Month: October 2015

The Barriers, The Innate Immune System, and Correlations to Inflammation

October 27, 2015 Immunology, Infectious Diseases No comments , , , , , ,

11th_Annual_Randy_Oler_Memorial_Operation_Toy_Drop_at_Fort_Bragg_N.C.,_Dec._6,_2008Defenses of the skin and Mucosa


The epidermis consists of stratified squamous cells, most of which are keratinocytes. Keratinocytes produce the protein keratin, which is not readily degraded by most microorganisms. As cells from the dermis are pushed outward into the epidermal region, they produce copious amounts of keratin and then die. This layer of dead keratinized cells forms the surface of the skin. The dead cells of the epidermis are continuously shed (desquamation). Thus, bacteria that manage to bind to epidermal cells are constantly being removed from the body.

Skin is dry and has an acidic pH (pH 5), two features that inhibit the growth of many pathogenic bacteria, which prefer a wet environment with a neutral pH (pH 7). The temperature of the skin (34 C to 35 C) is lower than that of body interior. Accordingly, bacteria that succeed in colonizing the skin must be able to adapt to the very different internal environment of the body if they manage to reach underlying tissue.

Hair follicles, sebaceous (fat) glands, and sweat glands are composed of simple epithelial cells and offer sites for potential breaches in the skin that could be used by some bacteria to move past the skin surface. These sites are protected by the peptidoglycan-degrading lysozyme and by lipids that are toxic to many bacteria.

The defenses of the skin do not completely prevent bacterial growth, as is evident from the fact that there are bacteria capable of colonizing the surface of the skin. The consist primarily of gram-positive bacteria, a mixture of cocci and rods. The commensal microbiota of the skin helps to protect against pathogenic bacteria by occupying sites that might be colonized by pathogenic bacteria. It also competes with incoming pathogens for essential nutrients. Some resident bacteria also produce bactericidal compounds which target other bacteria. The commensal microbiota does not completely prevent colonization of the skin by potential pathogens but hampers it enough so that the colonization by pathogenic bacteria is usually transient.

Mucosal Surfaces

The respiratory tract, gastrointestinal tract, and urogenital tract are topologically “inside” the body, but they are exposed constantly to the outer environment and foreign materials.

Internal surface areas/mucosal epithelia are comprised of only one epithelial layer. Mucosal epithelia have a temperature of around 37 C and a pH of 7.0 to 7.4. Mucosal epithelia are continuously bathed in fluids.

Mucosal cells are regularly replaced and old cells are ejected into the lumen. Thus, bacteria that manage to reach and colonize a mucosal surface are constantly being eliminated from the mucosal surface and can remain in the area only if they can grow rapidly enough to colonize newly produced cells.

Chemical and other innate defenses help to reduce the growth rates of bacteria sufficiently to allow ejection of mucus blobs and sloughing of mucosal cells to clear the bacteria from the area.

Mucus is an important defense that protect mucosal from bacteria. Mucus is a mixture of glycoproteins produced by goblet cells, a specialized cell type incorporated into the epithelial layer. Mucus has a viscous, slimy consistency, which allows it to act as a lubricant. Mucus plays a protective role because it traps bacteria and prevents them from reaching the surfaces of the mucosal. Mucus is constantly being produced, and excess mucus is shed in blobs that are expelled. Bacteria trapped in mucus are thus eliminated from the site.

In the gastrointestinal and urinary tracts, peristalsis and the rapid flow of liquids through the area remove the mucus blobs, along with the lumen contents.

In the respiratory tract and in the fallopian tubes, there are specialized cells, ciliated columnar cells, whose elongated protrusions (cilia) are continuously waving in the same direction. The waving action of the cilia propels mucus blob out of the area. Mucus has proteins that have antibacterial activity and these proteins include lysozyme, lactoperoxidase, toxic antimicrobial peptides (defensins, cathelicidins, histatins). Lactoferrin sequesters iron and deprives bacteria of this essential nutrient.

