Pathophysiology II - Columbia

1-3-07

1

Pathophysiology II

Pulmonary Vascular Changes

in Heart Disease

• Normal Circulatory DynamicsPhysiology

• Pulmonary HypertensionDefinitionClassificationPathologyPathophysiologyClinical ManifestationsDiagnosisTreatment

Pulmonary Circulation

• Low resistance, high compliance vascularbed

• Only organ to receive entire cardiac output(CO)

• Changes in CO as well as pleural/alveolarpressure affect pulmonary blood flow

• Different reactions compared to thesystemic circulation

• Normally in a state of mild vasodilation

Exercise

• Pulmonary blood flow increases up to 4-5x BL

• Increased flow accommodated by bothrecruitment and vasodilation

• Net effect is a decrease in pulmonaryvascular resistance (PVR)

• No further decrease in PVR once allvessels fully recruited and dilated

Physiology: Circulatory Hemodynamics

• Systemic CirculationPressure = Pressure drop across systemic circulation (mmHg) =

Systemic Arterial Pressure (SAPm) - Systemic Venous Pressure

(RAPm)

Flow = Systemic Blood Flow† = Cardiac Index (CI; l/m/M2)

Resistance = Systemic Vascular Resistance (SVR; units • M2)

• Pulmonary CirculationPressure = Pressure drop across pulmonary circulation (mmHg) =

Pulmonary Artery Pressure (PAPm) - Pulmonary Venous Pressure

(PCWPm)

Flow = Pulmonary Blood Flow† = Cardiac Index (CI; l/m/M2)

Resistance = Pulmonary Vascular Resistance (PVR; units • M2)

*pressure drop across vascular bed † without congenital systemic to pulmonary shunts

Pressure* = Flow x Resistance

1-3-07

2

Oudiz RJ, Langleben D. Advances in Pulmonary Hypertension 2005;4(3):15-25

Normal Hemodynamic Measurements

During Right Heart CatheterizationNormal Pulmonary Hemodynamics at

Sea Level (Rest and Mild Exercise) and

at Elevated Altitude (Rest)

3.30.91.7Pulmonary vascular

resistance, units

5.09.05.0Left atrial pressure

(mean), mmHg

6.012.06.0Cardiac output, L/min

38/14(26)30/13(20)20/10(15)

Pulmonary arterial

pressure, (mean)

mmHg

Altitude

(~15,000 ft)

Rest

Sea level

Mild

Exercise

Sea level

Rest

Pulmonary Hypertension:

Definition

PAP mean 25 mm Hg atrest or 30 mmHg withexercise

Pulmonary

Hypertension

Precapillary

Pulmonary

Hypertension

Postcapillary

Pulmonary

Hypertension


The Clinical Context

Localizing the Problem

Pre-capillary


Post-capillary

1-3-07

3

PH

PAH

pre-capillary

PulmonaryVenous

Hypertension

post-capillary

Lung disease

Hypoxemia

CTEPH

Misc, e.g.sarcoidosis,

schistosomiasis


Classification

Pre-capillary PH:

Pulmonary Arterial Hypertension

Definition

• PAP mean 25 mmHg at rest or 30 mmHg with exercise

AND

• PCWP or LVEDP 15 mmHg

• PVRI 3 units • m2

• No left-sided heart disease

PAH

Pre-capillary PH:Pulmonary Arterial Hypertension

Classification

Idiopathic or Familial PAH

Associated with (APAH)Connective tissue disease

Congenital heart disease

Portal hypertension

HIV infection

Drugs and toxins

Other

• thyroid disorders

• glycogen storage

disease

• Gaucher disease

• hereditary

hemorrhagic

telangiectasia

• hemoglobinopathies

• myeloproliferative

disorders

• splenectomy

High PA pressure and normal

“downstream” pressures

Post-capillary PH:Pulmonary Venous Hypertension

Definition

• PAP mean 25 mmHg at restor 30 mmHg with exercise

AND

• PCWP or LVEDP >15mmHg

LH disease

Left-sided atrial or

ventricular heart disease

Left-sided valvular heart

disease


Classification

• Left Heart Etiologies

– Aorta - coarct, stenosis

– LV -AS, AR, CM,constriction, myocardialdisease, MS, MR,ischemic heart disease,congestive heart failure,diastolic dysfunction

