Pathology: Myocardial Adaptation, Aging, And Failure

Front 1

Flowchart of Physiologic and Pathologic hypertrophy:

Back 1

pre-natal: hyperplasia
post-natal: hypertrophy

Note 3 kinds of increased workload.

Front 2

MYOCARDIAL ADAPTATION:

Back 2

Temporary changes may be physiologic (e.g. heart rate, resistance, output) without associated structural changes.

ADAPTATION involving structural changes (hypertrophy) may be physiologic or pathologic.

Front 3

Back 3

Top: normal
Bottom: LVH

Front 4

PHYSIOLOGIC HYPERTROPHY:

Back 4

*Increased cardiac size in response to chronic endurance exercise, pregnancy, etc
*Preservation of cardiac structure and function
*MILD increase in thickness of wall of LV (1.3 cm vs 1.1 cm)
*MILD increase in volume of LV
*L:W ratio of myocardial cells increased
*CAPABLE of REGRESSION (by apoptosis)

Front 5

CARDIAC ADAPTATION (FRANK STARLING):

Back 5

*Increased end diastolic volumes cause increased myocyte stretching.

*Stretched fibers contract more forcibly resulting in increased cardiac output.

*If stretched fibers can maintain adequate cardiac output, heart failure is compensated.

*Stretched fibers increase myocardial oxygen requirements.

*Ultimately, cardiac muscle cannot produce adequate output, resulting in decompensated heart failure.

Front 6

What characterizes PATHOLOGIC HYPERTROPHY:

Back 6

*Growth of heart is associated with changes in patterns of gene expression, cardiac architecture, and cardiac physiology.

*Afterload/Pressure OVERLOAD (Load against which heart contracts to eject blood; maximum tension of muscle mass at end of systole).

*Preload/Volume OVERLOAD (Maximum volume of blood at end of diastole).

Front 7

AFTERLOAD- PRELOAD/ TIME FACTOR: HOW ARE CONSEQUENCES INFLUENCED BY AMOUNT OF TIME?

Back 7

*Consequences are influenced greatly by the time of development of volume overload or pressure overload.

-Preload/Volume Overload: Mitral regurgitation (MR) due to ruptured papillary muscle vs MR due to chronic rheumatic valvular disease.

-Afterload/Pressure Overload: Massive pulmonary embolus vs slowly developing pulmonary hypertension.

Front 8

PATHOLOGIC HYPERTROPHY--What do we see in Afterload (pressure overload) states?

Back 8

*Increased cardiac mass.
*Hypertension, valvular stenosis.
*Sarcomere width is greater than length (W>L).
*Concentric hypertrophy.
*Little or no change in chamber volume.

Front 9

PATHOLOGIC HYPERTROPHY--What do we see in Preload (volume overload) states?

Back 9

*Valvular regurgitation, regional dysfunction after MI, dilated cardiomyopathy

*Increased cardiac mass with increased chamber volume

*Sarcomere length is greater than width (L>W)

*Eccentric hypertrophy

Front 10

Back 10

Middle is normal.
Left: Pressure overload
Right: Volume overload

Front 11

Diagram: How does the normal heart end up going to:
atrophy?
physiologic hypertrophy?
concentric hypertrophy?
eccentric hypertrophy?

Back 11

Again, note difference b/t pressure and volume overload.
Big pathologic differences b/t the two as well. Huge fibrosis and arrythmia risk in volume overload hearts.

Front 12

Back 12

MASSIVE CARDIOMEGALY/COR BOVINUM

Front 13

Back 13

LEFT VENTRICULAR HYPERTROPHY

Front 14

PATHOLOGIC HYPERTROPHY--what do we see from a microscopic point of view?

Back 14

*Increased size of myocardial cells (Increased numbers of sarcomeres).

*Increased nuclear size with BOXCAR appearance.

*No significant increase in capillaries, resulting in relative ischemia.

*Interstitial fibrosis.

