Chapter 4 CARDIOVASCULAR DISEASES
The cardiovascular system is one of the vital organ systems and its failure is one of the major causes of morbidity and the major cause of death in the Western world. The following epidemiologic facts show why the cardiovascular diseases are important for many human populations:
Many cardiovascular diseases, such as atherosclerosis, are preventable or treatable if recognized early (e.g., arterial hypertension). It is thus encouraging to note that the incidence of cardiovascular disease has decreased in the United States over the last 40 years. Public health initiatives to reduce smoking, combat hyperlipidemia, and motivate people to exercise and follow a healthier life style have had noticeable effects on the incidence of cardiovascular diseases and their major complications. Major advances have been made also in the early diagnosis of cardiovascular disease, treatment based on interventional cardiology, and heart transplantation.
Conduction system of the heart System of specialized cells capable of generating and conducting the electric currents essential for the automatic rhythmicity of the heart. It includes the sinoatrial node, atrioventricular node, the bundle of His and its main branches, and Purkinje fibers.
Coronary arteries Arteries providing blood to the heart. Two major arteries originate in the aorta from the coronary sinuses. The left coronary artery has two main branches: the left anterior descending (LAD), providing the blood to the anterior side of the left ventricle and the anterior part of the ventricular septum; and the left circumflex (LCX), which provides blood to the lateral side of the left ventricle. The right coronary artery (RCA) usually gives rise to the posterior descending artery (PDA). The PDA originates from the RCA in 90% of the population designated as having right coronary dominance. In 10% of cases left coronary dominance occurs, and the PDA originates from the LCX.
Myoglobin Oxygen-binding heme protein found in cardiac and skeletal muscle cells. It may spill out into the blood from necrotic muscle fibers and is thus a marker of myocardial cell necrosis occurring after myocardial infarction.
Pericardium Outer layer of the heart, composed of a mesothelial layer and underlying connective tissue. It covers the subepicardial fat tissue, which contains the branches of the coronary arteries and veins.
Renin Polypeptide hormone synthesized by juxtaglomerular (JG) cells in the kidney. It acts on angiotensinogen and is thus important for the aldosterone-mediated retention of sodium and water in the kidneys. It is synthesized in response to hypoperfusion of kidneys and is the primary mediator of renal hypertension.
Septum Part of the heart separating the left atrium from the right atrium, and the left ventricle from the right ventricle. It consists of fibrous tissue (fibrous septum) and muscle (muscular septum).
Troponin I and T Sarcomeric proteins regulating the contraction of myofibrils. In myocardial infarction these proteins are released into the blood. The elevation of troponin I or T in blood is evidence of myocardial necrosis.
Valve Mobile part of the cardiac orifice that separates atria from ventricles or the ventricles from the great vessels. Valves consist of a fibroelastic core covered with the endocardium. The mitral and tricuspid valves are attached to the papillary muscles with chordae tendineae. The aortic and pulmonary valves are semilunar and not attached to the muscles. At their base the valves are anchored to the annulus fibrosus, forming the connective tissue skeleton of the heart.
Ventricle Cardiac chamber that has a thick muscular wall accounting for most of the contractile power of the heart. The heart has two ventricles, the right and the left ventricle, separated one from each other by a predominantly muscular septum.
Arrhythmia Collective term used to describe several abnormalities of heartbeat, it includes, among others, tachycardia, bradycardia, premature ventricular beat, atrial or ventricular fibrillation, flutter, conduction defects, and heart block.
Clubbing of fingers Condition in which the amount of subcutaneous soft tissue of the terminal phalanges is increased, with curving of the nails, giving the fingers a drumstick appearance. It is commonly seen in cyanotic congenital heart diseases, such as tetralogy of Fallot. It is also encountered in chronic lung diseases with long-standing ventilatory problems.
C-reactive polypeptide, or protein (CRP) Acute-phase reactant secreted by the liver in response to cytokines released from inflammatory cells. Its concentration is elevated in blood in various inflammatory conditions, including the inflammation that occurs inside atherosclerotic blood vessels. As such it is an independent predictor of the risk for complications of atherosclerosis.
Cyanosis Bluish or purplish tinge to the skin and mucosae that becomes visible once the unoxygenated hemoglobin concentration exceeds 5 g/100 mL of blood, or the overall oxygen saturation is less than 85%. It may be classified as central or peripheral.
Dyspnea Shortness of breath that may be acute or chronic, episodic or continuous, exertional or resting. Usually it is a symptom of heart or lung disease. Exertional dyspnea or paroxysmal nocturnal dyspnea is usually a sign of heart disease.
Edema Accumulation of fluid in tissues and body cavities. Cardiogenic edema involves either lungs and pleural cavity (in left heart failure) or peripheral tissues of the lower extremities and abdominal cavity (in right heart failure).
Hypertension Elevated blood pressure in the arteries. It may be primary or idiopathic (90%), if the cause of hypertension is unknown, or secondary if the cause of hypertension is known. The most common causes of secondary hypertension are renal, endocrine, or vascular diseases.