– LA - Ball-valve thrombus,myxoma, cor triatriatum



Post-capillary

1-3-07

4

• Venous Etiologies

– Pulmonary Veins

–stenosis

–mediastinal fibrosis

–neoplasm

–pulmonary veno-

occlusive disease

Post-capillary



Pulmonary arterial Lung Pulmonary venous

PAP mean35 mmHg No obstruction

PCWP mean25 mmHg

Pulmonary arteriolar

obstruction

Pulmonary Venous HypertensionPhysiology

PAP mean45-100 mmHg

PCWP mean25 mmHg

Mixed (Pulmonary Venous and

Pulmonary Arterial Hypertension):

Definition

• PAP mean 25 mmHg at rest or 30

mmHg with exercise

• PCWP or LVEDP >15 mmHg

• PVRI 3 units • M2

• Increased Transpulmonary Gradient

Across Pulmonary Vascular Bed

Pathophysiology: Rest and Exercise

Pulmonary Hemodynamics

90mmHg-10mmHg = 10 units•M2

8 L/min/M2


5 L/min/M2

PAH(Pre-Cap)


8 L/min/M2


5 L/min/M2

Mixed PH(Pre-cap &Post-cap)


10 L/min/M2


5 L/min/M2

Pulm VenousPH (post-cap)

30mmHg-12mmHg = <1unit•M2

20 L/min/M2

15mmHg-10mmHg = 1 unit•M2

5 L/min/M2Normal

ExerciseRest

P = F x R P

F = R

PH: Medial Hypertrophy

In

PH: Intimal Fibrosis

1-3-07

5

PAH: Plexiform Lesions Pulmonary Venous HypertensionMicroscopic Features

Thickened Pulmonary Vein (VVG Stain)

Pulmonary Venous HypertensionMicroscopic Features

Thickened Muscular Pulm Art (VVG Stain)

Pathophysiology:

Hemodynamic Progression of PH

Time

PAP

PVR

CO

Pre-symptomatic/

Compensated

Symptomatic/

Decompensating

Symptom Threshold

Right Heart

Dysfunction

Declining/

Decompensated

Right Ventricular Dysfunction in

Pulmonary Hypertension

Right ventricular failure is a

consequence of chronic ischemia

on a hypertrophied pressure

overloaded ventricle

Normal Aortic Pressure and LV Coronary

Flow

1-3-07

6

Coronary Driving Pressure Gradient and

the Effect of Pulmonary HypertensionEffects of pulmonary hypertension

on RV myocardial perfusion

• Myocardial perfusion goes from beingboth systolic and diastolic to mostlydiastolic

• The RV hypertrophies, but coronaryblood supply remains unchanged

• RV work is dramatically increasedwithout a compensatory increase incoronary blood flow

• Tachycardia makes everything worse

PH: Progressive Right Heart Failure

Systemic

Pulmonary Arterial Hypertension:

Clinical Manifestations - Symptoms

•Dyspnea on Exertion/Rest

•Fatigue

•Chest Discomfort/Pain

•Cough

•Syncope/Presyncope

•Hemoptysis

•Edema

•Hoarseness

PAH: Clinical Manifestations

• Dyspnea

Reduced O2diffusion

Ventilation-perfusionmismatching

Low O2 transport

• Angina

RV ischemia

Left maincoronarycompression

• Syncope

Hypotension due tosystemic vasodilationand fixed pulmonaryresistance

Arrhythmia

• Edema, hepaticcongestion, ascites

RV failure

PAH: Findings on Physical Examination

• Tachypnea

• Jugular venous distention

• Right ventricular heave

• Right-sided fourth heart sound

• Loud pulmonic valve closure (P2)

• Tricuspid regurgitation murmur

• Pulmonary insufficiency murmur

• Hepatomegaly (pulsatile)

• Peripheral edema, ascites, pleural effusions

• Decreased peripheral perfusion

• Cyanosis

1-3-07

7

Pulmonary Venous PH: Symptoms

• Angina

• Syncope

• Congestive heart failure

• Dyspnea

• Hemoptysis

• Hoarseness

• Edema

• Ascites

• Paroxysmal nocturnal dyspnea

• Orthopnea

• Central and peripheral cyanosis

Pulmonary Venous PH:

Findings on Physical Examination

• Tachypnea, cough, wheezing

• Basilar crackles

• Central and peripheral cyanosis

• Specific signs Re: Left Heart or

Pulmonary Venous Hypertension

Etiology

• Signs of PH

Diagnosis of PH: Procedures

• Electrocardiogram

• Chest radiography

• Echocardiogram

• Ventilation perfusion scan (V/Q scan)

• Serologic studies, HIV

• Pulmonary function tests (PFT)

• Sleep study (if indicated)

• Arterial blood gases (ABG) (if indicated)

• Right-heart catheterization (with acutevasodilator testing if PAH)

PAH: Screening - ECG

RAD

RVH

RV

strain

RAE

Prominent Hilar

Pulmonary Arteries

Peripheral “Pruning”

RV Enlargement

PAH: Screening - CXR PAH: Findings on the Echocardiogram

• TR (tricuspid regurgitation)

• RVE (right ventricular enlargement)

• RAE (right atrial enlargement)

• RVH (right ventricular hypertrophy)

• Flattening of IVS (interventricularseptum)

• Dilated IVC/Hepatic veins

1-3-07

8

LVRVRV LV

Normal PH


Echocardiogram

• 4V2 = Pressure Gradient ( P) (Modified Bernoulli

Equation)

• RVSP - RAP mean = P

• RVSP = RAP mean + P

Echocardiogram

Estimate of RVSP

RA

RV

Velocity

Echocardiogram

PH: Congestive Heart Failure - CXRhilar fullness and haziness

Diagnosis of PH:

ECHO May Suggest an Underlying

Etiology

• LV diastolic dysfunction

• MS or MR

• LV systolic dysfunction

• Congenital heart disease, e.g. ASD,VSD, PDA

Post-capillary

pulmonary

venous

hypertension

1-3-07

9

Cardiac Catheterization

• To exclude congenital heart

disease

• To measure PCWP or LVEDP

• To establish severity and prognosis

• Acute vasodilator drug testing

Cardiac catheterization should be

performed in patients with suspected

pulmonary hypertension

• High index of suspicion

• Thorough and complete

evaluation

Diagnosis of Pulmonary

Hypertension

PAH

Pre-capillary PH:Pulmonary Arterial Hypertension

Classification

Idiopathic or Familial PAH

Associated with (APAH)Connective tissue disease

Congenital heart disease

Portal hypertension

HIV infection

Drugs and toxins

Other

• thyroid disorders

• glycogen storage

disease

• Gaucher disease

• hereditary

hemorrhagic

telangiectasia

• hemoglobinopathies

• myeloproliferative

disorders

• splenectomy

High PA pressure and normal

“downstream” pulmonary

venous pressures

Treatment: Pre-capillary PH -

Pulmonary Arterial Hypertension

• Treat associated conditions, e.g. thyroiddisease

• Early surgery to repair congenital heartdisease, e.g. VSD, PDA

However, if no longer “operable” due toprogressive pulmonary vascularobstructive disease, “corrective”surgery is contra-indicated

