V. HYPERTENSION. HEART ARRYTHMIAS.docx

**PATHOPHYSIOLOGY OF CARDIOVASCULAR SYSTEM** **ARTERIAL HYPERTENSION** **HEART ARRHYTHMIAS** **The structure and function of blood vessels** The general architecture and cellular composition of blood vessels are the same throughout the cardiovascular system. However, certain features of the vasc...

**PATHOPHYSIOLOGY OF CARDIOVASCULAR SYSTEM** **ARTERIAL HYPERTENSION** **HEART ARRHYTHMIAS** **The structure and function of blood vessels** The general architecture and cellular composition of blood vessels are the same throughout the cardiovascular system. However, certain features of the vasculature vary with and reflect distinct functional requirements at different locations. To withstand the pulsatile flow and higher blood pressures in arteries, arterial walls are generally thicker than the walls of veins. Arterial wall thickness gradually diminishes as the vessels become smaller, but the ratio of wall thickness to lumen diameter becomes greater. The basic constituents of the walls of blood vessels are *endothelial cells* and *smooth muscle cells*, and extracellular matrix (ECM), including elastin, collagen, and glycosoaminoglycans. The three concentric layers - *intima, media*, and *adventitia* - are most clearly defined in the larger vessels, particularly arteries. In normal arteries, the intima consists of a single layer of endothelial cells with minimal underlying subendothelial connective tissue. It is separated from the media by a dense elastic membrane called the *internal elastic lamina*. The smooth muscle cell layers of the media near the vessel lumen receive oxygen and nutrients by direct diffusion from the vessel lumen, facilitated by holes in the internal elastic membrane. However, diffusion from the lumen is inadequate for the outer portions of the media in large and medium-sized vessels, therefore these areas are nourished by small arterioles arising from outside the vessel (called *vasa vasorum*, literally "vessels of the vessels") coursing into the outer one half to two thirds of the media. The outer limit of the media of most arteries is a well-defined external *elastic lamina*. External to the media is the adventitia, consisting of connective tissue with nerve fibers and the vasa vasorum.Based on their size and structural features, arteries are divided into three types: (1) large or *elastic arteries*, including the aorta, its large branches (particularly the innominate, subclavian, common carotid, and iliac), and pulmonary arteries; (2) medium-sized or *muscular arteries*, comprising other branches of the aorta (e.g., coronary and renal arteries); and (3) small arteries (less than approximately 2 mm in diameter) and arterioles (20 to 100 μm in diameter), within the substance of tissues and organs The relative amount and configuration of the basic constituents differ along the arterial system owing to local adaptations to mechanical or metabolic needs. These structural variations, from location to location, are principally in the media and in the ECM. In the elastic arteries the media is rich in elastic fibers. This allows vessels such as the aorta to expand during systole and recoil during diastole, thus propelling blood through the peripheral vascular system. With aging, the aorta loses elasticity, and large vessels expand less readily, particularly when blood pressure is increased. Thus, the arteries of older individuals often become progressively tortuous and dilated (ectatic). In muscular arteries the media is composed predominantly of circularly or spirally arranged smooth muscle cells. In the muscular arteries and arterioles (see below), regional blood flow and blood pressure are regulated by changes in lumen size through smooth muscle cell contraction (vasoconstriction) or relaxation (vasodilation), controlled in part by the autonomic nervous system and in part by local metabolic factors and cellular interactions. Since the resistance of a tube to fluid flow is inversely proportional to the fourth power of the diameter (i.e., halving the diameter increases resistance 16-fold), small changes in the lumen size of small arteries caused by structural change or vasoconstriction can have a profound effect. Thus, arterioles are the principal points of physiologic resistance to blood flow. Capillaries, approximately the diameter of a red blood cell (7 to 8 μm), have an endothelial cell lining but no media. Collectively, capillaries have a very large total cross-sectional area; within the capillaries, the flow rate slows dramatically. With thin walls only and slow flow, capillaries are ideally suited to the rapid exchange of diffusible substances between blood and tissues. As normal tissue function depends on an adequate supply of oxygen through blood vessels, and since diffusion of oxygen in solid tissues is inefficient over distances of greater than approximately 100 μm, the capillary network of most tissues is very rich. Metabolically highly active tissues, such as the myocardium, have the highest density of capillaries. Blood from capillary beds flows initially into the postcapillary venules and then sequentially through collecting venules and small, medium, and large veins. In many types of inflammation, vascular leakage and leukocyte exudation occur preferentially in postcapillary venules. Relative to arteries, veins have larger diameters, larger lumens, and thinner and less well organized walls. Thus, because of their poor support, veins are predisposed to irregular dilation, compression, and easy penetration by tumors and inflammatory processes. The venous system collectively has a large capacity; approximately two thirds of all the blood is in veins. Reverse flow is prevented by venous valves in the extremities, where blood flows against gravity. Lymphatics are thin-walled, endothelium-lined channels that serve as a drainage system for returning interstitial tissue fluid and inflammatory cells to the blood. Lymphatics constitute an important pathway for disease dissemination through transport of bacteria and tumor cells to distant sites.  **Regional specializations of the vasculature. Although the basic organization of the vasculature is constant, the thickness and composition of the various layers differ according to hemodynamic forces and tissue requirements. (From Robbins-Cotran; Pathological basis of disease)** The arterial blood pressure reflects the rhythmic ejection of blood from the left ventricle into the aorta. It rises during systole as the left ventricle contracts and falls as the heart relaxes during diastole, giving rise to a pressure pulse. The *systolic blood pressure* reflects the rhythmic ejection of blood into the aorta. As blood is ejected from the left ventricle into the aorta, it stretches the vessel wall and produces a rise in aortic pressure. The extent to which the systolic pressure rises or falls with each cardiac cycle is determined by the amount of blood ejected into the aorta with each heart beat (*stroke volume*), the velocity of ejection, and the elastic properties of the aorta. Systolic pressure increases when there is a rapid ejection of a large stroke volume or when the stroke volume is ejected into a rigid aorta. The *diastolic blood pressure* is maintained by the energy that has been stored in the elastic walls of the aorta during systole. The *pulse pressure* is the difference between the systolic and diastolic pressures. It reflects the pulsatile nature of arterial blood flow and is an important component of blood pressure. The *mean arterial blood pressure* represents the average blood pressure in the systemic circulation. Mean arterial pressure can be estimated by adding one third of the pulse pressure to the diastolic pressure (diastolic blood pressure + pulse pressure/3). **Regulation of normal blood pressure.** Blood pressure is a function of *cardiac output* and *peripheral vascular resistance*, two hemodynamic variables that are influenced by multiple genetic, environmental, and demographic factors. The major factors that determine blood pressure variation within and between populations include age, gender, body mass index, and diet, particularly sodium intake. *Cardiac output* is highly dependent on blood volume, itself greatly influenced by the sodium homeostasis. *Peripheral vascular resistance* is determined mainly at the level of the arterioles and is affected by neural and hormonal factors. Normal vascular tone reflects the balance between humoral vasoconstricting influences (including angiotensin II, catecholamines, and endothelin) and vasodilators (including kinins, prostaglandins, and NO). Resistance vessels also exhibit autoregulation, whereby increased blood flow induces vasoconstriction to protect against tissue hyperperfusion. Other local factors such as pH and hypoxia, and the α- and β-adrenergic systems, which influence heart rate, cardiac contraction, and vascular tone, may also be important in regulating blood pressure. The integrated function of these systems ensures adequate perfusion of all tissues, despite regional differences in demand. C:\\Documents and Settings\\Feghiu Leonid\\Desktop\\Heart\\BP rg.jpg **Factors which control the blood pressure (From Robbins-Cotran; Pathological basis of disease)** **Short-term regulation of blood pressure.** The mechanisms for short-term regulation of blood pressure, those occurring over minutes or hours, are intended to correct temporary imbalances in blood pressure, such as occur during physical exercise and changes in body position. These mechanisms also are responsible for maintenance of blood pressure at survival levels during life-threatening situations. The short-term regulation of blood pressure relies mainly on neural and hormonal mechanisms, the most rapid of which are the neural mechanisms. ***Neural mechanisms.*** The neural control centers for the regulation of blood pressure is located in the reticular formation of the lower pons and medulla of the brain where integration and modulation of autonomic nervous system (ANS) responses occur. This area of the brain contains the vasomotor and cardiac control centers and is often collectively referred to as the *cardiovascular center.* The cardiovascular center transmits parasympathetic impulses to the heart through the vagus nerve and transmits sympathetic impulses to the heart and blood vessels through the spinal cord and peripheral sympathetic nerves. Vagal stimulation of the heart produces a slowing of heart rate, while sympathetic stimulation produces an increase in heart rate and cardiac contractility. Blood vessels are selectively innervated by the sympathetic nervous system. Increased sympathetic activity produces constriction of the small arteries and arterioles with a resultant increase in peripheral vascular resistance. The ANS control of blood pressure is mediated through intrinsic circulatory reflexes, extrinsic reflexes, and higher neural control centers. The *intrinsic reflexes,* including the *baroreflex* and *chemoreceptor-mediated reflex,* are located in the circulatory system and are essential for rapid and short-term regulation of blood pressure. The sensors for *extrinsic* *reflexes* are found outside the circulation. They include blood pressure responses associated with factors such as pain and cold. The neural pathways for these reactions are more diffuse, and their responses are less consistent than those of the intrinsic reflexes. Many of these responses are channeled through the hypothalamus, which plays an essential role in the control of sympathetic nervous system responses. Among higher-center responses are those caused by changes in mood and emotion. The *baroreceptors* are pressure-sensitive receptors located in the walls of blood vessels and the heart. The carotid and aortic baroreceptors are located in strategic positions between the heart and the brain. They respond to changes in the stretch of the vessel wall by sending impulses to cardiovascular centers in the brain stem to effect appropriate changes in heart rate and vascular smooth muscle tone. For example, the fall in blood pressure that occurs on moving from the lying to the standing position produces a decrease in the stretch of the baroreceptors with a resultant increase in heart rate and sympathetically induced vasoconstriction that causes an increase in peripheral vascular resistance. The *arterial chemoreceptors* are sensitive to changes in the oxygen, carbon dioxide, and hydrogen ion content of the blood. They are located in the carotid bodies, which lie in the bifurcation of the two common carotids, and in the aortic bodies of the aorta. Because of their location, these chemoreceptors are always in close contact with the arterial blood. Although the main function of the chemoreceptors is to regulate ventilation, they also communicate with cardiovascular centers in the brain stem and can induce widespread vasoconstriction. Whenever the arterial pressure drops below a critical level, the chemoreceptors are stimulated because of diminished oxygen supply and a buildup of carbon dioxide and hydrogen ions. In persons with chronic lung disease, systemic and pulmonary hypertension may develop because of hypoxemia. ***Humoral mechanisms.