Intermittent claudication Sudden pain in the lower extremities, precipitated by walking; it is so severe that it will cause limping or might force the affected person to stop walking. It is typically a consequence of atherosclerotic narrowing of major leg arteries.
Paroxysmal nocturnal dyspnea Form of dyspnea that occurs in patients with heart failure several hours after lying down. It is caused by increased venous return and the failure of the heart to propel the blood, leading to pulmonary congestion and edema and shortness of breath that wakes the patient.
Pulmonary edema Accumulation of fluid in the alveoli and interstitial spaces of the lung. It may be a consequence of transudation of serum in left ventricular failure, during early stages of ARDS, or as an inflammatory exudate in early stages of pneumonia.
Pulmonary hypertension Increased pressure inside the pulmonary artery and its branches. It may be a consequence of primary lung disease or chronic pulmonary congestion due to left heart failure or mitral valve disease. Pulmonary hypertension poses a strain on the right ventricle, causing its hypertrophy (“cor pulmonale”).
Amyloidosis of the heart Deposition of fibrillar extracellular material that binds Congo red and is β-pleated when examined by electron diffraction analysis. It may be part of generalized amyloidosis or may present as an isolated cardiac amyloidosis. Deposits of amyloid in the cardiac interstitium cause restrictive cardiomyopathy.
Aneurysm of aorta or arteries Localized dilatation of an artery, caused most often by atherosclerosis, but also by syphilis or various forms of arteritis. Berry aneurysms of the circle of Willis are congenital.
Aneurysm of the ventricle Dilatation of the ventricular lumen, most often as a late complication of myocardial infarction. The wall of the aneurysm is composed of fibrous scars and does not contract with the surrounding myocardium. Thrombi form within large ventricular aneurysms.
Angina pectoris Chest pain caused by cardiac ischemia related to stenosis, partial occlusion, or spasm of the coronary arteries. Three main forms are recognized: (1) stable or classical angina; (2) unstable or crescendo angina or preinfarctional angina; and (3) Prinzmetal’s angina, which is characterized by pain at rest, caused by functional narrowing of coronary arteries due to spasm.
Atheroma Hallmark of atherosclerosis, presenting as a bulging of the wall of the aorta or a circumferential narrowing of smaller elastic arteries. It consists of a central core composed of lipids, cell debris, and foam cells, and a fibrous cap covering it on the luminal side. Complicated atheromas may be calcified, or ruptured and filled with coagulated blood.
Atrial fibrillation Disturbance of normal atrial contraction, which is replaced by irregular twitching, best recognized by electrocardiogram (ECG). May predispose patient to formation of atrial mural thrombi.
Calcific aortic stenosis Narrowing of the aortic orifice due to the calcification of the valves. It is most often caused by wear and tear of old age, but can be a complication of congenital bivalvular aortic orifice and rheumatic endocarditis.
Carcinoid heart disease Cardiac disease caused by serotonin and other vasoactive substances released from gastrointestinal carcinoids that have metastasized to the liver. Cardiac changes include tricuspid and pulmonary valve stenosis and insufficiency and fibrosis of the atrial and ventricular lumen resulting from subendocardial fibrosis induced by vasoactive substances.
Cardiac tamponade Compression of the heart by fluid, usually blood, that has entered into the pericardial sac. The pressure exerted by the fluid prevents the diastolic filling of the cardiac chambers and is usually fatal.
Cardiogenic shock Systemic circulatory collapse caused by cardiac pump failure. It is characterized by hypotension and hypoperfusion of vital organs, causing ischemia of the brain, heart, kidneys, and other organs. Most often it is a complication of myocardial infarction.
Cardiomyopathy Term used to describe primary myocardial diseases unrelated to coronary atherosclerosis, hypertension, or infectious or rheumatic carditis. Cardiomyopathy may occur in three forms: (1) dilated cardiomyopathy, (2) hypertrophic cardiomyopathy, and (3) restrictive cardiomyopathy.
Congestive heart failure Clinical condition characterized by stagnation of blood retrograde to the failing heart. Left heart failure causes chronic passive congestion and edema of the lungs, whereas right heart failure results in congestive hepatomegaly, pitting edema of the lower extremities, ascites, and splenomegaly.
Constrictive pericarditis Form of chronic pericarditis or pericardial fibrosis encasing the heart and preventing its expansion during diastole. The cause of constrictive pericarditis is most often unknown, and it is assumed to be a complication of a healed viral pericarditis. Radiation, tuberculosis, or tumors can cause the same changes.
Cor pulmonale Clinical condition characterized by dilatation and strain of the right ventricle and possible right ventricular failure. Most often it is caused by left ventricular failure, but also by any other condition causing pulmonary hypertension.
Dilatation of the heart Widening of the cardiac chambers, usually due to the stretching of cardiac myocytes. Dilatation of the ventricles is the first adaptation to an increased demand for cardiac output, and during this response the dilatation is beneficial and reversible.
Endocarditis, infectious Inflammation caused by a bacterial infection of the valves or mural endocardium of the heart chambers. Bacteria destroy the valves, causing valvular defects and disturbing blood flow; emboli may occur and cause systemic symptoms.