Most mucosal surfaces are protected by a normal resident microbiota, except uterus and upper female genital tract and the urinary tract. Resident microbiota on mucosal surface predominately consists of gram-positive bacteria.

Special defenses of the gastrointestinal tract

The lumen of the stomach is an extremely acidic environment (pH ~2), which acts as a protective barrier to prevent bacteria from reaching more vulnerable areas, such as the small intestine and colon, where conditions are more favorable for bacterial growth. Bacteria ingested in foods are probably protected somewhat from the full impact of stomach acid by the buffering capacity of the food. Food increase the chance that some of the bacteria might survive long enough in the stomach to reach the small intestine.

Bile salts are steroids with detergent-like properties that are produced in the liver, stored in the gall bladder, and then released through the bile duct into the intestine.  The detergent-like properties of bile salts help to disrupt bacterial membranes, especially those of gram-negative bacteria.

Defenses of The Innate Immune System

Skin and mucosal surfaces (barriers) are highly effective in preventing pathogenic bacteria from entering tissue and blood, but from time to time, bacteria succeed in breaching these surfaces. Bacteria that get this far encounter a formidable defense force, the phagocytic cells (neutrophils, monocytes, macrophages, and dendritic cells), natural killer cells, and the proteins that help organize their activity. These cells, together with a set of blood proteins called complement and another set of proteins called cytokines are called the innate immune system. Innate immune system plays a key role in the defence reactions against foreign invaders and correlates with inflammation.

The Firepower of Innate Immune System

The firepower of the innate immune system is very effective in killing bacteria. The phagocyte first forms pseudopods that engulf the bacterium. After engulfment, the bacterium is encased in an endocytic vesicle called phagosome. Various lysosomal enzymes, antimicrobial peptides, membrane-permeabilizing proteins, and degrading proteins mediate nonoxidative killing. Oxidative killing occurs through the formation of toxic reactive oxygen species.

Unlike phagocytic cells, NK cells do not ingest their targets, although their mode of killing resembles that of phagocytes in many respects. NK cells store their toxic substances in granules. Binding to an infected human target cell stimulates the release of these granules. To distinguish a infected cell from a healthy cell, the NK cell use the MHC-I molecule. Healthy cells express MHC-I protein on their surfaces, and MHC-I binds to a second inhibitory receptor on the NK cell surface and halts the activation of the cytotoxic response. In contrast, infected cells express much less MHC-I on their surfaces than normal cells, and the activation response of the NK cell proceeds, leading to an attack on the infected cell. Thus, instead of ingesting a bacterium or infected cell, the innate cytotoxic NK cells bombard infected cells. Cytotoxic-cell granules contain a protein called perforin that insets into the membrane of a target cell and causes channels to form. These channels allow other granule proteins, a set of proteases called granzymes, to enter the target cell. One effect of this assult appears to be forcing the target cell to initiate apoptosis.

C3a and C5a are proinflammatory molecules that stimulate mast cells to release their granules, which contain vasoactive substance that increase the permeability of blood vessels and thus facilitate the movement of phagocytes from blood vessels into tissue. C5a also acts together with cytokines to signal phagocytes to leave the bloodstream and to guide them to the infection site. Once PMNs or monocytes have left the bloodstream, they move along a gradient of C5a to find the locus of infection. At the site of infection, C3b binds to the surface of the invading bacterium and makes it easier for phagocytes to ingest the bacterium. This activity is called opsonization.

Another role of activated complement components is direct killing of the bacterium. Activated components C5b recruits C6, C7, C8, and C9 to form a membrane-damaging complex in the membranes of some types of microorganisms. This complex is called the membrane attack complex (MAC). Formation of the MAC inactivates enveloped viruses and kills bacteria by punching holes in their membranes.

