Cardiovascular System Gilead -Topics in Human Pathophysiology Fall 2009 Drug Safety and Public Health Todays topic is the cardiovascular system. We’ll start by reviewing what we learned about blood.

Blood Consists of: Plasma Erythrocytes Leukocytes platelets– thrombocytes Vitamin K is required, as is Calcium. Vitamin K is made by bacteria in the gut, and is absorbed as a fat soluble vitamin with other digested fats. Damage to the liver may cause decreased bile production, thus interfering with Vit. K absorption. Vit K is also required for bone deposition and anticoagulation. The liver also makes many of the clotting proteins, so liver disease can directly inhibit clotting, causing excessive bleeding and anemia. Thrombocytopenia is the name for a low platelet count. Also important are those drugs that prevent clotting, the anticoagulants. Much of the risk in CVD is that clots may form at narrowed lesions in blood vessels – “thrombus”, or a clot that forms elsewhere and travels to location where it gets stuck “embolism”

Figure 7.8 Thrombocytes and clotting : Vitamin K is required, as is Calcium. Vitamin K is made by bacteria in the gut, and is absorbed as a fat soluble vitamin with other digested fats. Damage to the liver may cause decreased bile production, thus interfering with Vit. K absorption. Vit K is also required for bone deposition and anticoagulation. The liver also makes many of the clotting proteins, so liver disease can directly inhibit clotting, causing excessive bleeding and anemia. Thrombocytopenia is the name for a low platelet count.

Blood Production and Disorders Overview of blood production Disorders of erythrocytes Disorders of platelets Disorders of leukocytes

Blood Cell Production Occurs in bone marrow Also called hemopoiesis (hematopoiesis) Stem cells are rapidly dividing Requires iron, Vitamin B12 (and other B vitamins), other trace minerals, vitamins Controlled by chemical messengers Has 5 lines of production Lack of oxygen carrying capacity is called anemia

Blood Cell Formation Slide 13 Stem cells are located in red bone marrow Stem cells multiply and become specialized Mature blood cells Erythrocyte (red blood cell) Erythroblast Nucleus lost Neutrophil Granular leukocytes Eosinophil Myeloblast White blood cells Basophil Stem cell Monoblast Monocyte Agranular leukocytes Lymphocyte Lymphoblast Megakaryoblast Megakaryocyte Platelets

Blood Disorders Anemias Thrombocytopenia Leukocytopenia, leukocytosis Clotting factor disorders Lipid disorders Lack of oxygen carrying capacity is called anemia - problem is with RBC and hemoglobin. AIDS is also associated with anemia; CMV – cytomegalo virus is also a cause of anemia, as is hepatitis. The mechanisms are sometimes known, sometimes multifactorial Lack of platelets or clotting factors causes bleeding disorders Leukocytopenia – low WBC count, seen in AIDS Reference Viroj Wiwanitkit Tropical Anemia, Nova Science Publishers, 2007 Clotting factor disorders often caused by liver disease – hepatitis Lipid disorders like hypercholesteremia can be related to HAART- HIV therapy,and HIV is associated with iron deficiency anemia Many problems with nutrition or the digestive system can lead to deficits in hematopoiesis

Heart and Disease Structure and function Ischemic Heart Disease Lexiscan, Ranexa Heart Failure

Heart lives in thoracic cavity between the lungs It is surrounded by a double layered pericardium that protects it and provides lubrication

Heart is a double pump R side to lungs(pulmonary circuit), L side to systemic circuit Atria are filling chambers, ventricles are pumping chambers. Atrioventricular valves keep blood moving into large arteries (aorta and pulmonary trunk) during ventricular contraction (systole). The R AV valve is also “tricuspid”, the L AV valve is “mitral”, or “bicuspid” Semilunar valves prevent blood in aorta (aortic semilunar) and pulmonary trunk (pulmonic) from falling back into ventricles after contraction (diastole)

Figure 8.7b A closer look showing valves and chambers. Wall of ventricles is thick, the L side more so, for providing pressure on the blood to push it into arteries. Thus creating arterial blood pressure. Muscle is myocardium, specialized to beat in coordinated fashion, autorhythmic

Cardiac Cycle http://www.youtube.com/watch?v=D3ZDJgFDdk0&feature=rec-HM-rn Cardiac cycle 3 minute video

Figure 8.14 The conduction system of the heart that stimulates the muscle to contract. The sequence needs to be precise and coordinated. Arrythmias may occur as a result of hypoxia, or disease. The rate of contraction and strength of contraction is controlled by the NS sympathetic and parasympathetic nerves, as well as other chemical messengers that bind to receptors on heart tissue.