Floppy valves Congenital or acquired myxomatous degeneration of the valves accompanied by accumulation of sulfated glycosaminoglycans and a loss of collagen and elastic fibers. Mitral valve disease is found in 1% to 2% of adults; other valves are involved less often.
Hypertensive heart disease Complex heart disease caused by elevated arterial pressure. It is characterized by left ventricular hypertrophy and relative ischemia of the myocardium, which cannot get enough blood for its needs. Hypertension also predisposes to coronary atherosclerosis, which will contribute to myocardial ischemia.
Ischemic heart disease (IHD; also known as coronary heart disease) Group of circulatory diseases caused by inadequate oxygen due to coronary insufficiency. Most often it is caused by atherosclerotic narrowing or occlusion of coronary arteries. The most important clinical forms of IHD are (1) angina pectoris, (2) myocardial infarct, (3) congestive heart disease, and (4) sudden cardiac death.
Left ventricular failure Pump failure of the left ventricle manifesting with hypoperfusion of organs with arterial blood (forward failure) and stagnation of the blood in the lungs. It manifests with pulmonary congestion and edema.
Left ventricular hypertrophy Thickening of the left ventricular myocardium. Most often it is caused by arterial hypertension, but it may also be caused by stenosis of the aortic orifice or insufficiency of the mitral valve. It is also found in cardiomyopathies.
Mitral valve stenosis Functional disturbance resulting from the narrowing of the mitral orifice and valves, which cannot open completely during diastole. Most often (99%) it is a consequence of rheumatic endocarditis.
Myocardial infarct, subendocardial Ischemic necrosis of the subendocardial zone of the myocardium, most often circumferential. Typically caused by hypoperfusion without complete anatomic occlusion of a coronary artery. It is most often found in shock or as a complication of myocardial infarction. In typical cases it presents without Q wave changes in the ECG (“non-Q wave infarction”), and is not accompanied by pericarditis.
Myocardial infarct, transmural Localized area of ischemic necrosis of the myocardium caused by occlusion of a coronary artery. Most often it is a complication of thrombosis developing at the site of ruptured atheroma. Thomboemboli from the left ventricle are a less common cause.
Myxoma Benign cardiac tumor most often found in the left atrium (75%), less often in the right atrium (24%), and very seldom in other cardiac chambers. Tumor protrudes into the lumen of the atria and may act as a “ball-valve.” As such, it may temporarily occlude the mitral or tricuspid orifice and interrupt the blood flow. Also, parts of the tumor may detach and thus give rise to emboli.
Myxomatous degeneration of cardiac valves Deformation of cardiac valves accompanied by accumulation of sulfate glycosaminoglycans and a loss of normal collagen and elastic fibers forming the central core of the valves. In most instances the cause is unknown. It may occur in inborn errors of metabolism such as the Marfan’s syndrome and Ehlers-Danlos syndrome or various mucopolysaccharidoses. The mitral valve is most often involved, but all valves can be affected.
Pericarditis Inflammation of epicardium and pericardium (i.e., the visceral and parietal layer of the pericardial sac). It can manifest in several pathologic forms: serous, fibrinous, fibrinohemorrhagic, purulent, fibrous, or calcific.
Rheumatic heart disease Immune-mediated disease initiated by antigens on beta-hemolytic streptococci, usually after a streptococcal pharyngitis (“strep throat”). Clinically it is diagnosed by documenting the rheumatic fever (using the Jones criteria), establishing the link between the heart disease and the streptococcal infection (ASO titers high), and proving that the heart is damaged. Rheumatic carditis most often affects the cardiac valves of the left side of the heart.
Right ventricular hypertrophy Thickening of the wall of the right ventricle, typically caused by pulmonary hypertension. The most common cause of right ventricular hypertrophy is left ventricular hypertrophy.
Rupture of the ventricle Perforation of the wall of the left ventricle, usually caused by ischemic necrosis (transmutable infarct). Blood penetrates through the ventricular wall, filling the pericardial cavity and causing death due to pericardial tamponade.
Shunt A passage that allows abnormal blood flow between two cardiac chambers on the opposite sides of the septum dividing the left from the right heart. Blood flows through the shunt from the higher pressurized chamber to the chamber that is under less pressure.
Tricuspid valve insufficiency Functional disturbance resulting from incomplete closure of the tricuspid valves. May be congenital or acquired. Acquired tricuspid valve insufficiency can be a consequence of endocarditis or carcinoid heart disease.
Truncus arteriosus Congenital heart disease related to incomplete separation of the aorta from the fetal pulmonary artery. In this disease the aorta and the pulmonary artery form a single large blood vessel originating from the heart.
Valvular calcification Dystrophic calcification affecting valves previously damaged by endocarditis, or resulting from the wear and tear of old age. Congenitally abnormal or lax valves are especially prone to calcification.
Valvular insufficiency Circulatory disturbance caused by incomplete closure of a cardiac valve, resulting in regurgitation of blood from one chamber of the heart or a great vessel into another one of the heart chambers.