*** A number of hormones and humoral mechanisms contribute to blood pressure regulation, including the *renin-angiotensin-aldosterone mechanism* and *vasopressin.* Other humoral substances, such as epinephrine, a sympathetic neurotransmitter released from the adrenal gland, have the effect of directly stimulating an increase in heart rate, cardiac contractility, and vascular tone. The *renin-angiotensin-aldosterone mechanism* plays a central role in blood pressure regulation. Renin is an enzyme that is synthesized, stored, and released by the kidneys in response to an increase in sympathetic nervous system activity or a decrease in blood pressure, extracellular fluid volume, or extracellular sodium concentration. Most of the renin that is released leaves the kidney and enters the bloodstream, where it acts enzymatically to convert an inactive circulating plasma protein called *angiotensinogen* to angiotensin I. Angiotensin I travels to the small blood vessels of the lung, where it is converted to angiotensin II by the angiotensin-converting enzyme that is present in the endothelium of the lung vessels. Although angiotensin II has a half-life of several minutes, renin persists in the circulation for 30 minutes to 1 hour and continues to cause production of angiotensin II during this time. Angiotensin II functions in both the short-term and long-term regulation of blood pressure. It is a strong vasoconstrictor, particularly of arterioles and to a lesser extent of veins. The vasoconstrictor response produces an increase in peripheral vascular resistance (and blood pressure) and functions in the short-term regulation of blood pressure. A second major function of angiotensin II, stimulation of aldosterone secretion from the adrenal gland, contributes to the long-term regulation of blood pressure by increasing salt and water retention by the kidney. It also acts directly on the kidney to decrease the elimination of salt and water. *Vasopressin,* also known as antidiuretic hormone (ADH), is released from the posterior pituitary gland in response to decreases in blood volume and blood pressure, an increase in the osmolality of body fluids, and other stimuli. Vasopressin has a direct vasoconstrictor effect on blood vessels, particularly those of the splanchnic circulation that supplies the abdominal viscera. However, long-term increases in vasopressin cannot maintain volume expansion or hypertension, and vasopressin does not enhance hypertension produced by sodium-retaining hormones or other vasoconstricting substances. It has been suggested that vasopressin plays a permissive role in hypertension through its fluid-retaining properties or as a neurotransmitter that serves to modify ANS function. **Long-term regulation of blood pressure*.*** Long-term mechanisms control the daily, weekly, and monthly regulation of blood pressure. Although the neural and hormonal mechanisms involved in the short-term regulation of blood pressure act rapidly, they are unable to maintain their effectiveness over time. Instead, the long-term regulation of blood pressure is largely vested in the kidneys and their role in the regulation of extracellular fluid volume. ***Renal mechanism.*** The role that the kidneys play in blood pressure regulation is emphasized by the fact that many hypertension medications produce their blood pressure-- lowering effects by increasing salt and water elimination. According to the late Arthur Guyton, a noted physiologist, the extracellular fluid volume and the arterial blood pressure are regulated around an equilibrium point, which represents the normal pressure for a given individual. When the body contains an excess of extracellular fluid, the arterial pressure rises, and the rate at which water (*pressure diuresis*) and salt (*pressure natriuresis*) are excreted by the kidney is increased. Accordingly, there are two ways that arterial pressure can be increased using this model: one is by shifting the elimination of salt and water to a higher pressure level, and the second is by changing the extracellular fluid level at which diuresis and natriuresis occur. The function of the kidney in the long-term regulation of blood pressure can be influenced by a number of factors. For example, excess sympathetic nerve activity or the release of vasoconstrictor substances can alter the transmission of arterial pressure to the kidney. Similarly, changes in neural and humoral control of kidney function can shift the diuresis-natriuresis process to a higher fluid or pressure level, thereby initiating an increase in arterial pressure. ***Extracellular fluid volume.*** There are several ways that extracellular fluid volume regulates blood pressure. One is through a direct effect on cardiac output, and another is indirect, resulting from autoregulation of blood flow and its effect on peripheral vascular resistance. Autoregulatory mechanisms function in distributing blood flow to the various tissues of the body according to their metabolic needs. When the blood flow to a specific tissue bed is excessive, local blood vessels constrict, and when the flow is deficient, the local vessels dilate. In situations of increased blood volume and cardiac output, all of the tissues of the body are exposed to the same increase in flow. This results in a generalized constriction of arterioles and an increase in the peripheral vascular resistance (and blood pressure). According to the World Health Organization (VHO) normal values of systolic arterial pressure in aorta and large arteries vary between 110-130 mmHg, and diastolic pressure -- between 65-85 mmHg. All varieties of disturbances of systemic arterial pressure are divided into two categories: arterial hypertension and arterial hypotension. **Systemic arterial hypertension (SAH)** Hypertension is one of the leading causes of the global burden of disease. Approximately 7.6 million deaths (13--15% of the total) and 92 million disability-adjusted life years worldwide were attributable to high blood pressure in 2001. Hypertension doubles the risk of cardiovascular diseases, including coronary heart disease, congestive heart failure, ischemic and hemorrhagic stroke, renal failure, and peripheral arterial disease. Hypertension is present in all populations except for a small number of individuals living in primitive, culturally isolated societies. In industrialized societies, blood pressure increases steadily during the first two decades of life. The likelihood of hypertension increases with age, and among individuals age 60, the prevalence is 65.4%. *Systemic arterial hypertension* represents a permanent increase of systolic pressure higher than 140 and diastolic higher than 90 mmHg. The World Health Organization (WHO) has proposed the following values for all age groups. +-----------------------+-----------------------+-----------------------+ | **Blood pressure | **Systolic, mmHg** | **Diastolic, mmHg** | | classification** | | | +=======================+=======================+=======================+ | **Normal** | **\100** | | hypertension** | | | +-----------------------+-----------------------+-----------------------+ The product of *cardiac output* and *total peripheral resistance* (TPR) determines blood pressure (Ohm's law). Hypertension thus develops after an increase in cardiac output or TPR, or both. In the former case one speaks of *hyperdynamic hypertension* or *cardiac output hypertension,* with the increase in systolic pressure (SP) being much greater than that in diastolic pressure (DP). In *resistance hypertension*, SP and DP are either both increased by the same amount or (more frequently) DP more than SP. The latter is the case when the increased TPR delays ejection of the stroke volume. The increase of cardiac output in **hyperdynamic hypertension** is due to an *increase in either* *heart rate* or *extracellular volume*, leading to an increased venous return and thus an *increased* *stroke volume* (Frank--Starling mechanism). Similarly, an increase in *sympathetic activity* of central nervous system origin and/or *raised responsiveness to catecholamines* (caused by cortisol or thyroid hormone) can cause an increase in cardiac output (Fig.1) ***Resistance hypertension*** is caused mainly by abnormally high *peripheral vasoconstriction* (arterioles) or some other narrowing of peripheral vessels, but may also be due to an increased blood viscosity (increased hematocrit). Vasoconstriction mainly results from *increased sympathetic activity* (of nervous or adrenal medullary origin), raised responsiveness to catecholamines, or an increased concentration of *angiotensin II. Autoregulatory* *mechanisms* also include vasoconstriction. If, for example, blood pressure is increased by a rise in cardiac output various organs (kidneys, gastrointestinal tract) "protect" themselves against this high pressure. This is responsible for the frequently present vasoconstrictor component in hyperdynamic hypertension that may then be transformed into resistance hypertension. Additionally, there will be *hypertrophy* of the vasoconstrictor musculature. Finally, hypertension will cause *vascular damage* that will increase TPR (*fixation* of the hypertension).  **Fig.1 Principles of the development of hypertension** **(From S. Silbernagl and F. Lang; Color Atlas of Pathophysiology)** A small number of patients (approximately 5%) have underlying renal or adrenal disease (such as primary aldosteronism, Cushing syndrome, pheochromocytoma), narrowing of the renal artery, usually by an atheromatous plaque (renovascular hypertension) or other identifiable cause (*secondary hypertension*). *However, about 95% of hypertension is idiopathic (called essential hypertension) (Fig.2). This form of hypertension generally does not cause short-term problems*. When controlled, it is compatible with long life and is asymptomatic, unless a myocardial infarction, cerebrovascular accident, or other complication supervenes. **Types and causes of hypertension (Systolic and diastolic)** **(From Robbins-Cotran; Pathological basis of disease)** +-----------------------------------------------------------------------+ | **ESSENTIAL HYPERTENSION (90% to 95% of cases)** | +=======================================================================+ | **SECONDARY HYPERTENSION** | +-----------------------------------------------------------------------+ | ***Renal*** | +-----------------------------------------------------------------------+ |    Acute glomerulonephritis | | ---- -- -------------------------- | |    Chronic renal disease | |    Polycystic disease | |    Renal artery stenosis | |    Renal vasculitis | |    Renin-producing tumors | +-----------------------------------------------------------------------+ | ***Endocrine*** | +-----------------------------------------------------------------------+ |    Adrenocortical hyperfunction (Cushing syndrome, primary ald | | osteronism, congenital adrenal hyperplasia, licorice ingestion) | | ---- -- ----------------------------------------------------------- | | --------------------------------------------------------------------- | | ------------------------------------------------------ | |    Exogenous hormones (glucocorticoids, estrogen \[including p | | regnancy-induced and oral contraceptives\], sympathomimetics and tyra | | mine-containing foods, monoamine oxidase inhibitors) | |    Pheochromocytoma | |    Acromegaly | |    Hypothyroidism (myxedema) | |    Hyperthyroidism (thyrotoxicosis) | |    Pregnancy-induced | +-----------------------------------------------------------------------+ | ***Cardiovascular*** | +-----------------------------------------------------------------------+ |    Coarctation of aorta | | ---- -- -------------------------------- | |    Polyarteritis nodosa | |    Increased intravascular volume | |    Increased cardiac output | |    Rigidity of the aorta | +-----------------------------------------------------------------------+ | ***Neurologic*** | +-----------------------------------------------------------------------+ |    Psychogenic | | ---- -- --------------------------------- | |    Increased intracranial pressure | |    Sleep apnea | |    Acute stress, including surgery | +-----------------------------------------------------------------------+ C:\\Documents and Settings\\Feghiu Leonid\\Desktop\\Heart poze\\types HT).jpg **Fig. 2 Types of hypertension** **(From S. Silbernagl and F. Lang; Color Atlas of Pathophysiology)** A small percentage, perhaps 5%, of hypertensive persons show a rapidly rising blood pressure that, if untreated, leads to death within a year or two. Called *accelerated* or *malignant hypertension*, this clinical syndrome is characterized by severe hypertension (systolic pressure over 200 mm Hg, diastolic pressure over 120 mm Hg), renal failure, and retinal hemorrhages and exudates, with or without papilledema. It may develop in previously normotensive persons but more often is superimposed on pre-existing benign hypertension, either essential or secondary **Essential arterial hypertension (primary hypertension)** *Etiology*. Despite of the high frequency (affects approximately 10% of general population), etiology of essential arterial hypertension is unknown. Possible causes may be: - Chronic psychoemotional stress, repeated negative emotions; - Genetic defects of receptors, cellular membranes and membrane ion pumps; - Genetic defects of structures of vegetative nervous system, which participate in regulation of arterial pressure; To the development of essential hypertension contribute following risk factors: 1. Body overweight (approximately 1/3 of population with obesity arterial hypertension is noticed); 2. Diabetes mellitus (30-40% of cases of diabetes mellitus collocate with arterial hypertension); 3. Excessive consumption of salts; 4. Psychoemotional stress situations in case of calamities (earthquakes, floods, fire); 5. Hypodynamia a (sedentary life); 6. Excessive consumption of alcohol, caffeine. More women than men and more urbanites than country dwellers are affected by primary hypertension. In addition, chronic *psychological stress*, be it job-related (pilot, bus driver) or personality-based ("frustrated fighter" type), can induce hypertension. Especially in "salt-sensitive" people (1⁄3 of patients with primary hypertension; increased incidence when there is a family history) the *high NaCl intake* (10--15 g/d = 170--250 mmol/d) in the western industrialized countries might play an important role. While the organism is well protected against Na^+^ loss through an increase in aldosterone, those with an increased salt sensitivity are apparently relatively unprotected against a high NaCl intake. The actual **connection between NaCl sensitivity** **and primary hypertension** has not been fully elucidated, but the possibility is being considered that responsiveness to catecholamines is raised in people sensitive to NaCl. This results, for example, on psychological stress, in a greater than normal rise in blood pressure, on the one hand, due directly to the effect of increased cardiac stimulation and, on the other hand, indirectly as a result of increased renal absorption and thus retention of Na^+^ (rise in extracellular volume leads to hyperdynamic hypertension). Obesity and weight gain are strong, independent risk factors for hypertension. It has been estimated that 60% of hypertensives are \>20% overweight. Centrally located body fat is a more important determinant of blood pressure elevation than is peripheral body fat. Low dietary intakes of calcium and potassium also may contribute to the risk of hypertension. *Pathogenesis* of essential hypertension is very complicated and is studied insufficiently. There are several pathogenic mechanisms which are involved in the development primary hypertension: neurogenic mechanisms, hemodynamic factor, genetic component, humoral factor, hypertensive vascular reactivity and remodeling. *Genetic considerations in primary hypertension* Genetic factors play a definite role in determining blood pressure levels, as shown by studies comparing blood pressure in monozygotic and dizygotic twins, and other types of family studies, including comparisons of genetically related and adopted family members. Several strategies are being utilized in the search for specific hypertension-related genes. Animal models provide a powerful approach for evaluating genetic loci and genes associated with hypertension. Current evidence suggests that genes that encode components of the renin-angiotensin-aldosterone system, along with angiotensinogen and angiotensin-converting enzyme (ACE) polymorphisms, may be related to hypertension and to blood pressure sensitivity to dietary NaCl. Reduced renal sodium excretion in the presence of normal arterial pressure may be a key initiating event in essential hypertension and, indeed, a final common pathway for the pathogenesis of hypertension. Decreased sodium excretion may lead sequentially to an increase in fluid volume, increased cardiac output, and peripheral vasoconstriction, thereby elevating blood pressure. At the higher setting of blood pressure, enough additional sodium would be excreted by the kidneys to equal intake and prevent further fluid retention. Thus, an altered but steady state of sodium excretion would be achieved ("resetting of pressure natriuresis"), but at the expense of an increase in blood pressure. Single-gene disorders cause severe but rare forms of hypertension through several mechanisms. These include: - - - - Environmental factors can modify the impact of genetic determinants. Stress, obesity, smoking, physical inactivity, and heavy consumption of salt have all been implicated as exogenous factors in hypertension. In the future, it is possible that DNA analysis will predict individual risk for hypertension and target organ damage and will identify responders to specific classes of antihypertensive agents. *Role of neurogenic factors in development of essential hypertension.* The autonomic nervous system maintains cardiovascular homeostasis via pressure, volume and chemoreceptor signals. Adrenergic reflexes modulate blood pressure over the short term and adrenergic function, in concert with hormonal and volume-related factors, contributes to the long-term regulation of arterial pressure. The three endogenous catecholamines are *norepinephrine, epinephrine*, and *dopamine*. All three play important roles in tonic and phasic cardiovascular regulation. The activities of the adrenergic receptors are mediated by guanosine nucleotide-binding regulatory proteins (G proteins) and by intracellular concentrations of downstream second messengers. Norepinephrine and epinephrine are agonists for all adrenergic receptor subtypes, although with varying affinities. Based on their physiology and pharmacology, adrenergic receptors have been divided into two principal types: α and β. These types have been differentiated further into α~1~, α~2~, β~1~, and β~2~ receptors. Recent molecular cloning studies have identified several additional subtypes. α Receptors are occupied and activated more avidly by norepinephrine than by epinephrine, and the reverse is true for β receptors. α~1~ Receptors are located on postsynaptic cells in smooth muscle and elicit vasoconstriction. α~2~ Receptors are localized on presynaptic membranes of postganglionic nerve terminals that synthesize norepinephrine. When activated by catecholamines, α~2~ receptors act as negative feedback controllers, inhibiting further norepinephrine release. In the kidney, activation of α~1~-adrenergic receptors increases renal tubular reabsorption of sodium. Activation of myocardial β~1~ receptors stimulates the rate and strength of cardiac contraction and consequently increases cardiac output. β~1~ Receptor activation also stimulates renin release from the kidney. Circulating catecholamine concentrations may affect the number of adrenoreceptors in various tissues. Down regulation of receptors may be a consequence of sustained high levels of catecholamines and provides an explanation for decreasing responsiveness, or *tachyphylaxis*, to catecholamines. Conversely, with chronic reduction of neurotransmitter substances, adrenoreceptors may increase in number or be upregulated, resulting in increased responsiveness to the neurotransmitter. Chronic administration of agents that block adrenergic receptors may result in upregulation, and withdrawal of those agents may produce a condition of temporary hypersensitivity to sympathetic stimuli. Several reflexes modulate blood pressure on a minute-to-minute basis. One arterial baroreflex is mediated by stretch-sensitive sensory nerve endings in the carotid sinuses and the aortic arch. The rate of firing of these baroreceptors increases with arterial pressure, and the net effect is a decrease in sympathetic outflow, resulting in decreases in arterial pressure and heart rate. This is a primary mechanism for rapid buffering of acute fluctuations of arterial pressure that may occur during postural changes, behavioral or physiologic stress, and changes in blood volume. However, the activity of the baroreflex declines or adapts to sustained increases in arterial pressure such that the baroreceptors are reset to higher pressures. Patients with autonomic neuropathy and impaired baroreflex function may have extremely labile blood pressures with difficult-to-control episodic blood pressure spikes associated with tachycardia. In both normal-weight and obese individuals, hypertension often is associated with increased sympathetic outflow. Sympathetic outflow is also increased in obesity-related hypertension and in hypertension associated with obstructive sleep apnea. Baroreceptor activation via electrical stimulation of carotid sinus afferent nerves has been shown to lower blood pressure in patients with \"resistant\" hypertension. Moreover, chronic or repeated vasoconstrictive influences could cause thickening and rigidity of the involved vessels (*hypertensive vascular remodeling*). Drugs that block the sympathetic nervous system are potent antihypertensive agents, indicating that the sympathetic nervous system plays a permissive, although not necessarily a causative, role in the maintenance of increased arterial pressure. *Role of hemodynamic factors in development of essential hypertension*. Cardiac output and peripheral resistance are the two hemodynamic determinants of arterial pressure. Cardiac output is determined by stroke volume and heart rate; stroke volume is related to myocardial contractility and to the size of the vascular compartment. Peripheral resistance is determined by functional and anatomic changes in small arteries (lumen diameter 100--400 m) and arterioles. Increase in cardiac output or/and peripheral resistence will lead to hypertension (hyperdynamic or resistence hypertension) (see above). Vascular volume is a primary determinant of arterial pressure over the long term. The initial elevation of blood pressure in response to vascular volume expansion may be related to an increase of cardiac output due to increased diastolic filling of the heart and activation of Frank-Starling law such increasing the stroke volume. Sodium is predominantly an extracellular ion and is a primary determinant of the extracellular fluid volume. When NaCl intake exceeds the capacity of the kidney to excrete sodium, vascular volume initially expands and cardiac output increases. *Role of humoral factors in development of essential hypertension.