Figure 8.15 The ECG is how clinicians monitor the conduction system. Non invasive

Figure 8.11 The coronary arteries are what supply the heart with oxygen rich blood. Narrowing of these vessels by spasm or plaque is known as cardiovascular disease, and causes ischemia

Ischemic Heart Disease Coronary artery disease Myocardial ischemia Myocardial hypoxia Myocardial infarct Myocardial necrosis Most of the time there are no symptoms before a sudden death event, but some may experience angina, dizziness, shortness of breath, heart palpitations, nausea, feeling of pressure

Coronary Angiogram Narrowed spot in L coronary artery

Progression of atherosclerosis From wikipedia

Risk Factors for Cardiovascular Disease Age Male sex Heredity Smoking Diabetes mellitus Hypertension High cholesterol Obesity Lack of exercise

Diagnosis and Treatment of Ischemic Heart Disease BP monitoring Symptoms ECG Angiogram Stress Test Nuclear myocardial perfusion tests Symptoms include angina, dizziness, shortness of breath, heart palpitations, nausea, feeling of pressure

Lexiscan For myocardial perfusion imaging (MPI) A2A adenosine receptor agonist Vasodilates coronary arteries as if exercising Injected into blood stream prior to gamma camera scan Can give a good indication of myocardial perfusion Used as a testing method if the patient can not do stress test on treamill. Lexiscan is 2nd generation drug, after adenosine itself. It binds specifically to the A2A adenosine receptor. Adenosine is chemical messenger with actions in the brain and heart. Adenosine is given for severe tachycardia emergencies. “In humans, there are four adenosine receptors. Each is encoded by a separate gene and has different functions, although with some overlapping.[3] For instance, both A1 receptors and A2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow, while the A2A receptor also has broader antiinflammatory effects throughout the body.[4] These two receptors also have important roles in the brain,[5] regulating the release of other neurotransmitters such as dopamine and glutamate,[6][7][8] while the A2B and A3 receptors are located mainly peripherally and are involved in processes such as inflammation and immune responses. Most older compounds acting on adenosine receptors are nonselective, with the endogenous agonist adenosine being used in hospitals as treatment for severe tachycardia (rapid heart beat),[9] and acting directly to slow the heart through action on all four adenosine receptors in heart tissue,[10] as well as producing a sedative effect through action on A1 and A2A receptors in the brain. Xanthine derivatives such as caffeine and theophylline act as non-selective antagonists at A1 and A2A receptors in both heart and brain and so have the opposite effect to adenosine, producing a stimulant effect and rapid heart rate.[11] These compounds also act as phosphodiesterase inhibitors which produces additional antiinflammatory effects, and makes them medically useful for the treatment of conditions such as asthma, but less suitable for use in scientific research.[12] Newer adenosine receptor agonists and antagonists are much more potent and subtype-selective, and have allowed extensive research into the effects of blocking or stimulating the individual adenosine receptor subtypes, which is now resulting in a new generation of more selective drugs with many potential medical uses. Some of these compounds are still derived from adenosine or from the xanthine family, but researchers in this area have also discovered many selective adenosine receptor ligands which are entirely structurally distinct, giving a wide range of possible directions for future research.[13][14]” from wikipedia

Diagnosis and Treatment of Ischemic Heart Disease Coronary bypass surgery Angioplasty Stents Cholesterol lowering agents Anticoagulents Antianginal medications

Ranexa For angina Probably changes ion channels in walls of blood vessels serving the heart Can be taken with other anti-anginal meds Very effective Suggested for pts for whom the other antianginal meds don’t work.

Congestive Heart Failure Heart becomes weak Blood backs up in veins and capillaries Fluid excess in tissues Symptoms include shortness of breath, edema, difficulty breathing (especially when lying down,) difficulty exercising Causes include hypertension, lung disease, coronary artery disease, previous myocardial infarction, valve disease, cardiomyopathy

Congestive Heart Failure

Congestive Heart Failure Patient tissues fill with fluid, treatment is often diuretics to make sure the lungs stay clear of excess fluid. These only treat the edema, not the underlying cause. But also drugs to decrease the workload of the heart (ACE inhibitors, AgII blockers, B blockers, etc.) http://www.bangkokhospital.com/images/procedures/Congestive_Heart_Failure.jpg