The cardiovascular system comprises the heart and blood vessels, which are classified as arteries, arterioles, capillaries, venules, and veins. The right heart pumps the blood into the lungs, where it is oxygenated and returned to the left heart for distribution through several parallel arterial pathways into the peripheral tissues (Fig. 4-2). This chapter focuses mostly on the heart, and the blood vessels are discussed only as they contribute to heart diseases and their peripheral manifestations.
The heart is located inside the pericardial sac, which is itself located in the lower (supradiaphragmatic) part of the mediastinum. The heart occupies the central portion of the mediastinum, extending slightly to the right from the midline and projecting with its apex toward the left lateral side (Fig. 4-3). The great vessels (i.e., the superior and inferior vena cava, the aorta, the pulmonary artery, and the pulmonary veins) are attached to the heart at its “base,” which is located cranially and to the right of the apex. The contours of the heart are clearly visible in anteroposterior (AP) radiographic films.
Figure 4-3 Anatomic location of the heart in the thorax. In a radiograph the right border is made of the contours of the right atrium (RA) and right ventricle (RV). The inferior border is made of right ventricle and on the left lateral side of the apex of the left ventricle (LV). The left border is made of the contours of left atrial appendage and left ventricle, and along the upper margin the aortic arch.
In adults the anterior mediastinum contains the remnants of the thymus, which does not affect the function of the heart unless enlarged due to thymoma or lymphoma. The posterior side of the heart is in anatomic contact with the esophagus and the thoracic aorta. Transesophageal echocardiography may be used to assess the left atrium lying on the esophagus, but it may also provide data on the entire heart.
The heart has two atria and two ventricles (Fig. 4-4). The right atrium and ventricle contain unoxygenated (“venous”) blood, which has an oxygen saturation between 72% and 80%. The contracting right heart pumps the blood into the lungs, where is it oxygenated. The left atrium and ventricle contain oxygenated (“arterial”) blood with an oxygen saturation of 95% or more. The left ventricle propels the oxygenated blood into the periphery through the aorta and the arteries.
Figure 4-4 Cross section through the right and left heart and the great vessels. The range of systolic and diastolic pressures in each chamber is indicated. The oxygen saturation of blood in the right heart ranges from 72% to 80%, and is 95% or more in the left heart.
The atria and the ventricles and the great arteries are separated one from another by valves. These valves open and close during the cardiac contraction cycle, thus allowing the orderly flow of blood from one compartment to another. The closure and opening of the valves and the cardiac contractions account for the pressure gradients that develop differentially in each chamber.
The right atrium receives the venous blood from the upper and the lower venae cavae. The venous blood enters the right ventricle through the right atrioventricular (AV) orifice, which is tricuspid. The blood is pumped by the ventricle through a tricuspid pulmonary orifice into the pulmonary artery. The oxygenated blood returns to the heart through the pulmonary veins, which convey it to the left atrium. From the left atrium the blood passes through the left AV orifice, which is bicuspid and called mitral, and enters the left ventricle. The left ventricle pumps the blood into the aorta through the aortic valve.
The right coronary artery provides the blood for the entire right ventricle, the posterior side of the left ventricle, and the posterior side of the interventricular septum. In 90% of people it gives rise to the posterior descending coronary artery and is therefore by convention considered to be the dominant artery. It also provides the blood to the sinoatrial (SA) node in 60% and to the AV node in 90% of people.
The left coronary artery branches within 2.5 cm of its origin, giving rise to the left anterior descending (LAD) and left circumflex artery (LCX). The LAD provides blood to the anterior wall of the left ventricle, the apex of the heart, and the anterior part of the interventricular septum. The LCX provides the blood for the lateroposterior wall of the left ventricle.
> The heart is positioned diagonally, and thus the posterior wall of the ventricles is clinically known as the heart’s inferior surface. Accordingly, the pathologic term posterior wall infarct is clinically known as an inferior infarct.
The coronary arteries are located subepicardially on the external surface of the heart. The major veins follow the arteries. Because of their location these major vessels are not compressed by the contracting myocardium during the systole—a period of the cardiac cycle when the coronaries actually dilate to accommodate the influx of oxygenated blood. Coronary arteries have β2-adrenergic receptors, which react to stimuli from sympathetic nerves, thereby causing coronary vasodilatation. Parasympathetic stimulation also causes mild coronary vasodilatation.
Due to their location in the epicardial fat tissue the coronary arteries are at a distance from the endocardium. The nourishment of the endocardium is, however, not affected by this distance because the endocardium receives oxygen and nutrients from the ventricular blood. The zone that is at risk for hypoxia, however, is the subendocardial myocardium, which is beyond the supply zone from the ventricles and is the last to receive the blood from the coronary arteries.
> Subendocardial infarcts (also known as non-Q wave infarcts) are typically found in shock and other hypoperfusion states. These infarcts develop because the subendocardial myocardium is the last part of the ventricular muscle to receive oxygen from the coronaries, and if the blood pressure drops, it is the first to become ischemic.
The coronary arteries and their major branches are considered to be functionally terminal arteries. Although there are 40-μm or smaller caliber anastomoses between the major coronary arteries, these anastomoses are not sufficient to compensate for the occlusion of one coronary artery or its major branches. If a coronary artery become progressively stenotic these anastomoses can increase in size and become functional and provide blood to the relatively ischemic portion of the heart supplied normally by the other coronary.