* The renin-angiotensin-aldosterone system contributes to the regulation of arterial pressure primarily via the vasoconstrictor properties of angiotensin II and the sodium-retaining properties of aldosterone. Renin is an aspartyl protease that is synthesized as an enzymatically inactive precursor, *prorenin*. Most renin in the circulation is synthesized in the renal afferent renal arteriole. Prorenin may be secreted directly into the circulation or may be activated within secretory cells and released as active renin. Although human plasma contains two to five times more prorenin than renin, there is no evidence that prorenin contributes to the physiologic activity of this system. There are three primary stimuli for renin secretion: (1) decreased NaCl transport in the distal portion of the thick ascending limb of the loop of Henle that abuts the corresponding afferent arteriole (macula densa), (2) decreased pressure or stretch within the renal afferent arteriole (baroreceptor mechanism), and (3) sympathetic nervous system stimulation of renin-secreting cells via β~1~ adrenoreceptors. Conversely, renin secretion is inhibited by increased NaCl transport in the thick ascending limb of the loop of Henle, by increased stretch within the renal afferent arteriole, and by β~1~ receptor blockade. In addition, angiotensin II directly inhibits renin secretion due to angiotensin II type 1 receptors on juxtaglomerular cells, and renin secretion increases in response to pharmacologic blockade of either ACE or angiotensin II receptors. Once released into the circulation, active renin cleaves a substrate*, angiotensinogen*, to form an inactive decapeptide, *angiotensin I.* A converting enzyme, located primarily but not exclusively in the pulmonary circulation, converts angiotensin I to the active octapeptide, *angiotensin II*, by releasing the C-terminal histidyl-leucine dipeptide. The same converting enzyme cleaves a number of other peptides, including and thereby inactivating the vasodilator bradykinin (Fig.3). Acting primarily through angiotensin II type 1 (AT~1~) receptors on cell membranes, angiotensin II is a potent pressor substance, the primary tropic factor for the secretion of aldosterone by the adrenal zona glomerulosa, and a potent mitogen that stimulates vascular smooth muscle cell and myocyte growth. Independent of its hemodynamic effects, angiotensin II may play a role in the pathogenesis of atherosclerosis through a direct cellular action on the vessel wall. An angiotensin II type 2 (AT~2~) receptor has been characterized. It is widely distributed in the kidney and has the opposite functional effects of the AT1 receptor. The AT~2~ receptor induces vasodilation, sodium excretion, and inhibition of cell growth and matrix formation. Experimental evidence suggests that the AT~2~ receptor improves vascular remodeling by stimulating smooth muscle cell apoptosis and contributes to the regulation of glomerular filtration rate. AT~1~ receptor blockade induces an increase in AT~2~ receptor activity.  **Fig. 3 Renin-angiotensin-aldosterone axis.** (From Harrison\'s Principles of Internal Medicine, 18th Edition) Angiotensinogen, renin, and angiotensin II are also synthesized locally in many tissues, including the brain, pituitary, aorta, arteries, heart, adrenal glands, kidneys, adipocytes, leukocytes, ovaries, testes, uterus, spleen, and skin. Angiotensin II in tissues may be formed by the enzymatic activity of renin or by other proteases (tonin, chymase, and cathepsins). In addition to regulating local blood flow, tissue angiotensin II is a mitogen that stimulates growth and contributes to modeling and repair. Excess tissue angiotensin II may contribute to atherosclerosis, cardiac hypertrophy, and renal failure. Angiotensin II is the primary tropic factor regulating the synthesis and secretion of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone is a potent mineralocorticoid that increases sodium reabsorption by amiloride-sensitive epithelial sodium channels on the apical surface of the principal cells of the renal cortical collecting duct. Mineralocorticoid receptors also are expressed in the colon, salivary glands, and sweat glands. Aldosterone also has effects on non-epithelial targets. Aldosterone and/or mineralocorticoid receptor activation induces structural and functional alterations in the heart, kidney, and blood vessels, leading to myocardial fibrosis, nephrosclerosis, and vascular inflammation and remodeling, perhaps as a consequence of oxidative stress. These effects are amplified by a high salt intake and can contribute to development of hypertension. *Vascular hyperreactivity and remodeling in primary hypertension* Vascular radius and compliance of resistance arteries are also important determinants of arterial pressure. Resistance to flow varies inversely with the fourth power of the radius, and consequently, small decreases in lumen size significantly increase resistance. Vascular endothelium is a multifunctional tissue with a wealth of synthetic and metabolic properties; at baseline it has several constitutive activities critical for normal vessel homeostasis. Thus, endothelial cells maintain a non-thrombogenic blood-tissue interface, modulate vascular resistance, metabolize hormones, regulate inflammation, and affect the growth of other cell types, particularly smooth muscle cells. One of the vascular endothelial functions is to modulates vascular tone. The normal endothelium maintains a continuous release of nitric oxide, which is formed from L-arginine through the action of an enzyme called nitric oxide synthase. The production of nitric oxide can be stimulated by a variety of endothelial agonists, including acetylcholine, bradykinin, histamine, and thrombin. Shear stress on the endothelium resulting from an increase in blood flow or blood pressure also stimulates nitric oxide production and vessel relaxation. Nitric oxide also inhibits platelet aggregation and secretion of platelet contents, many of which cause vasoconstriction. In addition to nitric oxide, the endothelium also produces other vasodilating substances such as the prostaglandin prostacyclin, which produces vasodilation and inhibits platelet aggregation. The endothelium also produces a number of vasoconstrictor substances, including angiotensin II, vasoconstrictor prostaglandins, and a family of peptides called endothelins. There are at least three endothelins. Endothelin-1, made by human endothelial cells, is the most potent endogenous vasoconstrictor known. Receptors for endothelins also have been identified. Endothelium-dependent vasodilation is impaired in hypertensive patients due to low secretion of vasodilator local substances. By the contrary, endothelin production in patient with essential hypertension is increased. The predominant cellular element of the vascular media is the smooth muscle cells. Smooth muscle cells have the capacity to proliferate when appropriately stimulated (also stimulation by hemodynamic factors like increased pressure); they can also synthesize ECM collagen, elastin, and proteoglycans and elaborate growth factors and cytokines. The migratory and proliferative activities of smooth muscle cells are regulated by growth promoters and inhibitors. Promoters include PDGF, as well as endothelin-1, thrombin, fibroblast growth factor (FGF), interferon-γ (IFN-γ), and interleukin-1(IL-1). Inhibitors include heparan sulfates, nitric oxide, and TGF-β. Other regulators include the renin-angiotensin system (angiotensin II), catecholamines, the estrogen receptor, and osteopontin, a component of the ECM. In hypertensive patients, structural, mechanical, or functional changes may reduce the lumen diameter of small arteries and arterioles such worsening the evolution of hypertension. Hypertensive patients have stiffer arteries as a consequence of decreased vascular compliance due to structural changes in the vascular wall (hyperplasia and hypertrophy of the smooth muscle, hyperplasia of the intima). *Hypertensive* v*ascular remodeling* refers to geometric alterations in the vessel wall without a change in vessel volume. Ion transport by vascular smooth muscle cells may contribute to hypertension-associated abnormalities of vascular tone (*vascular hyperreactivity*) and vascular growth (*vascular remodeling*), both of which are modulated by intracellular pH. Three ion transport mechanisms participate in the regulation of pH: (1) Na^+^-H^+^ exchange, (2) Na^+^-dependent HCO~3~^---^Cl^--^ exchange, and (3) cation-independent HCO~3~^--^Cl^--^ exchange. Activity of the Na^+^-H^+^ exchanger is increased in hypertension, and this may result in increased vascular tone by two mechanisms. First, increased sodium entry may lead to increased vascular tone by activating Na^+^-Ca^2+^ exchange and thereby increasing intracellular calcium. Second, increased pH enhances calcium sensitivity of the contractile apparatus, leading to an increase in contractility for a given intracellular calcium concentration. Additionally, increased Na^+^- H^+^ exchange may stimulate growth of vascular smooth muscle cells by enhancing sensitivity to growth factors (FGF, PDGF, TGF). The same effects has increased blood level of angiotensin II. *Vascular injury due to hemodynamic stress in hypertension stimulates smooth muscle cell growth and associated matrix synthesis that thickens the intima*. Medial smooth muscle cells or smooth muscle precursor cells also migrate into the intima, proliferate, and synthesize ECM in much the same way that fibroblasts fill in a wound. It should be emphasized that the phenotype of neointimal smooth muscle cells is distinct from that of medial smooth muscle cells; neointimal smooth muscle cells do not contract like medial smooth muscle cells but have the capacity to divide. With persistent or recurrent insults, excessive thickening can cause narrowing or stenosis of small and medium-sized blood vessels. Hypertensive hypertrophic vascular remodeling (increased size and number of muscle cell and increased deposition of intercellular matrix, hyperplasia of the intima) results in decreased lumen size and hence contributes to increased peripheral resistance and such worsening hypertension (Fig.4). C:\\Documents and Settings\\Feghiu Leonid\\Desktop\\Heart\\intima.jpg **Fig.4 Hypertensive vascular remodeling** Schematic of intimal thickening, emphasizing smooth muscle cell migration and proliferation within the intima, with associated ECM synthesis. Intimal smooth muscle cells may derive from the underlying media or may be recruited from circulating precursors; they are shown in a different color from the medial cells to emphasize that they have a proliferative, synthetic, and noncontractile phenotype distinct from medial smooth muscle cells. **(From Robbins-Cotran; Pathological basis of disease).