Correlations Between Innate Immune System and Inflammation

Inflammation is one imporant response of vascular tissues to harmful stimuli, such as damaged tissues and the release of irritants, caused by infection. The inflammatory response recruits innate-immune cells from the blood vessels to the site of infection. Proinflammatory cytokines are induced by the complement cascade (C3a and C5a, phagocytes have receptors for C3b on their surface) and by mast cells (mast cells secrete vasoactive amines including histamine and serotonin) and activated phagocytes.


October 25, 2015 Infectious Diseases, Physiology and Pathophysiology No comments , , , , , , , ,

dreamstime_10999299high_feverBody Temperature System and Mechanisms could be found at thread "Mechanism of Thermoregulation" at

Body temperature, at any given point in time, represents a balance between heat gain and heat loss. Body heat is generated in the core tissues of the body, transferred to the skin surface by the blood, and released into the environment surrounding the body.

The thermostat

In the hypothalamus there is a thermostat, which controls and maintains the temperature of the individual. If the thermostat has been reset to a new point different from the normal value, the body would sense the difference between true body temperature and the new thermostat via temperature receptors, and after the signal being transmitted into the hypothalamus, the ratio of heat production to heat loss will be changed accordingly via temperature-regulating responses to make the body core temperature the same as the new thermostat. For example, if the thermostat had been reset to above 37℃, the temperature receptors then signal that the actual temperature is below the new set point, and the temperature-raising mechanisms are activated. Then the ratio of heat production to heat loss would increases and the actual body temperature starts to increase until the value equaling the new set point.


The body temperature of a health individual changes with circadian rhythm, with the lowest at 3 AM to 6 AM and highest at 3 PM to 6 PM. Generally a orally measured temperature higher than 37.2 C in the early morning or 37.7 in the late afternoon and evening is considered as fever.

Body temperature can be measured by several different methods and at many different sites. However, in critical ill patients the variability between sites may increase. For example, during open mouth breathing, sublingual temperature falls relative to tympanic membrane temperature. Likewise, skin temperature can fall relative to core temperature during cardiogenic shock due to a decrease in cutaneous blood flow. Because of this variability, mouth, skin, and axillary measurements are not recommended for use in critical ill patients.


Fever describes an elevation in body temperature that is caused by an upward displacement of the thermostatic set point of the hypothalamic thermoregulatory center. Many proteins, breakdown products of proteins, and certain other substances released from bacterial cell membranes can cause a change in the set point to rise. Fever is resolved when the condition that caused the increase in the set point is removed. Fevers that are regulated by the hypothalamus usually do not rise above 41 C, suggesting a built-in thermostatic safety mechanism.

Pyrogens are exogenous or endogenous substances that produce fever. Exgenous pyrogens are derived from outside the body and include such substances as bacterial products, bacterial toxins, or whole microorganisms. Exogenous pyrogens induce host cells to produce fever-producing mediators called endogenous pyrogens. When bacteria or breakdown products of bacteria are present in blood or tissues, phagocytic cells of the immune system engulf them. These phagocytic cells digest the bacterial products and then release pyrogenic cytokines (for information about inflammation mediators please refer to thread "Inflammation Mediators" at, principally interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-alpha), into the bloodstream for transport to the hypothalamus, where they exert their action. These cytokines induce prostaglandin E2 (PGE2), which is a metabolite of arachidonic acid. It is hypothesized that when interleukin (IL-1B) interacts with the endothelial cells of the blood-brain barrier in the capillaries of the organum vasculosum laminae terminalis (OVLT), which is in the third ventricle above the optic chiasm, PGE2 is released into the hypothalamus.

At this point, PGE2 binds to receptors in the hypothalamus to induce increases in the thermostatic set point through the second messenger cyclic adenosine monophosphate (cAMP). In response to the increase in its thermostatic set point, the hypothalamus initiates shivering and vasoconstriction that raise the body's core temperature to the new set point, and fever is established.