• Medical PAH Therapy

• Lung or Heart-Lung Transplantation

LH disease

Left-sided atrial or

ventricular heart disease

Left-sided valvular heart

disease


ClassificationAcute Pulmonary Edema

Treatment

• Upright posture

• Increase FiO2

• Intravenous diuretic, e.g. furosemide

• Vasodilator therapy, e.g. nitroprusside

• Intubation and mechanical ventilation

• Hemodynamic monitoring

• Narcotics, e.g. morphine

• Inotropic support, e.g. dopamine


Post-capillary

1-3-07

10

Acute Pulmonary Edema

• Cardiogenic Pulmonary Edema

• Noncardiogenic Pulmonary Edema

Ware L and Matthay M. N Engl J Med 2005;353:2788-2796

Physiology of Microvascular FluidExchange in the Lung



Representative Chest Radiograph fromPatient with Cardiogenic Pulmonary Edema





Representative Chest Radiograph from Patientwith Noncardiogenic Pulmonary Edema

1-3-07

11

Radiographic Features That May Help toDifferentiate Cardiogenic from

Noncardiogenic Pulmonary Edema

Adapted from:Ware L and Matthay M. N Engl J Med 2005;353:2788-2796

Usually presentNot usually presentAir bronchograms

Not usually presentPresentSeptal lines, i.e.Kerley’s B lines

Not usually presentPresentPeribronchial cuffing

Not usually presentPresentPleural effusions

Patchy or peripheralEven or centralDistribution of edema

Normal or balancedBalanced or invertedVascular distribution

Usually normalNormal or greater thannormal

Heart size

NoncardiogenicEdema

Cardiogenic EdemaRadiographic Feature

Algorithm for the ClinicalDifferentiation between Cardiogenic

and Noncardiogenic Pulmonary EdemaPatient with Acute Pulmonary

Edema

History, Physical Examination, andRoutine Laboratory Examination

Noncardiogenic Pulmonary EdemaLikely

Cardiogenic Pulmonary EdemaLikely

Pulmonary or nonpulmonaryinfection or history of aspiration

Hyperdynamic state white-cell count, pancreatitis orperitonitis

Brain natriuretic peptide level<100 pg/ml

History of myocardial infarctionor congestive heart failure

Low output state, third heartsound, peripheral edema,jugular venous distension

Elevated cardiac enzymes

Brain natriuretic peptide level>500 pg/ml

Chest RadiographNormal cardiac silhouettePeripheral infiltratesAbsence of Kerley’s B lines

Enlarged cardiac silhouetteCentral infiltratesPresence of Kerley’s B lines

Normal or small LV sizeNormal LV function

Enlarged LV sizeDecreased LV function

Diagnosis uncertain?

Echocardiogram

Diagnosis uncertain?

PCWP 18 mmHg Right Heart Catheterization PCWP >18 mmHg

And

Treatment: Post-capillary PH -


• Surgery to eliminate left-sided cardiacobstruction

• Heart transplantation for left ventricularfailure

• Additional medical and/or surgicaltreatment as needed

Specific re: left heart or pulmonaryvenous hypertension etiology

PAH treatment

Chronic Heart Failure Treatment

• Sodium restriction

• Afterload reduction, e.g. ACEinhibitors

• Inotropic support, e.g. digitalis

• Diuretics

• Beta-blockers

• Identification and treatment ofunderlying cause(s)


Post-capillary

Targeted Pulmonary Arterial

Hypertension Medical Treatment

Plexogenic and Thrombotic

Pulmonary Arteriopathy

Vascular Smooth

Muscle

HypertrophyPulmonary

Vasoconstriction

Vasodilator/Vasoconstrictor

Imbalance

Thrombosis in situ

Coagulation Abnormalities

Endothelial Proliferation and Dysfunction

Genetic Predisposition Vascular Injury

Pathobiology of PulmonaryArterial Hypertension

1-3-07

12


Imbalance



Vasodilator-antiproliferative/

vasoconstrictor-proliferative

Imbalance

•Deficient prostacyclin

•Excess thromboxane

•Excess endothelin

•Deficient nitric oxide

Pathobiology of Pulmonary Arterial

Hypertension

Plexogenic and Thrombotic

Pulmonary Arteriopathy

Pulmonary

Vasoconstriction

PAH: Decreased Expression ofProstacyclin Synthase in the Lung

Tuder et al. AJRCCM 1999


Imbalance

Pulmonary

Vasoconstriction



*p<0.05

Christman et al. NEJM 1992

PAH: Increased Thromboxane A2 Production PAH: Increased Expression of

Endothelin in the Lung

Giaid A et al. NEJM 1993

PAH: Decreased Nitric Oxide Synthase Expression in the Lung

Giaid et al. NEJM 1995

Humbert M, Sitbon O,Simonneau G: NEJM204;351:1425

1-3-07

13

Mechanisms Behind Current

Targeted PAH Medical Therapeutic

Options

Prostacyclinsynthase inendothelial cells

Nitric oxide synthaseexpression inendothelial cells

Lung and circulatingendothelin-1 levels

•Administerprostacyclin

•Enhance NO pathway

•Use endothelinreceptor antagonist

Abnormality in PAH Therapeutic Implication

Experience and Reason

“In Medicine one must pay attention not toplausible theorizing but to experience and

reason together . . . I agree that theorizing isto be approved, provided that it is based on

facts, and systematically makes itsdeductions from what is observed . . . But

conclusions drawn from unaided reason canhardly be serviceable; only those drawn from

observed fact.”

Hippocrates (460-377 BC): Precepts

Documents

Pathophysiology II - Columbia