** **SECONDARY HYPERTENSION** **Renal hypertension** The kidneys play an important role in blood pressure regulation as follows: Through the renin-angiotensin system, the kidney influences both peripheral resistance and sodium homeostasis. Renin is secreted by the juxtaglomerular cells of the kidney in response to fall in blood pressure. It converts plasma angiotensinogen to angiotensin I, which is then converted to angiotensin II by angiotensin converting enzyme. Angiotensin II raises blood pressure by increasing both peripheral resistance (direct action on vascular smooth muscle cells) and blood volume (stimulation of aldosterone secretion, and increase in distal tubular reabsorption of sodium). The kidney also produces a variety of vascular relaxing, or antihypertensive, substances (including prostaglandins and NO), which presumably counterbalance the vasopressor effects of angiotensin. When blood volume is reduced, the glomerular filtration rate falls, leading to increased reabsorption of sodium by proximal tubules, thereby conserving sodium and expanding blood volume. Natriuretic factors, including the natriuretic peptides secreted by atrial and ventricular myocardium in response to volume expansion, inhibit sodium reabsorption in distal tubules and thereby cause sodium excretion and diuresis. Natriuretic peptides also induce vasodilation and may be considered to represent endogenous inhibitors of the renin-angiotensin system. Virtually all disorders of the kidney may cause hypertension, and renal disease is the most common cause of secondary hypertension. Hypertension is present in \>80% of patients with chronic renal failure. In general, hypertension is more severe in glomerular diseases than in interstitial diseases such as chronic pyelonephritis. Conversely, hypertension may cause nephrosclerosis, and in some instances it may be difficult to determine whether hypertension or renal disease was the initial disorder. Proteinuria \>1000 mg/d and an active urine sediment are indicative of primary renal disease. *Renovascular hypertension* is renal hypertension due to an occlusive lesion of a renal artery. Renovascular hypertension is a potentially curable form of hypertension. Two groups of patients are at risk for this disorder: older arteriosclerotic patients who have a plaque obstructing the renal artery, frequently at its origin, and patients with fibromuscular dysplasia. Atherosclerosis accounts for the large majority of patients with renovascular hypertension. Obstruction of the renal artery leads to decreased renal perfusion pressure, thereby stimulating renin secretion with final activation of angiotensin II and secretion of aldosteron (see above the effects). Over time, as a consequence of secondary renal damage, this form of hypertension may become less renin dependent. However, renin activity and other components of the renin-angiotensin system may be elevated only transiently; over time, sodium retention and recruitment of other pressure mechanisms may contribute to elevated arterial pressure. The most effective medical therapies include an ACE inhibitor or an angiotensin II receptor blocker. *Renin-secreting tumors* are clear examples of other type of renin-dependent hypertension. In the kidney, these tumors include benign hemangio-pericytomas of the juxtaglomerular apparatus and, infrequently, renal carcinomas, including Wilms\' tumors. Renin-producing carcinomas also have been described in lung, liver, pancreas, colon, and adrenals. In these instances, in addition to excision and/or ablation of the tumor, treatment of hypertension includes pharmacologic therapies targeted to inhibit angiotensin II production or action. The kidney also produces a variety of vascular relaxing, or antihypertensive, substances (including prostaglandins PGA and PGE and NO), which presumably counterbalance the vasopressor effects of angiotensin. PGA and PGE are produced at the level of kidney medullary interstitium. Renal disorders associated with loss of renal parenchyma like, glomerulonephritis, chronic renal disease, polycystic disease can be associated with renal hypertension -- so-called *renoprive renal hypertension,* due to inability of the kidney to produce vasodilator biological substances. PGA has predominantly a local vasodilator effects, controlling the level of perfusion. PGE can have a general vasodilatatory effect. Lack of local vasodilatatory biological substances increases vasoconstriction of afferent arteriole with hypoperfusion and release of renin from the juxtaglomerular cells. **Endocrine hypertension** Endocrine hypertension can be found in a number of endocrine disorders due to hypersecretion of hormones. Most frequently these are *mineralocorticoid hypertension* (due to hypersecretion of aldosteron in primary or secondary hyperaldosteronism), *glucocorticoid hypertension* (due to hypersecretion of glucocorticoids, mainly cortisol) and *catecholaminic hypertension* (hypersecretion of catecholamines in pheochromocytoma). Several additional endocrine disorders, including thyroid diseases and acromegaly, cause hypertension. Mild diastolic hypertension may be a consequence of hypothyroidism, whereas hyperthyroidism may result in systolic hypertension. *Mineralocorticoid hypertension***.** Excess aldosterone blood levels due to primary or secondary aldosteronism represent the cause of mineralocorticoid hypertension. Primary aldosteronism is a potentially curable form of hypertension. In patients with primary aldosteronism, increased aldosterone production is independent of the renin-angiotensin system, and the consequences are sodium retention, hypertension, hypokalemia, and low plasma renin level. 60--70% of patients have an aldosterone-producing adrenal adenoma (Con syndrome). The tumor is almost always unilateral, and most often measures \30:1 in conjunction with a plasma aldosterone concentration \>555 mmol/L (\>20 ng/dL) reportedly has a sensitivity of 90% and a specificity of 91% for an aldosterone-producing adenoma. Additionally, hypokalemic hypertension may be a consequence of secondary aldosteronism, which is present in patients with liver cirrhosis, heart failure etc. High level of aldosteron in the blood is due to activation of the renin-angiotensin-aldosteron system or insufficient degradation of aldosteron in the liver. In these patients the plasma renin level is increased. *Glucocorticoid hypertension* is due to hypersecretion of glucocorticoids. Cushing\'s syndrome is related to excess cortisol production due either to excess ACTH secretion (from a pituitary tumor or an ectopic tumor) or to ACTH-independent adrenal production of cortisol. Hypertension occurs in 75--80% of patients with Cushing\'s syndrome. The mechanism of hypertension may be related to stimulation of mineralocorticoid receptors by cortisol leading to increased water and salt retention. Other mechanism is in relation with permissive effects of glucocorticoids on adrenoreceptors with increased cardiac output (effect on β1 receptors) and increased peripheral resistence (effects on α1 receptors). Additional mechanisms can be explained by the fact that cortisol increase hepatic production of angiotensinogen, by this way also enhancing the activity of renin-angiotensin-aldosteron system. *Catecholaminic hypertension* is in relation with presence of pheochromocytoma. Catecholamine-secreting tumors are located in the adrenal medulla (*pheochromocytoma*) or in extra-adrenal paraganglion tissue (*paraganglioma*) and account for hypertension in \~0.05% of patients. If unrecognized, pheochromocytoma may result in lethal cardiovascular consequences. Clinical manifestations, including hypertension, are primarily related to increased circulating catecholamines, although some of these tumors may secrete a number of other vasoactive substances. If there is predominant hypersecretion of adrenaline, the hypertension will be mainly systolic associated with tachycardia. A small percentage of patients, with epinephrine hypersecretion , may present with hypotension rather than hypertension. If there is predominant hypersecretion of noradrenaline, the hypertension is systole-diastolic, with less tachycardia. High blood level of catecholamines leads to vasoconstriction of renal afferent arteriole by this way activating the renin-angiotensin-aldosteron system, which is the other mechanism by which hypercatecholaminemia lead to high blood pressure. The initial suspicion of the diagnosis is based on symptoms and/or the association of pheochromocytoma with other disorders. Approximately 20% of pheochromocytomas are familial with autosomal dominant inheritance. Laboratory testing consists of measuring catecholamines in either urine or plasma. Surgical excision is the definitive treatment of pheochromocytoma and results in cure in \~90% of patients. Hypertension in *hypersecretion of thyroid hormones* is due to cardiogenic effects of T~3~ andT~4~ (positive chronotron and inotropic effects). Mainly this is a form of hypertension due to increased cardiac output (hemodynamic hypertension) which is associated with tachycardia (120 -- 160/min) and frequently with heart arrhythmias (mainly, atrial fibrillation). **Miscellaneous causes of hypertension** *Hemic hypertension* is due to increased volume as well as viscosity of the blood. This can be found in patients with polycythemic hypervolemia (erythremia, erythrocytosis, leukemic crisis). Increased blood volume represents increased preload to the heart that will activate the Frank-Starling law and increased contraction of the hear walls leading to increased stroke volume and ultimately will increase the cardiac output. Increased blood viscosity means increased resistence which also represents a determinant factor of blood pressure. Hypertension due to obstructive sleep apnea is being recognized with increasing frequency. Hypertension occurs in \>50% of individuals with obstructive sleep apnea. The severity of hypertension correlates with the severity of sleep apnea. Approximately 70% of patients with obstructive sleep apnea are obese. *Coarctation of the aorta* is the most common congenital cardiovascular cause of hypertension. The incidence is 1--8 per 1000 live births. It is usually sporadic but occurs in 35% of children with Turner syndrome. Even when the anatomic lesion is surgically corrected in infancy, up to 30% of patients develop subsequent hypertension and are at risk of accelerated coronary artery disease and cerebrovascular events. **Pathologic consequences of hypertension** Hypertension is an independent predisposing factor for heart failure, coronary artery disease, stroke, renal disease, and peripheral arterial disease. *Heart.* Heart disease is the most common cause of death in hypertensive patients. Hypertensive heart disease is the result of structural and functional adaptations leading to left ventricular hypertrophy, heart failure, abnormalities of blood flow due to atherosclerotic coronary artery disease and microvascular disease, and cardiac arrhythmias. Both genetic and hemodynamic factors contribute to left ventricular hypertrophy. Heart failure may be related to systolic dysfunction, diastolic dysfunction, or a combination of the two. *Brain.* Elevated blood pressure is the strongest risk factor for stroke. The incidence of stroke rises progressively with increasing blood pressure levels, particularly systolic blood pressure in individuals \>65 years. Hypertension also is associated with impaired cognition in an aging population, and longitudinal studies support an association between midlife hypertension and late-life cognitive decline. Hypertension-related cognitive impairment and dementia may be a consequence of a single infarct due to occlusion of a \"strategic\" larger vessel or multiple lacunar infarcts due to occlusive small vessel disease resulting in subcortical white matter ischemia. Cerebral blood flow remains unchanged over a wide range of arterial pressures (mean arterial pressure of 50--150 mmHg) through a process termed autoregulation of blood flow. In patients with the clinical syndrome of malignant hypertension, encephalopathy is related to failure of autoregulation of cerebral blood flow at the upper pressure limit, resulting in vasodilation and hyperperfusion. Signs and symptoms of *hypertensive encephalopathy* may include severe headache, nausea and vomiting (often of a projectile nature), focal neurologic signs, and alterations in mental status. Untreated, hypertensive encephalopathy may progress to stupor, coma, seizures, and death within hours. *Kidney.