> So-called paradoxical infarcts, that is, infarcts that develop in the left coronary artery supply zone due to a thrombus in the right coronary, and vice versa, are a consequence of newly developed anastomoses due to the gradual narrowing of the coronary artery that normally provides the blood to the infarcted area.
The inside of the heart is covered with endocardium, which is a layer continuous with the endothelium of blood vessels. The endocardium also covers the surface of the valves. The myocardium, or the muscle layer, is the primary contractile component of the heart. The pericardium forms the pericardial sac and also covers the external surface of the heart as epicardium.
The contractile myocytes form the bulk of the heart wall. Cardiac myocytes are striated muscle cells with centrally placed nuclei and well-developed cytoplasm. These branching cells are interconnected one with another through gap junctions called intercalated discs allowing easy passage of electric current through the myocardium.
Contractile function of cardiac myocytes depends on the proper functioning of sarcomeres and supporting structures in the cytoplasm.
Contractile units in the cytoplasm of cardiac myocytes are called sarcomeres (Fig. 4-6). They are composed of thick myosin filaments interdigitating with thinner actin filaments and a number of contraction-regulating proteins, such as tropomyosin and troponins (C, I, and T). During contraction the myosin filaments slide along one another, whereas during relaxation they slide in the opposite direction.
(Modified from Boon NA, Colledge NR, Walker BR [eds]: Davidson’s Principles and Practice of Medicine, 20th ed. Churchill-Livingstone, Edinburgh, 2006.)
The overlapping of actin and myosin filaments accounts for the striation of cardiac myocytes. Three regions are recognized by light microscopy: two lighter regions called I (isotropic), and a darker region called A (anisotropic). By electron microscopy the central part of the I region contains the Z line. Normal sarcomeres, measured from one Z line to another, vary in length from 1.5 μm in contracted muscle cells in systole to 2.2 μm in stretched muscle fibers in diastole.
The cell membrane of myocytes, also known as sarcolemma, invaginates into the cytoplasm, forming the so-called transverse tubular system (T tubules). The T system is an important regulator for the flux of calcium ions from outside into the cells and from one cellular compartment to another (Fig. 4-7). The T tubules are closely linked to the sarcoplasmic reticulum, a system of cisterns that serve as the main intracellular store of calcium. The sarcoplasmic reticulum and the T tubules form an integral system essential for the rapid transmission of electrical stimuli and the contraction–relaxation of myocytes.
Cardiac contractions depend on the interaction of the external innervation and the endogenous conduction system of the heart.
The heart receives parasympathetic innervation from the vagus and sympathetic innervation from sympathetic ganglia. The cholinergic parasympathetic stimuli, which are under normal circumstances predominant, stimulate the heart through the AV and SA node. Vagal stimulation has a negative chronotropic and inotropic effect; that is, it slows down the heartbeat and reduces the strength of the cardiac contraction. Sympathetic stimuli transmitted mostly through β1-adrenergic receptors have a positive chronotropic and inotropic effect. Sensory nerves, important for the cardiac reflexes, exit the heart through the vagus nerve.
The automatic contractility of the heart is regulated through the SA and AV node and the conduction system of the myocardium. The SA node is the source of initial impulses and accounts for the normal “sinus rhythm.” The depolarization wave is transmitted from the SA node to the internodal and interatrial fibers, which causes depolarization of the right and left atrium. The electric impulses cannot freely pass into the ventricle because the annulus fibrosus blocks their propagation. The only way that the impulses can get into the ventricle is by reaching first the AV node located on the atrial side of the annulus fibrosus. From the SA node the electric impulses enter the bundle of His, which penetrates the annulus fibrosus and allows the stimuli to pass from the atrium to the ventricle. Then they reach the Purkinje fibers and are transmitted to cardiac myocytes, causing their depolarization. These electrical events can be traced externally and if superimposed on one another can be recorded as an electrocardiographic tracing (Fig. 4-8).
Figure 4-8 Electric currents generated by depolarization of various parts of the conduction system and the myocardium. Superimposed one over another these electric impulses can be registered as the normal electrocardiographic (ECG) tracing. AV, atrioventricular; SA, sinoatrial.
(Modified from Boron WF, Boulpaep EL [eds]: Medical Physiology. Saunders, Philadelphia, 2003.)
The contraction of cardiac myocytes is closely related to changes in the plasma membrane. Sarcolemma, the plasma membrane of cardiac myocytes, is selectively permeable to ions. The differential distribution of ions inside and outside the myocytes accounts for the electric charge of the cells membrane, which in a resting cell is approximately -90 mV. If the cell is stimulated, the potential is reduced to a critical level, called threshold potential, whereupon the cell membrane undergoes depolarization, which is completed spontaneously according to the all-or-none law. The cell membrane is then repolarized by several mechanisms, and the cycle is repeated automatically.
Phase 3 (repolarization) due to closure of Ca2+ channels and an efflux of K+, leading to repolarization of the cell membrane. The excess of Na+ inside the cell and a net loss of K+ are corrected by active pumping of Na+ and K+ across the cell membrane by Na+/K+ ATPase.
