Cardiovascular diseases

Transcription

1 Cardiovascular diseases Slide1. The heart s task and work: During a life span, the heart works without resting as a double muscle pump with its regulated rhythm. On right side to refresh the blood with oxygen it pumps the blood to the direction of the lungs, and from left side the circulated blood reach every region of the body through the blood vessels. Within a single cardiac rhythm, the contraction and the relaxation are controlled by harmonized ion flows (currents) (Na +, K +, Ca 2+ ). In a typical lifetime (approx 70 years) with roughly three billion cycles, the heart pumps approximately million hl blood. Slide 2. Characteristics of cardiac muscle operation: Their operation shows the typical features of smooth and skeletal muscle. Quick, vegetative operation. Strong muscle contraction without resting The refractory period is already starts at the beginning of relaxation, therefore tetanic contraction can not be generated. The operation of cardiac muscle cells are based on all or nothing principle (a threshold stimulus triggers a maximal contraction). Slide 3. Characteristics of Cardiac Muscle Cells (CMC) 1. Forms a functional syncitium. a. Cellular bridges interconnect CMC's to each other. b. Intercalated discs form junctions between CMC's. These porous junctions permit ions of sodium and potassium to diffuse from cell to cell. This facilitates the spread of depolarization and repolarization throughout the myocardium. c. The entire myocardium behaves as a single coordinated unit. 2. Mitochondria are large and very abundant. CMC's are capable of producing high quantities of ATP. 3. The cisternae of the sarcoplasmic reticulum of CMC's are smaller than in skeletal muscle cells. As a result, CMC's must take Calcium ions from adjacent cells through the intercalated discs and from the extracellular environment. Slide 4. The generation and spread of cardiac rhythm Each heart beat originates as an electrical impulse from a small area of tissue in the right atrium of the heart called the sinus node or Sino-atrial node or SA node. The impulse initially causes both of the atria to contract, then activates the atrioventricular (or AV) node which is normally the only electrical connection between the atria and the ventricles, which can be called as main pumping chambers. The impulse then spreads through both ventricles via the Bundle of His and the Purkinje fibres causing a synchronised contraction of the heart muscle, and thus, the pulse.

2 In adults the normal resting heart rate ranges from 60 to 80 beats per minute. The resting heart rate in children is much faster. The detection the action potentials on body surface with electrodes produces the ECG (EKG) curve. Slide 5. Muscle energenetics The heart is polyphagous: Energy requirement is covered by burning of fatty acids (60-80%), carbohydrates (20-30%), proteins, lactate, ketons (0-10%). The oxidation a fatty acids produces high amount of energy, however relative oxygen demand is very high. Taking a unit of oxygen, the burning process of carbohydrates produces 15% higher energy. The energy that maintains the muscle contractibility is obtained from ATP. In heart main source of ATP is the metabolism of carbohydrates and fatty acids. The disturbance of glucose oxidation will result in the accumulation of lactic acid, that will enhance fatty acid breakdown. Finally heart energy demand fully depends on fatty acid oxidation. This will lead malfunction of contractibility. When the energy production shifted to direction of higher fatty metabolism, the ATP production will become economically expensive, but an insufficiency of ATP will be established. The energy production shifts to anaerob glucolysis, very soon a condition intracellular acidosis and lactate accumulation will be resulted. In parallel with the cytoplasmatic H+ and Ca2+ -ion accumulation in, there is a larger need of ATP to operate sarcoplasmatic Ca2+ pumps. Thus less energy remains for muscle contraction. In case of reperfusion the breakdown of pyruvate and the mechanical efficiency of heart remain reduced, but with high rate of fatty acid oxidation, the oxygen consumption will be high. In reperfusion the production of free radical will result in additional tissue damage. Slide 6. Ion distribution in muscle cell in resting condition Slide 7. The phases of the cardiac action potential The cardiac action potential is a specialized action potential in the heart, necessary for the electrical conduction system of the heart The cardiac action potential differs significantly in different portions of the heart. This differentiation of the action potentials allows the different electrical characteristics of the different portions of the heart. For instance, the specialized conduction tissue of the heart has the special property of depolarizing without any external influence. This is known as cardiac muscle automaticity. Cardiac muscle has some similarities to skeletal muscle, as well as important unique properties. Like skeletal myocytes (and axons for that matter), a given cardiac myocyte has a negative membrane potential when at rest. A notable difference between skeletal and cardiac myocytes is how each elevates the myoplasmic Ca 2+ to induce contraction. When skeletal muscle is stimulated by somatic motor axons, influx of Na + quickly depolarizes the skeletal myocyte and triggers calcium release from the sarcoplasmic reticulum. In cardiac myocytes, the release of Ca 2+ from the sarcoplasmic reticulum is induced by Ca 2+ influx into the cell through voltage-gated calcium channels on the sarcolemma. This phenomenon is called calcium-induced calcium release and increases the myoplasmic free Ca 2+ concentration causing muscle contraction. In both muscle types, after a delay (the absolute refractory