* The kidney is both a target and a cause of hypertension. Renal risk appears to be more closely related to systolic than to diastolic blood pressure. Proteinuria is a reliable marker of the severity of chronic kidney disease and is a predictor of its progression. Patients with high urine protein excretion (\>3 g/24 h) have a more rapid rate of progression than do those with lower protein excretion rates. Atherosclerotic, hypertension-related vascular lesions in the kidney primarily affect preglomerular arterioles, resulting in ischemic changes in the glomeruli and postglomerular structures. Glomerular injury also may be a consequence of direct damage to the glomerular capillaries due to glomerular hyperperfusion. With progressive renal injury there is a loss of autoregulation of renal blood flow and glomerular filtration rate, resulting in a lower blood pressure threshold for renal damage and a steeper slope between blood pressure and renal damage. The result may be a vicious cycle of renal damage and nephron loss leading to more severe hypertension, glomerular hyperfiltration, and further renal damage. Glomerular pathology progresses to glomerulosclerosis, and eventually the renal tubules may also become ischemic and gradually atrophic. The renal lesion associated with malignant hypertension consists of fibrinoid necrosis of the afferent arterioles, sometimes extending into the glomerulus, and may result in focal necrosis of the glomerular tuft. Clinically, *macroalbuminuria* (a random urine albumin/creatinine ratio \>300 mg/g) or *microalbuminuria* (a random urine albumin/creatinine ratio 30--300 mg/g) are early markers of renal injury. These are also risk factors for renal disease progression and cardiovascular disease. *Peripheral arteries.* In addition to contributing to the pathogenesis of hypertension, blood vessels may be a target organ for atherosclerotic disease secondary to long-standing elevated blood pressure. Hypertensive patients with arterial disease of the lower extremities are at increased risk for future cardiovascular disease. C:\\Documents and Settings\\Feghiu Leonid\\Desktop\\Heart poze\\consequences HT.jpg **Fig. 5 Consequences of arterial hypertension** **(From S. Silbernagl and F. Lang; Color Atlas of Pathophysiology)** **PULMONARY HYPERTENSION** The *mean pulmonary artery pressure* (15 mmHg) is determined by three variables, namely pulmonary vascular resistance (PVR), cardiac output, and left atrial pressure *Pulmonary hypertension* (PH) develops when one (or several) of the above variables is raised so much that at rest pulmonary pressure is *over 20mmHg*; on exercise it is above 32 mmHg (Fig.6). In principle, PH can have three **causes**: - - Increased left atrial pressure (normal is 5 mmHg) so-called *passive PHT*, for example, in mitral stenosis - Increased cardiac output, except in left-to right shunt. A rise in cardiac output alone will lead to (*hyperkinetic*) *PH* only in extreme cases, because the pulmonary vasculature is very distensible and additional blood vessels can be recruited. A rise in cardiac output (fever, hyperthyroidism, physical exertion) can, however, aggravate an existing PH due to other reasons. ***Acute PH*** almost always results from a reduction in the cross-sectional area of the vascular bed (of at least 50%, because of the high vascular distensibility), as by *pulmonary embolism*, i.e., migration of *thrombi* or (rarely) other emboli from their site of origin into the pulmonary arteries. If embolism arises, it is likely that additional (hypoxic) vasoconstriction will develop, which will then reduce the vascular cross-sectional area even more. Sudden vascular obstruction causes *acute cor pulmonale* (acute right heart load). In *acute PHT* the right ventricular systolic pressure can rise to over 60mmHg, but may become normal again within 30--60 minutes in certain circumstances, for example, if the thrombus has moved more distally, thus increasing the vascular cross-sectional area. Pressure may also be reduced by thrombolysis or possibly by diminished vasoconstriction. Embolism may result in *pulmonary infarction*, especially when medium-sized vessels are obstructed and at the same time the blood supply to the bronchial arteries is reduced (e.g., in pulmonary venous congestion or systemic hypotension). However, massive pulmonary embolism may also lead to *acute right heart failure* so that flow into the left ventricle and thus its output falls. This in turn leads to a decrease in systemic blood pressure and to *circulatory shock* and its consequences. *Among the **causes of chronic PHT** are:* - *Lung disease* (asthma, emphysema, chronic bronchitis or fibrosis, together accounting for \> 90% of chronic cor pulmonale cases); - Chronic *thromboembolism* and systemic *vascular disease*; - Extrapulmonary causes of abnormal pulmonary function (thoracic deformity, neuromuscular disease, etc.); - Removal of lung tissue (tuberculosis, tumors); - Chronic *altitude hypoxia* with hypoxic constriction ; - Idiopathic primary PHT of unknown etiology. In all these disorders the resistance in the pulmonary circulation is chronically elevated, due to either exclusion of large segments of the lung, or generalized vascular obstruction. The **consequence of** **chronic PHT** is *right ventricular hypertrophy* (*chronic cor pulmonale*) and ultimately *right ventricular failure*. The cause of *passive* *PHT* is primarily not in the lung but in the *left heart* (*postcapillary PHT*). Thus, almost all patients with *mitral valve disease* or *left heart failure* develop PHT.  **Fig.6 Causes and consequences of pulmonary hypertension** **(From S. Silbernagl and F. Lang; Color Atlas of Pathophysiology)** **CARDIAC ARRYTHMIAS** The normal cardiac impulse is generated by pacemaker cells in the *sinoatrial node* situated at the junction of the right atrium and the superior vena cava. This impulse is transmitted slowly through nodal tissue to the anatomically complex atria, where it is conducted more rapidly to the *atrioventricular node* (AVN), inscribing the P wave of the ECG. There is a perceptible delay in conduction through the anatomically and functionally heterogeneous AVN. The time needed for activation of the atria and the AVN delay is represented as the PR interval of the ECG. The AVN is the only electrical connection between the atria and the ventricles in the normal heart. The electrical impulse emerges from the AVN and is transmitted to the His-Purkinje system, specifically the common bundle of His, then the left and right bundle branches, and then to the Purkinje network, facilitating activation of ventricular muscle. In normal circumstances, the ventricles are activated rapidly in a well-defined fashion that is determined by the course of the Purkinje network, and this inscribes the QRS complex. Recovery of electrical excitability occurs more slowly and is governed by the time of activation and duration of regional action potentials. The relative brevity of epicardial action potentials in the ventricle results in repolarization that occurs first on the epicardial surface and then proceeds to the endocardium, which inscribes a T wave normally of the same polarity as the QRS complex. The duration of activation and recovery is determined by the action potential duration represented on the body surface ECG by the QT interval. The electrical events that normally take place in the heart are responsible for initiating each cardiac contraction. An action potential can be divided into three phases: the resting or unexcited state, depolarization, and repolarization. The inside of a cardiac cell, like all living cells, contains a negative electrical charge compared with the outside of the cell. During the *resting state,* the membrane is relatively permeable to potassium but much less so to sodium and calcium. Charges of opposite polarity become aligned along the membrane (positive on the outside and negative on the inside). *Depolarization* occurs when the cell membrane suddenly becomes selectively permeable to current-carrying ions such as sodium. Sodium ions enter the cell and result in a sharp rise of the intracellular potential to positivity. *Repolarization* involves reestablishment of the resting membrane potential. It is a complex and somewhat slower process, involving the outward flow of electrical charges and the return of membrane potential to its resting state. During repolarization, the membrane conductance or permeability for potassium greatly increases, allowing the positively charged potassium ions to move outward across the membrane. This outward movement of potassium removes positive charges from inside the cell; thus, the membrane again becomes negative on the inside and positive on the outside. The sodium potassium membrane pump also assists in repolarization by pumping positively charged sodium ions out across the cell membrane. **Cardiac action potential.** The action potential in cardiac muscle is typically divided into five phases: *phase 0*---upstroke or rapid depolarization, *phase 1*---early repolarization period, *phase 2*---plateau, *phase 3*---final rapid repolarization period, and *phase 4*--- diastolic depolarization. Cardiac muscle has three types of membrane ion channels that contribute to the voltage changes that occur during the phases of the cardiac action potential. They are the *fast sodium channels,* the *slow* *calcium channels,* and the *potassium channels.* During *phase 0,* in atrial and ventricular muscle and in the Purkinje system, the fast sodium channels in the cell membrane are stimulated to open, resulting in the rapid influx of sodium. The action potentials in the normal SA and AV nodes have a much slower upstroke and are mediated predominantly by the slow calcium currents. The point at which the sodium gates open is called the *depolarization threshold.* When the cell has reached this threshold, a rapid influx of sodium occurs. The exterior of the cell now is negatively charged in relation to the highly positive interior of the cell. This rapid influx of sodium produces a rapid, positively directed change in the transmembrane potential, resulting in the electrical spike and overshoot during phase 0 of the action potential. The membrane potential shifts from a resting membrane potential of approximately −90 millivolts (mV) to +20 mV. The rapid depolarization that constitutes phase 0 is responsible for the QRS complex on the electrocardiogram (ECG). Depolarization of a cardiac cell tends to cause adjacent cells to depolarize because the voltage spike of the cell's depolarization stimulates the sodium channels in nearby cells to open. Therefore, when a cardiac cell is stimulated to depolarize, a wave of depolarization is propagated across the heart, cell by cell. *Phase 1* occurs at the peak of the action potential and signifies inactivation of the fast sodium channels with an abrupt decrease in sodium permeability. The slight downward slope is thought to be caused by the influx of a small amount of negatively charged chloride ions and efflux of potassium. The decrease in intracellular positivity reduces the membrane potential to a level near 0 mV, from which the plateau, or phase 2, arises. *Phase 2* represents the plateau of the action potential. If potassium permeability increased to its resting level at this time, as it does in nerve fibers or skeletal muscle, the cell would repolarize rapidly. Instead, potassium permeability is low, allowing the membrane to remain depolarized throughout the phase 2 plateau. A concomitant influx of calcium into the cell through slow channels contributes to the phase 2 plateau. Calcium ions entering the muscle during this phase also play a key role in the contractile process. These unique features of the phase 2 plateau in these cells cause the action potential of cardiac muscle (several hundred milliseconds) to last 3 to 15 times longer than that of skeletal muscle and cause a corresponding increased period of contraction. The phase 2 plateau coincides with the ST segment of the ECG. *Phase 3* reflects final rapid repolarization and begins with the downslope of the action potential. During the phase 3 repolarization period, the slow channels close, and the influx of calcium and sodium ceases. There is a sharp rise in potassium permeability, contributing to the rapid outward movement of potassium and reestablishment of the resting membrane potential (−90 mV). At the conclusion of phase 3, the distribution of potassium and sodium returns membrane to the normal resting state. The T wave on the ECG corresponds with phase 3 of the action potential. *Phase 4* represents the resting membrane potential. During phase 4, the activity of the sodium-potassium pump contributes to maintenance of the resting membrane potential by transporting sodium out of the cell and moving potassium back in. Phase 4 corresponds to diastole. ***The fast and slow response.