Phase 4 (forward current) characterized by mild gradual depolarization of cell membrane due to Na+ influx accompanied by mild K+ efflux. During this phase the cell rests, and potential rises slowly to reach the initial threshold for the next depolarization.
Contraction of sarcomeres requires a marked increase of cystosolic calcium concentration so that it could start binding to troponin C.
During phase 2 of the myocyte action potential Ca2+ enters into the cytoplasm through the calcium channels and is transferred into the sarcoplasmic reticulum (Fig. 4-10). The entry of extracellular Ca2+ acts as a trigger for discharge of large amounts of Ca2+ stored inside the cisterns of the sarcoplasmic reticulum and to a lesser degree in mitochondria. Once the concentration of cytosolic calcium has risen 10-fold Ca2+ binds to troponin C, which inactivates troponin I, allowing it to induce conformational changes in tropomyosin, the principal regulator of actin–myosin interaction. Tropomyosin deblocks actin, allowing it to interact with myosin. This interaction is a multistep process that ultimately leads to contraction of the sarcomeres.
Figure 4-10 The role of calcium (Ca2+) in mediating the contraction of sarcomeres. The entry of Ca2+ from outside the cell triggers the release of Ca2+ from the sarcoplasmic reticulum and to a lesser extent from mitochondria. Free cytoplasmic Ca2+ binds to troponin C, which interacts with other troponins and tropomyosin enabling the contraction of sarcomeres. At the end of the contraction Ca2+ is released from the sarcomeres and returned to the sarcoplasmic reticulum. Tn-C, troponin C.
After the contraction occurs the calcium dissociates from tropomysin, which inhibits actin–myosin interaction, leading to relaxation of the sarcomeres. Free Ca2+ is pumped by Adenosine triphosphate (ATP)-dependent calcium pumps back into the sarcoplasmic reticulum and mitochondria, where it is stored. It is also exchanged for Na+ across the plasma membrane and extruded from the cell cytoplasm into the interstitial space. During the next action potential the entire cycle is repeated.
Contraction of the myocytes results in systole and the expulsion of the blood from the ventricles, whereas during diastole the ventricles dilate and fill with blood.
The cardiac cycle has two phases: systole, during which the myocardium of the ventricles contracts, and diastole, during which the ventricles dilate. The force of cardiac contraction is influenced by several factors, the most important of which are the preload, contractility of the myocytes, and the afterload (Fig. 4-11).
(Modified from Price AS, Wilson LM: Pathophysiology. Clinical Concepts of Disease Processes, 6th ed. Mosby, St. Louis, 2003.)
Preload refers to the end-diastolic volume (i.e., the amount of blood in the ventricles just before the contraction). The contraction of the ventricles increases in proportion to the increased preload (i.e., the venous return to the heart). This is in keeping with the Frank-Starling law of the heart, which states that “volume of blood ejected by the ventricle depends on the volume present in the ventricle at the end of diastole.” Many years after Frank and Starling defined their law, it was shown that the increased end-diastolic pressure leads to lengthening of the sarcomeres, which thereupon contract more forcefully (Fig. 4-12). In other words the energy of contraction is proportional to the initial length of the cardiac muscles. The Frank-Starling law works only within limits: if the optimal lengthening of sarcomere is exceeded, the contractions become less powerful.
Figure 4-12 Ventricular performance curve according to the Frank-Starling law of the heart. The cardiac output. The left ventricular (LV) stroke increases proportionately to the end-diastolic pressure (i.e., the length to the sarcomere). If the maximum permissible length is exceeded, the LV stroke decreases. Positive inotropic stimuli increase the LV stroke. Negative inotropic stimuli decrease contractility and reduce the LV stroke. CAD, coronary artery disease.
Increased contractility (positive inotropic effect) refers to faster contraction of myocytes or increased velocity of shortening at a constant preload. It can be achieved by sympathetic stimulation or with drugs that have, like digitalis, a positive inotropic effect. Sympathetic stimulation also has a positive chronotropic effect; that is, it increases the heart rate, which also contributes to increased cardiac output.
Decreased contractility (negative inotropic effect) is encountered under pathologic conditions, such as coronary heart disease, hypoxia, and acidosis. In such conditions the heart cannot increase cardiac output in response to increased end-diastolic pressure.
Afterload refers to the pressure and resistance against which the ventricles work. In the left ventricle, afterload may be caused by narrowing of the arteries or arterial hypertension, as well as by narrowing of the aortic valves by rheumatic disease or calcification. Afterload to the right ventricle results from various conditions causing pulmonary hypertension or left ventricular failure. Afterload must be overcome by increased cardiac work, but ultimately the heart fails.
The action of the heart occurs in repetitive cycles, which include coordination of myocardial contractility and opening and closing of valves.
The cardiac cycle can be monitored by recording the pressure in various chambers or in the aorta, by measuring the volume of blood in various chambers, by recording the electric potential in electrocardiographic (ECG) tracings, and by monitoring the opening and closing of valves using a cardiac phonograph (Fig. 4-13).