3 period), potassium channels reopen and the resulting flow of K + out of the cell causes repolarization to the resting state. The voltage-gated calcium channels in the cardiac sarcolemma are generally triggered by an influx in sodium during the "0" phase of the action potential. Slide 8. Main ventricular ion currents Slide Cardiac arrhythmias Arrhythmias: Irregularity of cardiac frequency or cardiac rhythm, caused by the generation of faulty cardiac stimulus or by abnormality of conduction Normal frequency: /min Tachycardia: > 100/min (tolerable , intolerable > 150) Bradycardia: < 60/min (tolerable 40-60, intolerable < 40) The operation abnormal heart rhythm (arrhythmic) can weaken the cardiac pump function The arrhythmia may interferes with the pump function in two different way: - If the rhythm too fast; the heart can not be filled up with proper amount blood, there is not enough time for ventricular filling - If the rhythm too slow; the heart cannot circulate the enough amount of blood, or its operation becomes non-coordinated. Either mechanism of arrhythmia step up, the heart will not be able to maintain the proper blood circulation, the symptom of cardiac failure will appear. Slide 11. Types of arrhytmias Supraventricular arrhytmias. Atrial arrhytmias Sinustachycardia Atrial fibrillation Sinusbradycardia Vetricular arrhytmias Ventricular extrasystoles Ventricular tachycardia Slide 12. Arrhythmic triggering and disposive factors Age. Naturally with aging, the cardiac muscle is weakened, loosing its original contractibility. This influences the conduction of electric impulses. Genetic background. The congenial cardiomyopathies influences the electric operation of the heart. Coronary and other cardiac diseases, earlier cardiac operation. The narrowed coronaries, cardiac infarct, mitral insufficiency, earlier cardiac operation, cardiomyopathies etc, are risk factor of arrhythmia. Diseases of thyroid gland. In case of hyperthyroidism, the over production thyroid hormone will accelerate the metabolism, that can trigger a faster heart beat leading to often atrial fibrillation. The low level of hormone (hypothyroidism) will result in bradycardia.

4 Medical drugs and medicative drugs. Certain pectoral and anti-chill drugs without obligatory prescription might contain ephedrin, might trigger arrhythmia. Hypertesion. Hypertension increases the risk of disease effecting coronary arteries, furthermore might thicken the wall of the left ventricle, which influences the electric conductibility. Overweight. Beside the chance to develop a coronary disease, the obesity increase the risk of arrhythmia generation. Diabetes. The untreated diabetes may result in an increased risk of coronary disease. Beside the low level of blood sugar (hypoglycemia) might provoke arrhythmia. Obstructive sleep apnoea. This disorder can result in episodes of bradycardia and atrial fibrillation Ion level abnormality. Different ions (K+, Na+, Ca2+, Mg2+) are essential for normal cardiac electrical operation. Too high or too low level of ion concentrations influences the electric activity and contribute to generation of arrhythmia. Extensive alcohol consumption. Modify the electric conductivity, generate atrial fibrillation, furthermore result in cardiomyopathy. Using variable stimulants: The extensive intake of caffeine and nicotine might lead to generation of arrhythmias. Consumption of narcotic drugs radically influences the cardiac operation. And the stress. Slide 13. A sudden cardiac death Sudden cardiac death is a cardiac originated death, where less than one hour passes between the appearance of the symptoms and the death. There is always some type of arrhythmic problem in the background. In Hungary 26 thousand cases/year, that is death of 70 men/day, thus this is leading the statistic of death causes. Without a help, in every minutes, the life chance is reduced by 10 percent, more 3-5 minutes a brain damage will occur. Although the sudden cardiac death threatens lot of people, it calls for alert, only when some famous sportsman is in case, the tragic death of Olympic winner, György Kolonits is well know. Slide 14. The LQT syndrome The long QT syndrome with QTc has two forms: Acquired and congenial The longed QT interval labels the activation of ventricles and reporalization. The elongation QT distance associated to reduced K + channel function. The syngenic long QT syndrome The frequency of occurrence not depend on ethnic groups: 1:5 10 thousands. 33% of the patiens are lacking any symptoms, but they are also exposed to sudden death risk. The other 67% have symptoms: syncope, cramps, palpitation, that evoked by heavy physical training, swimming, emotional stress or sudden sound effect, but occurs sometimes spontaneously or during sleeping. Romano-Ward syndrome, is the major variant of long QT syndrome. This disorder is a form of long QT syndrome, which is a heart condition that causes the cardiac muscle to take