*** There are two main types of action potentials in the heart - the fast response and the slow response. The *fast response* occurs in the normal myocardial cells of the atria, the ventricles, and the Purkinje fibers. It is characterized by the opening of voltage-dependent sodium channels called the *fast sodium channels.* The fast-response cardiac cells do not normally initiate cardiac action potentials. Instead, impulses originating in the specialized cells of the SA node are conducted to the fast response myocardial cells, where they effect a change in membrane potential to the threshold level. On reaching threshold, the voltage-dependent *sodium* channels open to initiate the rapid upstroke of the phase 1 action potential. The amplitude and the rate of rise of phase 1 are important to the conduction velocity of the fast response. Myocardial fibers with a fast response are capable of conducting electrical activity at relatively rapid rates (0.5 to 5.0 m/second), thereby providing a high safety factor for conduction. The *slow response* occurs in the SA node, which is the natural pacemaker of the heart, and in the conduction fibers of the AV node. The hallmark of these pacemaker cells is a *spontaneous phase 4 depolarization*. The membrane permeability of these cells allows a slow inward leak of current to occur through the slow channels during phase 4. This leak continues until the threshold for firing is reached, at which point the cell spontaneously depolarizes. Under normal conditions, the slow response, sometimes referred to as the *calcium current,* does not contribute significantly to myocardial depolarization in the atria and ventricles. Its primary role in normal atrial and ventricular cells is to provide for the entrance of calcium for the excitation-contraction mechanism that couples the electrical activity with muscle contraction. The rate of pacemaker cell discharge varies with the resting membrane potential and the slope of phase 4 depolarization. Catecholamines (epinephrine and norepinephrine) increase the heart rate by increasing the slope or rate of phase 4 depolarization. Acetylcholine, which is released during vagal stimulation of the heart, slows the heart rate by decreasing the slope of phase 4. The fast response of atrial and ventricular muscle can be converted to a slow pacemaker response under certain conditions. For example, such conversions may occur spontaneously in individuals with severe coronary artery disease, in areas of the heart where blood supply has been markedly compromised or curtailed. Impulses generated by these cells can lead to ectopic beats and serious arrhythmias.  **Changes in action potential recorded from a fast response in cardiac muscle cell (top) and from a slow response recorded in the sinoatrial and atrioventricular nodes (bottom).** The phases of the action potential are identified by numbers: phase 4, resting membrane potential; phase 0, depolarization; phase 1, brief period of repolarization; phase 2, plateau; phase 3, repolarization. The slow response is characterized by a slow, spontaneous rise in the phase 4 membrane potential to threshold levels; it has a lesser amplitude and shorter duration than the fast response. Increased automaticity (A) occurs when the rate of phase 4 depolarization is increased. (From C. Porth and G. Matfin; Pathophysiology. Concepts of altered health states). ***Absolute and relative refractory periods.*** The pumping action of the heart requires alternating contraction and relaxation. There is a period in the action potential curve during which no stimuli can generate another action potential. This period, which is known as the *absolute refractory period,* includes phases 0, 1, 2, and part of phase 3. During this time, the cell cannot depolarize again under any circumstances. When repolarization has returned the membrane potential to below threshold, although not to the resting membrane potential (−90 mV), the cell is capable of responding to a greater-than-normal stimulus. This condition is referred to as the *relative refractory period.* The relative refractory period begins when the transmembrane potential in phase 3 reaches the threshold potential level and ends just before the terminal portion of phase 3. After the relative refractory period is a short period, called the *supernormal excitatory period,* during which a weak stimulus can evoke a response. The supernormal excitatory period extends from the terminal portion of phase 3 until the beginning of phase 4. It is during this period that cardiac arrhythmias develop. In skeletal muscle, the refractory period is very short compared with the duration of contraction, such that a second contraction can be initiated before the first is over, resulting in a summated tetanized contraction. In cardiac muscle, the absolute refractory period is almost as long as the contraction, and a second contraction cannot be stimulated until the first is over. The longer length of the absolute refractory period of cardiac muscle is important in maintaining the alternating contraction and relaxation that is essential to the pumping action of the heart and for the prevention of fatal arrhythmia. **Mechanisms of cardiac arrhythmias** Heart muscle is unique among other muscles in that it is capable of generating and rapidly conducting its own electrical impulses or action potentials. These action potentials result in excitation of muscle fibers throughout the myocardium. Impulse formation and conduction result in weak electrical currents that spread through the entire body. These impulses are recorded on an electrocardiogram. Disorders of cardiac impulse generation and conduction range from benign arrhythmias that are merely annoying to those causing serious disruption of heart function and sudden cardiac death. The specialized cells in the conduction system manifest four inherent properties that contribute to the genesis of all cardiac rhythms, both normal and abnormal. They are automaticity, excitability, conductivity, and refractoriness. An alteration in any of these four properties may produce arrhythmias or conduction defects. ➤ Cardiac arrhythmias represent disorders of cardiac rhythm related to alterations in automaticity, excitability, conductivity, or refractoriness of specialized cells in the conduction system of the heart. ➤*Automaticity* refers to the ability of pacemaker cells in the heart to spontaneously generate an action potential. Normally, the SA node is the pacemaker of the heart because of its intrinsic automaticity. ➤ *Excitability* is the ability of cardiac tissue to respond to an impulse and generate an action potential. *➤ Conductivity* represent the ability of cardiac tissue to conduct action potentials. ➤*Refractoriness* represents temporary interruptions in conductivity related to the repolarization phase of the action potential *Bradyarrhythmias* typically arise from disturbances in impulse formation at the level of the sinoatrial node or from disturbances in impulse propagation at any level, including exit block from the sinus node, conduction block in the AV node, and impaired conduction in the His-Purkinje system. *Tachyarrhythmias* can be classified according to mechanism, including enhanced automaticity (spontaneous depolarization of atrial, junctional, or ventricular pacemakers), reentry (circus propagation of a depolarizing wavefront), or triggered arrhythmias (initiated by afterdepolarizations) occurring during or immediately after cardiac repolarization, during phase 3 or 4 of the action potential. **Heart arrhythmias due to alterations in impulse initiation: automaticity** The ability of certain cells in the conduction system to initiate an impulse or action potential spontaneously is referred to as *automaticity.* The SA node has an inherent discharge rate of 60 to 100 times per minute. It normally acts as the pacemaker of the heart because it reaches the threshold for excitation before other parts of the conduction system have recovered sufficiently to be depolarized. If the SA node fires more slowly or SA node conduction is blocked, another site that is capable of automaticity takes over as pacemaker. Other regions that are capable of automaticity include the atrial fibers that have plateau-type action potentials, the AV node, the bundle of His, and the bundle branch Purkinje fibers. These pacemakers have a slower rate of discharge than the SA node. The AV node has an inherent firing rate of 40 to 60 times per minute, and the Purkinje system fires at a rate of 20 to 40 times per minute. The SA node may be functioning properly, but because of additional precipitating factors, other cardiac cells can assume accelerated properties of automaticity and begin to initiate impulses. These additional factors might include injury, hypoxia, electrolyte disturbances, enlargement or hypertrophy of the atria or ventricles, and exposure to certain chemicals or drugs. The potential in the cells of the sinus node is a ***pacemaker potential***. It has *no* constant resting potential, but rises after each repolarization. The most negative value of the latter is called *maximal diastolic potential* (MDP -- 70 mV). It rises steadily until the *threshold potential* (TP -- 40 mV) is reached once more and an *action potential* (AP) is again triggered. The following changes in *ionic conductance* of the plasma membrane and thus of **ionic** **currents** cause these potentials: Beginning with the MDP, nonselective conductance is increased and influx of cations into the cell leads to slow depolarization (*prepotential* = PP or spontaneous diastolic depolarization). Once the TP has been reached, gCa now rises relatively rapidly, the potential rising more steeply so that an increased influx of Ca^2+^ produces the upstroke of the AP. While the potential overshoots to positive values, leading to an outward K^+^ flux, the pacemaker cell is again repolarized to the MDP. *Spontaneous diastolic depolarization* (phase 4 depolarization) underlies the property of automaticity (pacemaking) characteristic of cells in the sinoatrial (SA) and atrioventricular (AV) nodes, His-Purkinje system. Phase 4 depolarization results from the concerted action of a number of ionic currents, including K^+^ currents, Ca^2+^ currents, electrogenic Na, K-ATPase, the Na-Ca exchanger; however, the relative importance of these currents remains controversial. The rate of phase 4 depolarization and, therefore, the firing rates of pacemaker cells are dynamically regulated. Prominent among the factors that modulate the spontaneous diastolic depolarization is autonomic nervous system tone. The negative chronotropic effect of activation of the parasympathetic nervous system is a result of the release of acetylcholine that binds to muscarinic receptors, releasing G protein subunits that activate a potassium current in nodal and atrial cells. The resulting increase in K^+^ conductance opposes membrane depolarization, slowing the rate of rise of phase 4 of the action potential. The heart rate is lower if: -- The *rise of the slow depolarization becomes less steep*, -- The TP becomes less negative, -- The *MDP* becomes more negative so that spontaneous depolarization begins at a lower level; -- *Repolarization* in an AP starts later or is slower. What the first three processes have in common is that the threshold is reached later than before (Fig.7). Conversely, augmentation of sympathetic nervous system tone increases myocardial catecholamine concentrations, which activate both α and β adrenergic receptors. The effect of β~1~-adrenergic stimulation predominates in pacemaking cells, augmenting both L-type Ca current, thus C:\\Users\\Iuliana\\Desktop\\Heart\\synus tahycardia.jpg **Fig. 7 Changes in pacemaker potential** **(From S. Silbernagl and F. Lang; Color Atlas of Pathophysiology)** During sleep and in trained athletes at rest (*vagotonia*) and also in hypothyroidism, the rate can drop below 60 per minute (sinus bradycardia), while during physical exercise, excitement, fever or hyperthyroidism it may rise to