Lecture 28 Pulmonary Hypertension Pathophysiology Klassen 7 BLOOD PRESSURE Blood pressure = pressure inside blood vessels/heart o Relative to atmospheric pressure (mmHg) o Exerted on walls of blood vessels Blood pressure (BP) is directly proportional to: o Cardiac output (CO) – amount of blood / time (L/min) o Peripheral vascular resistance (PVR) – resistance through vessels SYSTEMIC BLOOD VESSELS: Resistance vessels (arteries): RESIST increase in BP o Vessels are stretched during cardiac ejection o Must be elastic to distend and recover o Must be dynamic to regulate BP MYOGENIC TONE/REACTIVITY: sustained & regulated vascular smooth muscle contraction in response to stretch/ pressure Convert high-pressure pulsatile to low-pressure non-pulsatile flow Capacitance vessels (veins): readily distend increasing CAPACITY with increased pressure o Accommodate increased blood volume ANATOMY OF VEINS & ARTERIES: 3 LAYERS 1. Tunica intima: inner layer Endothelial layer = lining Connective tissue = support Internal elastic lamina = stretch 2. Tunica media: THICKER IN ARTERIES Connective tissue = support External elastic lamina = stretch Vascular smooth muscle = myogenic tone 3. Tunica adventitia: THICKER IN VEINS Connective tissue = support Nerves = regulation Capillaries = nutrients for larger vessels PULMONARY HYPERTENSION: Severe, progressive, life-changing and life-threatening disorder of the heart and lungs o Characterized by increased pulmonary arterial pressure & secondary right ventricular failure Blood pressure in the pulmonary arteries is above normal o > 25 mmHg at rest or > 30 mmHg with exercise Increased morbidity/mortality via heart failure and death Patients with PH have a reduced quality of life MOST COMMON SYMPTOMS OF PH: Shortness of breath Chest pain Bluish lips, hand, and feet (cyanosis) Fatigue Swollen ankles and legs Dizziness & fainting NON-SPECIFIC SX delay diagnosis for 2 years!! PH VS. PAH PH: general term used to describe high blood pressure in the lung from any cause PAH: high blood pressure in the pulmonary arteries from diseases that affect the small vessels of the lung, causing them to narrow and impeded blood flow RISK FACTORS FOR PH: Family history: PH-causing gene mutation Obesity AND obstructive sleep apnea Gender: females > males Pregnancy: PH patients experience more severe sx, quicker disease progression and higher risk of mortality when pregnant Altitude: high altitude can aggravate PH Other diseases: congenital heart disease, lung disease, liver disease & connective tissue disorders (scleroderma, lupus) Drugs & toxins: methamphetamines and “fenphen” (diet drug) CLASSIFICATION OF PH: 1. Pulmonary arterial hypertension (PAH): a. Idiopathic (“primary pulmonary hypertension” b. Secondary to systemic disorders 2. Pulmonary hypertension due to left heart disease (pulmonary venous hypertension) 3. Pulmonary hypertension associated with respiratory disease and/or hypoxia a. COPD b. Interstitial lung disease c. OSA 4. Chronic thromboembolic/embolic pulmonary hypertension 5. Pulmonary hypertension from unclear mechanisms
Blood pressure = pressure inside blood vessels/heart o Relative to atmospheric pressure (mmHg) o Exerted on walls of blood vessels
Blood pressure (BP) is directly proportional to: o Cardiac output (CO) – amount of blood / time (L/min) o Peripheral vascular resistance (PVR) – resistance
through vessels
SYSTEMIC BLOOD VESSELS:
Resistance vessels (arteries): RESIST increase in BP o Vessels are stretched during cardiac ejection o Must be elastic to distend and recover o Must be dynamic to regulate BP
MYOGENIC TONE/REACTIVITY: sustained & regulated vascular smooth muscle contraction in response to stretch/ pressure
Convert high-pressure pulsatile to low-pressure non-pulsatile flow
Capacitance vessels (veins): readily distend increasing CAPACITY with increased pressure o Accommodate increased blood volume
Severe, progressive, life-changing and life-threatening disorder of the heart and lungs
o Characterized by increased pulmonary arterial pressure & secondary right ventricular failure
Blood pressure in the pulmonary arteries is above normal o > 25 mmHg at rest or > 30 mmHg with exercise
Increased morbidity/mortality via heart failure and death
Patients with PH have a reduced quality of life
MOST COMMON SYMPTOMS OF PH:
Shortness of breath
Chest pain
Bluish lips, hand, and feet (cyanosis)
Fatigue
Swollen ankles and legs
Dizziness & fainting NON-SPECIFIC SX delay diagnosis for 2 years!!
