BHCS20XX Cardiopulmonary Disease PDF

Cardiopulmonary disease (Pulmonary hypertension + Cor pulmonale) BHSC2001Z, 2013 & 2018  Pulmonary and systemic circulations Systemic Pulmonary Parameter Range Mean Range Mean Arterial 25/10 15 120/80 90 press...

Cardiopulmonary disease (Pulmonary hypertension + Cor pulmonale) BHSC2001Z, 2013 & 2018  Pulmonary and systemic circulations Systemic Pulmonary Parameter Range Mean Range Mean Arterial 25/10 15 120/80 90 pressure mmHg Capillary 6-9 7 10-30 17 pressure mmHg Venous 1-4 2 0-10 6 pressure mmHg Arterial M/D 3.7 5 15-25 20 ratio % Venous M/D 2-5 4 3-6 5 ratio % Vascular 1-4 3 10-25 15 resistance Blood flow 4-6 5 4-6 5  Arterial vasoconstriction and vasodilation Will change total peripheral resistance Examples of vasoactive agents Neural Hormonal Local Angiotensin II Vasoconstrictor: Sympathetic nerves Noradrenaline Endothelin-1 Vasodilator: Nitric oxide Adrenaline Metabolites Nitric oxide from nerves from endothelium CO2 Altered radius Arteriolar smooth smooth Arteriolar muscle muscle  Ventilation Perfusion Matching Blood ejected from the right side of the heart goes to the lungs to pick up as much oxygen as is possible The best transfer of oxygen will occur if the blood is directed to areas where there is the best ventilation and highest oxygen concentration There is no point in sending lots of blood through areas with poor ventilation and a low oxygen concentration In order to achieve this vasoconstriction occurs in areas with low oxygen concentration in the lungs When we get the right amount of blood going to well ventilated high oxygen areas and little going to poorly ventilated low oxygen areas this is called ventilation perfusion matching  Ventilation Perfusion Mismatch A mismatch occurs when we get insufficient blood going to areas of good ventilation and high oxygen concentration And/or We get too much blood going to areas where there is poor ventilation and a low oxygen concentration  Hypoxic Pulmonary Vasoconstriction - Mechanism We don’t exactly know how this happens but the following is one of the most favoured hypotheses: Located in the cell membrane of the vascular smooth muscle cells in the pulmonary tree is a potassium channel called Kv1.5 Under normal conditions reactive oxygen species (ROS) are produced by the electron transport chain in the mitochondria These ROS keep the potassium channel open, allowing the exit of potassium ions This causes hyperpolarisation (cell membrane pd more negative) This inhibits the calcium channels in the cell membrane Smooth muscle cell contraction can be initiated by calcium entry So less calcium coming in means less contraction  Hypoxic Pulmonary Vasoconstriction - Mechanism A decrease in oxygen will decrease the activity of the electron transport chain This will decrease ROS production This will inhibit the potassium channel This will cause depolarisation (cell membrane pd more positive) This stimulates the calcium channel This allows greater calcium entry that then triggers contraction  Normal Conditions Vascular smooth K+ Channel Ca2+ Channel muscle cell in lungs K+ ROS Contraction Mitochondrion  During Hypoxia Vascular smooth K+ Channel Ca2+ Channel muscle cell in Ca2 lungs + K+ ROS Contraction Mitochondrion  Pulmonary hypertension Haemodynamic abnormality common to a variety of conditions, characterised by increased right ventricular afterload. PAH developed depends on amount of vascular tree that is compromised. Normally pulmonary circulation not predisposed to become hypertensive. – Low pressure system – High capacity – large reserve – Thin walled  Background PAH, mean pulmonary arterial pressure of 25mmHg at rest/ Normal 15mmHg. COPD most common cause – Sleep apnoea – Cystic fibrosis – Occupational lung disorders – Interstitial lung disease – Pulmonary embolism - RV failure – High altitude, cor pulmonale – Alveolar hypoventilation, drive, physical impediments – Global HPV Pulmonary venous hypertension – mitral valve, LV dysfunction  Epidemiology Idiopathic = 0.1% all post mortem 2-4% portal hypertension 0.5% HIV Sclerosis 8-12% 23-53% connective tissue disease 1-14% lupus Huge incidence in congenital heart disease, 1/3 cause of death  Risk factors Definite – Fenfluramine – Toxic rapeseed oil – Aminorex – Dexfenfluramine Likely – Ampthetamines – Methamphetamines Possible – Cocaine – Phenylpropanolamine – St Johns wort – SSRI – Chemotherapy  Symptoms Dyspnoea Fatigue Dizziness Syncope Chest pain Palpitations Orthopnoea Cough Hoarseness Pathogenesis  Familial FPAH – autosomal dominant Mutations = 10-20 % chance of PAH Vascular homeostasis and embryologic development Transforming growth factors – Bone morphogenic protein receptor 2 (75%, exon) – Activin receptor kinase type 1 – Endoglin (EC glycoprotein) Transforming growth factor b signalling pathway ulated pathobiology in pulmonary arterial hypertens Vascular lesions in pulmonary arterial hypertension.  Thrombosis and PAH Vascular endothelial cells have both anti-thrombotic and pro-thrombotic properties (differential expression of proteins and enzymes on the cell membrane) Damage to the endothelial lining increases their pro- thrombotic properties In particular a protein called tissue factor is exposed at the cell membrane When tissue factor comes into contact with clotting factor X (in the circulating blood) this triggers the clotting pathway  Thrombosis and PAH Upon contact with tissue factor clotting factor X becomes factor Xa Factor Xa converts pro-thrombin into thrombin Thrombin converts soluble fibrinogen into insoluble fibrin Fibrin forms a meshwork which traps red blood cells Thrombin also activates platelets The combination of activated platelets with the fibrin meshwork and trapped red blood cells gives you a clot  Cor Pulmonale ‘Hypertrophy of the right ventricle resulting from diseases affecting the function and/or structure of the lung (excepting congenital defects and left heart)’ Leading to right ventricular failure Most common pulmonary embolus of large proximal pulmonary artery (acute) Most common (chronic) COPD  Effect of afterload on ventricular stroke volume Increasing afterload has less effect on left compared to right ventricular stroke volume Increasing afterload increases left ventricular stroke work, not  Cor pulmonale Right ventricular Changes at cellular hypertrophy level Relocation of Loss of myocytes cellular proteins Microtubules Myocardial oedema Calcium handling Depressed Fibrosis sarcomere contraction RV stiffness Poor endocardial perfusion Perfusion mismatch  ECG changes in Cor pulmonale P pulmonale in inferior leads Large R in V1 (RVH) with strain Unusual R/S in right precordial leads  Treatments Disease specific Lung transplantation Anti-coagulents, diuretics, Oxygen therapy, digoxin Calcium channel blockers Pulmonary vasodilator/remodelling therapy – Prostanoids (Epoprostenol, Treprostinil, Iloprost) – ET receptor blockers (Bosentan) – Phosphodiesterase inhibitors (Sildenafil, Tadalafil) Treatment with pulmonary dilators  Prognosis Average 2.8 years – 1 – 65% – 3 – 50% – 5 – 33% Greatest risk – Mean right atrial pressure >20mmHg – Mean pulmonary arterial pressure >85mmHg – Presence of other disease, COPD or scleroderma