Download - Pathophysiology II - Columbia
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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
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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
Pulmonary Hypertension:
The Clinical Context
Localizing the Problem
Pre-capillary
Localizing the Problem
Post-capillary
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PH
PAH
pre-capillary
PulmonaryVenous
Hypertension
post-capillary
Lung disease
Hypoxemia
CTEPH
Misc, e.g.sarcoidosis,
schistosomiasis
Pulmonary Hypertension:
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
Post-capillary PH:Pulmonary Venous Hypertension
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 PH:Pulmonary Venous Hypertension
Localizing the Problem
Post-capillary
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• Venous Etiologies
– Pulmonary Veins
–stenosis
–mediastinal fibrosis
–neoplasm
–pulmonary veno-
occlusive disease
Post-capillary
Post-capillary PH:Pulmonary Venous Hypertension
Localizing the Problem
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
50mmHg-10mmHg = 8 units•M2
5 L/min/M2
PAH(Pre-Cap)
75mmHg-35mmHg = 5 units•M2
8 L/min/M2
50mmHg-25mmHg = 5 units•M2
5 L/min/M2
Mixed PH(Pre-cap &Post-cap)
55mmHg-35mmHg = 2 units•M2
10 L/min/M2
35mmHg-25mmHg = 2 units•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
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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
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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
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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
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LVRVRV LV
Normal PH
Pulmonary Hypertension:
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
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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
Post-capillary PH:Pulmonary Venous Hypertension
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
Pulmonary Venous Hypertension
Post-capillary
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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
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
Ware L and Matthay M. N Engl J Med 2005;353:2788-2796
Ware L and Matthay M. N Engl J Med 2005;353:2788-2796
Physiology of Microvascular FluidExchange in the Lung
Ware L and Matthay M. N Engl J Med 2005;353:2788-2796
Representative Chest Radiograph from Patientwith Noncardiogenic Pulmonary Edema
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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 -
Pulmonary Venous Hypertension
• 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)
Pulmonary Venous Hypertension
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
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Vasodilator/Vasoconstrictor
Imbalance
Endothelial Proliferation and Dysfunction
Genetic Predisposition Vascular Injury
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
Vasodilator/Vasoconstrictor
Imbalance
Pulmonary
Vasoconstriction
Endothelial Proliferation and Dysfunction
Genetic Predisposition Vascular Injury
*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
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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