(Modified from Guyton AC, Hall JE, Textbook of Medical Physiology, 10th ed. Saunders, Philadelphia, 2000, p. 99.)
The cardiac cycle begins with the formation of an action potential inside the sinus node. This occurs during diastole when the muscle is relaxed and the ventricles dilated. Through the opening of the mitral and tricuspid valves the ventricles fill until the pressure inside the ventricles reaches the pressure in the atria. This part of the heart cycle is called diastasis. The impulses generated in the SA node are transmitted to the atrial musculature. Spreading of the depolarization through the atria is seen in ECG as the P wave. The impulses also reach the AV node from which they enter into the ventricles. The 0.10-second delay in the relay of the impulses to the atrial muscles and the entry of the electric current into the ventricles allows enough time for the atrial contraction, which typically precedes ventricular contraction before the arteriovenous (A-V) valves close.
The depolarization of the ventricles shows up in the ECG as the QRS complex, which leads to systolic contraction of the ventricles. At the beginning of systole the A-V valve closes to prevent the reflux of blood into the atrium once the ventricle begins contracting. The closure of the A-V valve is heard as the first heart sound (S1). It is low in pitch and continues relatively long after the closure. Initially the ventricular contraction is isovolumic, but then the aortic valve opens and the blood ejection phase begins. During this phase the blood is ejected into the aorta from the left ventricle and into the lungs from the right ventricle. At the end the volume of the blood in the ventricles decreases dramatically.
At the end of systole the aortic valve closes and diastole begins with isovolumic relaxation of the ventricles. The closure of the aortic valve is heard as the second heart sound (S2). At the end of the isovolumic relaxation the A-V valve opens and the rapid filling (inflow) phase of diastole begins; the cycle is then repeated. The third cardiac sound (S3) can be heard during the period of rapid filling in young persons; in older persons S3 is a sign of ventricular dysfunction. The fourth cardiac sound (S4) is produced by atrial contraction. These phases of the systole and diastole are presented in Figure 4-14. Heart sounds are shown in Figure 4-15.
The four phases of the ventricular systole and diastole can be best presented as a pressure–volume loop.
Changes in the ratio of left ventricular volume and intraventricular pressure during the four periods of the cardiac cycle are shown in Figure 4-16. This pressure–volume loop has four parts, as follows:
Ejection. At point C the aortic valve opens and the period of ejection of blood into the aorta begins. The intraventricular pressure continues rising but then declines slightly. The volume of blood in the left ventricle drops from 120 mL to less than 50 mL.
Figure 4-16 Pressure–volume loop of the heart during the contraction–relaxation cycle. The left ventricular pressure (ordinate) is plotted against the left ventricular volume (abscissa). A, Mitral valve opens and diastolic filling of the ventricles begins. A–B corresponds to diastolic filling. B, Mitral valve closes at the end of diastole and isovolumic contraction of the ventricles begins. B–C corresponds to isovolumic contraction of the ventricle. C, Aortic valve opens and the ejection of blood from the ventricle begins. C–D corresponds to the ejection phase of systole. D, Aortic valve closes and end-systolic volume is reached, whereupon the ventricles relax. D–A corresponds to isovolumic ventricular relaxation.
At the end of diastole each ventricle contains approximately 110 to 120 mL of blood, known as end-diastolic volume. Stroke volume output during systole equals 70 mL, and the remaining 40 to 50 mL is called the end-systolic volume. The ejection fraction is calculated as the percentage of end-diastolic volume that is ejected from the ventricle. In normal healthy persons it is in the range of 60%. Stroke volume output can be increased during strong cardiac contractions, which reduce the end-systolic volume to 10 to 20 mL, as well as by increasing the end-diastolic volumes of the ventricle (Fig. 4-17).
The evaluation of suspected cases of cardiovascular disease includes taking a complete history and performing a physical examination, standard laboratory tests, and specialized tests aimed at detecting specific diseases.
Family and personal history may provide valuable clues about the nature of cardiovascular disease (Table 4-1). Many cardiovascular diseases are multifactorial and have a tendency to affect several members of a family. Some, such as congenital heart diseases, are typically found in children; others, such as cardiomyopathies, may be diagnosed at any age. Still others, such as atherosclerosis and congestive heart failure, are more prevalent in the elderly.
|TYPE OF RISK FACTOR||SPECIFIC DISEASES–RISK FACTOR ASSOCIATIONS|
|Aging||Atherosclerosis: Coronary heart disease|
|Medical and surgical procedures||Sepsis: Endocarditis|
|External mechanical factors|
Symptoms and signs of cardiovascular disease vary from one patient to another. Bear in mind that the most prevalent cardiovascular disease, atherosclerosis, affects the arteries in many parts of the body and can manifest with cardiac, cerebral, or renal symptoms, just to mention a few. Here we concentrate predominantly on heart disease and discuss the most important signs and symptoms pointing to a specific heart disease. The most important signs and symptoms noticed by taking the patient’s history and performing the physical examination are as follows:
Chest discomfort and pain are closely related sensations that vary in intensity. Minor pain may be perceived as discomfort, and pain often begins as discomfort that gradually intensifies. Clinically it is customary to subdivide chest pain into two groups: cardiac and noncardiac. The most common causes of acute chest discomfort and pain are listed in Table 4-2.