Basic Concepts in Laboratory Testings

October 24, 2015 Uncategorized No comments , , , , , , ,


Accuracy is defined as the extent to which the mean measurement is close to the true value. A sample spiked with a known quantity of an analyte is measured repeatedly; the mean measurement is calculated. A highly accurate assay means that the repeated analyses produce a mean value that is the same as or very close to the known spiked quantity.

Accuracy of a qualitative assay is calculated as the sum of the true positives and true negatives divided by the number of samples tested.


Precision refers to assay reproducibility. An assay with high precision means that the methodology is consistently able to produce results in close agreement.


A biomarker is a marker (not necessarily a quantifiable laboratory parameter) defined by the National Institutes of Health as "A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention." Biomarkers are used to diagnose and stage disease, assess disease progression, or assess response to therapeutic interventions.

Many biomarkers are common laboratory parameters. For example, glycosylated hemoglobin A1c is used to diagnose diabetes and assess long-term glucose control in people with diabetes.

Noninvasive Versus Invasive Tests

A noninvasive test is a procedure that examines fluids or other substances obtained without using a needle, tube, device, or scope to penetrate the skin or enter the body. An invasive test is a procedure that examines fluids or tissues obtained by using a needle, tube, device, or scope to penetrate the skin or enter the body.

Predictive Value

The predictive value is used to assess a test's reliability. To a positive test result, the predictive value indicates the percent of positive that are TPs. To a negative test result, the predictive value indicates the percent of negative that are TNs. The higher the predictive value, the lower the chance of false-positive (or false-negative) result.

Predictive value of positive test = TP/(TP + FP)

Predictive value of negative test = TN/(TN + FN)

Sensitivity and Specificity

The sensitivity of a test refers to the ability of the test to identify positive results in patients who actually have the disease. The higher the test sensitivity, the lower the chance of a false-negative result.

Sensitivity = TP/(TP+FN)

Specificity refers to the percent of negative results in people without the disease. The higher the specificity, the lower the chance of a false-positive result.

Specificity = TN/(TN+FP)

Afterload and Its Components

October 21, 2015 Cardiology, Critical Care, Physiology and Pathophysiology, Respirology No comments , , , , , , , , , , ,


Also see information about afteroad in Pharmacy Profession Forum at

Afterload in the intact heart reflects the resistance that the ventricle must overcome to empty its contents. It is more formally defined as the ventricular wall stress that develops during systolic ejection. Wall stress (σ), like pressure, is expressed as force per unit area and, for the left ventricle, may be estimated from Laplace relationship:

σ = (P x r)/(2 x h) [Laplace Equation]

where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g., hypertension) or an increased chamber size (e.g., a dilated left ventricle). Conversely, as would be expected from Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the force is distributed over a greater mass per unit surface area of ventricular muscle.

Components of Afterload

The forces that contribute to ventricular afterload can be identified by their relationship to the variables in the Laplace equation. The component forces of ventricular afterload include end-diastolic volume (EDV/preload), pleural pressure, vascular impedance, and peripheral vascular resistance.

Pleural Pressure

Since afterload is a transmural wall tension, it will be influenced by the pleural pressure surrounding the heart. Therefore, negative pressure surrouding the heart will impede ventricular emptying by opposing the inward movement of the ventricular wall during systole. This effect is responsible for the transient decrease in systolic blood pressure that occurs during the insiratory phase of spontaneous breathing. When the inspiratory drop in systolic pressure is greater than 15 mm Hg, the condition is called "pulsus paradoxus" (which is a misnomer, since the response is not paradoxical, but is an exaggeration of the normal response).

Conversely, positive pressures surrounding the heart will promote ventricular emptying by facilitating the inward movement of the ventricular wall during systole. When intrathoracic pressure rises during a positive-pressure breath, there is a transient rise in systolic blood pressure, reflecting an increase in the stroke output of the heart. The inspiratory rise in blood pressure during mechanical ventilation is known as "reverse pulsus paradoxus". The "unloading" effect of positive intrathoracic pressure is the basis for the use of positive-pressure breathing as a "ventricular assist" maneuver for patients with advanced heart failure.