well above 100 per minute (sinus tachycardia). In both cases the rhythm is regular, while the rate varies in sinus arrhythmia. This arrhythmia is normal in juveniles and varies with respiration, the rate accelerating in inspiration, slowing in expiration. The SA node may be functioning properly, but because of additional precipitating factors, other cardiac cells can assume accelerated properties of automaticity and begin to initiate impulses. These additional factors might include injury, hypoxia, electrolyte disturbances, enlargement or hypertrophy of the atria or ventricles, and exposure to certain chemicals or drugs. **Sinus node arrhythmias** In a healthy heart driven by sinus node discharge, the rate ranges between 60 and 100 beats per minute. On the ECG, a P wave may be observed to precede every QRS complex. Historically, normal sinus rhythm has been considered the "normal" rhythm of a healthy heart. In normal sinus rhythm, a P wave precedes each QRS complex, and the RR intervals, remain relatively constant over time. Alterations in the function of the SA node lead to changes in rate or rhythm of the heartbeat. Years ago, it was believed that sinus rhythm should be regular; that is, all RR intervals should be equal. Today, it is accepted that a more optimal rhythm is respiratory sinus arrhythmia. *Respiratory sinus arrhythmia* is a cardiac rhythm characterized by gradual lengthening and shortening of RR intervals (Fig.8, D). This variation in cardiac cycles is related to intrathoracic pressure changes that occur with respiration and resultant alterations in autonomic control of the SA node. Inspiration causes acceleration of the heart rate, and expiration causes slowing. Respiratory sinus arrhythmia accounts for most heart rate variability in healthy individuals. Decreased heart rate variability has been associated with altered health states, including myocardial infarction, congestive heart failure, hypertension, diabetes mellitus, and prematurity in infants.  **Fig. 8 Electrocardiographic (ECG) tracings of rhythms originating** **in the sinus node** \(A) Normal sinus rhythm (60 to 100 beats per minute). (B) Sinus bradycardia (\100 beats per minute). (D) Respiratory sinus arrhythmia, characterized by gradually lengthening and shortening of RR intervals (From C. Porth and G. Matfin; Pathophysiology. Concepts of altered health states). *Sinus bradycardia*. Sinus bradycardia describes a slow (\100 beats per minute) that has its origin in the SA node (Fig.8, C). A normal P wave and PR interval should precede each QRS complex. The mechanism of sinus tachycardia is enhanced automaticity related to sympathetic stimulation or withdrawal of vagal tone (see above). Sinus tachycardia is a normal response during fever and exercise and in situations that incite sympathetic stimulation. It may be associated with congestive heart failure, myocardial infarction, and hyperthyroidism. Pharmacologic agents such as atropine, isoproterenol, epinephrine, and quinidine also can cause sinus tachycardia. *Sinus arrest*. Sinus arrest refers to failure of the SA node to discharge and results in an irregular pulse. An escape rhythm develops as another pacemaker takes over. Sinus arrest may result in prolonged periods of asystole and often predisposes to other arrhythmias. Causes of sinus arrest include disease of the SA node, digitalis toxicity, myocardial infarction, acute myocarditis, excessive vagal tone, quinidine, acetylcholine, and hyperkalemia or hypokalemia. **Arrhythmias due to disturbances in excitability** *Excitability* describes the ability of a cell to respond to an impulse and generate an action potential. Myocardial cells that have been injured or replaced by scar tissue do not possess normal excitability. For example, during the acute phase of an ischemic event, involved cells become depolarized. These ischemic cells remain electrically coupled to the adjacent non-ischemic area; current from the ischemic zone can induce reexcitation of cells in the non-ischemic zone. An *ectopic pacemaker* is an excitable focus outside the normally functioning SA node. These pacemakers can reside in other parts of the conduction system or in muscle cells of the atria or ventricles. A *premature contraction* or extrasystole occurs when an ectopic pacemaker initiates a beat. Premature contractions do not follow the normal conduction pathways, they are not coupled with normal mechanical events, and they often render the heart refractory or incapable of responding to the next normal impulse arising in the SA node. They occur without incident in persons with healthy hearts in response to sympathetic nervous system stimulation or other stimulants such as caffeine. In the diseased heart, premature contractions may lead to more serious arrhythmias. **Causes of extrasystole as disorders of excitability in the heart are:** -- A *less negative diastolic membrane potential* in the cells of the conduction system or myocardium. This is because depolarization also results in the potential losing its stability and depolarizing spontaneously; - Afterdepolarizations and triggered automaticity or *depolarizing after-potentials which* can occur during repolarization ("early") or after its end ("late") (Fig.9). *Afterdepolarizations and triggered automaticity.* Triggered automaticity or activity refers to impulse initiation that is dependent on afterdepolarizations. Afterdepolarizations are membrane voltage oscillations that occur during an action potential (*early afterdepolarizations*) or after it (*delayed afterdepolarizations*). *Early afterdepolarizations* (EAD) occur during the action potential and interrupt the orderly repolarization of the myocyte. *EADs* occur when the AP duration is markedly prolonged, which registers in the ECG as a prolonged QT interval (long QT syndrome). *Causes of EAD* are bradycardia (ex in hypothyroidism, β1 block), hypokalemia, hypomagnesemia (loop diuretics), and certain drugs such as the Na^+^ channel blockers quinidine, procainamide, and disopyramide, as well as the Ca^2+^ channel blockers verapamil and diltiazem. Certain genetic defects in the Na^+^ channels or in one of the K^+^ channels lead to EAD due to a lengthening of the QT interval. If such EAD occur in the Purkinje cells, they trigger ventricular ES in the more distal myocardium (the myocardium has a shorter AP than the Purkinje fibers and is therefore already repolarized when the DAP reaches it). Traditionally, EADs have been thought to arise from action potential prolongation and reactivation of depolarizing currents, but more recent experimental evidence suggests a previously unappreciated interrelationship between intracellular calcium loading and EADs. Cytosolic calcium may increase when action potentials are prolonged. This, in turn, appears to enhance L-type Ca current, further prolonging action potential duration as well as providing the inward current driving EADs. The interrelationship among intracellular \[Ca^2+^\] and EADs may be one explanation for the susceptibility of hearts that are calcium loaded (e.g., in ischemia or congestive heart failure) to develop arrhythmias, particularly on exposure to action potential--prolonging drugs. The delayed afterdepolarizations (DADs) are usually preceded by posthyperpolarization that changes into postdepolarization. If the amplitude of the latter reaches the threshold potential, a new AP is triggered. The cellular feature common to the induction of DADs is the presence of an increased Ca^2+^ load in the cytosol and sarcoplasmic reticulum. Digitalis glycoside toxicity, catecholamines, and ischemia all can enhance Ca^2+^ loading sufficiently to produce DAD. Accumulation of lysophospholipids in ischemic myocardium with consequent Na^+^ and Ca^2+^ overload has been suggested as a mechanism for DADs and triggered automaticity. Cells from damaged areas or cells that survive a myocardial infarction may display spontaneous release of calcium from the sarcoplasmic reticulum, and this may generate \"waves\" of intracellular calcium elevation and arrhythmias. Structural heart disease such as cardiac hypertrophy and failure may also delay ventricular repolarization (so-called *electrical remodeling*) and predispose to arrhythmias related to abnormalities of repolarization. The abnormalities of repolarization in hypertrophy and heart failure are often magnified by concomitant drug therapy or electrolyte disturbances. C:\\Users\\Iuliana\\Desktop\\Heart\\causes extrasystole.jpg **Fig. 9. Mechanisms of heart excitability disturbances** **(From S. Silbernagl and F. Lang; Color Atlas of Pathophysiology)** Almost all tachyarrhythmias are the result of a phenomenon known as *reentry*. Under normal conditions, an electrical impulse is conducted through the heart in an orderly, sequential manner. The electrical impulse then dies out and does not reenter adjacent tissue because that tissue has already been depolarized and is refractory to immediate stimulation. However, fibers that were not activated during the initial wave of depolarization can recover excitability before the initial impulse dies out, and they may serve as a link to reexcite areas of the heart that were just discharged and have recovered from the initial depolarization. This activity disrupts the normal conduction sequence. Reentry may occur anywhere in the conduction system. The functional components of a reentry circuit can be large and include an entire specialized conduction system, or the circuit can be microscopic. It can include myocardial tissue, AV nodal cells, junctional tissue or the ventricles. Factors contributing to the development of a reentrant circuit include ischemia, infarction, and elevated serum potassium levels. For reentry to occur, there should be several predisposing factors: the maximal length of the loop *s* has increased, for example, in ventricular hypertrophy, the refractory time tR has shortened, and/or the velocity of the spread of excitation \" is diminished (Fig.10  **Fig.10 Schematic diagram of reentry** A. The circuit contains two limbs, one with slow conduction. B. A premature impulse blocks in the fast pathway and conducts over the slow pathway, allowing the fast pathway to recover so that the activation wave can reenter the fast pathway from the retrograde direction. C. During sustained reentry utilizing such a circuit, a gap (excitable gap) exists between the activating head of the wave and the recovering tail. D. One mechanism of termination of reentry occurs when the conduction and recovery characteristics of the circuit change and the activating head of the wave collides with the tail, extinguishing the tachycardia. **(From S. Silbernagl and F. Lang; Color Atlas of Pathophysiology)** There are several forms of reentry. The first is *anatomic reentry*. It involves an anatomic obstacle around which the circulating current must pass and results in an excitation wave that travels in a set pathway. Arrhythmias that arise as a result of anatomic reentry are paroxysmal supraventricular tachycardias, as seen in Wolff-Parkinson-White syndrome, atrial fibrillation, atrial flutter, AV nodal reentry, and some ventricular tachycardias. *Functional reentry* does not rely on an anatomic structure to circle; but instead depends on the local differences in conduction velocity and refractoriness among neighboring fibers that allow an impulse to circulate repeatedly around in area. *Spiral reentry* is the most common form of this type of reentry. It is initiated by a wave of electrical current that does not propagate normally after meeting refractory tissue. The broken end of the wave curls, forms a vortex, and permanently rotates. This phenomenon suppresses normal pacemaker activity and can result in atrial fibrillation. Structural heart disease is associated with changes in conduction and refractoriness that increase the risk of reentrant arrhythmias. Chronically ischemic myocardium exhibits a downregulation of the gap junction channel protein (connexin 43) that carries intercellular ionic current. The border zones of infarcted and failing ventricular myocardium exhibit not only functional alterations of ionic currents b