Cardiac pain is transmitted to the cerebral sensory cortex through the sympathetic and parasympathetic autonomic nerve fibers. The parasympathetic fibers are part of the vagus nerve. The sympathetic sensory fibers enter the upper five to six thoracic and lower cervical ganglia and from there interconnect with afferent fibers leading the sensations into the sensory cortex. Because these sensory fibers communicate with other sensory nerves it is not always possible to determine the exact origin of pain. Accordingly it is important to remember that pain originating from many other organs may be perceived as cardiac, and conversely, pain of cardiac origin may be misinterpreted as stemming from other organs.
Ischemic cardiac pain originates from the myocardium that is not receiving enough oxygen for its needs. Typically this kind of pain is characteristic of ischemic coronary heart disease and is found in patients who have angina pectoris or who have had or are having a myocardial infarction (MI). Similar pain is experienced by patients who have aortic stenosis preventing normal perfusion of the coronary arteries.
Ischemic cardiac discomfort and pain are described as heaviness or pressure or squeezing behind the sternum (retrosternal pain). The pain has an epicenter over the sternum radiating to the arm, neck, and lower jaw. Most often it radiates into the left arm along the ulnar side (Fig. 4-18). Less commonly it may be bilateral, and occasionally it may radiate to the back, usually along the left scapula. The pain is usually related to exercise, but in MI it may be of sudden onset and occur during sleep or rest. The pain of angina is usually short-lived and can be relieved by nitroglycerine, in contrast to the pain of MI, which is often crushing and of longer duration.
Figure 4-18 Ischemic cardiac pain. A, The pain most often radiates to the ulnar side of the left arm. B, Less often the pain radiates to the right side, the neck, and the face, or to the dorsal side of the chest.
Pericardial pain is caused by pericarditis and is typically most intense behind the sternum or at the apex of the heart. It is described as stabbing, burning, or piercing. It lasts longer than ischemic pain and is unrelated to exercise. It may be aggravated by lying down, coughing, deep inspiration, or movement. It can be partially relieved by leaning forward or preventing chest movements. Pericardial pain is usually not radiating outside the chest.
Patients typically complain that they feel their “heart beating fast” or “skipping beats.” This very common symptom may be correlated with irregularities of the pulse. It may be caused by the following functional irregularities of heartbeat:
Dyspnea is a sense of difficulty in breathing or shortness of breath. Note that it is a subjective feeling and reflects the patients’ consciousness of increased respiratory effort. Furthermore, the sensation of shortness of breath is very common, and accordingly dyspnea is also a physiological phenomenon that occurs whenever there is a “hunger for air” due to strenuous exercise, a sudden rush of activity (e.g., a fast sprint), adjusting to high altitudes (“mountain sickness”), and even in anxiety states.
An important aspect of cardiac dyspnea is the sensation of chest tightness and shortness of breath. These symptoms result from impulses emanating from mechanoreceptors in the lungs, sensory stimuli from the chest wall, and those generated by the chemoreceptors reacting to the reduced concentration of oxygen in the blood. All these afferent signals act on the respiratory center to generate an adequate ventilatory response, perceived by the individual as a “respiratory effort” or “labored breathing” (Fig. 4-19).
When a patient presents with dyspnea it is most important to establish whether it is acute or chronic and to decide whether it is of cardiac or noncardiac origin. The most common form of noncardiac dyspnea is respiratory dyspnea caused by a variety of bronchopulmonary diseases, such as bronchial asthma, chronic obstructive pulmonary disease, and pneumonia (Fig. 4-20). Systemic diseases such as acidosis or neuromuscular diseases such as myasthenia gravis also may affect breathing and cause dyspnea. All these diseases can be excluded from the differential diagnosis by taking a thorough history, performing a complete physical examination, and conducting any necessary additional testing.
Once the pulmonary dyspnea has been excluded and cardiac dyspnea is suggested, it is important to decide whether the symptom is related to high-, normal-, or low-output heart failure. This determination allows the physician to decide whether the dyspnea is related to intrinsic heart failure presenting usually as low-output heart failure or some other condition, such as anemia or hyperthyroidism, which present with high-output failure. Obesity typically manifests with dyspnea with normal cardiac output.
Dyspnea on effort may be the first sign of heart failure and is often associated with anginal pain. The patient typically complains of being short of breath after climbing up the stairs or strenuously walking. Usually it is progressive and can become incapacitating.
Dyspnea at rest is a common sign of heart disease and is usually related to pulmonary congestion and edema due to left heart failure. Orthopnea is a term used to describe breathing discomfort experienced while the patient is lying down that is relieved by sitting up in bed or using several pillows. Paroxysmal nocturnal dyspnea typically wakes the patient, who has a feeling of suffocation. It may be associated with wheezing or coughing and is occasionally called “cardiac asthma.” A common cause of this form of dyspnea is tachyarrhythmia, which may be noticed by the patient. Acute heart failure, as in MI, can also cause nocturnal dyspnea.