Vascular impedance is the force that opposes the rate of change in pressure and flow, and it is expressed primarily in the large, proximal arteries, where pulsatile flow is predominant. Impedance in the ascending aorta is considered the principal afterload force for the left ventricle, and impedance in the main pulmonary arteries is considered the principal afterload force for the right ventricle. Vascular impedance is a dynamic force that changes frequently during a single cardiac cycle, and it is not easily measured in the clinical setting.


(Systemic) vascular resistance is the force that opposes non-pulsatile or steady flow, and is expressed primarily in small, terminal blood vessels, where non-pulsative flow is predominant. About 75% of the vascular resistance is in arterioles and capillaries. In the beginning of arterioles, although the blood pressure is still pulsatile, the vascular smooth muscles have autoregulation function so the blood flow is steady. Becasue the flow is steady, the mean arterial pressure had been created to equal the "average" arterial pressure during a cardac cycle, under which the amount of blood flow per time is the same. So the relationship between SVR, MAP, and CO is:

SVR = (MAP – RAP) / CO

Similarly, the relationship between PVR, PAP, and CO is:

PVR = (PAP – LAP) / CO

However, SVR and PVR are not considered to be accurate representations of the resistance to flow in the pulmonary and systemic circulations. Because vascular impedance is not easily measured, vascular resistance is often used as a clinical measure of ventricular afterload. But animal studies have shown a poor correlation between direct measures of ventricular wall tension (true afterload) and the calculated vascular resistance. This is consistent with the notion that vascular impedance is the principal afterload force for ventricular emptying. However, the contribution of vascular resistance to afterload cannot be determined with the SVR and PVR because these parameters do not represent the actual resistance to flow in the circulatory system.

Determinants of Myocardial Oxygen Consumption



Myocyte contraciton is the primary factor determining myocardial oxygen consumption (MVO2) above basal levels. Therefore, factors that enhance tension development by the caridac muscle cells, the rate of tension development, or the number of tension generating cycles per unit time will increase MVO2. For example, doubling heart rate approximately doubles MVO2 because ventricular myocytes are generating twice the number of tension cycles per minute. Increasing inotropy also increases MVO2 because the rate of tension development is increased as well as the magnitude of tension, both of which result in increased ATP hydrolysis and oxygen consumption. Increasing afterload, because it increases tension development, also increases MVO2. Increasing preload (e.g., ventricular end-diastolic volume) also increases MVO2; however, the increase is much less than what might be expected because of the LaPlace relationship.

The LaPlace relationship has been discussed above. If we substitute ventricular end-diastolic volume/EDV for ventricular radius, we get below new LaPlace equation:

Screen Shot 2016-07-18 at 1.16.30 PMThis relationship indicates that a 100% increase in venticular volume (V) incrases wall tension (T) by only 26%. In contrast, increasing intraventricular pressure (P) by 100% increases wall tension by 100%. For this reason, wall tension, and therefore MVO2, is far less sensitive to changes in ventricular volume than pressure.

Physiologic Adapations and Maladaptations in Heart Failure

October 20, 2015 Cardiology, Physiology and Pathophysiology No comments , , , , , , , , , , , , , , , , ,

Basic Concepts


The concept of preload in the intact heart was described by physiologists Frank and Starling a century ago. The preload can be though of as the amount of myocardial stretch at the end of diastole, just before contraction. Measurements that correlate with myocardial stretch, and that are often used to indicate the preload on the horizontal axis, are the ventricular end-diastolic volume (EDV).


Afterload in the intact heart reflects the resistance that the ventricle must overcome to empty its contents. It is more formally defined as the ventricular wall stress that develops during systolic ejection. Wall stress (σ), like pressure, is expressed as force per unit area and, for the left ventricle, may be estimated from Laplace relationship:

σ = (P x r)/(2 x h)

where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g., hypertension) or an increased chamber size (e.g., a dilated left ventricle). Conversely, as would be expected from Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the force is distributed over a greater mass per unit surface area of ventricular muscle.