5 longer than usual to recharge between beats. If untreated, the irregular heartbeats can lead to fainting, seizures, or sudden death. Inheritance Romano-Ward syndrome is inherited in an autosomal dominant pattern. It is the most common form of inherited long QT syndrome, affecting an estimated 1 in 5,000 people worldwide, although more people may be affected but never experience any signs or symptoms of the condition. Causes Mutations in the KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A genes cause Romano-Ward syndrome. The proteins made by most of these genes form channels that transport positivelycharged ions, such as potassium and sodium, in and out of cells. Mutations in any of these genes alter the structure or function of channels, which changes the flow of ions between cells. A disruption in ion transport alters the way the heart beats, leading to the abnormal heart rhythm characteristic of Romano-Ward syndrome. LQT1 LQT1 is the most common type of long QT syndrome, making up about 30 to 35 percent of all cases. The LQT1 gene is KCNQ1 which has been isolated to chromosome 11p15.5. KCNQ1 codes for the voltage-gated potassium channel KvLQT1 that is highly expressed in the heart. Mutations to the KCNQ1 gene can be inherited in an autosomal dominant or an autosomal recessive way in the same family. The the autosomal homozygous recessive mutations of this gene, KVLQT1 leads to severe prolongation of the QT interval (due to near-complete loss of the IKs ion channel), and is associated with increased risk of ventricular arrhythmias and congenital deafness (Jervell and Lange-Nielsen syndrome) Most individuals with LQT1 show paradoxical prolongation of the QT interval with infusion of epinephrine. Jervell and Lange-Nielsen syndrome, a type of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. If untreated, the irregular heartbeats, called arrhythmias, can lead to fainting, seizures, or sudden death. It is caused specifically by mutation of the KCNE1 and KCNQ1 genes In untreated individuals with JLNS, about 50 percent dies by the age of 15 years due to ventricular arrhythmias. LQT2 The LQT2 type is the second most common gene location that is affected in long QT syndrome, making up about 25 to 30 percent of all cases. This long QT syndrome most likely involves mutations of the human ether-a-go-go related gene (HERG) on chromosome 7. The HERG gene (also known as KCNH2) is part of the rapid component of the potassium rectifying current (IKr). (The IKr current is mainly responsible for the termination of the cardiac action potential, and therefore the length of the QT interval.) The normally functioning HERG gene enables the protection against early after depolarization (EADs). Slide 15. Acquired forms Several drugs might be in associated to QTc extension.