Front 15

Back 15

L: normal
R: myocardial hypertrophy
*Huge nuclei, huge amounts of DNA.

Front 16

Back 16

Cardiac Myocyte on EM
A=Nucleus
B=Z-line
C=A-band
D= Mitochondria

Front 17

Back 17

HEART/ INTERSTITIAL FIBROSIS
C=Collagen

Front 18

Back 18

Interstitial Fibrosis/ Myocardium on trichrome stain.
Blue=Fibrosis

Front 19

Back 19

L: Concentric Hypertrophy of Left ventricle
Middle: Normal
R: Eccentric Hypertrophy of Both ventricles

Front 20

MYOCARDIAL HYPERTROPHY--what happens at the nuclear level?

what 3 genes are implicated?

Back 20

*Increased mRNA
*Increased protein synthesis
*Induction of immediate early genes:
c-fos
egr-1
c-jun

Front 21

PATHOLOGIC HYPERTROPHY--discuss molecular changes:

Back 21

*Reexpression of fetal gene program (ANP, fetal myosin, etc).

*Recapitulation of fetal metabolic program (glycolysis).

*Reorganization of sarcomeres.

*Altered calcium homeostasis.

*Changes in myocyte contractility/relaxation.

*Death of myocytes by apoptosis --> fibrosis.

*Electrical remodeling (alterations in expression/function of ion transporting proteins).

Front 22

CARDIAC HYPERTROPHY--what initiates the molecular changes?

Back 22

*Mechanical stimuli (e.g. stretching or mechanotransduction via integrins)--> Activation of receptor mediated signaling pathways--> hypertrophy.

*Integrins can signal myocyte to produce various growth factors that serve as ligands (paracrine/ autocrine).

*Ligands (e.g. Angiotensin II, ET-1, NE, IGF-I, TGF-B; some stimulate fibroblasts to produce extracellular matrix--> Interstitial fibrosis).

*Ligands bind to and activate G-protein coupled receptors and receptor tyrosine kinases (MAPK, PI3K).

*Initiation of intracellular signaling cascades.

Front 23

Summary chart of mechanical stress in Myocardial Hypertrophy:

Back 23

Front 24

Summary of events from Robbins of events leading to Cardiac Hypertrophy and eventually dysfunction:

Back 24

Front 25

REGRESSION OF HYPERTROPHY--how does it occur? 3

Back 25

*Suppression of pro- growth pathways

*Activation of protein degradative pathways

*Ubiquitin proteosome system

(Fibrosis can't ever reverse)

Front 26

LEFT SIDED CARDIAC FAILURE: what causes it?

Back 26

*Ischemic heart disease (CAD)
*Systemic hypertension
*Aortic and mitral valve disease
*Primary myocardial disease

Front 27

LEFT SIDED CARDIAC FAILURE: what do you see?

Back 27

*Hypertrophy and dilatation of LV

*Myocyte hypertrophy and variable interstitial fibrosis

*Dilatation of LA with increased risk of atrial fibrillation

*Stasis in atrial appendage--> thrombus--> formation--> embolization

Front 28

LEFT SIDED CARDIAC FAILURE: PULMONARY CONGESTION AND EDEMA--

Back 28

*Perivascular and interstitial edema--> Edema of alveolar septa--> Edema fluid in alveolar spaces--> 

*Extravasation of RBCs--> Phagocytosis of RBCs with accumulation of iron (hemosiderin) in macrophages (heart failure cells).

Front 29

Back 29

PULMONARY EDEMA from left side heart failure.
Yellow arrow points to Edema Fluid.

Front 30

Back 30

PULMONARY EDEMA
E=Edema Fluid/ Low Power

Front 31

Back 31

PULMONARY EDEMA
Arrows=Congestion
E=Edema Fluid/ High Power

Front 32

Back 32

*LUNG HEART FAILURE CELLS
*Yellow-brown pigment= iron (hemosiderin) containing macrophages

Front 33

LEFT SIDED CARDIAC FAILURE

Back 33

*Decreased renal perfusion--> Activation of renin-angiotensin-aldosterone system--> Retention of salt and water.
*Pre-renal azotemia (precursor to kidney disease).
*Hypoxic encephalopathy.