Pathophysiology of Heart Failure

The pathophysiology of heart failure is complex and must be understood at multiple levels. Traditionally, research has focused on the hemodynamic changes of the failing heart, considering the heart as an isolated organ. However, studies of the failing heart have emphasized the importance of understanding changes at the cellular level and the neuro-hormonal interactions between the heart and other organs of the body.

Hemodynamic Changes

From a hemodynamic standpoint, heart failure can arise from worsening systolic or diastolic function or, more frequently, a combination of both.

Systolic Dysfunction

In systolic dysfunction, the isovolumic systolic pressure curve of the pressure-volume relationship is shifted downward (A). This reduce the stroke volume of the heart with a concomitant decrease in cardiac output. To maintain cardiac output, the heart can respond with three compensatory mechanisms:

1.Increased return of blood to the heart (preload) can lead to increased contraction of sarcomeres. In the pressure-volume relationship, the heart operates at a' instead of a, and stroke volume increases, but at the cost of increased end-diastolic pressure (D).

2.Second, increase release of catecholamines can increase cardiac output by both increasing the heart rate and shifting the systolic isovolumetric curve to the left (C).

3.Cardiac muscle can hypertrophy and ventricular volume can increase, which shifts the diastolic curve to the right (B).

Screen Shot 2015-10-18 at 7.15.43 PMAlthough each of these compensatory mechanisms can temporarily maintain cardiac output, each is limited in its ability to do so, and if the underlying reason for systolic dysfunction remains untreated, the heart ultimately fails.

Diastolic Dysfunction

Screen Shot 2015-10-18 at 8.49.51 PMIn diastolic dysfunction, the position of the systolic isovolumic curve remains unchanged (contractility of the myocytes is preserved). However, the diastolic pressure-volume curve is shift to the left, with an accompanying increase in left ventricular end-diastolic pressure and symptoms of heart failure. Diastolic dysfunction can be present in any disease that causes decreased relaxation, decreased elastic recoil, or increased stiffness of the ventricle.

Neurohormonal Changes

After an injury to the heart, increased secretion of endogenous neurohormones and cytokines is observed. Initially, increased activity of the adrenergic system and the renin-angiotensin system provides a compensatory response that maintains perfusion of vital organs. However, over time these changes can lead to progressive deterioration of cardiac function.

Sympathetic Nervous System

Increased sympathetic activity occurs early in the development of heart failure. Elevated plasma norepinephrine levels cause increased cardiac contractility and an increased heart rate that initially help maintain cardiac output. However, continued increases lead to increased preload (as a result of venous vasoconstriction) and afterload (from arterial vasoconstriction), which can worsen heart failure. In addition, sympathetic hyperactivity causes deleterious cellular changes.


Reduced renal blood pressure stimulates the release of renin and increases the production of angiotensin II. Both angiotensin II and sympathetic activation cause efferent glomerular arteriolar vasoconstriction, which helps maintain the glomerular filtration rate despite a reduced cardiac output. Angiotensin II stimulates aldosterone synthesis, which leads to sodium resorption and potassium excretion by the kidneys. However, a vicious circle is initiated as continued hyperactivity of the renin-angiotensin system leads to severe vasoconstriction, increased afterload, and further reduction in cardiac output and glomerular filtration rate.


Heart failure is associated with increases release of vasopressin from the posterior pituitary gland. Vasopressin is another powerful vasoconstrictor that also promotes reabsorption of water in the renal tubules (collecting ducts).