6 Anti-angina drugs, Anti arrhythmic drugs Anti microbial drugs (erythromycin, cotrimoxazol) Anti fungi drugs Anti-depressive drugs Anti-histamines Anti psychotic drugs, Lipid reducing drugs, Antidiabetic drugs Organic phosphates etc. Slide 16. Genes associated to congenial Long QT syndromes Slide Ischemia A local blockage of blood supply effecting the cardiac muscle tissue. Ischemic heart disease, which is caused by insufficient blood supply to regions of the myocardium, is a major form of cardiovascular disease. Some factors that establish local blockage in blood circulation: narrowing (coarctation) caused by pathologic vessel wall stiffening of the arteries (ie. atherosclerosis), blood vessel compression (ie. by tumor), a blockage by blood-clot, are other material that gets into the bloodstream. The shortage of blood supply associate to accumulation of harmful mediators, result in a very quick tissue damage (death). In case of the cardiac tissue: this is the infarct. The basic problem generated by interrupted or blocked blood supply: An improper blood supply of myocardium is established which result in temporary or constant tissue hypoxia. Reversible": if the ischemic condition is ceased (reperfusion), and normal metabolic, functional, electrophysiological condition is re-established. Irreversible, if the continued ischemic condition result in tissue necrosis, an infarct is generated Stenosis (vessel narrowing) -> mild ischemia Occlusion (vessel blockage) -> grave ischemia Angina pectoris: a clinical symptom triggered by the insufficiency of myocardial blood supply. Characterized by sharp chest pain. Slide High cholestrol Among the cardiovascular diseases, high blood cholestrol is the most frequent death causative in the highly developed countries, which beside inherited factors is influenced by lifestyle (heavy smoking, excessive alcohol, fatty meals, and stress) Two kinds of lipoproteins carry cholesterol throughout your body. It is important to have healthy levels of both:

7 Low-density lipoprotein (LDL) cholesterol is called bad cholesterol. High LDL cholesterol leads to a buildup of cholesterol in arteries. The higher the LDL level in your blood, the greater chance for getting heart disease. High-density lipoprotein (HDL) cholesterol is called good cholesterol. HDL carries cholesterol from other parts of your body back to your liver. The liver removes the cholesterol from your body. The higher your HDL cholesterol level, the lower your chance of getting heart disease. The genetic effect on blood cholestrol: The variation of apolipoprotein-b (APOB) and the apolipoprotein-e genes (APOE), as Low- Density lipoprotein (LDL) cholesterol receptors, are greatly influences the individual level of blood cholestrol. Slide 20. High blood pressure (hypertony) Widespreaded cronical illness, in which arteric blood pressure constantly exceeds the of 140 Hgmm systolic and 90 Hgmm dyastolic values. Persistent hypertension is one of the risk factors for stroke, myocardial infarction, heart failure and arterial aneurysm, and is a leading cause of chronic kidney failure. Moderate elevation of arterial blood pressure leads to shortened life expectancy. The genetic background of hypertony: A peptide hormone, angiotensinogen, important constuent of the renin-angiotesin system, that controls water-saline household, tonicity of blood vessels, thus possesses an important role the regulation of blood pressure. The frequent molecular variant of angitensinogen can be associated to essencial hypertony, hypertony in pregnancy, or to hypertonic response of certain drug treatment Slide 21. The symptoms associated to high blood pressure The hypertonia frequently mostly has no complain, however certain sign associate to it: headache, dizziness, fatigue, dyspnoea, nosebleeding, vision problem, angina pectoris, or organ complication damage (ie cardiac) by high blood pressure About 90 95% of cases are termed "primary hypertension", which refers to high blood pressure for which no medical cause has been found. The remaining 5 10% of cases (secondary hypertension) are caused by other conditions that affect the kidneys, arteries, heart, or endocrine system. Known risk factor, effecting everybody: Inherited factor; obesity; passive lifestyle; stress; excessive meal salting Slide 22. Complication associated to high blood pressure Coronary diseases (infarct danger); Cardiac failure; Brain damage (ie. hemorrhages), resulting paralysis, confused speech, inability of thinking Kidney failure; Stenosis (engraving the effect of diabetes, smoking, high cholestrol) The hypertony does not cause complain for longer period, often diagnosed late, when some organ damage appear.

8 Eldely people are the most endangered ones Slide Brain circulation disturbance (stroke) A stroke, (cerebrovascular accident), is a rapidly developing loss of brain functions due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage (thrombosis, arterial embolism), or a hemorrhage (leakage of blood). The affected area of the brain is unable to function, leading to inability to move one or more limbs, inability to speech, or an inability to the visual field. Stroke prevention, risk reduction: Reducing, controlling risk factors: regular check up of blood tension, blood sugar and fatty acids, treatment known heart diseases, reducing the consumption of alcohol and smoking, healthy meals and regular physical training. Genetic background: In ischemic stroke, the screening of frequent mutation and polymorphysm is suggested for V. factor Leiden-mutation, and for the polymorhysm of angiotensin converting enzyme. V. factor Leiden-mutation causes an activated protein-c resistance, the presence of mutation, mainly in venous circulation, may trigger thrombolytic reaction.