Front 34

RIGHT SIDED CARDIAC FAILURE--what causes it?

Back 34

*Most commonly caused by left sided failure.

*Associated with lung disorders ("cor pulmonale"):
-Parenchymal diseases of lung.
-COPD.
-Disorders of pulmonary vasculature (Primary pulmonary hypertension, thrombo-emboli, etc).

Front 35

RIGHT SIDED CARDIAC FAILURE--what pathologic changes do you see?

Back 35

*Hypertrophy and dilatation of RV
*Myocyte hypertrophy with variable interstitial fibrosis
*Dilatation of RA
*Pericardial effusions

Front 36

Back 36

RIGHT VENTRICULAR HYPERTROPHY

Front 37

Back 37

RIGHT VENTRICULAR HYPERTROPHY in xs.

Front 38

Back 38

BILATERAL ECCENTRIC HYPERTROPHY AND DILATATION/ COR BOVINUM. This is late stage.

Front 39

Back 39

RIGHT VENTRICULAR HYPERTROPHY resultant from TRANSPOSITION OF GREAT VESSELS.

Front 40

RIGHT SIDED CARDIAC FAILURE--what do you see in the body's other tissues?

Back 40

*Passive congestion of liver with variable centrilobular necrosis (Nutmeg liver) with possible progression to cardiac sclerosis.

*Congestive splenomegaly.

*Pleural, pericardial, peritoneal (ascites) effusions.

*Peripheral edema.

Front 41

Back 41

NUTMEG LIVER, gross view.
Dark areas= centers of lobules
top left--actual nutmeg.

Front 42

Back 42

NUTMEG LIVER
Central Vein is visible. Periphery is spared. This is passive liver congestion as a result of Right side heart failure.

Front 43

Back 43

LIVER in CARDIAC SCLEROSIS
Blue= collagen (fibrosis)
Later stage than nutmeg liver; a result of right heart failure.

Front 44

HEART FAILURE-- ∆ b/t systolic and diastolic:

Back 44

SYSTOLIC: Insufficient cardiac output due to loss of myocardial contractility

DIASTOLIC: Cardiac output is preserved at rest, but LV is abnormally stiff or restricted

Front 45

AGING CHANGES in MYOCARDIUM:

Back 45

*Increased mass
*Increased subepicardial fat
*Brown atrophy (Lipofucsin)
*Basophilic degeneration
*Amyloid deposition (transthyretin)

Front 46

AGING CHANGES in the HEART structure:

Back 46

*Increased LA cavity size, decreased LV cavity size, sigmoid shaped ventricular septum--> hypertrophy.

*Aortic valve calcification, mitral annulus calcification, fibrous thickening of leaflets, Lambl’s excrescences.

*Increased tortuosity and cross sectional diameters of coronary vessels, plaques.

*Dilated ascending aorta, fragmentation of elastica and plaque formation.

Front 47

Back 47

*Lambl’s Excrescences on aortic valve. Fibrin that has become organized. Occurs in aging hearts.
*Small filiform processes near closure lines of valve. Arise from organized thrombi.

Front 48

Back 48

BROWN ATROPHY
Occurs in aging hearts. Or patients who have prolonged disease.

Front 49

Back 49

*BROWN ATROPHY (LIPOFUSCIN)
*Arrows=Lipofuscin

Front 50

Back 50

BASOPHILIC DEGENERATION. A change you can see in the heart; a by-product of glycogen metabolism.

Front 51

Back 51

CARDIAC AMYLOIDOSIS
A=Amyloid Deposits

*In aging hearts.

Front 52

Back 52

CARDIAC AMYLOIDOSIS
A= Congo Red; Red=amyloid
B= Congo Red Polarized; Green= Amyloid and White= Collagen