Cytokines and Others

Heart failure is associated with the release of cytokines and other circulating peptides. Cytokines are a heterogeneous family of proteins that are secreted by macrophages, lymphocytes, monocytes, and endothelial cells in response to injury. The interleukins (ILs) and tumor necrosis factor (TNF) are the two major groups of cytokines that may have an important pathophysiologic role in heart failure. Upregulation of the gene responsible for TNF with an acompanying increase in circulating plasma levels of TNF has been found in patients with hear failure. TNF appears to have an important role in the cycle of myocyte hypertrophy and cell death (apoptosis). Preliminary in vitro data suggest that IL-1 may accelerate myoctye hypertrophy. Another peptide important for mediating some of the pathophysiologic effects observed in heart failure is the potent vasoconstrictor endothelin, which is released from endothelial cells. Preliminary data have suggested that excessive endothelin release may be responsible for hypertension in the pulmonary arteries observed in patients with left ventricular heart failure. Endothelin is also associated with myocyte growth and deposition of collagen in the interstitial matrix.

Cellular Changes

Pathophysiologic chanages at the cellular level are very complex and include changes in Ca2+ handling, adrenergic receptros, contractile apparatus, and myocyte structure.

Ca2+ Handling

In heart failure, both delivery of Ca2+ to the contractle apparatus and reuptake of Ca2+ by the sarcoplasmic reticulum are slowed. Decreased levels of messenger ribonucleic acid (mRNA) for the specialized Ca2+ release channels have been reported by some investigators. Similarly, myocytes from failing hearts have reduced levels of mRNA for the two sarcoplasmic reticulum proteins phospholamban and Ca2+-ATPase.

Changes of Adrenergic Receptors

Two major classes of adrengeric receptors are found in the human heart. Alpha1-adrenergic receptors are important for induction of myocardial hypertrophy; levels of alpha1 receptors are slightly increased in heart failure. Heart failure is associated with significant beta-adrenergic receptor desensitization as a result of chronic sympathetic activation. This effect is mediated by downregulation of beta1-adrenergic receptors, downstream uncoupling of the signal transducton pathway, and upregulation of inhibitory G proteins. All of these changes lead to a further reduction in myocyte contractility.

Contractile Apparatus

Cardiac myocytes cannot proliferate once they have matured to their adult form. However, these is a constant turnover of the contractile proteins that make up the sarcomere. In response to the hemodynamic stresss associated with heart failure, angiotensin II, TNF, norepinephrine, and other molecules induce protein synthesis via intranuclear mediators of gene activity. This causes myoctye hypertrophy with an increase in sarcomere numbers and a re-expression of tetal and neonatal forms of myosin and troponin. Activation of this primitive program results in the development of large myocytes that do not contract normally and have decreased ATPase activity.

Myocyte Structure Changes

The heart enarges in response to continued hemodynamic stress. Changes in myocardial size and shape associated with heart failure are collectively referred to as left ventricular remodeling. Several tissue is associated with myocyte loss via a process of necrosis, apoptosis (programmed cell death). Unlike the process of necrosis, apoptotic cells initially demonstrate decreased cell volume without disrutpion of the cell membrane. However, as the apoptotic process continues, the myocyte ultimately dies, and "holes" are left in the myocardium. Loss of myocytes places increased stress on the remaining myoctes. The process of apoptosis is accelerated by the proliferative signals that stimulate myocyte hypertrophy such as TNF. Although apoptosis is a normal process that is essential in organs made up of proliferating cells, in the heart apoptosis initiates a vicious circle whereby cell death causes increased stress that leads to hypertrophy and further acceleraton of apoptosis.

A second tissue change observed in heart failure is an increased amount of fibrous tissue in the interstitial spaces of the heart. Collagen deposition is due to activation of fibroblasts and myocyte death. Endothelin release leads to interstitial collagen deposition. The increase in connective tissue increase chamber siffness and shifts the diastolic pressure-volume curve to the left.

Finally, heart failure is associated with gradual dilation of the ventricle. Myocyte "slippage" as a result of activation of collagenases that disrupt the collagen network may be responsible for this process.