PH VS. PAH
PH: general term used to describe high blood pressure in the lung from any cause
PAH: high blood pressure in the pulmonary arteries from diseases that affect the small vessels of the lung, causing them to narrow and impeded blood flow
RISK FACTORS FOR PH:
Family history: PH-causing gene mutation
Obesity AND obstructive sleep apnea
Gender: females > males
Pregnancy: PH patients experience more severe sx, quicker disease progression and higher risk of mortality when pregnant
Drugs & toxins: methamphetamines and “fenphen” (diet drug)
CLASSIFICATION OF PH: 1. Pulmonary arterial hypertension (PAH):
a. Idiopathic (“primary pulmonary hypertension” b. Secondary to systemic disorders
2. Pulmonary hypertension due to left heart disease (pulmonary venous hypertension) 3. Pulmonary hypertension associated with respiratory disease and/or hypoxia
Induction of pulmonary smooth muscle cell proliferation AND migration
Increase extracellular matrix synthesis deposition of elastin, collagen, and fibronectin 3. THROMBOSIS: occlusion of arteries/arterioles and thrombotic clots form in situ (in pulmonary vessels)
Debate over chronic warfarin anticoagulation & survival 4. INFLAMMATION: due to injury/damage, disease, or increased blood flow
NORMAL LUNG PHYSIOLOGY: HIGH FLOW, LOW PRESSURE, AND LOW RESISTANCE CIRCULATION
Pulmonary arteries: blood into gas exchange o Elastic: conducting vessel, ≥ 500 um, no elastin, highly distensible o Muscular: 100-500 um, no elastin, non distensible o Arterioles: ≤ 100 um, thin intima & single elastic lamina
Equivalent to aorta as it is part of systemic circulation
Bronchial arteries: nutrition to the airways
Equivalent to coronary arteries supplying blood to heart
Progressive and fatal chronic condition with no known cure o Arteries of lungs become closed off or scarred, impeding blood flow continuous high BP in the lungs
Increases risk of RIGHT HEART FAILURE (ventricle pumping to lungs) o Sx: swelling, nausea, chest heaviness and/or palpitations
PHYSICAL SX OF PAH:
Breathlessness or SOB, especially with activity
Fainting and/or feeling tired all the time
Lightheadedness, especially when climbing stairs or standing up
and is essential for maintenance and normal response to injury Mutation PH
Idiopathic pulmonary arterial hypertension (IPAH) o Patients w/o family history and w/o an identified
genetic abnormality
CHEMICAL MEDIATORS:
Mediator Levels in PAH Function
Endothelin-1 Elevated levels
Levels correlate with disease severity & prognosis
Deleterious effects: o Fibrosis o Hypertrophy & cell proliferation o Inflammation o Vasoconstriction
Arachidonic acid metabolites
Prostacyclin: LOW LEVELS
Thromboxane A2: HIGH LEVELS
Prostacyclin
Potent vasodilator
Anti-proliferation
Inhibits platelet activation
Thromboxane
Potent vasoconstrictor
Promotes proliferation
Platelet activation
Vasoactive Intestinal Peptide (VIP)
Decreased levels Member of glucagon-growth hormone-releasing superfamily o Activates platelets o Promotes smooth muscle cell proliferation
NOS3 (Nitric Oxide)
Decrease in endothelial cells
Potent vasodilator (mediated by cGMP)
Inhibitor of platelet activation
Anti-proliferative properties
2. PULMONARY HYPERTENSION ASSOCIATED LEFT HEART DISEASE
AS A CONSEQUENCE OF….
Left ventricular dysfunction
Mitral and aortic valve disease
Cardiomyopathy
Cor-triatriatum (3 atria congenital defect)
Pericardial disease
PATHOPHYSIOLOGY: 1. Increase in left atrium pressure 2. Backward transmission of the pressure to ventricle 3. Vascular resistance & pressure gradient across the lungs falls 4. Further increases in atrial pressure 5. Further increase in ventricle pressure & vascular resistance is chronic 6. When ventricle ≥ 25 mmHg chronically structural changes 7. Increase in pulmonary resistance 8. Disproportionate elevation in circulatory system = failure
3a. PULMONARY HYPERTENSION ASSOCIATED WITH HYPOXIC LUNG DISEASES
Common cause of mild pulmonary hypertension
ASSOIATED CONDITIONS:
COPD
Interstitial lung diseases
Sleep-disordered breathing
Alveolar hypoventilation disorders
MECHANISM: HYPOXIA induces…
Vasoconstriction and muscularization of distal vessels
Medial hypertrophy of more proximal arteries
Loss of vessels & lung parenchyma
Intimal thickening
3b. PULMONARY HYPERTENSION ASSOCIATED WITH COPD:
RIGHT VENTRICLE FAILURE results from ischemia not pressure o Alveolar hypoxia induced pulmonary vasoconstriction o Academia & hypercarbia o Compression of pulmonary vessels by high lung volume o Loss of small vessels in regions of the emphysema & lung
destruction o Increase blood viscosity = polycythemia
3c. PULMONARY HYPERTENSION ASSOCIATED WITH INTERSTITIAL LUNG DISEASES
Mechanism o Hypoxia o Loss of effective pulmonary
vasculature from lung destruction
Hemodynamic profile is distinct IPAH
4. PULMONARY HYPERTENSION CUASED BY CHRONIC THROMBOEMBOLIC DISEASE (CTEPH)
Pulmonary embolism = typical initiator for PH
Mechanism: o Hypercoagulable state (minority of pts) o Lupus anticoagulant (10-20%) o Protein C, protein S, and antithrombin III deficiencies (5%)
5. PULMONARY HYPERTENSION DUE TO UNKNOWN MECHANISM
Blood disorders: polycythemia vera and essential thrombocythemia
