



Pathogenesis

Causes % M:F Age *

Aortic root Dilated annulus 50 3:1 70-90

Aortic valve 50 Bicuspid 15 12:1 50-70 Endocarditis 15 4:1 30-50 Iatrogenic 10 1:1 30-70 Rheumatic 5 1:2 50-70 Other 5 1:1 Any


Pathology: Aortic Regurgitation Current Frequency of Common Types

Aortic Aneurysm Normal (Ant View)

Aorta Ao

Pathology: Aortic Regurgitation Aortic Root Dilatation Type

Diagram (JACC Img 2012;5:441)

Highest Aortic

Sinotubular Junction

Annulus Tri-Radiate

Crown

Mid Anatomic

VA Junction

Lowest AV-MV Continuity

Commissures

Outward Displacement of the Three Commissures Will

Produce Aortic Regurgitation


Autopsy Hearts (Aortic Aspect)


Normal Valve (For Comparison)

Rulers Are

Same Size

Marfan Syndrome

Enlarged & Stretched Cusps

Annular Dilatation


Normal Valve (For Comparison)

Rulers Are

Same Size

Autopsy Specimen (Opened LV)

Prolapse of Conjoined Cusp

Pathology: Aortic Regurgitation Congenitally Bicuspid Type

Atypical Bicuspid AV

Cusp Prolapse & Annular Dilatation

Fenestrated Raphe

Typical Bicuspid AV (>90%)

Pathology: Aortic Regurgitation Congenitally Bicuspid Type

Autopsy Heart

Scar Retraction (2/3 Loss)

LV

Ao

Pathology: Aortic Regurgitation Rheumatic (Postinflammatory) Type

Scar Retraction of Cusps

No Annular Dilatation

Surgical Valve

Comparison of Surgical Specimens (Ao Aspect)

Bicuspid 15%

Rheumatic 5%

Aortic Root Disease 50%

Pathology: Aortic Regurgitation Three Common Types

Common Denominator: Little or No Calcification


Aortic Stenosis

Mitral Stenosis



Pathogenesis


Aortic Stenosis

Mitral Stenosis



Pathogenesis

Autopsy Hearts (Aortic Aspects)

Pathogenesis: Aortic Stenosis Two Most Common Forms

Degenerative (60%) Bicuspid (30%)

Inheritance: autosomal dominant

trait, with incomplete penetrance

Mutation: Notch-1 gene encoding

for membrane receptor important

for normal cardiac development

Association: defective microfibrils

in aortic valve & ascending aorta

(BAV plus ascending aortopathy)

Pathogenesis: Aortic Stenosis Congenitally Bicuspid Type

Valve consequences: weakening,

with annular dilatation & with cusp

prolapse, fibrosis & calcification

Calcification process: similar to

degenerative AS but 20 yrs earlier

Aortic consequences: weakening,

with dilatation, aneurysm formation,

dissection, and rupture

Pathogenesis: Aortic Stenosis Congenitally Bicuspid Type

Calcium, Collagen & Inflammation (H&E)

Calcium

Inflammation

Collagen

Pathogenesis: Aortic Stenosis Degenerative Type

Initial inciting event

Increased mechanical stress (along

flexion areas near valve annulus)

Reduced shear stress (post cusp)

Result: endothelial injury/disruption

Endothelial damage

Lipoprotein accumulation: LDL, LP(a) progenitor cells, valve interstitial cells

Lipoprotein oxidation: very cytotoxic

Stimulate inflammation & calcification


Inflammatory process

Cellular adhesion molecules (CAMs)

Monocytes become macrophages

T cells: pro-inflammatory cytokines

(TGF-, TNF-α & IL-1-)

Inflammatory cell types

T cells (most prevalent leukocyte)

Macrophages/histiocytes (plentiful)

Plasma cells, B cells & mast cells


Inflammation (Microscopy, Special Stains)

T Cells

(CD3) B Cells

(CD20)

Mac’s

(CD68)

Mast

Cells

(SAB)


Neoangiogenesis (neovascularization)

In areas of intense inflammation

(T cells) & adjacent calcification

expression of ICAM-1 & VCAM-1

Portal of entry for inflammatory cells

Hemorrhages occur frequently (iron)

Valve interstitial cells

Fibroblast-like cells in all valve layers

Inflammation induces myofibroblasts


Valvular myofibroblasts

Responsible for accelerated fibrosis

Produce matrix metalloproteinases

NOS uncoupling, with NO

Develop angiotensin receptors

Transform into osteoblast-like cells

Valvular calcification

Begins as nodules of hydroxyapatite

Later remodeling may include bone


Osteoblastic calcification

From valve myofibroblasts, circulating osteoblastic progenitor cells

Cellular osteoblast-like phenotype

Alkaline phosphatase, osteopontin, osteocalcin, osteonectin, bone sialoprotein, tenascin-C & BMP-2

Dystrophic calcification

Less common than osteoblastic

Microfocal gross mass (CaPO4)


Disorders of Ca-P metabolism

Osteoporosis, chronic hemodialysis,

vitamin D receptor polymorphisms

& Paget disease of bone

Atherosclerosis risk factors

Hyperlipidemia, hypertension, age &

diabetes mellitus

But calcification in valves differs from

that in atherosclerotic arteries


Diagram (Circulation 2005;111:3316)


©2013 MFMER | 3266944-73

Update on Clinical-Pathologic Correlates of Valvular Heart Disease

93rd Annual Meeting of the

American Association

for Thoracic Surgery

Minneapolis, MN, May 6, 2013

BASIC SCIENCE LECTURE

William D Edwards, MD, FACC Dept of Lab Medicine & Pathology

Mayo Clinic, Rochester, MN

Documents

BASIC SCIENCE LECTURE Update on Clinical-Pathologic ...webcast.aats.org/2013/files/Monday/20130506_auditorium_0745_10.00... · Heart Disease 93rd Annual Meeting ... BASIC SCIENCE